JP2001278882A - Acylhydrazine derivative, method for producing the same and use threrof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an acylhydrazine derivative having inhibitory actions on activated blood coagulation factor X. SOLUTION: This compound is represented by the formula [wherein, R denotes a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R1 and R2 denote each hydrogen atom or a hydrocarbon group which may be substituted; R1 and R2 or the substituent group of X1 and R2 may mutually be bound to form a ring which may be substituted; X1 and X2 denote each a direct bond or an alkylene group which may be substituted or imino group which may be substituted; D denotes oxygen atom or sulfur atom; A denotes N(R3)-Y or N=Y; R3 denotes hydrogen atom, a hydrocarbon group which may be substituted or an acyl group: Y denotes a chain hydrocarbon group which may be substituted or a cyclic group which may be substituted; and Z denotes (1) amino group which may be substituted, (2) imidoyl group which may be substituted or (3) a nitrogen-organic heterocyclic group which may be substituted] or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to activated blood coagulation X.
The present invention relates to a novel acylhydrazine derivative useful as a medicine, which has an anticoagulant effect by inhibiting factor (FXa), a method for producing the same, and a use thereof.

[0002]

2. Description of the Related Art In the prevention and treatment of myocardial infarction, cerebral thrombosis, etc., it is important to suppress the formation of thrombus. Various thrombin inhibitors such as antithrombin agents and platelet aggregation inhibitors have been researched and developed. I have. However, not only platelet aggregation inhibitors but also antithrombin agents suppress platelet aggregation together with anticoagulant activity, and therefore these agents have side effects showing a bleeding tendency, and their safety is problematic. On the other hand, FXa inhibitors specifically inhibit only coagulation factors and are used as anticoagulants. To date, compounds having an FXa inhibitory action have been described in, for example, JP-A-7-112970, JP-A-5-208946, WO 96/16940, and W.
O 96/40679 and WO 96/10022, Journal of Medicinal Chemistry 41 33
57 (1998) and the like.

[0003]

The above-mentioned compounds having an FXa inhibitory action do not have a sufficient FXa inhibitory action.
Since oral administration does not show sufficient activity, it cannot be said that practically satisfactory results have been obtained as pharmaceuticals.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a novel FXa-specific inhibitory agent which has an inhibitory effect on FXa, is effective by oral administration, and is useful as a safe drug for the prevention or treatment of diseases based on thrombus or infarction. An acyl hydrazine derivative is provided. The present inventors have conducted various studies and found that two nitrogen atoms (a nitrogen atom in —N (R ² ) — and a nitrogen atom in —N (R ³ ) — or —N =) were added to the carbonyl group. It has specificity in its chemical structure in that it has an amino group which may be substituted consecutively and a terminal, an imidoyl group which may be substituted or a nitrogen-containing heterocyclic group which may be substituted. ,formula

Embedded image [In the formula, R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ¹ and R ² each represent a hydrogen atom or an optionally substituted hydrocarbon group, The substituents of R ¹ and R ² or X ¹ and R ² may be bonded to each other to form an optionally substituted ring, and X ¹ and X ² may each be a bond or substituted A good alkylene group or an imino group which may be substituted, D represents an oxygen atom or a sulfur atom,
Represents a -N (R ³⁾ -Y- or -N = Y-, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group, Y good chain substituted Z represents (1) an amino group which may be substituted, (2) an imidoyl group which may be substituted, or (3) a substituted or unsubstituted cyclic group. Shows a good nitrogen-containing heterocyclic group. And a salt thereof (hereinafter sometimes abbreviated as compound (I)) for the first time, and this compound has unexpectedly excellent FXa inhibition based on its specific chemical structure. It has been found that it has activity and can be safely orally administered as a medicament for the prophylactic / therapeutic agent for diseases based on thrombus or infarction, and based on these, completed the present invention.

That is, the present invention provides (1) a compound (I); (2) a prodrug of the compound (I); and (3) a compound according to the above (1), wherein R is an optionally substituted hydrocarbon group. (4) the compound according to (1), wherein R is an optionally substituted heterocyclic group; (5) R is an aryl group optionally substituted with a halogen atom or C _2-4 alkenyl. (6) a compound according to (1), wherein R is a naphthyl group optionally substituted with a halogen atom; (7) a benzopyranyl group optionally substituted with R, wherein R is a halogen atom. (8) R ¹ and R ² are bonded to each other to form -NX ¹ -C
Expression with DN-

Embedded image Wherein X ³ is an optionally substituted C _1-2 alkylene, X ⁴ is an optionally substituted C _1-3 alkylene,
Represents an oxygen atom or a sulfur atom. Compound of (1) wherein to form a group represented by]; (9) R ¹ and R ² are bonded to each other, -N-X ¹ -C
Expression with DN-

Embedded image [In the formula, n is 1 or 2, m ″ is 1 or 2, R ⁸ is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, a substituted An optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted Thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted A carbamoyl group or an optionally substituted thiocarbamoyl group)
Represents an oxygen atom or a sulfur atom. Compound of (1) wherein to form a group represented by]; (10) R ¹ and R ² are bonded to each other, -N-X ¹ -
Formula with CD-N-

Embedded image [In the formula, n represents 1 or 2, and m represents 2 or 3. (11) a compound according to (10), wherein n = 1 and m = 2; (12) a substituent of X ¹ and R ² Combine to form -X
^The divalent group represented by ¹ -CD-N (R ² )-

Embedded image [In the formula, X ⁵ represents a bond or an optionally substituted methylene, X ⁶ represents an optionally substituted C _2-3 alkylene, and D represents an oxygen atom or a sulfur atom. Compounds of the of the proximal (1), wherein represented by]; (13) substituents and R ² X ¹ 'bonded to each other, -X
^The divalent group represented by ¹ -CD-N (R ² )-

Embedded image [In the formula, n ′ represents 0 or 1, and m ′ represents 2 or 3. ]
(14) the compound according to (13), wherein n ′ = 0 and m ′ = 2; (15) R ¹ and R ² are each a hydrogen atom or The compound according to the above (1), which is an optionally substituted lower alkyl group; (16) the optionally substituted imino group is a group represented by the formula -N (R ⁴ )
- wherein, R ⁴ is a hydrogen atom, a hydrocarbon which may be substituted hydrogen group or an acyl group] wherein a group represented by (1) a compound according; (17) X ¹ is a methylene (18) The compound according to (1), wherein X ² is a bond; (19) R ³ is a hydrogen atom, a lower alkyl group which may be substituted, formyl or substituted. (20) The compound according to (1), wherein R ³ is a hydrogen atom or an optionally substituted lower alkyl group; (21) Y is substituted (22) The compound according to the above (1), which is an optionally substituted cyclic hydrocarbon group; (22) the above (1), wherein A is —N (R ³ ) —Y— and Y is phenylene which may be substituted (23) a compound as described above; (24) the compound according to (1), wherein Y is an optionally substituted piperidine residue; (25) the nitrogen-containing compound, wherein Z is optionally substituted (26) The compound according to (1), wherein D is an oxygen atom; (27) 4- (7-chloro-2H-benzopyran-3-sulfonyl)-
1- [1- (4-pyridyl) piperidin-4-ylamino] -2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1- [1-
(4-pyridyl) piperidin-4-ylamino] -2-piperazinone, 4- (6-bromonaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylamino] -2-piperazinone, Four-
(7-bromo-2H-benzopyran-3-sulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylamino] -2-piperazinone, 4-
(6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4-
Pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4- (6-bromonaphthalene-2-sulfonyl) -1- {methyl
[1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4- (7-bromo-2H-benzopyran-3-sulfonyl)-
1- {methyl [1- (4-pyridyl) piperidin-4-yl] amino}-
2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1- {ethyl [1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4- (6-chloronaphthalene- 2-sulfonyl) -1- {methyl [1- (2-methyl-4-pyridyl) piperidine-
4-yl] amino} -2-piperazinone, {[4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1-piperazinyl] [1- (2-
Methyl-4-pyridyl) -4-piperidinyl] amino} acetic acid, 4-
(6-chloronaphthalene-2-sulfonyl) -1-{[1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxylic acid, 4- (6-chloronaphthalene-2- Sulfonyl) -1-
{Methyl [1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxylic acid, 4- (6-chloronaphthalene
2-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxamide, 4- (6-chloronaphthalene-2-sulfonyl)- 1-
{Methyl [1- (2-methyl-4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxamide, 4- (6-
(Chloronaphthalene-2-sulfonyl) -6-hydroxymethyl-
1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-
Piperazinone, 6-aminomethyl-4- (6-chloronaphthalene
2-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone, 6-acetylaminomethyl-4- (6-chloronaphthalene-2-sulfonyl) -1 -{Methyl [1
-(4-pyridyl) -4-piperidinyl] amino} -2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1-{[1- (4-
Pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazineacetic acid and 4- (6-chloronaphthalene-2-sulfonyl)-
1-{[1- (2-methyl-4-pyridyl) -4-piperidinyl] amino}
(28) a compound selected from the group consisting of -6-oxo-2-piperazineacetic acid or a salt thereof; (28) a prodrug of the compound or a salt thereof according to (27);

(29) A pharmaceutical composition comprising the compound of the above (1) or a salt thereof; (30) a composition of the above (29) which is an anticoagulant; (31) an activity. (2) which is an activated blood coagulation factor X inhibitor
9) A composition according; (32) myocardial infarction, wherein an agent for the prophylaxis or treatment of cerebral thrombosis or deep vein thrombosis (29) The composition according; (33) (II) RSO ₂ Q wherein Q represents a leaving group, and other symbols have the same meanings as described in the above (1). Or a salt thereof and a compound of the formula (III)

Embedded image [The symbols in the formula have the same meanings as described in the above (1). Or a salt thereof; or a compound represented by the formula (IV)

Embedded image [In the formula, Q ¹ represents a leaving group, and other symbols have the same meanings as described in the above (1). Or a salt thereof and a compound of the formula (V)

Embedded image [The symbols in the formula have the same meanings as described in the above (1). Or a salt thereof; or a compound represented by the formula (VI):

Embedded image [The symbols in the formula have the same meanings as described in the above (1). Or a salt thereof, and a compound represented by the formula (VII):

Embedded image Wherein, A ¹ is Q ¹ -Y- or O = Y- indicates, Q ¹
Represents a leaving group, and other symbols have the same meanings as described in the above (1). With a compound represented by the formula: or a salt thereof;

Embedded image [In the formula, Q ³ represents a hydrogen atom or a leaving group, and the other symbols have the same meanings as described in the above (1). Or a salt thereof and a compound of the formula (IX)

Embedded image [In the formula, Q ⁴ represents a hydrogen atom or a leaving group, and other symbols have the same meanings as described in the above (1). Wherein the compound represented by the formula (1) or a salt thereof is reacted with
(34) a process for producing the compound or a salt thereof described above;

Embedded image [Wherein, L ^1a and L ^2a each represent a hydrogen atom or an amino-protecting group, and indicate that R ^{1 ′} and R ^{2 ′} are bonded to each other to form an optionally substituted ring. Or that R ^{1 ′} is a hydrogen atom or an optionally substituted hydrocarbon group, and that the substituent of X ¹ and R ^{2 ′} are bonded to each other to form an optionally substituted ring. The other symbols have the same meanings as described in the above (1). (35) R ^{1 ′} and R ^{2 ′} are bonded to each other to form —NX ¹
Formula with -CD-N-

Embedded image Wherein X ³ is an optionally substituted C _1-2 alkylene, X ⁴ is an optionally substituted C _1-3 alkylene,
Represents an oxygen atom or a sulfur atom. (36) The compound according to the above (34), which forms a group represented by the formula: (36) wherein R ^{1 ′} and R ^{2 ′} are bonded to each other to form —NX ¹
Formula with -CD-N-

Embedded image [In the formula, n is 1 or 2, m ″ is 1 or 2, R ⁸ is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, a substituted An optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted Thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted A carbamoyl group or an optionally substituted thiocarbamoyl group)
Represents an oxygen atom or a sulfur atom. (37) the compound according to the above (34), which forms a group represented by the formula: (37) wherein R ^{1 ′} and R ^{2 ′} are bonded to each other to form —NX ¹
Formula with -CD-N-

Embedded image [In the formula, n represents 1 or 2, and m represents 2 or 3. (38) the compound of the above (37), wherein n = 1 and m = 2; and (39) the substituent of X ¹ and R ^{2 ′.} Combined with each other,
The divalent group represented by X ¹ -CD-N (R ^{2 ′} ) —

Embedded image [In the formula, X ⁵ represents a bond or an optionally substituted methylene, X ⁶ represents an optionally substituted C _2-3 alkylene, and D represents an oxygen atom or a sulfur atom. (40) The compound according to the above (34), which represents a group represented by the formula: (40) wherein the substituent of X ¹ and R ^{2 ′} are bonded to each other, and
The divalent group represented by X ¹ -CD-N (R ^{2 ′} ) —

Embedded image [In the formula, n ′ represents 0 or 1, and m ′ represents 2 or 3. ]
(41) the compound according to the above (40), wherein n ′ = 0 and m ′ = 2;

Embedded image [Wherein R ^{1 ′} and R ^{2 ′} indicate that they are bonded to each other to form an optionally substituted ring,
^{1 ′} represents a hydrogen atom or an optionally substituted hydrocarbon group, and the substituent of X ¹ and R ^{2 ′} are bonded to each other to form an optionally substituted ring, The symbols have the same meaning as in claim 1. (43) an enzyme inhibitor or a receptor modulator comprising a compound having a divalent group as a partial structure represented by the following formula or a salt thereof; (43) the above-mentioned (4) which is an activated blood coagulation factor X inhibitor;
(44) an agent according to (42), which is a prophylactic / therapeutic agent for myocardial infarction, cerebral thrombosis or deep vein thrombosis; (45) an effective amount of the compound according to (1) or a salt thereof (46) a method of inhibiting blood coagulation in a mammal, comprising administering to the mammal an effective amount of the compound or a salt thereof according to (1). (47) a method of inhibiting activated blood coagulation factor X; (47) myocardial infarction, cerebral thrombosis or deep vein thrombosis in a mammal, which comprises administering an effective amount of the compound or a salt thereof according to (1) above to the mammal. (48) Use of the compound or its salt according to (1) for the manufacture of a medicament for inhibiting blood coagulation; (49) A medicament for inhibiting activated blood coagulation factor X Manufacture of (50) Use of the compound or a salt thereof according to the above (1); (50) Use of the compound or a salt thereof according to the above (1) for the manufacture of a medicament for preventing or treating myocardial infarction, cerebral thrombosis or deep vein thrombosis. And the like.

In the above formula, R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. R
Examples of the hydrocarbon group of the `` optionally substituted hydrocarbon group '' include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, and the like, and among them, an aryl group and the like are preferable. . Examples of the "aliphatic hydrocarbon group" as an example of the hydrocarbon group include a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group. Here, as the alkyl group,
For example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-
Methylpropyl, n-hexyl, isohexyl, 1,1
-Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl, C _1-10 alkyl group such as nonyl (preferably C _1-6 alkyl etc.)
And the like. Examples of the alkenyl group include vinyl, allyl, isopropenyl, 2-methylallyl, 1-
Propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-
C _2- such as butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like ₆ alkenyl groups and the like. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,
2-pentynyl, 3-pentynyl, 4-pentynyl, 1
-Hexynyl, 2-hexynyl, 3-hexynyl, 4-
And C _2-6 alkynyl groups such as hexynyl and 5-hexynyl.

The "alicyclic hydrocarbon group" as an example of the hydrocarbon group includes, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group and a cycloalkadienyl group. Can be Here, examples of the “cycloalkyl group” include C _3-9 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl. As the “cycloalkenyl group”, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,
3-cyclohexen-1-yl, 1-cyclobutene-1
And _C3-9 cycloalkenyl groups such as -yl, 1-cyclopenten-1-yl, 1-cyclohexen-1-yl and 1-cyclohepten-1-yl. As the “cycloalkadienyl group”, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadiene-1
-Yl, 2,5-cyclohexadien-1-yl and the like
_4-6 cycloalkadienyl group and the like. Examples of the "aryl group" as an example of the hydrocarbon group include a monocyclic or condensed polycyclic aromatic hydrocarbon group, for example, a C _6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. And phenyl, 1-naphthyl, 2-naphthyl and the like are particularly preferable. Examples of the hydrocarbon group include the above-mentioned alicyclic hydrocarbon group such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, and fluorenyl. Bicyclic or tricyclic hydrocarbon groups derived from the condensation of two to three identical or different groups (preferably two or more groups) selected from aromatic hydrocarbon groups are exemplified.

The heterocyclic group of the "optionally substituted heterocyclic group" for R is selected, for example, from the oxygen atom, sulfur atom, nitrogen atom and the like as the atoms (ring atoms) constituting the ring system. 1 to 3 heteroatoms (preferably 1
Or at least one (preferably 1 to 4)
, More preferably 1 or 2), a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like. As the “aromatic heterocyclic group”, an aromatic monocyclic heterocyclic group (for example, furyl, thienyl,
Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,
3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,3-triazolyl, 1,
5- or 6-membered aromatic monocyclic heterocyclic groups and aromatic condensed heterocyclic groups such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like (for example, benzofuranyl, isobenzofuranyl, Benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl , Buteridinyl, carbazolyl, α-carbolinyl,
β-carbolinyl, γ-carbolinyl, acridinyl,
Phenoxazinyl, phenothiazinyl, phenazinyl,
Phenoxathiinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,
2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5
- a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4
An 8- to 12-membered aromatic condensed heterocyclic group such as triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl and the like (preferably as described above for 5 to 6 members) A heterocyclic ring obtained by condensing an aromatic monocyclic heterocyclic group with a benzene ring or a heterocyclic ring obtained by condensing two identical or different heterocyclic rings of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group;
More preferred are the aforementioned heterocyclic rings in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, particularly preferably benzofuranyl, benzopyranyl, benzo [ b ] thienyl and the like. "Non-aromatic heterocyclic group"
As, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl,
3 such as morpholinyl, thiomorpholinyl, piperazinyl, etc.
A saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) of 8 to 8 members (preferably 5 to 6 members), or 1,2,3,4-tetrahydroquinolyl; Non-aromatic heterocyclic ring in which part or all of the above-mentioned aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group is partially or entirely double-bonded, such as 1,2,3,4-tetrahydroisoquinolyl And the like. Examples of the substituent of the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R include, for example, an optionally substituted alkyl group and an optionally substituted alkenyl Group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group,
An optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted amino group,
An optionally substituted imidoyl group (e.g., of the formula -C
(U ′) = NU (wherein U and U ′ each represent a hydrogen atom or a substituent (U preferably represents a hydrogen atom), etc.), and may be substituted. An amidino group (for example, formula -C (NT'T ") = NT, wherein T, T 'and T" each represent a hydrogen atom or a substituent (T preferably represents a hydrogen atom) Etc.), an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group,
Optionally substituted thiocarbamoyl group, optionally substituted sulfamoyl group, halogen atom (for example, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine etc.), cyano group, nitro group, sulfonic acid-derived An acyl group, an acyl group derived from a carboxylic acid and the like are mentioned, and these optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions. Further, the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R may have an oxo group, for example, when R is benzopyranyl, R
May form benzo-α-pyronyl, benzo-γ-pyronyl and the like.

The aryl group in the "optionally substituted aryl group" as a substituent includes, for example, C _6-14 aryl groups such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl. Here, as a substituent of the aryl group, a lower alkoxy group (for example, a C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, etc.), a halogen atom (for example, fluorine, chlorine,
Bromine, iodine, etc.), lower alkyl groups (eg, C _1-6 alkyl groups such as methyl, ethyl, propyl, etc.), lower alkenyl groups (eg, C _2-6 alkenyl groups such as vinyl, allyl, etc.), lower alkynyl groups (eg, For example, a C _2-6 alkynyl group such as ethynyl and propargyl, etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a cyano group, an optionally substituted amidino group, a carboxyl group, a lower alkoxycarbonyl Group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like), carbamoyl group which may be substituted (for example, C _1-6 alkyl or acyl group (for example, formyl,
Carbamoyl optionally substituted with C _2-6 alkanoyl, benzoyl, optionally halogenated C _1-6 alkoxy-carbonyl, optionally halogenated C _1-6 alkyl-sulfonyl, benzenesulfonyl, etc. And the like, and one or three of these optional substituents may be substituted at substitutable positions. As the "optionally substituted amino group", "optionally substituted hydroxyl group", and "optionally substituted amidino group" as the substituent, the `` optionally substituted amino group '' represented by R “Optionally substituted amino group”, “optionally substituted hydroxyl group”, and “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” may have And the same as the “amidino group which may be substituted”. Examples of the cycloalkyl group in the “optionally substituted cycloalkyl group” as the substituent include C 5, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
<sub>And a 3-7</sub> cycloalkyl group. Here, examples of the substituent of the cycloalkyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”. Examples of the cycloalkenyl group in the “optionally substituted cycloalkenyl group” as a substituent include C <sub>3-6</sub> cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Here, as the substituent of the optionally substituted cycloalkenyl group, the same number of the same substituents as in the above-mentioned “optionally substituted aryl group” can be mentioned. Examples of the alkyl group in the “optionally substituted alkyl group” as a substituent include, for example, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, And C1-6 alkyl such as 3,3-dimethylbutyl and 3,3-dimethylpropyl. Here, as the substituent of the alkyl group, the same number of the same substituents as in the above-mentioned “optionally substituted aryl group” can be mentioned. Examples of the alkenyl group in the “optionally substituted alkenyl group” as a substituent include vinyl, allyl, isopropenyl, 2-methylallyl,
1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1
-Butenyl, 2-methyl-2-butenyl, 3-methyl-
2-butenyl, 1-pentenyl, 2-pentenyl, 3-
And C <sub>2-6</sub> alkenyl groups such as pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. Here, examples of the substituent of the alkenyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”. Examples of the alkynyl group in the `` optionally substituted alkynyl group '' as a substituent include, for example, ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-
C _2-6 alkynyl groups such as butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl are No. Here, examples of the substituent of the alkynyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”.

The heterocyclic group in the “optionally substituted heterocyclic group” as a substituent is selected from oxygen, sulfur, nitrogen and the like as atoms (ring atoms) constituting a ring system. 1 to 3 hetero atoms (preferably 1
Or at least one (preferably 1 to 4)
, More preferably 1 or 2), a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like. As the “aromatic heterocyclic group”, an aromatic monocyclic heterocyclic group (for example, furyl, thienyl,
Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,
3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,3-triazolyl, 1,
5- or 6-membered aromatic monocyclic heterocyclic groups and aromatic condensed heterocyclic groups such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like (for example, benzofuranyl, isobenzofuranyl, Benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl , Carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo1 , 5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, , 2,4-triazolo [4,3- a] pyridyl, 1,2,4-triazolo [4,3
- b] pyridazinyl, etc.) 8-12 membered aromatic fused Hajime Tamaki such as (preferably, the 5 or 6-membered aromatic monocyclic heterocyclic group and is heterocyclic or said fused with a benzene ring 5 And a 6-membered aromatic monocyclic heterocyclic group in which two identical or different heterocyclic rings are condensed). Examples of the “non-aromatic heterocyclic group” include 3- to 8-membered (preferably 5 to 6) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.
Membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group), or 1,2,
Part or all of the double bonds of the aromatic monocyclic heterocyclic group or the aromatic condensed heterocyclic group such as 3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc. And a non-aromatic heterocyclic group saturated with.

Examples of the substituent which the “optionally substituted heterocyclic group” may have include lower alkyl groups (for example, C _1-6 alkyl groups such as methyl, ethyl, propyl and the like). A lower alkenyl group (eg, a C _2-6 alkenyl group such as vinyl or allyl); a lower alkynyl group (eg, a C _2-6 alkynyl group such as ethynyl or propargyl); an acyl group (eg, formyl, acetyl, propionyl, pivaloyl) C _1-6 alkanoyl, benzoyl, etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), Examples include an optionally substituted imidoyl group and an optionally substituted amidino group. A `` optionally substituted heterocyclic group '' as a substituent may have `` optionally substituted amino group '', `` optionally substituted hydroxyl group '',
The “optionally substituted imidoyl group” and the “optionally substituted amidino group” include the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” for R. `` Optionally substituted amino group '', `` optionally substituted hydroxyl group '', `` optionally substituted imidoyl group '', and `` optionally substituted And the amidino group which may be used. "Optionally substituted amino group" as a substituent which the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R may have, " An optionally substituted imidoyl group ", an" optionally substituted amidino group ",
Examples of the substituent in the “optionally substituted hydroxyl group” and the “optionally substituted thiol group” include, for example,
Halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.)
And optionally halogenated C _1-6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy,
A lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl) which may be substituted with a substituent selected from 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2-trichloroethoxy and the like. C _1-6 such as, isobutyl, t-butyl, pentyl, hexyl, etc.
An alkyl group), an acyl group (C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl, etc.), optionally halogenated C
_1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,
Trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), optionally halogenated C _1-6 alkyl-sulfonyl, benzenesulfonyl, etc.), and a heterocyclic group (“substituted or substituted” represented by R). The same as the "heterocyclic group" in the "good heterocyclic group", preferably pyridyl, more preferably 4-pyridyl, etc.), and the like, and the "optionally substituted amino group" in the substituent may be mentioned. An “amino group” is an optionally substituted imidoyl group (eg, C _1-6 alkylimidoyl (eg, formyl imidoyl, acetylimidoyl, etc.), C _1-6 alkoxyimidoyl, C _1-6 alkylthioimide yl, amidino, etc.), one to two C _1-6 alkyl may be substituted by such amino group which may be substituted, also, two substituents May form a cyclic amino group together with the nitrogen atom. In such a case, examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl and Lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,
C _1-6 alkyl groups such as t-butyl, pentyl, hexyl and the like, aralkyl groups (eg C _7-10 aralkyl groups such as benzyl and phenethyl), and aryl groups (eg phenyl, 1-naphthyl, 2-naphthyl and the like) 3 to 8 members (preferably 5 to ₆ ) such as 1-piperazinyl, 1-pyrrolyl and 1-imidazolyl which may have
And 6-membered cyclic amino.

"Optionally substituted carbamoyl group"
Examples thereof include an unsubstituted carbamoyl, an N-monosubstituted carbamoyl group and an N, N-disubstituted carbamoyl group. “N-monosubstituted carbamoyl group” means a carbamoyl group having one substituent on a nitrogen atom, and examples of the substituent include lower alkyl groups (eg, methyl,
A C _1-6 alkyl group such as ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc., a lower alkenyl group (eg, vinyl, allyl,
Isopropenyl, propenyl, butenyl, pentenyl,
A C _2-6 alkenyl group such as hexenyl, etc.), a cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an aryl group (eg, phenyl, 1-naphthyl,
A C _6-10 aryl group such as naphthyl, etc.), an aralkyl group (eg, a C _7-10 aralkyl group such as benzyl and phenethyl, preferably a phenyl-C _1-4 alkyl group, etc.), and an arylalkenyl group (eg, cinnamyl etc.) A C _8-10 arylalkenyl group, preferably a phenyl-C _2-4 alkenyl group, etc.), and a heterocyclic group (for example, “substituted hydrocarbon group” represented by R as “substituent” And the like as the "heterocyclic group").
The lower alkyl group, lower alkenyl group, cycloalkyl group, aryl group, aralkyl group, arylalkenyl group, and heterocyclic group may have a substituent, for example, a hydroxyl group, a substituted An amino group such as a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (eg, It may have one or two substituents such as formyl, acetyl, propionyl, pivaloyl and other C _1-6 alkanoyl, benzoyl and the like), carboxyl group and C _1-6 alkoxy-carbonyl group. ], Halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro groups, cyano groups, carboxyl groups, C
_1-6 alkoxy-carbonyl group, lower alkyl group optionally substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), 1 to 5 halogen atoms (eg, fluorine, chlorine, Lower alkylthio group optionally substituted with bromine, iodine, etc., 1 to 5
And a lower alkoxy group which may be substituted with a plurality of halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.). Examples of the lower alkyl group include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. , Ethyl and the like are preferred. The said lower alkylthio groups, such as methylthio, ethylthio, n- propylthio, isopropylthio, n- butylthio, isobutylthio, sec- butylthio, tert- butylthio, pentylthio, C _1-6 alkylthio group such as a hexylthio and the like, Particularly, methylthio, ethylthio and the like are preferable. Examples of the lower alkoxy group include methoxy, ethoxy, n
-C _1-6 alkoxy groups such as -propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and methoxy, ethoxy and the like are particularly preferable. Further, these substituents may be the same or different from each other.
Alternatively, it is preferable that two or three (preferably one or two) are substituted.

"N, N-disubstituted carbamoyl group" means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is the above-mentioned "N-monosubstituted carbamoyl group". And the other examples thereof include, for example, lower alkyl groups (for example, methyl, ethyl, propyl, isopropyl, butyl,
C _1-6 alkyl groups such as t-butyl, pentyl, hexyl, etc., C _3-6 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl groups (eg, benzyl, phenethyl, etc.) And preferably a phenyl-C _1-4 alkyl group). In some cases, two substituents may form a cyclic amino group together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl group include 1-azetidinylcarbonyl and 1-pyrrolidinyl. Carbonyl, piperidinocarbonyl, a lower alkyl group at the 4-position (eg, methyl, ethyl, propyl, isopropyl, butyl, t-
C _1-6 alkyl groups such as butyl, pentyl, hexyl and the like; aralkyl groups (eg C _7-10 aralkyl groups such as benzyl and phenethyl); and aryl groups (eg C _1-6 such as phenyl, 1-naphthyl and 2-naphthyl). _6-10 aryl group, etc.), hydroxyl group, C _1-6 alkoxy group, carboxyl group,
Piperidinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl optionally oxidized with a sulfur atom, 1-piperazinylcarbonyl and a lower alkyl group at the 4-position which may have a C _1-6 alkoxy-carbonyl group, etc. (For example, C such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.)
_An aralkyl group (eg, benzyl,
A C _7-10 aralkyl group such as phenethyl), an aryl group (eg, C _7-10 such as phenyl, 1-naphthyl,
_{And 6- to} 8-membered (preferably 5 to 6-membered) cyclic amino-carbonyls such as 1-piperazinylcarbonyl which may have a _6-10 aryl group and the like. Examples of the substituent of the “optionally substituted thiocarbamoyl group” and “optionally substituted sulfamoyl group” include the same substituents as those of the aforementioned “optionally substituted carbamoyl group”. .

The carboxyl group which may be esterified includes, in addition to a free carboxyl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group and the like. As the "lower alkoxycarbonyl group", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert
- butoxycarbonyl, pentyloxycarbonyl, iso-pentyloxycarbonyl, C _1-6 alkoxy such as neopentyl oxycarbonyl - group and the like, among methoxycarbonyl, ethoxycarbonyl,
A C _1-3 alkoxy-carbonyl group such as propoxycarbonyl is preferred. As the “aryloxycarbonyl group”, for example, a C _7-12 aryloxy-carbonyl group such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like are preferable. As, for example benzyloxycarbonyl, C _7-10 aralkyloxycarbonyl phenethyl oxycarbonyl "aralkyloxycarbonyl group" - such as a carbonyl group (preferably, C _6-10
Aryl-C _1-4 alkoxy-carbonyl) is preferred. The “aryloxycarbonyl group” and the “aralkyloxycarbonyl group” may have a substituent,
As the substituent, the same number as the substituents of the aryl group and the aralkyl group as examples of the substituent of the N-monosubstituted carbamoyl group described above are used. Examples of the “acyl group derived from sulfonic acid” as the substituent include those in which the above-mentioned “N-monosubstituted carbamoyl group” has one substituent on a nitrogen atom bonded to a sulfonyl, and the like. And acyl such as C _1-6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl. As the “acyl group derived from a carboxylic acid” as the substituent, a hydrogen atom or the aforementioned “N-
A mono-substituted carbamoyl group in which one substituent on the nitrogen atom is bonded to a carbonyl; preferably formyl, acetyl, propionyl,
And acyl such as C _1-6 alkanoyl such as pivaloyl and benzoyl. The R, preferably a hydrocarbon group which may be substituted, among others, can be an aryl group (preferably substituted with a halogen atom or a C _2-4 alkenyl, substituted with a halogen atom or a C _2-4 alkenyl _Optionally substituted C _6-14 aryl groups such as 1-naphthyl and 2-naphthyl, more preferably naphthyl _optionally substituted with a halogen atom, particularly preferably a halogen atom at the 6-position. 2-naphthyl, etc. are preferred. As R, a heterocyclic group which may be substituted is preferable, and among them, a heterocyclic group which may be substituted by a halogen atom (preferably, benzofuranyl group, benzopyranyl group, etc., more preferably, benzopyranyl group) Is preferred.

In the above formula, the “optionally substituted hydrocarbon group” represented by R ¹ and R ² or R ^{1 ′} includes:
For example, the same as the “optionally substituted hydrocarbon group” for R can be mentioned, and among them, the optionally substituted lower (C _1-4 ) alkyl group is preferable. R ¹ and R ² may be bonded to each other to form a ring, and R ¹ and R ² may be bonded to each other to form —NX ¹ —C
Together with DN-, it may form a "optionally substituted divalent nitrogen-containing heterocyclic group". As the “divalent nitrogen-containing heterocyclic group” in the “optionally substituted divalent nitrogen-containing heterocyclic group”, a nitrogen atom other than a carbon atom may be used as an atom (ring atom) constituting a ring system. A divalent 5- to 8-membered nitrogen-containing heterocyclic group containing 2 or 3 (preferably a divalent 5- to 8-membered nitrogen-containing heterocyclic group composed of a carbon atom and two nitrogen atoms); Can be These “divalent nitrogen-containing heterocyclic groups” have an oxo group or a thioxo group on a carbon atom adjacent to the nitrogen atom to which the substituent represented by R ² is bonded, and have a “divalent 5 to 8 A 2-membered nitrogen-containing cyclic amide group ". Specific examples of the" divalent 5- to 8-membered nitrogen-containing cyclic amide group "include, for example, 2-
Oxoimidazolidin-1,3-diyl, 2-oxoimidazolone-1,3-diyl, 2-oxopiperazine-
1,4-diyl, 2-oxo-1,2,3,4-tetrahydropyrazine-1,4-diyl, 2-oxohomopiperazine-1,4-diyl, 5-oxohomopiperazine-
1,4-diyl, 2-oxo-1,4-diazacyclooctane-1,4-diyl, 5-oxo-1,4-diazacyclooctane-1,4-diyl, 2-oxo-1, 5
-Diazacyclooctane-1,5-diyl, 5-oxo-2,3-dehydrohomopiperazine-1,4-diyl,
3-oxo-1,2,4-triazacyclohexane-1,
4-diyl, 3-oxo-1,2,3,4-tetrahydro-1,2,4-triadyne-1,4-diyl, 6-oxo-1,2,4-triazacyclohexane-1,4- Diyl and the like.

As the substituent of the "divalent nitrogen-containing heterocyclic group which may be substituted" in the above-mentioned "divalent nitrogen-containing heterocyclic group", in addition to one oxo group or thioxo group, for example, An optionally substituted hydroxyl group, an optionally substituted mercapto group, a halogen atom (for example, fluorine,
Chlorine, bromine, iodine, etc.), nitro group, cyano group, oxo group, optionally substituted amino group, optionally substituted lower alkyl group, optionally substituted lower alkylidene group, substituted A lower aralkylidene group, a lower alkoxy group which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), a carboxyl group which may be esterified, Carbamoyl group, thiocarbamoyl group which may be substituted, sulfamoyl group which may be substituted, and the like (preferably lower alkyl group which may be substituted, carboxyl group which may be esterified, And a carbamoyl group which may be substituted, and the like. Properly from 1 to 2) may be substituted. Here, as the substituent of the “optionally substituted amino group”, 1 to 2 optionally substituted alkyl groups, optionally substituted carbamoyl groups,
Thiocarbamoyl group which may be substituted, sulfamoyl group which may be substituted, carboxyl group which may be esterified, acyl group derived from sulfonic acid, acyl group derived from carboxylic acid, and the like. An optionally substituted alkyl group, an `` optionally substituted carbamoyl group, '' an `` optionally substituted thiocarbamoyl group, '' an `` optionally substituted sulfamoyl group,
As the “carboxyl group which may be esterified”, the “acyl group derived from sulfonic acid” and the “acyl group derived from carboxylic acid”, the “optionally substituted hydrocarbon group” represented by R described above may be used. `` Optionally substituted alkyl group '', `` optionally substituted carbamoyl group '', `` optionally substituted thiocarbamoyl group '', `` optionally substituted sulfamoyl group '',
The same as "carboxyl group which may be esterified", "acyl group derived from sulfonic acid" and "acyl group derived from carboxylic acid" may be mentioned, and "amino group which may be substituted" is preferable. Examples include (1) lower (C <sub>1-6</sub> ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and (2) mono- or di-lower. (C
<sub>1-6)</sub> alkylcarbamoyl group, (3) methanesulfonyl, C <sub>1-6</sub> alkylsulfonyl such as ethanesulfonyl,
(4) formyl, acetyl, propionyl, C <sub>1-6</sub> alkanoyl and (5) an amino, etc. may have 1 to 2 substituents selected from benzoyl pivaloyl, and the like. Examples of the lower alkyl group in the “optionally substituted lower alkyl group” include C <sub>1-6</sub> alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. And the like, and particularly preferably methyl, ethyl and the like. Examples of the substituent include a halogen atom (eg, fluorine,
Chlorine, bromine, iodine, etc.), C <sub>1-6</sub> alkyl or acyl group (eg, formyl, C <sub>2-6</sub> alkanoyl, benzoyl,
Optionally substituted halogenated C <sub>1-6</sub> alkoxy-carbonyl, optionally halogenated C <sub>1-6</sub> alkyl-sulfonyl, benzenesulfonyl) amino group, carboxyl group, C <sub>1- 6</sub> alkoxy-carbonyl group, C <sub>1-6</sub> alkyl or acyl group (eg, formyl, C <sub>2-6</sub> alkanoyl, benzoyl, optionally halogenated C <sub>1-6</sub> alkoxy-carbonyl, optionally halogenated C Carbamoyl group, hydroxyl group, C <sub>6-10</sub> aryl, C <sub>6-10</sub> aryloxy, C <sub>6-10</sub> aryl-C <sub>1-4</sub> alkoxy, etc. which may be substituted with <sub>1-6</sub> alkyl-sulfonyl, benzenesulfonyl and the like. And
These optional substituents may be substituted at 1 to 5 (preferably 1 or 2) at substitutable positions. Examples of the “optionally substituted lower alkylidene group” include C <sub>1-6</sub> alkylidene such as methylidene and ethylidene. Examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.). , Amino group,
Examples thereof include a carboxyl group and a hydroxyl group. These optional substituents may be substituted at 1 to 5 (preferably 1 to 5) at substitutable positions.
Or two) may be substituted. Examples of the “optionally substituted lower aralkylidene group” include C <sub>6-10</sub> aryl-C <sub>1-4</sub> alkylidene such as benzylidene, and the substituent is, for example, a halogen atom (eg, fluorine, chlorine, bromine). , Iodine, etc.), an amino group, a carboxyl group, a hydroxyl group, etc., and 1 to 5 (preferably 1 or 2)
) May be substituted. As the lower alkoxy group in the "lower alkoxy group optionally substituted with a halogen atom or the like", for example, C-methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like <sub>1 -6</sub> alkoxy group and the like, in particular methoxy, ethoxy, etc. are preferable. In addition, the lower alkoxy group may be a “lower alkyl group that may be substituted” in the “optionally substituted lower alkyl group” which the “optionally substituted divalent nitrogen-containing heterocyclic group” may have as a substituent. And an alkyl group ". As the “optionally esterified carboxyl group”, those similar to the optionally esterified carboxyl group as a substituent of the aforementioned “optionally substituted hydrocarbon group” represented by R can be used. No. Examples of the “optionally substituted carbamoyl group”, “optionally substituted thiocarbamoyl group” and “optionally substituted sulfamoyl group” include the aforementioned “optionally substituted carbon The same as the carbamoyl group which may be substituted, the thiocarbamoyl group which may be substituted, and the sulfamoyl group which may be substituted as the substituent of the "hydrogen group". In the "optionally substituted hydroxyl group" and "optionally substituted mercapto group" as a substituent which the "divalent nitrogen-containing heterocyclic group" may have, "hydroxyl group" and "mercapto group" Examples of the substituent which the group may have include a lower alkyl group which may be substituted, a carboxyl group which may be esterified, a carbamoyl group which may be substituted, and a thio group which may be substituted. Examples include a carbamoyl group, an optionally substituted sulfamoyl group, an acyl group derived from sulfonic acid, and an acyl group derived from carboxylic acid. Examples of the lower alkyl group include methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
A C <sub>1-6</sub> alkyl group such as pentyl and hexyl is exemplified. Examples of the substituent which the lower alkyl group may have include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), Aryl groups [eg, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), lower alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-
C <sub>1-6</sub> alkyl groups such as ert-butyl, pentyl, hexyl, etc.), lower alkoxy groups (eg, methoxy, ethoxy, n
-Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and other C <sub>1-6</sub> alkoxy groups, etc.), each of which may be substituted with phenyl or naphthyl], optionally substituted hydroxyl groups (E.g., the same as an optionally substituted hydroxyl group as a substituent of the "optionally substituted hydrocarbon group" represented by R), an optionally substituted thiol group (e.g., The same as the optionally substituted thiol group as a substituent of the “optionally substituted hydrocarbon group” represented by R, and the optionally substituted amino group (for example, as described above) The same as the optionally substituted amino group as a substituent of the "optionally substituted hydrocarbon group" for R), an optionally esterified carboxyl group Examples, such as the same as the esterified carboxyl group which may be as the substituent of the "optionally substituted hydrocarbon group" represented by the R) and the like. In the “optionally substituted mercapto group”, a sulfur atom may be oxidized, and has, for example, a structure represented by S (O) k [k is an integer of 0 to 2]. May be. In the above-mentioned `` hydroxyl group which may be substituted '' and `` optionally substituted mercapto group '' as a substituent which the above-mentioned `` divalent nitrogen-containing heterocyclic group '' may have, `` hydroxyl group '' and `` `` A carboxyl group which may be esterified '', a `` A carbamoyl group which may be substituted '', a `` A thiocarbamoyl group which may be substituted '', An optionally substituted sulfamoyl group ", an" acyl group derived from sulfonic acid "
And the "acyl group derived from a carboxylic acid" includes, as a substituent of the "optionally substituted hydrocarbon group" represented by R, "optionally esterified carboxyl group", "substituted Carbamoyl group ",
Examples include the same as the “optionally substituted thiocarbamoyl group”, “optionally substituted sulfamoyl group”, “sulfonic acid-derived acyl group” and “carboxylic acid-derived acyl group”.

As the above-mentioned “divalent nitrogen-containing heterocyclic group”, for example,

Embedded image Wherein X ³ is an optionally substituted C _1-2 alkylene, X ⁴ is an optionally substituted C _1-3 alkylene,
Represents an oxygen atom or a sulfur atom. Is preferably a group represented by the formula

Embedded image [In the formula, n is 1 or 2, m ″ is 1 or 2, R ⁸ is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, a substituted An optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted Thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted A carbamoyl group or an optionally substituted thiocarbamoyl group)
Represents an oxygen atom or a sulfur atom. ] Is more preferable. Here, the “C _1-2 alkylene” in the “ _optionally substituted C _1-2 alkylene” for X ³ includes linear alkylene such as methylene, ethylene and the like. `` <sub>1-2</sub> alkylene '' is the above-mentioned `` optionally substituted divalent nitrogen-containing heterocyclic group ''
May have the same group as the substituent which the “divalent nitrogen-containing heterocyclic group” may have. Examples of the “C _1-3 alkylene” in the “ _optionally substituted C _1-3 alkylene” for X ⁴ include linear alkylene such as methylene, ethylene and propylene. “C _1-3 alkylene” is the same as the above-mentioned “optionally substituted bivalent nitrogen-containing heterocyclic group” in the “optionally substituted divalent nitrogen-containing heterocyclic group” May be provided. In the above formula, “optionally substituted hydroxyl group”, “optionally substituted mercapto group”, “nitro group”, “cyano group”, “optionally substituted amino group” represented by R ⁸ , "Optionally substituted lower alkyl group", "optionally substituted lower alkoxy group", "optionally esterified carboxyl group", "optionally substituted carbamoyl group", "substituted The optionally substituted thiocarbamoyl group '' and the `` optionally substituted sulfamoyl group '' include the above-mentioned `` optionally substituted divalent nitrogen-containing heterocyclic group '' `` Group '' may have as a substituent `` optionally substituted hydroxyl group '', `` optionally substituted mercapto group '', `` nitro group '', `` cyano group '', `` optionally substituted '' Amino group ""Optionally substituted lower alkyl group", "optionally substituted lower alkoxy group", "optionally esterified carboxyl group", "optionally substituted carbamoyl group", "substituted An optionally substituted thiocarbamoyl group "
And the same as "optionally substituted sulfamoyl group". Among them, the above-mentioned "divalent nitrogen-containing heterocyclic group" includes a compound represented by the formula

Embedded image [In the formula, n represents 1 or 2, and m represents 2 or 3. And the like are preferred. In the above formula, m is preferably 2 and n is preferably 1. As the above-mentioned “divalent nitrogen-containing heterocyclic group”, 2-oxopiperazine-1,4-
Diyl is most preferred.

Further, the substituent of X ¹ and R ² may be bonded to each other to form a ring, and -X ¹ -CD-N (R ² )-
May form a “divalent nitrogen-containing heterocyclic group which may be substituted”. As the “divalent nitrogen-containing heterocyclic group” in the “optionally substituted divalent nitrogen-containing heterocyclic group”, a nitrogen atom other than a carbon atom may be used as an atom (ring atom) constituting a ring system. 1 to 3 divalent 5- to 8-membered nitrogen-containing heterocyclic group (preferably,
Divalent 5- to 7-membered nitrogen-containing heterocyclic group composed of a carbon atom and one nitrogen atom). These “divalent nitrogen-containing heterocyclic groups” have an oxo group or a thioxo group on a carbon atom adjacent to the nitrogen atom to which the substituent represented by R ² is bonded, and have a “divalent 5 to 8 A "membered nitrogen-containing cyclic amide group", and as a substituent of the "divalent nitrogen-containing heterocyclic group" in the "optionally substituted divalent nitrogen-containing heterocyclic group", R ¹ and R ² is the same as the substituent which the “divalent nitrogen-containing heterocyclic group” may have in the “optionally substituted divalent nitrogen-containing heterocyclic group” formed by bonding to each other. Can be Examples of the “divalent nitrogen-containing heterocyclic group” formed by bonding the substituent of X ¹ and R ² to each other include, for example, such “optionally substituted divalent nitrogen-containing heterocyclic group” represented by the formula

Embedded image [In the formula, X ⁵ represents a bond or an optionally substituted methylene, X ⁶ represents an optionally substituted C _2-3 alkylene, and D represents an oxygen atom or a sulfur atom. ] Is preferable. Here, indicated by X ⁵ "methylene"
May have the same group as the substituent which may be possessed by the `` divalent nitrogen-containing heterocyclic group which may be substituted '' in the above-mentioned `` optionally substituted divalent nitrogen-containing heterocyclic group ''. Good. Also, X
Represented by ⁶ "optionally substituted C _2-3 alkylene"
As the "C _2-3 alkylene", ethylene, etc. linear alkylene such as propylene and the like, the "C _2-3 alkylene", the above-mentioned "optionally substituted divalent nitrogen-containing in It may have the same group as the substituent which the “divalent nitrogen-containing heterocyclic group” in the “heterocyclic group” may have. Above all, the expression

Embedded image [In the formula, n ′ represents 0 or 1, and m ′ represents 2 or 3. ]
And the like are preferred. In the above formula, m ′ is 2
And n ′ is preferably 0. Examples of the above-mentioned “divalent nitrogen-containing heterocyclic group” include 2-pyrrolidone-1,
3-Diyl is most preferred. Examples of the “alkylene group” in the “optionally substituted alkylene group” for X ¹ and X ² include linear lower (C _1-6 ) alkylene such as methylene, ethylene, propylene, butylene, pentylene and the like. And methylene,
C _1-4 alkylene such as ethylene is preferred. As the substituent of the “alkylene group”, a lower alkyl group which may be substituted [optionally substituted as a substituent of the aforementioned “optionally substituted divalent nitrogen-containing heterocyclic group” Preferably, a lower alkyl group (e.g., methyl, ethyl, n-propyl,
C _1-6 alkyl such as isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.)], an optionally substituted carbamoyl group, [the above-mentioned “optionally substituted divalent nitrogen-containing And the like as the “carbamoyl group which may be substituted” as a substituent of the “heterocyclic group”, preferably a carbamoyl group, an N-mono-lower (C
_1-6 ) alkylcarbamoyl group, N, N-di-lower (C _1-6 ) alkylcarbamoyl group, etc.), cyano group, halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.),
A hydroxyl group and a carboxyl group which may be esterified (the same as the “carboxyl group which may be esterified” as a substituent of the “hydrocarbon group which may be substituted” represented by R described above) And any one of these optional substituents may be substituted at one to three substitutable positions. Examples of the “optionally substituted imino group” for X ¹ and X ² include, for example,
N (R ⁴ )-[wherein, R ⁴ represents a hydrogen atom or a substituent]
R ⁴ includes a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group (preferably a hydrogen atom, an optionally substituted hydrocarbon group), and the like. preferable. In the above formula, examples of the “optionally substituted hydrocarbon group” represented by R ⁴ include the same as the “optionally substituted hydrocarbon group” represented by R. In the above formula, the “acyl group” represented by R ⁴ includes a “sulfonic acid-derived acyl group” and a “carboxylic acid” as substituents of the “optionally substituted hydrocarbon group” represented by R described above. Examples of the "acyl group derived from" include formyl, an optionally substituted lower ( _C2-5 ) alkanoyl group, and the like, and more preferably a lower ( _C2-5 ) alkanoyl group. In the formula, X ¹ is preferably methylene, and X ² is preferably a bond. In the above formula, D represents an oxygen atom or a sulfur atom (preferably, an oxygen atom). In the above formula, A is-
N (R ³ ) —Y— or —N ア シ ル Y—, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y represents an optionally substituted chain carbon atom. It represents a hydrogen group or an optionally substituted cyclic group. As the “optionally substituted hydrocarbon group” for R ³ , the same as the “optionally substituted hydrocarbon group” for R can be mentioned, and for the “acyl group” for R ³ "as,
It may be mentioned those similar to the "acyl group derived from a sulfonic acid" and "acyl group derived from a carboxylic acid" as the substituent of the "optionally substituted hydrocarbon group" represented by the R, R ³ Preferred are a hydrogen atom, an optionally substituted lower (C _1-4 ) alkyl group, formyl, an optionally substituted lower (C _2-5 ) alkanoyl group and the like. More preferred are lower (C _1-4 ) alkyl groups and the like. As the “chain hydrocarbon group” in the “optionally substituted chain hydrocarbon group” represented by Y, the “linear hydrocarbon group” as the “optionally substituted hydrocarbon group” represented by R Divalent or trivalent group formed by removing one or two hydrogen atoms from one carbon atom in the “state of a branched or branched (preferably straight chain) aliphatic hydrocarbon group”. , And more specifically,
An optionally substituted C _1-6 alkylene group (X ¹
And the same as the “alkylene group which may be substituted” represented by X ² ), and a substituent 置換 CH— (CH ₂ ) _k — [ Where:
k represents an integer of 0 to 5]. As the substituent which the “chain hydrocarbon group” as the “optionally substituted chain hydrocarbon group” represented by Y may have, an optionally substituted lower alkyl group [ A lower alkyl group (e.g., methyl, etc.), such as the same as the aforementioned "optionally substituted lower alkyl group" as a substituent of the "optionally substituted divalent nitrogen-containing heterocyclic group", Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
C _1-6 alkyl such as butyl, etc.), an optionally substituted carbamoyl group, and “substituted or substituted as a substituent of the aforementioned“ optionally substituted divalent nitrogen-containing heterocyclic group ”. Carbamoyl group, N-mono-lower (C _1-6 ) alkyl carbamoyl group, N, N-di-lower (C _1-6 ) alkyl carbamoyl group, etc. Group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, a carboxyl group which may be esterified (as a substituent of the “optionally substituted hydrocarbon group” represented by R above) The same as the "carboxyl group which may be esterified"), and one or three of these optional substituents may be substituted at substitutable positions. Further, “an optionally substituted chain hydrocarbon group” represented by Y (preferably, optionally substituted C
"Chain hydrocarbon group" in _1-6 alkylene group)
Any methylene group may be substituted with an oxo group to form a carbonyl group. Specific examples thereof include -CH ₂
Formula in which a methylene group of —CH ₂ — is substituted with an oxo group—
(C = O) -CH ₂ - and a group represented by the like.
As the substituent for the “optionally substituted cyclic group” for Y, the same substituents as those for the above-mentioned “divalent nitrogen-containing heterocyclic group” can be used. Examples of the “cyclic group” of the “optionally substituted cyclic group” for Y include a divalent or trivalent cyclic hydrocarbon group or a heterocyclic group (preferably a heterocyclic group). As the “hydrocarbon group” as the “cyclic group” of the “optionally substituted cyclic group” for Y, a saturated or unsaturated cyclic divalent or trivalent hydrocarbon group can be mentioned. Here, as the saturated cyclic divalent hydrocarbon group, a cycloalkyl group (for example, C _3-9 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl, preferably A group in which one hydrogen atom at any position (preferably a different carbon atom, more preferably a carbon atom at the most distant position) such as C _5-7 cycloalkyl, more preferably cyclohexyl, etc. is removed (for example, _C5-7 cycloalkylene, preferably 1,4-cyclohexylene and the like). Here, as the unsaturated cyclic divalent hydrocarbon group, a cycloalkenyl group (for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexene C _1-6 cycloalkenyl group such as -1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc.), cycloalkadienyl group (eg, 2,4-cyclopentadien-1-yl) , 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene C4-6 cycloalkadienyl group dien-1-yl, etc.), an aryl group (e.g., phenyl, C _6-10 aryl naphthyl Group and the like, preferably phenyl)
And the like, in which one hydrogen atom at any position (preferably, a different carbon atom, more preferably, a carbon atom at the most distant position) is removed, and among them, phenylene is preferable, and in particular, 1,4 -Phenylene is preferred.
Examples of the “divalent hydrocarbon group” include C _5-7 cycloalkylene (preferably 1,4-cyclohexylene and the like),
Phenylene (preferably 1,4-phenylene and the like) and the like are preferable. Here, as the “saturated or unsaturated cyclic trivalent hydrocarbon group”, the above “saturated or unsaturated cyclic divalent hydrocarbon group” is hydrogen from any carbon atom having a bond. And groups formed by removing one atom. The “divalent heterocyclic group” as the “cyclic group” of the “optionally substituted cyclic group” represented by Y is an oxygen atom other than a carbon atom as an atom (ring atom) constituting a ring system. And a 5- to 6-membered member containing at least one (preferably 1 to 3, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from a sulfur atom and a nitrogen atom Examples thereof include a divalent aromatic heterocyclic group and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group). As the “divalent aromatic heterocyclic group”, for example, furan, thiophene, pyrrole,
Oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5
-Oxadiazole, 1,3,4-oxadiazole,
5 such as 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole and the like Membered aromatic heterocycles and, for example, pyridine, pyridazine, pyrimidine, 1,2,4-triazine, 1,3,5-
Examples thereof include a divalent group obtained by removing two hydrogen atoms from two different ring atoms such as a 6-membered aromatic heterocycle such as triazine. Examples of the “divalent non-aromatic heterocyclic group” include 5- to 6-membered saturated or unsaturated (preferably saturated) non-aromatic groups such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholine, thiomorpholine, and piperazine. And a heterocyclic group (aliphatic heterocyclic group). As the “trivalent heterocyclic group” as the “cyclic group” of the “optionally substituted cyclic group” represented by Y, the above “divalent non-aromatic heterocyclic group” has a bond And a group formed by adding one bond to any atom. Y is preferably phenylene which may be substituted, piperidine which may be substituted and the like. In the above formula, A represents a formula

Embedded image The group represented by is preferably used.

Z represents (1) an amino group which may be substituted, (2) an imidoyl group which may be substituted, or (3) a nitrogen-containing heterocyclic group which may be substituted. Z
As the substituent in the "optionally substituted amino group" represented by the same as the above-mentioned "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R In some cases, two substituents may form a cyclic amino group together with a nitrogen atom. In such a case, the cyclic amino group may be, for example, 1
- azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and 4-position a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, t- butyl, pentyl, and the like C _1-6 alkyl groups hexyl) , An aralkyl group (for example, a C _7-10 aralkyl group such as benzyl and phenethyl), an aryl group (for example, a C _6-10 aryl group such as phenyl, 1-naphthyl and 2-naphthyl) and the like. 3 such as 1-piperazinyl
And a cyclic amino group having 8 to 8 members (preferably 5 to 6 members). Examples of the cyclic amino group include the same substituents as those described above for the "optionally substituted hydrocarbon group" for R. It may have a similar number. Further, the “optionally substituted hydrocarbon group” as a substituent in the “amino group substituted with an optionally substituted hydrocarbon group” represented by Z may be “optionally substituted at the α-position. When containing an "imino group", the "optionally substituted amino group" represented by Z forms an amino group substituted with a "substituted or imidoyl group" represented by Z described below,
For example, the formula -N (R ")-C (R ') = NR-"
[Wherein, R ″ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ′ ″ represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or Represents an acyl group derived from an acid, and R ′ represents a hydrogen atom, a hydrocarbon group optionally substituted, an acyl group derived from a carboxylic acid, an amino group optionally substituted, a mercapto group optionally substituted or And a hydroxyl group which may be substituted] are also included in the “optionally substituted amino group” for Z. Further, in the “optionally substituted imidoyl group”, when R ′ represents a mercapto group or a hydroxyl group, and R ′ ″ represents a hydrogen atom, the “optionally substituted imidoyl group” has the formula
-C (= O) -NH ₂ or -C (= S) may be a group represented by -NH _2. In the above formula, the `` optionally substituted hydrocarbon group '' represented by R ′ ″, R ′ and R ″ includes the `` optionally substituted hydrocarbon group '' represented by R described above. Similar ones include R '''
And the carboxylic acid-derived acyl group represented by R ′ includes the carboxylic acid-derived acyl group as a substituent which the aforementioned “optionally substituted hydrocarbon group” represented by R may have. And acyl groups.
As the "optionally substituted hydroxyl group" represented by
Examples of the substituent which the aforementioned “optionally substituted hydrocarbon group” represented by R may have include the same as the “optionally substituted hydroxyl group”, and represented by R ′ As the “optionally substituted amino group”, the “optionally substituted hydrocarbon group” represented by the aforementioned R
Has 1 to 2 same as the "optionally substituted amino group" as a substituent which may have, or the "optionally substituted hydrocarbon group" represented by R described above. And an optionally substituted amino group. In the compound represented by the formula (I), a compound in which R ′ ″ is an acyl group derived from a carboxylic acid is useful as a prodrug of a compound in which R ′ ″ is a hydrogen atom. Examples of the “acyl group derived from a carboxylic acid” represented by R ′ ″ include, for example,
Examples of the substituent that the “optionally substituted hydrocarbon group” represented by R may have, such as “acyl group derived from a carboxylic acid”, include “R represented by R” An acyl group derived from a carboxylic acid is, for example, a group represented by the formula -C
A carboxyl group which may be esterified, such as a group represented by OOR '''' (wherein R '''' represents an optionally substituted hydrocarbon group), Is also good.
"Optionally substituted hydrocarbon group" for R ""
Examples thereof include the same as the aforementioned “optionally substituted hydrocarbon group” represented by R.
"Optionally substituted hydrocarbon group" for R ""
Preferred examples of the “hydrocarbon group” in the above include, for example, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryl-C _1-4 alkyl And the like. Examples of the substituent that the “hydrocarbon group” may have include, for example, the same as the substituents that the “optionally substituted hydrocarbon group” represented by R ¹ may have Similar numbers are included. Expression-
As the group represented by COOR "", among others, C _1-6
Alkoxy-carbonyl group (eg, methoxycarbonyl,
Ethoxycarbonyl, isopropoxycarbonyl, etc.), C _1-6 alkanoyloxy-C _1-6 alkoxy-carbonyl group (eg, pivaloyloxymethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, acetoxy-tert-butoxycarbonyl, etc.) , A C _1-6 alkoxy-carbonyloxy-C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyloxymethoxycarbonyl, etc.), 5-C _1-4 alkyl-2-oxo-dioxolen-4-yl-C _{1- 6} alkoxy-carbonyl groups (eg, 5
-Methyl-2-oxo-dioxolen-4-ylmethoxycarbonyl) and the like. As the “optionally substituted amino group” for Z, more specifically, for example, a mono- group which may be further substituted with an amino group, a C _6-10 aryl group (preferably phenyl) or the like
Or a di-lower (C _1-6 ) alkylamino group (eg, methylamino, ethylamino, benzylmethylamino, dimethylamino, diethylamino, diisobutylamino, diisopropylamino, N-ethyl-t-butylamino,
Benzylmethylamino, etc.), formula -N (R ″)-C
(R ′) = NR ′ ″ wherein R ″ represents a hydrogen atom or an optionally substituted hydrocarbon group (preferably a hydrogen atom or a lower (C _1-6 ) alkyl group). R ′ ″ represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group derived from a carboxylic acid (preferably, a hydrogen atom or an acyl group derived from a carboxylic acid); R ′ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted hydroxyl group (preferably a hydrogen atom, a lower ( C _1-6) alkyl group, an amino group or a mono- - or di - lower (C _1-6) an alkyl amino group)], a group represented by (e.g., guanidino, formimidoyl-amino group, acetimidoyl Amino group, etc.) and a 5- to 6-membered cyclic amino group (eg, For example, a piperidino group) and the like are used. Examples of the "optionally substituted imidoyl group" for Z include, for example, a group represented by the formula -C (R ')
= NR- "[the symbols in the formula have the same meanings as described above], and the like. Here, R ′ may be an optionally substituted amino group (preferably, amino, methylamino, ethylamino, propylamino, dimethylamino,
Diethylamino, hydrazino, piperidino, piperazino, morpholino, thiomorpholino, etc.);
The `` optionally substituted imidoyl group '' represented by
Forming an optionally substituted amidino group; Specific examples of such an optionally substituted amidino group include:
An amidino group which may be substituted with one or two lower (C _1-6 ) alkyl groups, lower (C _1-6 ) alkanoyl groups, benzoyl groups, etc. (for example, amidino, N-methylamidino, N-ethyl Amidino, N-propylamidino, N,
N′-dimethylamidino, N, N′-diethylamidino,
N-methyl-N′-diethylamidino, N-formylamidino, N-acetylamidino, and the like).
In the above formula, preferred examples of R ′ ″ include hydrogen, a lower alkyl group (for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl);
Acyl groups (eg formyl, acetyl, propionyl,
C _1-6 alkanoyl such as pivaloyl; benzoyl; C _1-8 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl and the like;
And C _7-10 aralkyloxycarbonyl such as phenethyloxycarbonyl), a hydroxyl group and the like. Preferred examples of R ′ include hydrogen, lower alkyl group (for example, C ₇ such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like). _1-6 alkyl group), an optionally substituted amino group (for example, 1 to 2 same or different lower alkyl groups (for example, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl) An amino group, a hydrazino group which may be substituted with an acyl group (for example, C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, benzoyl, etc.),
A 5- to 6-membered cyclic amino group (eg, piperidino, thiomorpholino, morpholino, piperazino, etc.), a hydroxyl group, a lower alkoxy group (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy) Group), a mercapto group, a lower alkylthio group (eg, a C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.). In the above formula, R ′ ″ is preferably hydrogen. In the above formula,
R ′ is preferably hydrogen, a lower alkyl group or an optionally substituted amino group, and among them, a lower alkyl group or an optionally substituted amino group is preferable,
In particular, an optionally substituted amino group (preferably an amino _optionally substituted with C _1-4 alkyl) is preferred.

As the "nitrogen-containing heterocyclic group" in the "optionally substituted nitrogen-containing heterocyclic group" for Z, a nitrogen atom other than a carbon atom is used as an atom (ring atom) constituting a ring system. An aromatic nitrogen-containing heterocyclic group containing at least one (preferably 1 to 3), and optionally containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom; And an aromatic nitrogen-containing heterocyclic group (aliphatic heterocyclic group). Examples of the “aromatic nitrogen-containing heterocyclic group” include, for example, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazol-1-yl, 1H-imidazole-4-yl and the like), pyrazolyl, 1,2,3 -Oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3 -Triazolyl, 1,2,4-triazolyl (1,2,4-triazolyl-1-yl, 1,2,4-triazolyl-4-yl etc.), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl) ), Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and an aromatic monocyclic nitrogen-containing heterocyclic group and its N-oxide form. Also, preferably an aromatic monocyclic nitrogen-containing heterocyclic group 5-6 membered, especially, imidazolyl, etc. pyridyl are preferred. As pyridyl, 4-pyridyl which may have a substituent at the 2-position (eg, an optionally substituted lower alkyl group or the like) is preferable. As the “non-aromatic nitrogen-containing heterocyclic group”, in addition to the partially reduced form of the above-mentioned “aromatic nitrogen-containing heterocyclic group” (eg, imidazolinyl, tetrahydropyrimidinyl, etc.), for example, azetidinyl, pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinyl (such as 1-piperazinyl), homopiperazinyl, and the like. Among them, a 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group is preferable. As the substituent for the “nitrogen-containing heterocyclic group” represented by Z, the same substituents as those for the above-mentioned “heterocyclic group” represented by R can be used. Further, the nitrogen atom constituting the nitrogen-containing heterocyclic group may be oxidized. Also, Z
May be bonded to each other to form a ring (eg, a benzene ring or the like). As Z, an optionally substituted nitrogen-containing heterocyclic group or the like is preferable, and particularly, an optionally substituted aromatic nitrogen-containing heterocyclic group or the like is preferable. Compound (I) includes 4- (7-chloro-
2H-benzopyran-3-sulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylamino] -2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4 -Pyridyl) piperidin-4-ylamino] -2-piperazinone, 4- (6-bromonaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) piperidin-4-
Ilamino] -2-piperazinone, 4- (7-bromo-2H-benzopyran-3-sulfonyl) -1- [1- (4-pyridyl) piperidine-4
-Ylamino] -2-piperazinone, 4- (6-chloronaphthalene
-2-sulfonyl) -1- {methyl [1- (4-pyridyl) piperidine-
4-yl] amino} -2-piperazinone, 4- (6-bromonaphthalene-2-sulfonyl) -1- {methyl [1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4 -(7-bromo-2H-
Benzopyran-3-sulfonyl) -1- {methyl [1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4- (6-
Chloronaphthalene-2-sulfonyl) -1- {ethyl [1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4-
(6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (2-
Methyl-4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, {[4- (6-chloronaphthalene-2-sulfonyl) -2-
Oxo-1-piperazinyl] [1- (2-methyl-4-pyridyl) -4-
Piperidinyl] amino} acetic acid, 4- (6-chloronaphthalene-2-
Sulfonyl) -1-{[1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxylic acid, 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [ 1- (4-pyridyl) -4-
Piperidinyl] amino} -6-oxo-2-piperazinecarboxylic acid, 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl
[1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-
Piperazinecarboxylic acid amide, 4- (6-chloronaphthalene-
2-sulfonyl) -1- {methyl [1- (2-methyl-4-pyridyl) -4-
Piperidinyl] amino} -6-oxo-2-piperazinecarboxamide, 4- (6-chloronaphthalene-2-sulfonyl) -6-hydroxymethyl-1- {methyl [1- (4-pyridyl) -4-piperidinyl ] Amino} -2-piperazinone, 6-aminomethyl-4- (6-
Chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone, 6-acetylaminomethyl-4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1-{[1- (4-pyridyl)- 4-piperidinyl] amino} -6-
Oxo-2-piperazineacetic acid, 4- (6-chloronaphthalene-2-
Sulfonyl) -1-{[1- (2-methyl-4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazineacetic acid or a salt thereof is particularly preferably used. Compound (I)
Is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, that is, a compound that is converted into compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like. And a compound which is converted to the compound (I) by hydrolysis or the like by stomach acid or the like. As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated (for example, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.), Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, and borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl) Or dimethylaminomethylcarbonylated compound) or the carbohydrate of compound (I) Sill group is esterified,
Amidated compounds (for example, the carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, and the like. These compounds can be produced from compound (I) by a method known per se. The prodrug of compound (I) is available from Hirokawa Shoten 19
The compound may be converted to the compound (I) under physiological conditions as described in “Development of Pharmaceuticals”, 1990, Vol. 7, pp. 163 to 198, Molecular Design.

Examples of the salt of compound (I) include pharmacologically acceptable salts, such as acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, and the like. Methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, acid addition salts with acids such as sulfuric acid, for example, sodium, Metal salts such as potassium, magnesium and calcium, for example, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N
Organic salts such as -methylmorpholine.

Compound (I) or a salt thereof can be produced, for example, by the following methods A to D. Each compound described in the following reaction formulas may form a salt as long as it does not inhibit the reaction, and examples of such a salt include those similar to the salt of compound (I). Method A

Embedded image Method B

Embedded image Method C

Embedded image Method D

Embedded image

Method A Formula RSO ₂ Q (II) wherein Q is a leaving group, and other symbols are as defined above. (I)
I) or a salt thereof and formula (III)

Embedded image [The symbols in the formula are as defined above. Compound (I) can be produced by reacting the compound (III) or a salt thereof. In the above formula (II), Q
Represents a leaving group. Examples of the leaving group represented by Q include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or a reactive derivative of sulfonic acid (eg, sulfonic anhydride, active sulfonic amide (eg, 1,2 , 4-triazolide,
Imidazolide, etc.), quaternary amine sulfonyl compounds (eg, N-methylpyrrolidinium salt, etc.), bissulfonylimides (eg, N-phenylbissulfonylimide, etc.) and the like. This method is carried out by reacting compound (II) or a salt thereof with compound (III) or a salt thereof. As the salt of compound (II) or (III), the above-mentioned compound (I) and an acid addition salt are used. Acid addition salts with the acids formed. This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, for example, dioxane, tetrahydrofuran,
Ethers such as diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate and n-butyl acetate, for example, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, Halogenated hydrocarbons such as 2-dichloroethane, and hydrocarbons such as n-hexane, benzene, and toluene; amides such as formamide, N, N-dimethylformamide, and N, N-dimethylacetamide;
For example, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and nitriles such as acetonitrile and propionitrile, as well as dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent. This reaction may be carried out in the presence of a base if necessary.Examples of such a base include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogencarbonate. Triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N,
Tertiary amines such as N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used. In the reaction, about 1 to about 5 mol, preferably about 1 to about 3 mol of compound (II) is used per 1 mol of compound (III). The reaction temperature ranges from about -80 ° C to about 1
00 ° C, preferably from about -50 ° C to about 80 ° C.
The reaction time varies depending on the type of compound (II) or (III), the type of solvent, the reaction temperature and the like, but is usually about 1 minute to about 7 minutes.
2 hours, preferably from about 15 minutes to about 24 hours.

Method B Formula (IV)

Embedded image [In the formula, Q ¹ represents a leaving group (eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a free carboxylic acid such as a hydroxyl group, a salt thereof (an inorganic salt, an organic salt, etc.) or a reactive derivative thereof) (Eg, groups forming an acid halide, ester, acid azide, acid anhydride, mixed acid anhydride, active amide, active ester, active thioester, etc.), and other symbols have the same meanings as described above. And a compound (IV) represented by the formula (V)

Embedded image [The symbols in the formula are as defined above. The compound (I) can be produced by reacting the compound (V) represented by the formula In this method, compound (V) or its salt and free acid (IV) or its salt (inorganic salt, organic salt, etc.) or its reactive derivative (for example, acid halide, ester, acid azide, acid anhydride, mixed acid anhydride) , An active amide, an active ester, an active thioester, etc.). Examples of the salt of the compound (V) include an acid addition salt of the above-mentioned compound (I) with an acid which forms an acid addition salt. As the inorganic salt used for the compound (IV), an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, etc.) and the like, and as the organic salt, a trimethylamine salt,
Triethylamine salt, tert-butyldimethylamine salt,
Dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like are used. Examples of the acid halide include acid chloride and acid bromide, and examples of the ester include lower alkyl esters such as methyl and ethyl, and examples of the mixed acid anhydride include mono-C _1-4 alkylcarbonic acid mixed acid anhydride (eg, free acid). (IV) and monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, mono
Mixed acid anhydrides with tert-butyl carbonate, monobenzyl carbonate, mono (p-nitrobenzyl) carbonate, monoallyl carbonate, etc.), C _1-6 aliphatic carboxylic acid mixed acid anhydrides (for example, free acid (IV) and acetic acid) , Cyanoacetic acid, propionic acid, butyric acid,
Mixed acid anhydrides with isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, etc.), C _7-11 aromatic carboxylic acid mixed acid anhydrides (eg free acid (IV) Mixed anhydrides with benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc.), and mixed sulfonic acid anhydrides (e.g., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) As an active amide, for example, an amide with a nitrogen-containing heterocyclic compound (eg, an acid amide with free acid (IV) and pyrazole, imidazole, benzotriazole, etc.). the C _1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, etc.), C _1-6 alkoxy (e.g. methoxy, et Alkoxy, propoxy, isopropoxy, butoxy, tert- butoxy, etc.), a halogen atom (e.g. fluorine, chlorine, bromine), oxo, thioxo,
C _1-6 alkylthio (eg, methylthio, ethylthio,
Propylthio, butylthio, etc.). Examples of the active ester include organic phosphates (eg, diethoxy phosphate,
Diphenoxyphosphate, etc.), p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester,
Examples include N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyridone ester, and the like. As the active thioester, an aromatic heterocyclic thiol compound [these heterocyclics are C
_1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl, etc.), C _1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-
Ester with, for example, 2-pyridylthiol), which may be substituted with a halogen atom (eg, fluorine, chlorine, bromine, etc.), C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, butylthio, etc.). Ester, 2-benzothiazolyl thiol ester]
And the like. This reaction is generally performed in a solvent, and if necessary, a base or a condensing agent (for example, carbodiimides (DC
C, WSC, DIC, etc.) and a phosphoric acid derivative (eg, diethyl cyanophosphate, DPPA, BOP-Cl, etc.).
As such a solvent and a base, the solvent and the base described in the above-mentioned method A can be used as they are. The reaction is performed with the compound (I
The compound (V) is used in an amount of about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the V). Reaction temperature is about -5
0 ° C to about 150 ° C, preferably about -20 ° C to about 100 ° C. The reaction time varies depending on the type of compound (IV) or (V), the type of solvent and base, the reaction temperature and the like, but is usually about 1 minute to about 100 hours, preferably about 1 hour.
5 minutes to about 48 hours.

Method C Formula (VI)

Embedded image [The symbols in the formula are as defined above. Compound (VI) or a salt thereof of the formula (VII) A ¹ -X ² -Z [wherein represented by], A ¹ is Q ² -Y- or O = Y- indicates, Q ²
Is a leaving group (eg, a halogen atom, formula R ⁵ —SO ₂ —O—
(Wherein, R ⁵ represents a lower alkyl group which may be substituted with a halogen atom or a phenyl group which may have a substituent), and the other symbols are as defined above. Show the same significance. The compound (I) or a salt thereof can be produced by reacting the compound (I) or a salt thereof. This method is performed by reacting compound (VI) with compound (VII). In the above formula (VII),
The halogen atom represented by Q ^2, such as chlorine, bromine, and iodine. In the above formula, examples of the lower alkyl group which may be substituted with a halogen atom represented by R ⁵ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and neopentyl. Tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
Examples thereof include C _1-6 alkyl groups such as 3,3-dimethylbutyl and 2-ethylbutyl, and among them, C _1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl are preferable. Examples of the lower alkyl group substituted by a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) represented by R ⁵ include, for example, trichloromethyl, trifluoromethyl and the like. As the substituent of the phenyl group represented by R ⁵ , for example, a lower alkyl group (the above-mentioned R
⁵ , lower alkoxy groups (eg, C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy), halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) ),
Nitro groups, cyano groups, carboxyl groups and the like are used.

The reaction of this method is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Such solvents include, for example, methanol, ethanol, propanol,
Alcohols such as isopropanol, butanol, tert-butanol, for example, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether,
Ethers such as diisopropyl ether and ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate and n-butyl acetate, for example, dichloromethane, chloroform, carbon tetrachloride, trichlene,
Halogenated hydrocarbons such as 2-dichloroethane and the like, for example, hydrocarbons such as n-hexane, benzene and toluene, for example, formamide, N, N-dimethylformamide, N,
Amides such as N-dimethylacetamide, for example, acetonitrile, nitriles such as propionitrile and the like,
Dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent. This reaction may be carried out in the presence of a base. Examples of such a base include alkali metal hydrides such as potassium hydride and sodium hydride, for example, lithium ethoxide, lithium-tert-butoxide, and sodium methoxy. , Sodium ethoxide, carboxyl-tert-
Metal alkoxides having 1 to 6 carbon atoms such as butoxide, for example, inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogencarbonate, for example, triethylamine, tri (n-propyl) amine , Tri (n-butyl) amine,
Diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-
Tertiary amines such as dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used. In the reaction, about 1 to about 100 mol, preferably about 1 to about 50 mol of compound (VII) is used per 1 mol of compound (VI). The reaction temperature is about -30 ° C to about 250 ° C, preferably about -10 ° C to about 200 ° C. The reaction time depends on the type of compound (VI) or (VII),
The time is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours, depending on the type of the solvent, the reaction temperature and the like. Further, the compound (VI) or a salt thereof is reacted with the compound (VII) having an oxo group or a salt thereof to produce a compound (I) in which the substituent A has a double bond, followed by a reductive amination reaction. In addition, compound (I) in which substituent A has a single bond or a salt thereof can also be produced. As the reducing agent used in the present reductive alkylation reaction, lithium aluminum hydride, trimethoxylithium aluminum hydride, tri-tert-butoxylithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, borohydride Metal-hydrogen complex compounds such as sodium, sodium trimethoxyborohydride, sodium borohydride, sodium triacetoxyborohydride, lithium borohydride, lithium borohydride lithium, lithium triethylborohydride, and triethylsilane Is preferably used. Further, a catalytic reduction method using a catalyst may be used. Examples of the catalyst include palladium catalysts such as palladium black, palladium carbon, palladium-silica gel, palladium-barium sulfate, platinum oxide, platinum carbon, platinum catalysts such as platinum black, rhodium carbon, rhodium catalysts such as rhodium alumina, ruthenium oxide, The reaction is carried out in a hydrogen atmosphere using a ruthenium catalyst such as ruthenium carbon, Raney nickel or the like. The amount of the catalyst to be used is about 0.0001 to about 2 mol, preferably about 0.0, per 1 mol of compound (I).
01 to about 1 mole. The present catalytic reduction reaction is generally performed at normal pressure, but may be performed under pressure if necessary. Such pressure is usually about 1 to about 150 atm, preferably about 1 to about 100 atm. This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, and ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether. For example, esters such as ethyl formate, ethyl acetate and n-butyl acetate, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane, and the like, for example, n-hexane, benzene, toluene and the like Hydrocarbons, for example, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide,
For example, in addition to organic acids such as formic acid, acetic acid and trifluoroacetic acid, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide and the like are used alone or as a mixed solvent. This reaction may be carried out in the presence of an acid, if necessary. Examples of such an acid include hydrochloric acid, hydrobromic acid, sulfuric acid,
Mineral acids such as phosphoric acid and perchloric acid, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and camphorsulfonic acid; and organic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid. Used. The amount of these acids to be used is about 0.01 to about 20 mol, preferably about 0.1 to about 10 mol, per 1 mol of compound (I).
Is a mole. The reaction temperature is about -30 ° to about 150 ° C, preferably about -10 ° to about 120 ° C. The reaction time varies depending on the type of compound (I), the type of solvent and the reaction temperature, but is usually about 10 minutes to about 72 hours, preferably about 15 minutes to about 48 hours. Further, among the compounds represented by the formula (VI), the compound in which R ³ is an acyl group is a novel compound, and is useful as a synthetic intermediate of the compound represented by the formula (I) or a salt thereof. .

Method D Formula (VIII)

Embedded image Wherein, Q ³ is a leaving group (such as hydrogen atoms when attached to a nitrogen atom of Y or X ^2, a halogen atom when bonded to a carbon atom of the Y or X ^2, a cyano group, a cross-coupling reaction can during Do for example, boron, tin, atomic group bonded with magnesium or the like, wherein R ⁶ -SO ₂ -O- (wherein, R ⁶
Represents a lower alkyl group which may be substituted with a halogen atom or a phenyl group which may have a substituent)), and other symbols have the same meanings as described above. ]
And a salt thereof with a compound of formula ZQ ⁴ (I
X) [wherein, when Z is not an optionally substituted amino group, Q ⁴ represents a leaving group (halogen atom, formula R ⁷ —SO ₂ —
O- (wherein R ⁷ represents a lower alkyl group which may be substituted with a halogen atom or a phenyl group which may have a substituent), for example, boron capable of performing a cross-coupling reaction , Tin, magnesium, etc.), and when Z is an amino group which may be substituted, Q ⁴ represents a hydrogen atom and the other symbols have the same meanings as described above. . With the compound (IX) or a salt thereof to produce the compound (I). In the above formula, the halogen atom represented by Q ^3, chlorine, bromine, and iodine. R ⁶ and R ⁷ each represent a lower alkyl group which may be substituted with a halogen atom or a phenyl group which may have a substituent. As the lower alkyl group represented by R ⁶ and R ⁷ , for example, methyl, ethyl, propyl, isopropyl,
Examples thereof include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like, and among them, methyl, ethyl, propyl, isopropyl and butyl are preferred. Examples of the halogen atom include fluorine, chlorine, bromine, iodine, and the like. These halogen atoms may be substituted at 1 to 9, preferably 1 to 5 at any position. Examples of the substituent of the phenyl group which may have a substituent include lower alkyl (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, butyl, etc.) and lower alkoxy group (eg, methoxy, ethoxy, A C _1-6 alkoxy group such as propoxy and butoxy), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, and a carboxy group. In this method, compound (I) is produced by reacting compound (VIII) or a salt thereof with compound (IX) or a salt thereof. This reaction is generally performed in the presence of a base. Such bases include, for example, alkali metal hydrides such as sodium hydride and potassium hydride, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like. Alkaline earth metal hydroxide, sodium carbonate, potassium carbonate and other alkali metal carbonates, sodium hydrogen carbonate,
Inorganic bases such as alkali metal bicarbonates such as potassium bicarbonate, for example trimethylamine, triethylamine,
Diisopropylethylamine, pyridine, picoline, N
-Methylpyrrolidine, N-methylmorpholine, 1,5-
Diazabicyclo [4.3.0] non-5-ene, 1,4-
Organic bases such as diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, lithium salts such as methyllithium, n-butyrolithium, sec-butyrolithium, tert-butyrolithium;
Lithium amides such as lithium diisopropylamide are preferably used. This reaction is generally performed in a solvent.
As such a solvent, the solvent described in the above-mentioned method A is used as it is. The reaction is carried out in an amount of about 0.8 to 10 mol, preferably about 0.9 to 5 mol, and about 1 to about 100 mol, preferably about 1 to about 20 mol, of compound (IX) per 1 mol of compound (VIII). Used. Reaction temperature is about -10
C. to about 250.degree. C., preferably about -5.degree. C. to about 200.degree. The reaction time varies depending on the compound (VIII), the compound (IX), the type of the base or the solvent, the reaction temperature and the like, but is usually about 1 hour.
Minutes to about 200 hours, preferably about 5 minutes to about 100 hours. This reaction can be promoted by using a metal catalyst in some cases. Examples of such a metal catalyst include palladium compounds (e.g., palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium, dichlorobis (triethylphosphine) palladium,
Tris (dibenzylideneacetone) dipalladium-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, etc.), nickel compounds (e.g., tetrakis (triphenylphosphine) nickel, bis (triethylphosphine) nickel chloride , Bis (triphenylphosphine) nickel chloride, etc.], rhodium compounds [eg, tri (triphenylphosphine) rhodium chloride, etc.], among which palladium compounds are preferred. The amount of these catalysts to be used is about 1-0.00000 per 1 mol of compound (VIII).
1 mole, preferably about 0.1 to 0.00001 mole. This reaction may be performed in a sealed tube. In the compound (I), the compound wherein Z is an amidino group which may be substituted is a compound wherein Q ³ is a cyano group (VII
It can be produced by reacting I) or a salt thereof with a lower alcohol to produce an imino ether, and then reacting with an amine. As lower alcohols,
Examples thereof include C _1-4 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol. This reaction is usually performed in a solvent. As such a solvent, the solvent described in the above-mentioned method A is used as it is, but alcohols may be used as it is. This reaction may be carried out using ordinary acids (eg, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, acetic acid, and trifluoroacetic acid) and The reaction is performed in the presence of a base (eg, potassium methoxide, sodium methoxide, sodium ethoxide, potassium-tert-butoxide, and the like). These acids and bases may be used in a large excess from the catalytic amount (about 0.001 mol). The reaction temperature is about -50 ° C to about 15
0 ° C, preferably about -20 ° C to about 100 ° C. The reaction time varies depending on the type of compound (VIII), acid, base or solvent, but is usually about 30 minutes to about 240 hours, preferably about 1 hour to about 120 hours. Imino ethers include amines (eg, ammonia; primary amines such as methylamine, ethylamine, and propylamine); dimethylamine, diethylamine, methylethylamine, di-n-
Propylamine, pyrrolidine, piperidine, morpholine, piperazine, secondary amines such as 1-methylpiperazine; and aromatic amines such as aniline and N-methylaniline) to produce compound (I). This reaction is usually performed in a solvent, and any solvent may be used as such a solvent, as long as the reaction is not hindered, but the solvent described in the above-mentioned method A is preferably used. Further, amines may be used as a solvent as it is. The reaction temperature is generally about -20 ° C to about 200 ° C, preferably about -1 ° C.
0 ° C to about 150 ° C. Reaction time is imino ether,
The time is usually about 30 minutes to about 240 hours, preferably about 1 hour to about 120 hours, depending on the type of amine, solvent and reaction temperature. This reaction may be carried out in a sealed tube if necessary.

The starting compounds (III), (IV), (VI) and (VIII) used in the above-mentioned production methods A to D are produced, for example, by a method known per se or a method analogous thereto as shown below. be able to.

Embedded image

Method E Formula (X)

Embedded image [In the formula, L ¹ is a protecting group for an amino group, and other symbols are as defined above. And a salt thereof represented by the formula (V):

Embedded image [Wherein the symbols are as defined above. With the compound (V) or a salt thereof to obtain a compound of the formula (XIII)

Embedded image [The symbols in the formula are as defined above. To produce a compound (XIII) represented by the formula: Formulas (X) and (XII)
In I), examples of the protecting group represented by L ¹ include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.), a C _1-6 alkyl-sulfonyl group, and a tert-butyloxycarbonyl group. Benzyloxycarbonyl group, allyloxycarbonyl group, fluorenylmethyloxycarbonyl group, arylcarbonyl group (eg, phenylcarbonyl, naphthylcarbonyl, etc.), arylsulfonyl group (eg, phenylsulfonyl, naphthylsulfonyl, etc.), C _1-6 alkyl Oxy-
A carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), a C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.), a methyl group, an aralkyl group (eg, benzyl, diphenylmethyl, trityl group, etc.) are used. These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro groups and the like. The reactive derivative, reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out by the reactive derivative described in the reaction of compound (IV) with compound (V) in method B, reaction conditions and the like, or a method analogous thereto. .

Method F Formula (XII)

Embedded image [In the formula, L ¹ is a protecting group for an amino group, and other symbols are as defined above. And a salt thereof represented by the formula (VII):

Embedded image [Wherein the symbols are as defined above. With a compound (VII) or a salt thereof represented by the formula (XII)
I)

Embedded image [The symbols in the formula are as defined above. To produce a compound (XIII) represented by the formula: The reactive derivative, reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out by the reactive derivative described in the reaction of compound (VI) with compound (VII) in method C, reaction conditions and the like or a method analogous thereto. .

Method G Formula (X)

Embedded image [Wherein the symbols are as defined above. And a salt thereof represented by the formula:

Embedded image [In the formula, L ² is a protecting group for an amino group, and other symbols are as defined above. By reacting the hydrazine derivative represented by the formula (I) or a salt thereof, and then selectively deprotecting the amino-protecting group of the hydrazine to obtain a compound of the formula (XII)

Embedded image [Wherein the symbols are as defined above. ] Or a salt thereof. The reactive derivative, reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out by the reactive derivative described in the reaction of compound (IV) with compound (V) in method B, reaction conditions and the like, or a method analogous thereto. . As a method for selectively removing the protecting group for the amino group on the hydrazine side, a method known per se or a method analogous thereto is used, for example, a method using an acid, a base, reduction, ultraviolet light, palladium acetate or the like is used.

Method H Formula (VII)

Embedded image [Wherein the symbols are as defined above. A compound (VII) or a salt thereof represented by the formula:

Embedded image [In the formula, L ³ is a protecting group for an amino group, and other symbols are as defined above. By reacting the hydrazine derivative of the formula (V)

Embedded image [Wherein the symbols are as defined above. Or a salt thereof. The reactive derivative, reaction conditions, reaction solvent, reaction time and the like in this reaction are carried out by the reactive derivative described in the reaction of compound (VI) with compound (VII) in method C, reaction conditions and the like or a method analogous thereto. . As a method for removing the protecting group for the amino group, a method known per se or a method analogous thereto is used, for example, a method using an acid, a base, reduction, ultraviolet light, palladium acetate, or the like is used.

Method I Formula (XI)

Embedded image [The symbols in the formula are as defined above. By aminating the amide nitrogen atom of compound (XI)
Formula (XII)

Embedded image [The symbols in the formula are as defined above. ] Or a salt thereof. Examples of the aminating agent used in the present amination reaction include O-acylhydroxylamine such as O-diphenylphosphinylhydroxylamine, O-hydroxylamine, and O- (2,4,6-trimethylbenzenesulfonyl) hydroxylamine. And the like are preferably used. This reaction is generally performed in the presence of a base. Such bases include, for example, alkali metal hydrides such as sodium hydride and potassium hydride, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like. Alkaline earth metal hydroxide, sodium carbonate, alkali metal carbonates such as potassium carbonate, sodium hydrogen carbonate, inorganic bases such as alkali metal hydrogen carbonate such as potassium hydrogen carbonate, for example, sodium methylate, sodium ethylate, potassium methylate, alkali metal alcoholates such as potassium tert-butoxy, for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine,
1,5-diazabicyclo [4.3.0] non-5-ene,
1,4-diazabicyclo [2.2.2] octane, 1,8-
Organic bases such as diazabicyclo [5.4.0] -7-undecene, methyllithium, n-butyrolithium, sec-
Lithium salts such as butyrolithium and tert-butyrolithium, and lithium amides such as lithium diisopropylamide are preferably used. This reaction is generally performed in a solvent. As such a solvent, the solvent described in the above-mentioned method A is used as it is. In the reaction, about 1 to about 100 mol, preferably about 1 to about 20 mol of a base is used per 1 mol of compound (XI), but in some cases, a base may be used as a solvent. The reaction temperature is about -100 ° C to about 200
° C, preferably from about -78 ° C to about 100 ° C. The reaction time depends on the type of compound (XI), aminating agent, base or solvent,
Although it varies depending on the reaction temperature and the like, it is generally about 1 minute to about 200 hours, preferably about 5 minutes to about 100 hours.

Method J Formula (XIII)

Embedded image [The symbols in the formula are as defined above. By deprotecting the amino protecting group of the compound (XIII) or a salt thereof represented by the formula (III):

Embedded image [The symbols in the formula are as defined above. ] Or a salt thereof can be produced. As a method for removing the protecting group for the amino group, a method known per se or a method analogous thereto is used, for example, acid, base, reduction, ultraviolet light,
A method using palladium acetate or the like is used.

Method K Formula (XIV)

Embedded image Or formula (XV)

Embedded image [The symbols in the formula are as defined above. The compound (XIV) and the compound (XV) represented by the formula:
SO ₂ Q [The symbols in the formula are as defined above. By sulfonylation with a compound represented by the formula (IV):

Embedded image Or formula (VI)

Embedded image [The symbols in the formula are as defined above. And compound (VI) or a salt thereof.

Method L Formula (VIII)

Embedded image [The symbols in the formula are as defined above. The compound (VIII) or a salt thereof represented by the following formula (I)
I) and compound (XVI), compound (IV) and compound (X
VII) and compound (VI) and compound (XVIII)
And can be produced in the same manner as in the methods A, B and C, respectively.

[0038]

Embedded image Also, in the above method G, the formula obtained before the deprotection step is obtained.

Embedded image [Wherein, L ¹ and L ² each represent an amino-protecting group, and the other symbols have the same meanings as described above. A compound represented by the formula:

Embedded image [Wherein, L ^1a and L ^2a each represent a hydrogen atom or an amino-protecting group, and the other symbols have the same meanings as described above. In the compound represented by the formula or a salt thereof,

Embedded image [Wherein, L ^1a and L ^2a each represent a hydrogen atom or an amino-protecting group, and indicate that R ^{1 ′} and R ^{2 ′} are bonded to each other to form an optionally substituted ring. Or that R ^{1 ′} is a hydrogen atom or an optionally substituted hydrocarbon group, and that the substituent of X ¹ and R ^{2 ′} are bonded to each other to form an optionally substituted ring. And other symbols are as defined above. Or a salt thereof is a novel compound, and is useful as a synthetic intermediate of the compound represented by the formula (I) or a salt thereof.
In the above formula, examples of the protecting group for the amino group represented by L ^1a and L ^2a include those similar to the protecting group for the amino group represented by L ^1. As a substituent of the “hydrocarbon group” and the “optionally substituted heterocyclic group”, “acyl group derived from sulfonic acid” or “acyl group derived from carboxylic acid” may be used.
Further, it is preferable that one of L ^1a and L ^2a is not a hydrogen atom, and it is particularly preferable that L ^1a is a protecting group for an amino group and L ^2a is a hydrogen atom. Such synthetic intermediate, bonded R ^{1 'and} R ^2' each other, -N-X ¹ -CD-N- with formula

Embedded image Wherein X ³ is an optionally substituted C _1-2 alkylene, X ⁴ is an optionally substituted C _1-3 alkylene,
Represents an oxygen atom or a sulfur atom. And a compound forming a group represented by the formula: wherein R ^{1 ′} and R ^{2 ′} are bonded to each other to form a group together with —NX ¹ —CD—N—

Embedded image [In the formula, n is 1 or 2, m ″ is 1 or 2, R ⁸ is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, a substituted An optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted Thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted A carbamoyl group or an optionally substituted thiocarbamoyl group)
Represents an oxygen atom or a sulfur atom. More preferably a compound that forms a group represented by], inter alia, by combining R 1 ^'and R ^2' each other, -N-X ¹ -CD-N- with formula

Embedded image [In the formula, n represents 1 or 2, and m represents 2 or 3. A compound forming a group represented by the formula (more preferably, n = 1
And m = 2). In addition, the synthetic intermediate has a structure in which the substituent of X ¹ and R ^{2 ′} are bonded to each other,
The divalent group represented by X ¹ -CD-N (R ^{2 ′} ) —

Embedded image [In the formula, X ⁵ represents a bond or an optionally substituted methylene, X ⁶ represents an optionally substituted C _2-3 alkylene, and D represents an oxygen atom or a sulfur atom. ] May be a compound which is a group represented by the substituents X ¹ and R
^{2 ′} are bonded to each other to form a divalent group represented by —X ¹ —CD—N (R ^{2 ′} ) —

Embedded image [In the formula, n ′ represents 0 or 1, and m ′ represents 2 or 3. ]
A compound represented by the formula (more preferably, n ′ =
0 and m ′ = 2) are more preferred. The starting compound (I) used in the above-mentioned production methods A to L
I), (III), (IV), (V), (VI), (V
II), (VIII), (IX), (X), (XI),
(XII), (XIV), (XV), (XVI), (X
VII) and (XVIII) can be produced by a method known per se or a method analogous thereto. When a compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method, and when obtained as a salt, converted to a free form or another salt according to a conventional method. You can also. The compound (I) thus obtained can be obtained from the reaction mixture by a method known per se, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin-layer chromatography, or the like. Can be separated and purified. Compound (I)
Can be produced according to a means known per se, for example, by adding an inorganic acid or an organic acid to compound (I). When stereoisomers may exist in compound (I), both of these individual isomers and mixtures thereof are, of course, included in the scope of the present invention. If desired, these isomers may be produced individually. You can also. Further, the compound (I) or a salt thereof may be a hydrate,
Both hydrates and non-hydrates are included in the scope of the present invention. Also, the formula

Embedded image [Wherein R ^{1 ′} and R ^{2 ′} indicate that they are bonded to each other to form an optionally substituted ring,
^{1 ′} represents a hydrogen atom or an optionally substituted hydrocarbon group, and the substituent of X ¹ and R ^{2 ′} are bonded to each other to form an optionally substituted ring, The symbols are as defined above. Or a salt thereof (including compound (I); and preferably a compound represented by the formula

Embedded image [In the formula, ring B represents an optionally substituted piperazinone ring, and R ³ has the same meaning as described above. Or a salt thereof having a divalent group represented by the following formula:

Embedded image [In the formula, ring E represents an optionally substituted pyrrolidone ring, and R ^{1 ′} and R ³ have the same meaning as described above. The compound having a divalent group as a partial structure or a salt thereof represented by the following formula) is a compound (m) containing various peptides (including proteins).
imic: mimics) (particularly, at the site where various peptides exhibit physiological activity, has the effect of mimicking the peptides).
They are useful as receptor modulators (eg, receptor antagonists, receptor agonists, etc.), ion channel modulators (eg, ion channel antagonists, ion channel agonists, etc.). That is, it is possible to inhibit the formation of an enzyme-substrate complex by mimicking the catalytic site of the enzyme and / or the binding site of the substrate, and to mimic the ligand of the receptor to mimic the receptor. Can also be used as agonists or antagonists. Such enzyme inhibitors include, for example, an activated blood coagulation factor X inhibitor, a thrombin inhibitor, an activated blood coagulation factor inhibitor such as an activated blood coagulation factor VII inhibitor, a plasmin inhibitor, a kallikrein inhibitor, Nitric oxide synthase inhibitor, HIV reverse transcriptase inhibitor, HIV protease inhibitor, farnesyl transferase inhibitor, various matrix metalloprotease inhibitors, tyrosine phosphatase inhibitors, cyclin-dependent kinase inhibitors, protein tyrosine kinases Inhibitors, various protein kinase inhibitors, telomerase inhibitors, cathepsin inhibitors,
Elastase inhibitor, phosphodiesterase inhibitor, various serine protease inhibitors, interleukin-1β
Converting enzyme inhibitors, various cysteine protease inhibitors, and the like. Receptor modulators include fibrinogen receptors such as glycoprotein (GP) IIb / IIIa, integrins (vitronectin receptors), thrombin receptors,
Orphan receptor, nuclear receptor, adrenergic receptor,
Histamine receptor, angiotensin II receptor, endothelin receptor, leukotriene receptor, thromboxane receptor, chemokine receptor, opioid receptor, adenosine receptor, tachykinin receptors such as substance P and neurokinin, bradykinin receptor, prosta Glandin receptor, dopamine receptor, serotonin receptor, adrenocorticotropic hormone releasing factor (CRF) receptor, LH-RH receptor, somatostatin receptor, glucagon receptor, various G
Protein-coupled receptor, insulin-like growth factor receptor (IG
F), epidermal growth factor (EGF), fiber cell growth factor (FG)
F), platelet-derived growth factor (PDGF), hepatocyte growth factor (H
GF), vascular endothelial cell growth factor (VEGF), transforming growth factor (TGF), nerve growth factor (NGF), tumor necrosis factor (TNF)
Various growth factor receptors such as erythropoietin (EP
O), thrombopoietin (TPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CS
F) and various stimulatory receptors, interleukin-
1, various cytokine receptors such as interleukin-6 and interleukin-8, antagonists and agonists of receptors such as hormone receptors, and ion channel regulators such as calcium, potassium and chlorine. Examples include ion channel antagonists and agonists. Such enzyme inhibitors, receptor modulators (eg,
Intermediate compounds (XIX), which are particularly useful as scaffolds that mimic peptides in the molecular design of receptor antagonists, receptor agonists, etc., ion channel modulators (eg, ion channel antagonists, ion channel agonists, etc.) and (XXVIII) can be synthesized, for example, by the following method or the following method.

Embedded image

Embedded image [Wherein each symbol is as defined above] Method for producing compound (XIX) Method M: can be synthesized by performing an acylation reaction of hydrazine compound (XX) in the molecule. It is usually carried out using a solvent that does not participate in the reaction, and in the case of condensation with a carboxylic acid, it is preferable to use a condensing agent. Further, the reaction can be carried out under a base or an acid catalyst. Method N: can be synthesized by a ring closure reaction of acid hydrazide compound (XXI). When Q ⁴ is a leaving group, the reaction is preferably performed in the presence of a base. Q ⁴ may be a hydroxyl group. In this case, Q ⁴ can be synthesized by performing a Mitsunobu reaction. Q ⁴
When forming a conjugated double bond together with R ^8, it can be easily synthesized by performing conjugate addition reaction in the presence of a base catalyst. Method O: Compound (XXII) can be synthesized by performing a ring closure reaction in the presence of a base. Method P: By reacting an amino acid hydrazide compound (XXIII) with 1,2-dibromo (which may have a leaving group such as iodo or trifluoromethanesulfonyloxy instead of bromo) in the presence of a base, Can be synthesized. Method Q: The piperazinone compound (XXIV) can be synthesized by performing an amination reaction using an amination reagent such as O-diphenylphosphinylhydroxylamine in the presence of a base such as sodium hydride. Method R: Compound (XXVII) can be synthesized by cyclizing carbonyl compound (XXV) or (XXVI) or a protected acetal thereof in the presence of an acid catalyst. Subsequently, the compound (XXIX) can be synthesized by hydrogenating the compound (XXVII) according to the method S. Method for producing compound (XXVIII) Method M: A hydrazine compound (XXIX) can be synthesized by performing an acylation reaction in a molecule. It is usually carried out using a solvent that does not participate in the reaction, and in the case of condensation with a carboxylic acid, it is preferable to use a condensing agent. Further, the reaction can be carried out under a base or an acid catalyst. Method N: can be synthesized by a ring closing reaction of acid hydrazide compound (XXX). Q ⁴ is a leaving group (for example, dimethylsulfonium group, bromine, iodine, various sulfonyloxy groups, etc.)
In this case, the reaction is preferably performed in the presence of a base. Q ⁴ may be a hydroxyl group. In this case, Q ⁴ can be synthesized by performing a Mitsunobu reaction. Method Q: The pyrrolidinone compound (XXXI) can be synthesized by performing an amination reaction using an amination reagent such as O-diphenylphosphinylhydroxylamine in the presence of a base such as sodium hydride.

The compound (I) of the present invention or a salt thereof is low-toxic and safe, inhibits FXa and has an anticoagulant effect. Therefore, it can be used in animals, particularly mammals (eg, humans, monkeys, cats, pigs, horses, Cow, mouse, rat, guinea pig,
For dogs, rabbits, etc.), for example, it is useful for the prevention or treatment of the following diseases, and especially for the prevention or treatment of cerebral infarction due to atrial fibrillation, deep vein thrombosis, and the like. Brain: Atrial fibrillation cerebral infarction, acute ischemic stroke, acute cerebral thrombosis, cerebral vasospasm after subarachnoid hemorrhage, Alzheimer's disease, transient ischemic attack (TIA), mixed dementia, cerebrovascular / multiple Infarct dementia, heart: acute myocardial infarction, sequelae of myocardial infarction, unstable angina,
Angina pectoris, stent placement or PTCA (percutaneous intracoronary angioplasty) and vascular reocclusion and stenosis after coronary intervention such as atherectomy, peripheral: deep vein thrombosis, peripheral vascular disease, adult respiratory distress syndrome, Chronic kidney disease (eg, diabetic nephropathy, chronic glomerulonephritis, IgA nephropathy, etc.), diabetic circulatory disorder, pain, neuropathy, etc .: thrombocytopenia due to dialysis, thrombocytopenia during major surgery, arteriosclerosis, cancer Metastasis, systemic inflammatory response syndrome (SIR
S) or pancreatic intravascular coagulation syndrome (DIC) occurring in patients with pancreatitis and cancer, rejection at the time of transplantation, organ protection or function improvement at the time of transplantation, various organ failures caused by the progression of shock or DIC (eg, lung failure) , Liver failure, renal failure, heart failure, etc.)

The compound (I) of the present invention or a salt thereof can be administered orally or parenterally as it is or by mixing a pharmacologically acceptable carrier. When the preparation of the present invention containing compound (I) or a salt thereof is administered orally, examples of the dosage form include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (soft capsules) Preparations), syrups, emulsions, suspensions and the like. Examples of the dosage form for parenteral administration include injections, injections, drops, suppositories and the like. The content of the compound (I) or a salt thereof in the preparation of the present invention varies depending on the form of the preparation, but is usually 2 to 85% by weight, preferably 5 to 70% by weight based on the whole preparation.

As a method for producing the compound (I) or a salt thereof in the above-mentioned dosage form, a known production method generally used in the art can be applied. In the case of producing the above-mentioned dosage form, if necessary, an excipient, a binder, a disintegrant, a lubricant, a sweetener, an interfacial agent usually used in the field of formulation when producing the dosage form. It can be produced by appropriately containing an appropriate amount of an activator, a suspending agent, an emulsifier and the like. For example, when compound (I) or a salt thereof is prepared into a tablet, the compound (I) or a salt thereof can be prepared by adding an excipient, a binder, a disintegrant, a lubricant and the like, and is prepared into pills and granules. In this case, it can be produced by including an excipient, a binder, a disintegrant and the like. In the case of powders and capsules, excipients, etc., in the case of syrups, sweeteners, etc., in the case of emulsions or suspensions, suspending agents, surfactants And an emulsifier.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder,
Mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like can be mentioned. Examples of binders include 5-10% by weight starch paste, 10-2%
0% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like. Examples of disintegrants include starch, calcium carbonate and the like. Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like. Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like. Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like. Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite and the like. Examples of the emulsifier include gum arabic, tragacanth, gelatin, polysorbate 80 and the like. Further, when the compound (I) or a salt thereof is produced in the above-mentioned dosage form, a coloring agent, a preservative, a fragrance, a flavoring agent, a stabilizer, a thickener and the like usually used in the field of purification may be used, if desired. An appropriate amount can be added.

The preparation of the present invention containing compound (I) or a salt thereof is stable, has low toxicity and can be used safely. The daily dose varies depending on the condition and weight of the patient, the type of compound, the administration route, and the like. For example, in the case of oral administration to a patient with thrombosis, the daily dose of an adult (body weight of about 60 kg) is effective. About 1 to 1000 mg, preferably about 3 to 300 mg as a component (compound (I) or a salt thereof)
mg, more preferably about 10 to 200 mg, which can be administered once or in two or three divided doses. When the compound (I) of the present invention or a salt thereof is administered parenterally, it is usually administered in the form of a liquid (eg, injection). The single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but for example, in the form of an injection, usually about 0.01 mg to about 100 m per kg of body weight.
g, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, is administered by intravenous injection. Injections include intravenous injections,
Examples include subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like, and sustained-release preparations include iontophoretic transdermal agents. Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention or a salt thereof in a sterile aqueous or oily liquid. Examples of aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.), and suitable solubilizing agents such as alcohols. (Eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, Polysorbate 8)
0, HCO-50) and the like. Examples of the oily liquid include sesame oil and soybean oil, which may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. In addition, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.)
And the like. The prepared injection solution is usually filled into an ampoule. The preparation of the present invention may contain a thrombolytic agent (eg, TPA, heparin, urokinase, etc.), an Alzheimer's therapeutic agent (eg, avan, curan, etc.), a cholesterol therapeutic agent (eg, HMG-CoA reductase inhibitor such as simvastatin, pravastatin, etc.) ), TG lowering drugs (such as clofibrate), AII antagonists (such as Blopress), antiplatelet drugs (such as aspirin),
It can be used in combination with a Ca antagonist (for example, calslot, amlodipine, etc.), or by mixing an appropriate amount of these pharmaceutical ingredients.

[0044]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is further described in the following Reference Examples, Examples, Formulation Examples and Experimental Examples, which are merely illustrative and do not limit the present invention. Changes may be made without departing from the scope of the present invention. Elution in column chromatography in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography). T
In LC observation, Merck (M
Erf) 60F254, the developing solvent used was the solvent used as the elution solvent in column chromatography, and the detection method was a UV detector. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh) also manufactured by Merck was used. NMR spectra were measured on a Varian Gemini 200 type spectrometer using tetramethylsilane as internal or external reference and all δ values are given in ppm. IR spectrum is Shimadzu FTZR
It was measured with a -8200 type spectrometer. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. The percentage in the solution represents the number of grams in 100 ml of the solution. The symbols in Reference Examples and Examples have the following meanings. s: singlet d: doublet t: triplet q: quartet dd: double doublet m: multiplet br: broad brs: broad singlet broad singlet) J: coupling constant WSC: water-soluble carbodiimide THF: tetrahydrofuran DMF: dimethylformamide DMSO: dimethylsulfoxide HOBt: 1-hydroxybenztriazole

[0045]

EXAMPLES Reference Example 1 4- (tert-butoxycarbonyl) -2-piperazinone 2-piperazinone (3.00 g) and acetonitrile (50 ml)
Di-tert-butyl dicarbonate (7.20 g) was added dropwise to the mixture of
Stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the precipitated crystals were washed with ether to give the title compound as colorless crystals.
(4.77 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.33-3.43 (2H,
m), 3.64 (2H, t, J = 5.3Hz), 4.09 (2H, s), 6.40-6.70
(1H, br). IR (KBr): 1696, 1667, 1400, 1341, 1130 cm ^-1 .

Reference Example 2 4-benzyloxycarbonyl-2-piperazinone 2-piperazinone (10 g), benzyl chlorocarbonate (20.5
g), sodium carbonate (31.8 g), ethyl acetate (200 ml),
A mixture of water (200 ml) was stirred at room temperature for 2 hours. The organic layer was separated, washed with brine, dried (MgSO ₄ ), and concentrated. The resulting crystals were collected by filtration, washed with ethyl acetate-ether,
Dried to give the title compound as colorless crystals (18.5 g) ¹ H-NMR (CDCl ₃ ) δ: 3.35-3.47 (2H, m), 3.71 (2H, t,
J = 5.4Hz), 4.17 (2H, s), 6.22-6.42 (1H, br), 7.37
(5H, s). IR (KBr): 1711, 1663, 1412, 1337, 1287 cm ^-1 .

Reference Example 3 4-benzyloxycarbonyl-1,2,3,4-tetrahydropi
Razin-2-one N-benzyloxycarbonylglycine (10.5 g), 2,2-
Diethoxyethylamine (7.33 g) in acetonitrile (5
0 ml), WSC (10.5 g) was added to the solution under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, ethyl acetate and diluted hydrochloric acid were added to the residue, and the organic layer was separated. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried (MgSO ₄ ) and concentrated. P- to the residue
Toluenesulfonic acid (951 mg) and toluene (150 ml) were added, and the mixture was heated under reflux for 30 minutes. After cooling, ethyl acetate was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried (Mg
After SO ₄ ), the mixture was concentrated. The obtained crystals were collected by filtration, washed with ether and dried to give the title compound (7.37 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.30 (2H, s), 5.22 (2H, s), 5.5
0-5.68 (1H, m), 6.29-6.48 (1H, m), 7.38 (5H, s),
7.50-8.00 (1H, br) .IR (KBr): 1698, 1649, 1410, 1321, 1107, 957, 760 c
m ^-1 .

Reference Example 4 4-benzyloxycarbonyl-1- (tert-butoxycarbo)
Nylamino) -2-oxo-1,2,3,4-tetrahydropyrazine Method 1 tert-butoxycarbonylhydrazine (3.96 g), N-benzyloxycarbonyl-N- (2,2-diethoxyethyl) glycine (9.76 g ) In acetonitrile (100 ml) solution
(5.75 g) was added and the mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the residue obtained by concentrating the reaction solution, and the mixture was partitioned. The organic layer was washed with water, aqueous sodium bicarbonate, aqueous citric acid and brine, dried and concentrated. The resulting residue is
(200 ml), and p-toluenesulfonic acid hydrate (2
85 mg) and stirred at 100 ° C. for 90 minutes. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give a colorless oil.
-Benzyloxycarbonyl-1- (tert-butoxycarbonylamino) -2-oxo-1,2,3,4-tetrahydropyrazine
(1.84 g) was obtained. Method 2 tert-butoxycarbonylhydrazine (53 g), bromoacetaldehyde dimethyl acetal (63.88 g), potassium carbonate (52 g), potassium iodide (62.7 g) and DMF
(350 ml) of the mixture was stirred at 70 ° C. for 15 hours. The insoluble material was removed by filtration, and the filtrate was N-benzyloxycarbonylglycine.
(79 g), HOBt (58 g) and WSC (87 g) were added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the residue obtained by concentrating the reaction solution, and the mixture was partitioned. The organic layer was washed with water, aqueous sodium bicarbonate, aqueous citric acid and brine, dried and concentrated. The obtained residue was dissolved in toluene (1200 ml), p-toluenesulfonic acid hydrate (16.4 g) was added in four portions every 30 minutes, and the mixture was stirred at 100 ° C for 10 hours.
The reaction solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 4-benzyloxycarbonyl-1- (tert-butoxycarbonylamino) -2-oxo-1, a colorless oil. 2,3,4-Tetrahydropyrazine (19.36 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s),
4.44 (2H, s), 5.21 (2H, s)
s), 5.70 (1H, m), 6.38 (1
H, m), 6.66 (1H, brs), 7.
37 (5H, s). IR (KBr): 3281, 1705, 142
1, 1400, 1368, 1346, 124
8, 1161 cm ^-1 .

[0049] Reference Example 5 1-(tert Butokishika Ruboniruamino) -4- (6 - click
Rollo naphthalene-2-sulfonyl) -2-piperazine non Method 1 4-benzyloxycarbonyl-1-(tert-butoxycarbonylamino) -2-oxo-1,2,3,4-tetrahydropyrazine
(1.8 g) and a solution of 10% palladium on carbon (300 mg) in methanol (40 ml) were stirred at room temperature for 15 hours under a hydrogen atmosphere. After filtering off the catalyst, the reaction mixture was concentrated to give a colorless oil.
1- (tert-butoxycarbonylamino) -2-piperazinone was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 3.18 (2H, t, J = 5.
6Hz), 3.61 (2H, s), 3.63 (2H, t, J = 5.6Hz), 6.78 (1
H, brs). 6-chloronaphthalene-2 was added to a solution of the obtained 1- (tert-butoxycarbonylamino) -2-piperazinone in ethyl acetate (20 ml) and 10% aqueous sodium carbonate solution (20 ml) at 0 ° C.
-Sulfonyl chloride (1.36 g) was added, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give colorless amorphous 1- (tert-butoxycarbonylamino) -4- (6-chloronaphthalene-2-sulfonyl). -2-
Piperazinone (848 mg) was obtained. Method 2 6-chloronaphthalene-2-sulfonyl chloride was added to a solution of 2,2-dimethoxyethylamine (3 g) and triethylamine (4.318 g) in tetrahydrofuran (120 ml) at 0 ° C.
(7.45 g) was added little by little, and the mixture was stirred at 0 ° C. for 30 minutes. Water and ethyl acetate were added to the reaction solution, the organic layer was separated, washed with an aqueous citric acid solution and brine, dried, and concentrated.
N- (2,2-dimethoxyethyl) -6-chloro-2- as a colorless oil
Naphthalenesulfonamide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.09 (2H, t, J = 5.6Hz), 3.31 (6H,
s), 4.35 (1H, t, J = 5.6Hz), 4.76 (1H, m), 7.56 (1
H, dd, J = 2.0, 8.8Hz), 7.80-7.95 (4H, m), 8.41 (1H,
s) .N- (2,2-dimethoxyethyl) -6-chloro-2-naphthalenesulfonamide was dissolved in DMF (100 ml), oily sodium hydride (1.16 g) was added, and the mixture was cooled to 0 ° C. A solution of ethyl bromoacetate (4.843 g) in tetrahydrofuran (15 ml) was added dropwise, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to give N- (2,2-dimethoxyethyl) -N- (6-chloroform as a colorless oil. 2-Naphthalenesulfonyl) glycine ethyl ester was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.0Hz), 3.37 (6H,
s), 3.38 (2H, d, J = 5.4Hz), 3.99 (2H, q, J = 7.0Hz),
4.28 (2H, s), 4.50 (1H, t, J = 5.4Hz), 7.55 (1H, d
d, J = 1.8, 8.8Hz), 7.80-7.95 (4H, m), 8.40 (1H, s) .N- (6-Chloro-2-naphthalenesulfonyl) -N- (2,2-dimethoxyethyl) glycine Acetone in ethyl ester (100 m
l) and 4N hydrochloric acid (50 ml) were added, and the mixture was stirred at 50 ° C for 2 hours. After the acetone was distilled off, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and concentrated. Residue is ethanol (70 m
l), tert-butyl carbazate (3.76 g) was added, and the mixture was stirred at 70 ° C for 2 hours. The resulting crystals were collected by filtration and washed with diisopropyl ether to give colorless crystals of N- [2- (tert-
Butoxycarbonylhydrazono) ethyl] -N- (6-chloro-2
-Naphthalenesulfonyl) glycine ethyl ester (10.89
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.0Hz), 1.48 (9H,
s), 3.95-4.15 (6H, m), 7.18 (1H, t, J = 5.4Hz), 7.5
6 (1H, dd, J = 2.0, 8.8Hz), 7.80-8.00 (5H, m), 8.42
(1H, s). N- [2- (tert-butoxycarbonylhydrazono) ethyl] -N-
(6-Chloro-2-naphthalenesulfonyl) glycine ethyl ester (10.85 g) and acetic acid (2.60 g) in methanol (50 m
l) and a suspension of tetrahydrofuran (50 ml) were added little by little to sodium cyanoborohydride (2.11 g) at 0 ° C, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated, ethyl acetate was added to the residue, and the mixture was washed with aqueous sodium hydrogen carbonate and brine, and concentrated to give the title compound as colorless crystals (9.86 g). ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s),
3.51 (2H, m), 3.72 (2H,
m), 3.88 (2H, s), 6.63 (1
H, brs), 7.60 (1H, dd, J =
1.8, 8.8 Hz), 7.78 (1H, d
d, J = 1.8, 8.8 Hz), 7.88-7.
98 (3H, m), 8.35 (1H, s).

[0050] Reference Example 6 1-(tert Butokishika Ruboniruamino) -4- (7 - click
Loro-2H-benzopyran-3-sulfonyl) -2-piperazinone 4-benzyloxycarbonyl-1- (tert-butoxycarbonylamino) -2-oxo-1,2,3,4-tetrahydropyrazine
(2.93 g) and a solution of 10% palladium on carbon (600 mg) in methanol (40 ml) were stirred at room temperature for 15 hours under a hydrogen atmosphere. After filtering off the catalyst, the reaction mixture was concentrated to give a colorless oil.
1- (tert-butoxycarbonylamino) -2-piperazinone was obtained. The obtained 1- (tert-butoxycarbonylamino)-
2-piperazinone and diisopropylethylamine (1.
7g-chloro-4H-4-oxobenzopyran-3-sulfonyl chloride in a solution of 31 g) in dichloromethane (30 ml) under ice-cooling
(2.36 g) was added little by little, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water and brine, dried and concentrated. The residue obtained was dissolved in a methanol (50 ml) solution, sodium borohydride (320 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. . The reaction solution was concentrated, and water and an aqueous solution of potassium hydrogen sulfate were added to the residue, followed by extraction with ethyl acetate. The residue obtained by concentrating the solvent was dissolved in dichloromethane (50 ml), triethylamine (5.126 g) was added, followed by methanesulfonyl chloride (1.938 g) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with aqueous sodium bicarbonate, aqueous citric acid and brine, dried and concentrated. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 1-colorless solid. (tert-Butoxycarbonylamino) -4- (7-chloro-2H-benzopyran-3-sulfonyl) -2-piperazinone (1.456 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.60-3.80 (4H,
m), 4.01 (2H, s), 4.90 (2H, d, J = 1.2Hz), 6.69 (1H,
brs), 6.93 (1H, d, J = 1.8Hz), 7.00 (1H, dd, J = 1.8,
8.2Hz), 7.14 (1H, d, J = 8.2Hz), 7.30 (1H, d, J = 1.2
Hz).

Reference Example 7 1- (tert-butoxycarbonylamino) -4- (4-vinylphene)
Nylsulfonyl) -2-piperazinone In the same manner as in Reference Example 5, 4-benzylphenylsulfonyl chloride was used instead of 6-chloronaphthalene-2-sulfonyl chloride to give 4-benzyloxycarbonyl-1- (te
A colorless amorphous title compound (2.12 g) was obtained from (rt-butoxycarbonylamino) -2-oxo-1,2,3,4-tetrahydropyrazine (2.5 g). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.43 (2H, t, J = 5.
4Hz), 3.71 (2H, t, J = 5.4Hz), 3.81 (2H, s), 5.48 (1
H, d, J = 11.0Hz), 5.91 (1H, d, J = 17.6Hz), 6.68 (1H,
brs), 6.77 (1H, dd, J = 11.0, 17.6Hz), 7.57 (2H, d,
J = 8.4Hz), 7.75 (2H, d, J = 8.4Hz).

Reference Example 8 1- (4-Pyridyl) -4-piperidone 1,4-dioxa-8-azaspiro [4.5] decane (150 g), 4-chloropyridine hydrochloride (190 g), triethylamine (320 g) ) And ethanol
(800 ml) was reacted at 150 ° C. for 15 hours in a sealed tube. The reaction solution was concentrated, and the residue was made alkaline with a 6N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The residue obtained by drying and concentrating is triturated from hexane, collected by filtration and dried to give a pale yellow solid, 8- (4-pyridyl)
-1,4-Dioxa-8-azaspiro [4.5] decane (172 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.78 (4H, m), 3.51 (4H, m), 4.0
0 (4H, s), 6.68 (2H, d, J = 6.6Hz), 8.25 (2H, d, J =
6.6 Hz). 4N hydrochloric acid (7 ml) was added to a solution of 8- (4-pyridyl) -1,4-dioxa-8-azaspiro [4.5] decane (172 g) in acetone (700 ml).
00 ml) and stirred at 50 ° C. for 20 minutes. Acetone was distilled off, and the residue was made alkaline with an aqueous sodium hydroxide solution, and then extracted with dichloromethane. The residue obtained after drying and concentration was crystallized from ether, collected by filtration and dried to give the title compound (119 g) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 2.57 (4H, t, J = 6.0Hz), 3.75 (4
H, t, J = 6.0Hz), 6.72 (2H, d, J = 6.2Hz), 8.33 (2H,
d, J = 6.2Hz).

Reference Example 9 1-amino-4-benzyloxycarbonyl -2-piperazinone 4- (benzyloxycarbonyl) -2-piperazinone (4.685
g) was dissolved in DMF (170 ml) and oily sodium hydride (800 mg) was added under ice-cooling. After stirring at room temperature for 30 minutes, O-diphenylphosphinylhydroxylamine (4.
896 g) and stirred at 50 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried and concentrated to give the title compound 1-amino-4-benzyloxycarbonyl-2-piperazinone (4.8 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 3.56 (2H, t, J = 5.4Hz), 3.79 (2
(H, t, J = 5.4Hz), 4.22 (2H, s), 4.46 (2H, brs), 5.15
(2H, s), 7.36 (5H, s).

Reference Example 10 4-benzyloxycarbonyl-1- [1- (tert-butoxycal)
Bonyl) -4-piperidinylamino] -2 -piperazinone 1-amino-4-benzyloxycarbonyl-2-piperazinone
(2.49 g) and a solution of 1- (tert-butoxycarbonyl) -4-piperidone (1.99 g) in ethanol (40 ml) were refluxed for 15 hours while being dehydrated using a Soxhlet filled with molecular sieves 4A. Concentrate the reaction mixture to
4-Benzyloxycarbonyl-1-{[1- (tert-butoxycarbonyl) -4-piperidinylidene] amino} -2-piperazinone was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.26 (2H, m), 2.5
3 (2H, m), 3.50-3.90 (8H, m), 4.23 (2H, s), 5.17
(2H, s), 7.37 (5H, s). The obtained 4-benzyloxycarbonyl-1-{[1- (tert-butoxycarbonyl) -4-piperidinylidene] amino} -2-piperazinone was treated with methanol (40 ml Acetic acid (1.2 g) was added under ice cooling, followed by sodium cyanoborohydride (943 mg), and the mixture was stirred at room temperature for 30 minutes.
The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate.
The extract was washed with brine, dried, concentrated and purified by column chromatography (ethyl acetate) to give a colorless amorphous substance.
4-benzyloxycarbonyl-1- [1- (tert-butoxycarbonyl) -4-piperidinylamino] -2-piperazinone (3.7
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (2H, m), 1.45 (9H, s), 1.7
5 (2H, m), 2.78 (2H, m), 3.08 (1H, m), 3.52 (2H, m
m), 3.76 (2H, m), 4.05 (2H, m), 4.21 (2H, s), 5.16
(3H, s), 7.36 (5H, s).

Reference Example 11 1- [1- (tert-butoxycarbonyl) -4-piperidinylamide
No] -4- (6-chloronaphthalene-2- sulfonyl) -2-piperazi
Non -benzyloxycarbonyl-1- [1- (tert-butoxycarbonyl) -4-piperidinylamino] -2-piperazinone (3.7
g) and a solution of 10% palladium on carbon (800 mg) in methanol (150 ml) were stirred at room temperature for 15 hours under a hydrogen atmosphere. After the catalyst was removed by filtration, the reaction solution was concentrated to give a colorless oil 1-
[1- (tert-butoxycarbonyl) -4-piperidinylamino]
2-Piperazinone was obtained. Ethyl acetate (30 ml) of the obtained 1- [1- (tert-butoxycarbonyl) -4-piperidinylamino] -2-piperazinone and 10% aqueous solution of sodium carbonate
(30 ml) To the solution was added 6-chloronaphthalene-2-sulfonyl chloride (2.24 g) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give a colorless amorphous 1- [1- (tert-butoxycarbonyl)-
[4-Piperidinylamino] -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (3.55 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (2H, m), 1.45 (9H, s), 1.6
0 (2H, m), 1.86 (1H, m), 2.50-2.75 (4H, m), 2.94
(2H, m), 3.28 (2H, m), 3.40-3.60 (4H, m), 3.86 (2
H, s), 4.08 (2H, m), 7.14-7.27 (3H, m), 7.34 (1H,
s).

Reference Example 12 4-benzyloxycarbonyl-1- [1- (4-pyridyl) -4-pi
Perijinirua amino] -2-piperazinone 1-amino-4-benzyloxycarbonyl-2-piperazinone
(21.92 g) and 1- (4-pyridyl) -4-piperidone (15.
A solution of 51 g) in ethanol (500 ml) was refluxed for 24 hours while dehydrating using a Soxhlet filled with Molecular Sieves 4A. The reaction solution was concentrated, the residue was dissolved in methanol (300 ml), acetic acid (18.26 g) was added under ice-cooling, sodium cyanoborohydride (7.16 g) was added, and the mixture was stirred at 0 ° C for 3 hours. The reaction solution was concentrated, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, dried and concentrated to give pale yellow amorphous 4-benzyloxycarbonyl-1- [1- (4-pyridyl) -4-piperidinylamino] -2-piperazinone ( 25.29 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.43-1.61 (2H, m), 1.93-2.02 (2
H, m), 3.14-3.40 (3H, m), 3.53-3.58 (2H, m), 3.76-
3.81 (2H, m), 3.96-4.03 (2H, m), 4.22 (2H, s), 5.1
6 (2H, s), 5.20-5.40 (1H, br), 6.86 (2H, d, J = 7.2H
z), 7.37 (H, s), 8.11 (2H, d, J = 7.2Hz) .IR (KBr): 2934, 2317, 1696, 1645, 1601, 1539, 1418
cm ^-1 .

Reference Example 13 1- [1- (4-pyridyl) -4-piperidinylamino] -2-piperazi
Non trihydrochloride 4-benzyloxy-1- [1- (4-pyridyl) -4-piperidinylamino] -2-piperazinone (25.29 g) and 4
Normal ethyl acetate solution (15.5 ml) in methanol (300 m
l) To the solution was added 10% palladium carbon (containing 50% water, 5.00 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the reaction solution was concentrated. Residue is ethanol (300 m
l) and added 4N hydrochloric acid ethyl acetate solution (31 ml). The precipitated crystals were collected by filtration and dried to give colorless crystals of 1- [1-
(4-Pyridyl) -4-piperidinylamino] -2-piperazinone trihydrochloride (20.16 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.32-1.47 (2H, m), 1.0-1.99
(2H, m), 3.22-3.46 (5H, m), 3.68-3.75 (4H, m), 4.09
-4.16 (2H, m), 7.22 (2H, d, J = 7.4Hz), 7.38 (2H, br
s), 8.03-8.21 (2H, m), 10.25 (2H, brs), 13.80 (1H,
brs).

Reference Example 14 4-benzyloxycarbonyl-1- {methyl [1- ( tert-buty
Kishikaruboni) -4- piperidinyl] amino} -2-piperazine
Non -benzyloxycarbonyl-1- [1- (tert-butoxycarbonyl) -4-piperidinylamino] -2-piperazinone (9.00
g), potassium carbonate (3.46 g) and methyl iodide (2
A solution of 9.81 g) in DMF (100 ml) was stirred at 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, water (200 ml) was added to the residue, and a mixture of ethyl acetate and tetrahydrofuran (1: 1, 12
0 ml x 3). The extract was washed with water and brine, dried and concentrated. The residue was crystallized from diisopropyl ether to give the title compound (8.55 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.30 (2H, m), 1.45 (9H,
s), 1.60-1.85 (2H, m), 2.68-2.79 (2H, m), 2.79 (3
H, s), 3.25-3.60 (3H, m), 3.67-3.72 (2H, m), 4.02-
4.12 (2H, m), 4.12 (2H, s), 5.16 (2H, s), 7.36 (5
H, s) .IR (KBr): 2930, 1694, 1669, 1427 cm ^-1 .

Reference Example 15 4-benzyloxycarbonyl-1- {methyl [1- ( 4-pyridi
) -4-Piperidinyl] amino} -2-piperazinone 4-benzyloxycarbonyl-1- {methyl [1- (tert-butoxycarbonyl) -4-piperidinyl] amino} -2-piperazinone (8.49 g) The acetic acid (20 ml) solution was allowed to stir at room temperature for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure, 4-
Chloropyridine hydrochloride (4.35 g), triethylamine (1
A mixture of 1.54 g) and ethanol (180 ml) was reacted in a sealed tube at 150 ° C. for 18 hours. The reaction solution was concentrated, and the residue was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with dichloromethane. The extract was washed with water and brine, dried and concentrated, and the resulting residue was subjected to silica gel column chromatography (dichloromethane: 10: 1).
The mixture was purified with methanol containing 20% ammonia water (20: 1) to give the title compound (2.23 g) as a pale yellow amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.55 (2H, m), 1.70-2.05 (2
H, m), 2.82 (3H, s), 2.82-2.96 (2H, m), 3.25-3.65
(3H, m), 3.68-3.73 (2H, m), 3.81-3.87 (2H, m), 4.1
4 (2H, s), 5.16 (2H, s), 6.65 (2H, d, J = 6.8Hz), 7.
37 (5H, s), 8.25 (2H, d, J = 6.8Hz) .IR (KBr): 2953, 2878, 1705, 1667, 1597, 1512, 1414
cm ^-1 .

Reference Example 16 1- {Methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-
Piperazinone dihydrochloride 4-benzyloxycarbonyl-1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (2.22 g)
10% palladium on carbon (50% water, 0.1%) was added to a methanol (50 ml) solution of 4N and 4N ethyl acetate hydrochloride solution (2.6 ml).
44g) was added and stirred at room temperature for 5 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the reaction solution was concentrated to obtain the title compound (2.13 g) as a pale yellow amorphous. ¹ H-NMR (DMSO-d ₆ ) δ: 1.12-1.50 (2H, br), 1.88-2.10
(2H, br), 2.73 (3H, s), 3.17-3.80 (9H, m), 4.15-
4.21 (2H, m), 7.21 (2H, d, J = 7.2Hz), 8.21 (2H, br
s), 10.00-10.35 (2H, br), 13.70-13.90 (1H, br).

Reference Example 17 4- (7-bromo-4H-4-oxobenzopyran-3 -sulfonyl)-
1- [1- (tert-butoxycarbonyl) -4-piperidinylamide
[No] -2-piperazinone 4-benzyloxycarbonyl-1- [1- (tert-butoxycarbonyl) -4-piperidinylamino] -2-piperazinone (3.19
g) and 10% palladium on carbon (0.64 g) in methanol (50 ml) were stirred at room temperature for 15 hours under a hydrogen atmosphere. After filtering off the catalyst, the reaction mixture was concentrated to give a colorless oil.
1- [1- (tert-Butoxycarbonyl) -4-piperidinylamino] -2-piperazinone (1.93 g) was obtained. The obtained 1- [1-
(tert-butoxycarbonyl) -4-piperidinylamino] -2-
7-Bromo-4H-4-oxobenzopyran-3-sulfonyl chloride (2.33 g) was added little by little to a solution of piperazinone (193 g) and N-ethyldiisopropylamine (1.27 g) in dichloromethane (60 ml) under ice-cooling. The mixture was stirred for 2 hours. The reaction solution was washed with water and brine, dried and concentrated, and the resulting residue was subjected to silica gel column chromatography (hexane:
The residue was purified by ethyl acetate (1: 5) and crystallized from ethyl acetate to give the title compound (1.60 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.39 (2H, m), 1.45 (9H,
s), 1.70-1.76 (2H, m), 2.70-2.81 (2H, m), 3.00-3.2
0 (1H, m), 3.57-3.62 (2H, m), 3.80-3.85 (2H, m),
3.98-4.04 (2H, m), 4.14 (2H, s), 5.00-5.25 (1H, b
r), 7.65 (1H, dd, J = 8.4, 1.6Hz), 7.78 (1H, d, J = 1.
6Hz), 8.08 (1H, d, J = 8.4Hz), 8.66 (1H, s) .IR (KBr): 2926, 1669, 1653, 1607, 1557, 1472, 145
6, 1422 cm ^-1 .

Reference Example 18 4- (7-bromo-2H-benzopyran-3-sulfonyl) -1- [1- (te
rt-butoxycarbonyl) -4-piperidinylamino] -2 -pi
Perazinone 4- (7-bromo-4H-4- oxobenzopyran -3-sulfonyl)-
1- [1- (tert-butoxycarbonyl) -4-piperidinylamino] -2-piperazinone (1.53 g) in methanol (25 ml)
And sodium hydroxide (148 mg) under ice-cooling.
Stirred for hours. The reaction solution was concentrated, ethyl acetate was added to the residue, and the mixture was washed with aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The residue obtained by concentrating the solvent was treated with dichloromethane (20
0 ml), triethylamine (0.98 g) was added,
Subsequently, methanesulfonyl chloride (0.33 g) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with water and brine, dried and concentrated, and the obtained residue was crystallized from diethyl ether to give the title compound (1.03 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.41 (2H, m), 1.45 (9H,
s), 1.72-1.79 (2H, m), 2.72-2.83 (2H, m), 3.05-3.1
9 (1H, m), 3.56-3.65 (4H, m), 3.95 (2H, s), 4.00-
4.07 (2H, m), 4.87 (2H, s), 5.13 (1H, d, J = 4.6Hz),
7.06 (1H, d, J = 8.0Hz), 7.09 (1H, d, J = 1.8Hz), 7.1
6 (1H, dd, J = 8.0, 1.8Hz), 7.28 (1H, s). IR (KBr): 2920, 1686, 1655, 1597, 1480, 1420 cm ^-1 .

Reference Example 19 4- (7-bromo-2H-benzopyran-3-sulfonyl) -1- (4-pi
Perijiniruamino) -2-piperazine Non 4- (7-bromo -2H- benzopyran-3-sulfonyl) -1- [1- (te
To a solution of [rt-butoxycarbonyl) -4-piperidinylamino] -2-piperazinone (980 mg) in tetrahydrofuran (20 ml) was added dropwise a 4N hydrochloric acid ethyl acetate solution (2.6 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and water and a 1N aqueous solution of sodium hydroxide were added to the residue, followed by extraction with dichloromethane, washing with brine and drying over magnesium sulfate. The residue obtained by concentrating the solvent was crystallized from diisopropyl ether to give the title compound as colorless crystals (616 m
g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.22 (2H, m), 1.63-1.69
(2H, m), 2.35-2.45 (2H, m), 2.88-3.05 (3H, m), 3.2
5-3.57 (7H, m), 3.84 (2H, s), 4.98 (2H, s), 5.47 (1
H, d, J = 4.8Hz), 7.19 (1H, d, J = 1.8Hz), 7.25 (1H, d
d, J = 8.0, 1.8Hz), 7.40 (1H, d, J = 8.0Hz), 7.48 (1H,
s).

Reference Example 20 2- [1- (tert-butoxycarbonyl) -4-piperidinyl] -N-
[4- (6-chloronaphthalene-2- sulfonyl) -2-oxo-1-pi
Perazinyl] acetamide 1- (tert-butoxycarbonyl) -4-piperidinylacetic acid (44
0 mg), 1-amino-4-benzyloxycarbonyl-2-piperazinone (541 mg), triethylamine (273 mg) and HOBt (333 mg) in DMF (30 ml) solution.
g) was added and the mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the residue obtained by concentrating the reaction solution, and the mixture was partitioned.The organic layer was washed with water, aqueous sodium bicarbonate, aqueous citric acid and brine, dried and concentrated to give a colorless amorphous N -(4-benzyloxycarbonyl-2-oxo-1-piperazinyl) -2- [1
-(tert-Butoxycarbonyl) -4-piperidinyl] acetamide (840 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, m), 1.45 (9H, s), 1.7
3 (2H, m), 2.00 (1H, m), 2.17 (2H, d, J = 7.0Hz), 2.
71 (2H, m), 3.67 (2H, m), 3.87 (2H, m), 4.10 (2H, m
m), 4.28 (2H, s), 5.16 (2H, s), 7.36 (5H, s), 7.76
(1H, br). N- (4-benzyloxycarbonyl-2-oxo-1-piperazinyl) -2- [1- (tert-butoxycarbonyl) -4-piperidinyl]
Acetamide (840 mg) and 10% palladium on carbon (50
(0 mg) in methanol (35 ml) was stirred under a hydrogen atmosphere at room temperature for 15 hours. After removing the catalyst by filtration, the reaction solution is concentrated and N- (2-oxo-1-piperazinyl) -2- [1- (tert-butoxycarbonyl) -4-piperidinyl] is obtained as a colorless syrup.
Acetamide was obtained. A solution of the obtained 2- [1- (tert-butoxycarbonyl) -4-piperidinyl] -N- (2-oxo-1-piperazinyl) acetamide in ethyl acetate (40 ml) and a 10% aqueous sodium carbonate solution (40 ml). To the mixture was added 6-chloronaphthalene-2-sulfonyl chloride (470 mg) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried and concentrated, and the residue obtained was purified by silica gel column chromatography (ethyl acetate) and crystallized from ethyl acetate to give the title compound as colorless crystals (420 mg) ) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (2H, m), 1.44 (9H, s), 1.7
1 (2H, m), 1.94 (1H, m), 2.10-2.25 (2H, m), 2.67
(2H, m), 3.54 (2H, m), 3.72 (2H, m), 3.89 (2H, s),
4.07 (2H, m), 7.52 (1H, s), 7.61 (1H, dd, J = 2.0,
8.8Hz), 7.79 (1H, dd, J = 1.8, 8.8Hz), 7.90-8.00 (3H,
m), 8.36 (1H, s).

Reference Example 21 4- (6-chloronaphthalene-2-sulfonyl) -1- [methyl (4-pi
Peridinyl) amino] -2-piperazinone hydrochloride 1-{[1- (tert-butoxycarbonyl) piperidinyl] methylamino} -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (10.42 g) in methanol (40 ml) to the suspension
A 4 N solution of hydrochloric acid in ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 5 hours. Ethyl acetate (50 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration and dried to give the title compound as colorless crystals (9.
21 g) were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.42 (2H, m), 1.60-1.90
(2H, m), 2.50 (3H, s), 2.60-2.90 (3H, m), 2.98-3.52
(7H, m), 3.70 (2H, s), 7.74 (1H, dd, J = 8.8, 2.0H
z), 7.90 (1H, dd, J = 8.8, 2.0Hz), 8.19 ((1H, d, J =
(8.8 Hz), 8.27-8.31 (2H, m), 8.31-8.65 (3H, m).

[0066] Reference Example 22 tert-butyl 3-methylation-5-oxo-1-Pi Perajinkaruboki
Z-chloride (9.5 ml) was added dropwise to a mixture of silate 2-amino-1-propanol (5.0 g), sodium carbonate (21.2 g), ethyl acetate (50 ml) and water (50 ml), and the mixture was allowed to stand at room temperature for 1 hour. Stirred. The organic layer was separated, washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The crystals obtained by concentration were collected by filtration, washed with ethyl acetate-ether, and dried to give benzyl (2-hydroxy-1-methylethyl) carbamate (11.0 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 6.6 Hz), 2.27-2.4
7 (1H, m), 3.42-3.73 (2H, m), 3.73-3.95 (1H, m),
4.80-5.03 (1H, m), 5.10 (2H, s), 7.26-7.45 (5H,
m). IR (KBr): 3316, 1688, 1539, 1267, 1046 cm ^-1 . Oxalyl chloride (3.5 ml) in methylene chloride (64
ml) was cooled to -78 ° C under a nitrogen atmosphere, and a solution of dimethyl sulfoxide (6.4 ml) in methylene chloride (32 ml) was added dropwise over 1 hour. Then, benzyl (2-hydroxy-1-methylethyl) carbamate (6.4
g) in methylene chloride (64 ml) was added dropwise over 1 hour.
After stirring at −65 to −55 ° C. for 1 hour, the mixture was cooled again to −78 ° C.
Triethylamine (17 ml) was added. The reaction solution was heated to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain benzyl (1-methyl-2-oxoethyl) carbamate as a yellow oil. Next, sodium cyanoborohydride (3.8 g) was added to a mixture of the product, glycine ethyl ester hydrochloride (4.7 g), acetic acid (3.6 ml), and methanol (120 ml), and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. After drying the organic layer with magnesium sulfate,
Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give pale yellow oily ethyl 2-[[2-[[(benzyloxy) carbonyl] amino] propyl] amino] acetate ( 4.9 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.40 (6H, m), 2.20-2.80 (3
H, m), 3.25-3.50 (1H, m), 3.63-3.95 (1H, m), 4.02-
4.30 (2H, m), 4.90-5.50 (4H, m), 7.10-7.50 (5H,
m). Ethyl 2-[[2-[[(benzyloxy) carbonyl] amino] propyl] amino] acetate (1.9 g), sodium carbonate (1.4 g), ethyl acetate (20 ml) and water (20 ml) )), And di-tert-butyl dicarbonate (1.6 ml) was added dropwise thereto, followed by stirring at room temperature for 2 hours. The organic layer was separated, washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give ethyl 2-[[2-
[[(Benzyloxy) carbonyl] amino] propyl] (tert
[-Butoxycarbonyl) amino] acetate (2.3 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 6.6 Hz), 1.26
(3H, t, J = 7.0 Hz), 1.40, 1.46 (total 9H, s for e
ach), 3.05-3.65 (2H, m), 3.70-4.00 (3H, m), 4.17 (2
H, q, J = 7.0 Hz), 5.08 (2H, s), 5.25-5.45 (1H,
m), 7.25-7.45 (5H, m). Ethyl 2-[[2-[[(benzyloxy) carbonyl] amino] propyl] (tert-butoxycarbonyl) amino] acetate (2.3 g) and 10% palladium on carbon ( A solution of 0.23 g) in methanol (46 ml) was stirred at room temperature for 1 hour under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was stirred at 50 ° C. for 1 hour, and concentrated under reduced pressure to give the title compound as a colorless amorphous powder (1.
1 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 6.6 Hz), 1.47
(9H, s), 2.80-3.15 (1H, m), 3.50-3.75 (1H, m), 3.7
5-4.10 (1H, m), 3.90 (1H, d, J = 18.6 Hz), 4.24 (1
H, d, J = 18.6 Hz), 6.25-6.60 (1H, m) .IR (KBr): 2976, 1696, 1682, 1335, 1246, 1175 cm ^-1 .

[0067] Reference Example 23 tert-butyl 3-methylation-5-oxo-4 - [[1- (4-pyridinyl)
- 4-piperidinyl] amino] -1-piperazinecarboxylate key Shiray
To- tert-butyl 3-methyl-5-oxo-1-piperazinecarboxylate (1.1 g) was dissolved in DMF (20 ml), and oily sodium hydride (0.25 g) was added under ice cooling. After stirring at 50 ° C. for 1 hour, O-diphenylphosphinylhydroxylamine (1.3 g) was added, and the mixture was stirred at 50 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with dichloromethane. The extract is dried and concentrated to give a yellow oil
rt-Butyl 4-amino-3-methyl-5-oxo-1-piperazinecarboxylate was obtained. This product and 1- (4-pyridinyl)
A solution of -4-piperidone (0.91 g) in ethanol (23 ml) was refluxed for 15 hours while being dehydrated using a Soxhlet filled with Molecular Sieves 4A. The reaction solution was concentrated, the residue was dissolved in methanol (20 ml), acetic acid (0.61 ml) was added under ice-cooling, sodium cyanoborohydride (0.65 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated, the residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried, concentrated, and purified by basic silica gel column chromatography (NH-DM1020, Fuji Silysia Chemical, ethyl acetate). Thus, the title compound (1.2 g) was obtained as a colorless crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 6.6 Hz), 1.48
(9H, s), 1.35-1.60 (2H, m), 1.78-1.97 (2H, m), 2.8
2-3.03 (2H, m), 3.10-3.33 (1H, m), 3.35-3.70 (2H, m
m), 3.73-4.03 (4H, m), 4.15-4.45 (1H, m), 4.90 (1
H, d, J = 4.4 Hz), 6.65 (2H, d, J = 6.6 Hz), 8.25
(2H, d, J = 6.6 Hz).

Reference Example 24 1- (tert-butyl) 3-methyl 5-oxo -1,3-piperazine
Dicarboxylate NZ-DL-asparagine (30 g) [Z = benzyloxycarbonyl], dimethylformamide (200 ml) and water (20
0 ml) was added [bis (trifluoroacetoxy) iodo] benzene (72.7 g). After stirring at room temperature for 1 hour, pyridine (18.3 ml) was added, and the mixture was further stirred for 12 hours. The reaction system was concentrated under reduced pressure, and the residue was separated with a 5N aqueous solution of sodium hydroxide and diethyl ether.The aqueous layer was further treated with tetrahydrofuran (100 ml) and dicarbonate.
Tert-butyl (28.6 ml) was added. After stirring at room temperature for 1 hour, the reaction system was adjusted to pH 3 with concentrated hydrochloric acid, separated and extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. Next, the obtained residue, potassium carbonate (23.4 g) and dimethylformamide (150 m
l) Iodomethane (10.5 ml) was added to the mixture of
Stir for 1 hour. After completion of the reaction, the reaction system was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was crystallized from hexane / ethyl acetate to give methyl 2-, a colorless crystalline powder.
[[(Benzyloxy) carbonyl] amino] -3-[(tert-butoxycarbonyl) amino] propanoate (24 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 3.55 (2H, t,
J = 5.2 Hz), 3.76 (3H, s), 4.32-4.48 (1H, m), 4.70-
4.95 (1H, m), 5.12 (2H, s), 5.67-5.88 (1H, m), 7.28
-7.43 (5H, m). IR (KBr): 1715, 1520, 1254, 1167 cm ^-1 . Methyl 2-[[(benzyloxy) carbonyl] amino] -3-
Trifluoroacetic acid (20 ml) was added dropwise to a toluene solution (20 ml) of [(tert-butoxycarbonyl) amino] propanoate (4.3 g), stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give colorless crystalline powder of methyl 3-amino-2-[[(benzyloxy) carbonyl] amino] propanoate trifluoroacetate (4.4%).
g) was obtained. ¹ H-NMR (CD ₃ OD) δ: 3.12-3.52 (2H, m), 3.76 (3H, s),
4.40-4.58 (1H, m), 5.13 (2H, s), 7.23-7.45 (5H,
m). Methyl 3-amino-2-[[(benzyloxy) carbonyl] amino] propanoate trifluoroacetate (8.9 g), triethylamine (30.6 ml) and dimethylformamide (89 ml) were mixed with chloroacetic acid. A solution of ethyl (7.8 ml) in dimethylformamide (20 ml) was slowly added dropwise. After stirring at room temperature for 12 hours, triethylamine (20.4 ml) was added again, a solution of ethyl chloroacetate (5.2 ml) in dimethylformamide (15 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 6 hours. Water and ethyl acetate were added to the system, and the layers were separated. The organic layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purification in 4) gave colorless oily methyl 2-[[(benzyloxy) carbonyl] amino] -3-[(2-ethoxy-2-oxoethyl) amino] propanoate (6.6 g). ¹ H-NMR (CD ₃ OD) δ: 1.27 (3H, t, J = 7.4 Hz), 2.96
(1H, dd, J = 4.6, 12.6Hz), 3.12 (1H, dd, J = 4.8,
12.6 Hz), 3.37 (2H, s), 3.77 (3H, s), 4.18 (2H, q,
J = 7.4 Hz), 4.35-4.48 (1H, m), 5.13 (2H, s), 5.7
2-5.87 (1H, m), 7.28-7.42 (5H, m). IR (KBr): 3331, 2953, 1728, 1526, 1209 cm ^-1 . Methyl 2-[[(benzyloxy) carbonyl] amino]- 3-
[(2-ethoxy-2-oxoethyl) amino] propanoate
(6.6 g), sodium hydrogen carbonate (3.3 g), ethyl acetate (6
6 ml) and water (66 ml) in a mixture of di-tert-butyl dicarbonate.
(4.9 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The organic layer was separated, washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give a colorless oil, methyl 2-[[(benzyloxy) carbonyl] amino] -3-[(tert-butoxycarbonyl) (2 -Ethoxy-2-oxoethyl) amino] propanoate (8.4 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.39,
1.44 (total 9H, s foreach), 3.46-4.02 (7H, m), 4.
17 (2H, q, J = 7.0 Hz), 4.14-4.62 (1H, m), 5.02-5.2
0 (2H, m), 5.74-6.18 (1H, m), 7.20-7.40 (5H, m). Methyl 2-[[(benzyloxy) carbonyl] amino] -3-
A solution of [(tert-butoxycarbonyl) (2-ethoxy-2-oxoethyl) amino] propanoate (8.4 g) and 10% palladium on carbon (0.84 g) in methanol (84 ml) was stirred at room temperature for 1 hour under a hydrogen atmosphere. . After removing the catalyst by filtration, triethylamine (10.6 ml) was added to the filtrate, and the mixture was further heated to 50 ° C.
For 1 hour. The solvent was distilled off under reduced pressure, and the residue was crystallized from hexane / ethyl acetate to give the title compound (4.5 g) as a colorless crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.81 (3H, s), 3.5
5-4.25 (5H, m), 6.62-6.78 (5H, m) .IR (KBr): 1748, 1694, 1424, 1248, 1148 cm ^-1 .

Reference Example 25 1- (tert-butyl) 3-methyl 5-oxo-4-[[1- (4-pyr
Jiniru) -4-piperidinyl] amino] -1,3-Pipera Jinjika
Dissolve ruboxylate 1- (tert-butyl) 3-methyl 5-oxo-1,3-piperazine dicarboxylate (4.5 g) in DMF (90 ml),
Under ice cooling, oily sodium hydride (0.84 g) was added. 50
After stirring at C for 1 hour, O-diphenylphosphinylhydroxylamine (4.5 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried and concentrated, and the yellow oily 1- (tert-butyl) 3-methyl 4-amino-5-oxo-
1,3-Piperazine dicarboxylate was obtained. This product and
A solution of 1- (4-pyridinyl) -4-piperidone (3.1 g) in ethanol (90 ml) was refluxed for 15 hours while dehydrating using a Soxhlet filled with Molecular Sieves 4A. The reaction solution was concentrated, the residue was dissolved in methanol (90 ml), acetic acid (2.1 ml) was added under ice cooling, followed by sodium cyanoborohydride (2.2 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried, concentrated, and purified by basic silica gel column chromatography (ethyl acetate: methanol = 20: 1) to give a pale color. The title compound (3.8 g) was obtained as a yellow amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.60 (2H, m), 1.45 (9H,
s), 1.70-1.98 (2H, m), 2.80-3.05 (2H, m), 3.13-4.6
0 (8H, m), 3.76 (3H, s), 5.03 (1H, d, J = 3.8Hz),
6.64 (2H, d, J = 6.6 Hz), 8.25 (2H, d, J = 6.6 H
z) .IR (KBr): 2980, 1748, 1698, 1672, 1597, 1397, 124
6, 1136 cm ^-1 .

Reference Example 26 (3S) -1,3-bis (tert-butoxycarbonylamino) -2-pi
To a solution of loridone Boc-L-methionine (9.972 g) [Boc: tert-butoxycarbonyl] and tert-butyl carbazate (5.29 g) in acetonitrile (100 ml) was added WSC (9.202 g), and the mixture was added at room temperature for 5 hours.
Stirred for hours. Ethyl acetate and water were added to the residue obtained by concentrating the reaction solution, and the organic layer was washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to give 2- (Boc-L-methionyl) as a colorless oil. Tert-Butyl-1-hydrazinecarboxylate was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.47 (9H, s), 1.9
0-2.20 (5H, m), 2.64 (2H, m), 4.35 (1H, m), 5.18
(1H, brd, J = 8.8 Hz), 6.44 (1H, brs), 8.08 (1H, brs) .The obtained tert-butyl 2- (Boc-L-methionyl) -1-hydrazinecarboxylate acetone (20 ml) solution in methyl iodide (1
7 ml, 240 mmol) and stirred at room temperature overnight. The reaction solution is concentrated, and ether is added to the obtained residue to form a powder, which is collected by filtration, washed with ether, and dried to give a colorless solid tert-butyl methylsulfonium 2- (Boc-L-methionyl) -1-hydrazinecarboxylate Iodide (19.14 g) was obtained. To a solution of 2- (Boc-L-methionyl) -1-hydrazinecarboxylate tert-butyl methylsulfonium iodide (18 g) in DMF (200 ml) was added oily sodium hydride (3.93 g) under ice-cooling, and the mixture was stirred at room temperature. Stir for 3 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated, and the residue was powdered by adding an isopropyl ether / hexane (1/1) solution. , Collected by filtration, washed with an isopropyl ether / hexane (1/1) solution and dried to give the title compound as a colorless solid
(5.7 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.47 (9H, s), 2.0
0 (1H, m), 2.62 (1H, m), 3.40-3.70 (2H, m), 4.23
(1H, m), 5.13 (1H, brs), 6.65 (1H, brs) .IR (KBr):
3289, 1713, 1699, m 1505, 1368, 1250, 1167 cm ^-1 . [Α] _D = + 5.1 ° (c = 0.993, CHCl ₃ ).

Reference Example 27 (3S) -1,3-bis (tert-butoxycarbonylamino) -2-pi
It was synthesized from 2- (Boc-D-methionine) in the same manner as in Loridone Reference Example 26. [α] _D = -5.3 ° (c = 1.006, CHCl ₃ ).

Reference Example 28 (3S) -1-amino-3- (6-chloronaphthalene- 2-sulfonylua
To a solution of ( mino) -2-pyrrolidone (3S) -1,3-bis (tert-butoxycarbonylamino) -2-pyrrolidone (1.0 g) in methanol (10 ml) was added a 4N hydrochloric acid ethyl acetate solution (10 ml). In addition, the mixture was stirred at room temperature for 30 minutes. Dichloromethane (30 ml) and triethylamine (1.6 g) were added to the residue obtained by concentrating the reaction solution, and 6-chloronaphthalene-2-sulfonyl chloride was added at 0 ° C.
(830 mg) was added and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, extracted with dichloromethane, dried and concentrated. The obtained residue was washed with ether to give the title compound as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 2.05 (1H, m),
2.50 (1H, m), 3.35-3.55
(2H, m), 3.83 (1H, t, J =
9.0 Hz), 4.08 (2H, s), 7.5
5 (1H, dd, J = 2.0, 8.8 Hz),
7.80-8.05 (4H, m), 8.46
(1H, s). IR (KBr): 3059 (br), 170
3, 1329, 1159, 1136, 1080
cm ^-1 .

Reference Example 29 (3S) -3- (tert-Butoxycarbonylamido
ノ) -1- [1- (4-Pyridyl ) -4-piperidinylamino] -2-pyro
To a solution of lidone (3S) -1,3-bis (tert-butoxycarbonylamino) -2-pyrrolidone (3.15 g) in methanol (10 ml) was added
A normal solution of hydrochloric acid in ethyl acetate (20 ml) was added, followed by stirring at room temperature for 30 minutes. Dichloromethane (30 ml) and triethylamine (6.06 g) were added to the residue obtained by concentrating the reaction solution, and di-tert-butyl dicarbonate (2.62 g) was added at 0 ° C., followed by stirring at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, extracted with dichloromethane, dried and concentrated. The obtained residue is washed with hexane to give a colorless solid (3S) -1-amino-3- (tert-butoxycarbonylamino) -2-pyrrolidone
(1.89 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.91 (1H, m), 2.6
0 (1H, m), 3.40-3.55 (2H, m), 4.13 (2H, s), 4.19
(1H, t, J = 9.0Hz), 5.08 (1H, brs) .IR (KBr): 3300, 1694, 1169 cm ^-1 . (3S) -1-amino-3- (tert-butoxycarbonylamino)- 2-
A solution of pyrrolidone (1.84 g) and 1- (4-pyridyl) -4-piperidone (1.51 g) in ethanol (30 ml) was refluxed for 15 hours while being dehydrated using a Soxhlet filled with molecular sieves 4A. Concentrate the reaction solution (3S)
-3- (tert-butoxycarbonylamino) -1- [1- (4-pyridyl) -4-piperidinylideneamino] -2-pyrrolidone (3.57 g)
Was obtained as a syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.10 (1H, m), 2.4
0-2.70 (5H, m), 3.45-3.80 (6H, m), 4.17 (1H, m),
5.08 (1H, br), 6.68 (2H, d, J = 6.6Hz), 8.30 (2H, d,
J (6.6 Hz). IR (KBr): 1690, 1597, 1514 cm ^-1 . (3S) -3- (tert-butoxycarbonylamino) -1- [1- (4-pyridyl) -4-piperidinylidene Amino] -2-pyrrolidone (3.5
7 g) in methanol (40 ml).
(2.05 g) was added, followed by sodium cyanoborohydride (807 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, an aqueous solution of sodium carbonate was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried, concentrated, and purified by column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1) to give a colorless amorphous substance. The title compound (2.56 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.51 (2H, m), 1.9
3 (2H, m), 2.03 (1H, m), 2.61 (1H, m), 2.95 (2H, m
m), 3.28 (1H, m), 3.40-3.50 (2H, m), 4.19 (1H, m),
4.55 (1H, br), 5.14 (1H, brs), 6.66 (2H, d, J = 6.6
Hz), 8.24 (2H, d, J = 6.6Hz) .IR (KBr): 1694, 1599, 1514, 1366, 1289, 1250, 123
. 3, 1167 cm ^-1 Reference Example 30 1- (tert-butyl) 3-methyl 4 - [[1- (2-methyl-4-pyridinium
Dinyl) -4-piperidinyl] amino] -5-oxo-1,3-pipe
Razine dicarboxylate 1- (tert-butyl) 3-methyl 5-oxo-1,3-piperazine dicarboxylate (3.15 g) was dissolved in DMF (63 ml), and oily sodium hydride (0.59 g) was added. After stirring at 50 ° C. for 1 hour, the mixture was cooled to room temperature, O-diphenylphosphinylhydroxylamine (3.13 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried and concentrated to obtain 1- (tert-butyl) 3-methyl 4-amino-5-oxo-1,3-piperazinedicarboxylate as a yellow oil. This product and 1- (2-methyl-4-pyridinyl) -4
A mixture of -piperidone (2.3 g) and ethanol (63 ml) was refluxed for 15 hours with dehydration using a Soxhlet filled with molecular sieves 4A. The reaction solution was concentrated, the residue was dissolved in methanol (63 ml), acetic acid (1.45 ml) was added under ice-cooling, sodium cyanoborohydride (1.53 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture is concentrated, the residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried and concentrated, and then subjected to basic silica gel column chromatography (ethyl acetate: methanol =
20: 1) to give the title compound as a pale yellow amorphous powder
(3.4 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.36-1.66 (2H, m), 1.44 (9H,
s), 1.86-2.14 (2H, m), 2.56 (3H, s), 3.10-4.66 (13
H, m), 5.02 (1H, d, J = 3.6 Hz), 6.69 (1H, d, J =
2.6 Hz), 6.85 (1H, dd, J = 2.6, 7.4 Hz), 7.89 (1H,
d, J = 7.4 Hz). Reference Example 31 4-Chloro-2-chloromethane Chirupirijin hydrochloride 4-chloro-2-hydroxymethylpyridine (430 mg),
A solution of thionyl chloride (0.43 ml) and DMF (1 drop) in chloroform (10 ml) was heated under reflux for 2 hours. The reaction solution was concentrated to give the title compound (0.44 g) as a brown powder. ¹ H-NMR (CDCl ₃ ) δ: 4.95 (2H, s), 7.57 (1H, dd, J = 2.
0,5.8 Hz), 7.81 (1H, d, J = 1.8Hz), 8.59 (1H, d, J =
5.8 Hz). Reference Example 32 4-Chloro-2-methoxymethyl-pyridin-4-chloro-2-chloromethyl-pyridine hydrochloride (0.43 g)
, Sodium methoxide (1.11 g), methanol (15
ml) was stirred at room temperature for 10 hours and at 70 ° C. for 7 hours.
The reaction solution was concentrated, water and methylene chloride were added to the residue, and the organic layer was separated. The extract was washed with saturated aqueous sodium hydrogen carbonate, dried and concentrated to give the title compound (0.28 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 3.49 (3H, s), 4.57 (2H, s), 7.20
(1H, dd, J = 2.0,5.2 Hz), 7.46-7.47 (1H, m), 8.45
Used in (1H, d, J = 5.6Hz ). Reference Example 33 4-Chloro-2-ethoxy-methylpyridine Reference Example 32 In the same manner as, sodium ethoxide (1.09 g) in place of sodium methoxide, methanol The title compound (550 mg) was obtained as a brown oil using ethanol in place of the above. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 6.9Hz), 3.64 (2H,
q, J = 7.0Hz), 4.62 (2H, s), 7.20 (1H, dd, J = 1.9,5.
4 Hz), 7.49 (1H, d, J = 1.8Hz), 8.44 (1H, d, J = 5.4H)
z). Reference Example 34 4-chloro-2-dimethylamino-methylpyridine Reference Example 32 In the same manner as the title compound as a brown oil using 50% aqueous dimethylamine solution (1.44 g) instead of sodium methoxide ( 530 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.30 (6H, s), 3.58 (2H, s), 7.19
(1H, dd, J = 2.0,5.2Hz), 7.46 (1H, d, J = 1.8Hz), 8.45
(1H, d, J = 5.4Hz ). Reference Example 35 4-Chloro-2-Aminome Chirupirijin in Reference Example 32 by the same process as a brown oil with 25% aqueous ammonia solution (30 ml) in place of sodium methoxide The title compound (1.22 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.79 (2H, br), 3.96 (1H, s), 3.98
(1H, s), 7.16-7.21 (1H, m), 7.37 (1H, dd, J = 2.0,
Reference Example 36 4-Chloro-2- acetylaminomethylpyridine 4-chloro-2- aminomethylpyridine (0.57 g) and acetic anhydride (1.5 ml) were obtained . 9.8 Hz), 8.45 (1H, d, J = 5.2 Hz). The THF (10 ml) solution was added at room temperature for 14 hours,
Stirred at 0 ° C. for 4 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue obtained by concentrating the reaction solution, and the mixture was partitioned. The organic layer was washed with brine, dried and concentrated. The obtained residue is subjected to silica gel column chromatography (ethyl acetate:
Purification by methanol = 20: 1) gave the title compound (190 mg) as a yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 2.09 (3H, s), 4.54 (1H, d, J = 5.
2 Hz), 6.60 (1H, br), 7.17-7.28 (2H, m), 8.43 (1H,
d, J = 5.6 Hz). Reference Example 37 4-chloro-2- (1-hydroxy-1-methyl ethyl Le) pyrid
To a solution of 1.5 M methyllithium diethyl ether solution (6.0 ml) in diethyl ether (15 ml) was added 4-chloropyridine-2.
A solution of -carboxylic acid in diethyl ether (15 ml) was added dropwise at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with a saturated ammonium chloride solution and diethyl ether, and the organic layer was washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1) to give the title compound (459 mg) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (6H, s), 4.56 (1H, s), 7.21
(1H, dd, J = 1.9, 5.5Hz), 7.41 (1H, d, J = 1.4H
z), 8.42 (1H, d, J = 5.6 Hz). Reference Example 38 Methyl 6-methylpyridine-2-carboxylate N-oxide Methyl 6-methylpyridine-2-carboxylate hydrochloride (5.8 g)
A mixture of m-chloroperbenzoic acid (15.24 g) and dichloromethane (200 ml) was stirred at room temperature for 20 hours and at 50 ° C for 6 hours. After a small amount of sodium sulfite was added at 0 ° C., an aqueous potassium carbonate solution was added to make the solution basic. The mixture was extracted with dichloromethane, and the organic layer was dried and concentrated. The obtained residue is subjected to silica gel column chromatography (ethyl acetate:
Hexane = 5: 1 to ethyl acetate: methanol = 20:
Purify in 1) to give the title compound as a brown oil (2.29 g)
I got ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 4.01 (3H, s), 7.20
(1H, t, J = 7.6 Hz), 7.35 (1H, dd, J = 2.2, 8.0 H
z), 7.44 (1H, dd , J = 2.2, 7.6 Hz). Reference Example 39 4-chloro-6-methylpiperidin-lysine-2-carboxylate 6-methylpyridin-2-carboxylate N- oxide
A mixture of (2.29 g), a 4N solution of hydrogen chloride in ethyl acetate (5 ml) and ethyl acetate (15 ml) was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution and phosphorus oxychloride (17.90
The mixture of g) was heated and stirred at 90 ° C. for 2 hours. The residue obtained by concentrating the reaction solution was diluted with ice water, and an aqueous potassium carbonate solution was added to make the solution basic. The mixture was extracted with dichloromethane, and the organic layer was dried and concentrated. A solution of the obtained residue and triethylamine (5 ml) in ethanol (50 ml) was heated under reflux for 10 hours. The reaction solution was concentrated, water and ethyl acetate were added to the residue, the organic layer was separated, dried and concentrated to give the title compound (1.74 g) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 2.65
(3H, s), 4.47 (2H, q, J = 7.1 Hz), 7.35 (1H, d, J =
1.4 Hz), 7.94 (1H, d, J = 1.8 Hz). Reference Example 40 4-Chloro-2-hydroxymethyl Shimechiru 6-methylpyridine 4-chloro-6-methylpyridine-2-carboxylate (0.80
To a solution of g) in methanol (30 ml) was added sodium borohydride (1.51 g) little by little at room temperature, and the reaction solution was heated to reflux for 2 hours. Water and ethyl acetate were added to the residue obtained by concentrating the reaction solution, the organic layer was separated, dried and concentrated to give the title compound (0.60 g) as a brown powder. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 3.62 (1H, br), 4.7
0 (2H, s), 7.09 (2H, s). Reference Example 41 A solution of 2- (4-chloro-2-pyridinyl) acetamide 4-chloro-2-methylpyridine (1.28 g) in diethyl ether (15 ml) was prepared. 2M lithium diisopropylamide heptane / THF solution (6.0 ml) was added dropwise at -70 ° C,
For 30 minutes. Thereto diethyl carbonate (1.45 ml) -7
The mixture was added dropwise at 0 ° C, and the reaction solution was stirred at -70 ° C for 1 hour. After the temperature of the reaction solution was returned to room temperature, aqueous sodium bicarbonate and dichloromethane were added, the organic layer was separated, dried and concentrated. 13% with the obtained residue
A mixture of ammonia methanol solution (5 ml) was heated and stirred at 75 ° C. for 7 hours. The reaction solution was concentrated, and diethyl ether was added to the residue obtained to give a powder, which gave the title compound (0.47 g) as a brown powder. ¹ H-NMR (CDCl ₃ ) δ: 3.73 (2H, s), 5.46 (1H, br), 7.0
6 (1H, br), 7.23-7.26 (1H, m), 7.32 (1H, d, J = 2.0
Hz), 8.47 (1H, d, J = 5.2 Hz). Reference Example 42 1- (2-hydroxymethyl-4-pyridyl) -4-piperidone In the same manner as in Reference Example 8, 4-chloropyridine hydrochloride was prepared. Instead 4-chloro-2-hydroxymethylpyridine (3.14 g)
Was used to give the title compound (3.11 g) as a brown powder. ¹ H-NMR (CDCl ₃ ) δ: 2.57 (4H, t, J = 6.1 Hz), 3.76
(4H, t, J = 6.3 Hz), 4.68 (2H, s), 6.62-6.67 (2H,
m), 8.27 (1H, d, J = 5.4 Hz). Reference Example 43 1- (tert-butyl) 3-methyl 5-oxo-4-[[1- (2-hydr
Rokishimechiru-4-pyridinyl) -4-piperidinyl] amino] -
1,3-piperazinedicarboxylate In the same manner as in Reference Example 25, 1- (2-hydroxymethyl-4-pyridyl) was used instead of 1- (4-pyridinyl) -4-piperidone.
The title compound (1.23 g) was obtained as pale yellow amorphous powder using -4-piperidone (1.51 g). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.84-1.90 (2H,
m), 2.33 (3H, m), 2.89-3.01 (2H, m), 3.23-3.49 (3
H, m), 3.76 (3H, s), 3.81-3.93 (3H, m), 4.15-4.27
(2H, m), 4.44-4.53 (2H, m), 4.63 (2H, m), 5.02 (1
H, d, J = 3.6 Hz), 6.57-6.59 (2H, m), 8.20 (1H, d,
J = 6.4, 2.2 Hz). Reference Example 44 1- (2-methyl-4-pin-lysyl) -4-piperidone piperidone hydrochloride hydrate (68.98 g), 4-chloro-2-picoline (47.7 g), acetic acid Sodium (36.8 g) and acetic acid (500
After the mixture was refluxed for 15 hours, the reaction solution was concentrated, the obtained residue was dissolved in water, alkalified by adding potassium carbonate, extracted with dichloromethane, dried and concentrated.
The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 30: 1) to give the title compound as a pale yellow oil (59.
1 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s), 2.56 (4H, t, J = 6.
2Hz), 3.73 (4H, t, J = 6.2Hz), 6.54-6.60 (2H, m), 8.
22 (1H, d, J = 5.8 Hz). Reference Example 45 Methyl 1- (tert-butoxycarbonylamino) -4-[(6-
Loro-2-naphthyl) sulfonyl] -6-oxo-2-piperazine
Acetate (6-chloro-naphthalene-2-sulfonyl) glycine-tert-butyl ester (17.79 g), methyl 4-bromocrotonate (1
A mixture of 3.426 g), potassium carbonate (8.28 g) and DMF (150 ml) was stirred at 50 ° C. for 1 hour. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with water and brine, dried, and concentrated.The residue obtained was crystallized from ether to give colorless crystals.
Methyl 4-[(tert-butoxycarbonylmethyl) (6-chloro-naphthalene-2-sulfonyl) amino] -2-butenoate (25.13
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (9H, s), 3.71 (3H, s), 3.9
9 (2H, s), 4.14 (2H, dd, J = 1.4, 5.4Hz), 5.96 (1H,
dt, J = 17.8, 1.4Hz), 6.81 (1H, dt, J = 17.8, 5.4Hz),
7.55 (1H, dd, J = 8.8, 2.2Hz), 7.80-7.95 (4H, m), 8.
39 (1H, s) .Methyl 4-[(tert-butoxycarbonylmethyl) (6-chloro-naphthalene-2-sulfonyl) amino] -2-butenoate (22.7 g)
Was added to a toluene (30 ml) solution of the above, and the mixture was stirred at room temperature for 1.5 hours. The residue obtained by concentrating the reaction solution was crystallized from ether-hexane to give colorless crystals.
Methyl 4- [carboxymethyl (6-chloro-naphthalene-2-sulfonyl) amino] -2-butenoate (19.35 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.71 (3H, s), 4.09 (2H, s), 4.1
2 (2H, d, J = 5.8Hz), 5.94 (1H, d, J = 15.8Hz), 6.75
(1H, dt, J = 15.8, 5.8Hz), 7.57 (1H, dd, J = 8.8,2.0H
z), 7.75-7.95 (4H, m), 8.40 (1H, s) .Methyl 4- [carboxymethyl (6-chloro-naphthalene-2-sulfonyl) amino] -2-butenoate (796 mg), carbamic acid -
tert-butyl (265 mg), HOBt (367 mg) in acetonitrile
(20 ml) solution was added with WSC (575 mg) and stirred at room temperature for 15 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate.
After washing with brine, the residue obtained by drying and concentration was crystallized from ether-hexane to give colorless crystals of 4-[[2- (N'-tert.
-Butoxycarbonylhydrazino) -2-oxoethyl] (6-
Methyl chloro-naphthalene-2-sulfonyl) amino] -2-butenoate (1.05 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.66 (3H, s), 3.9
5 (2H, s), 4.16 (2H, d, J = 6.2Hz), 5.91 (1H, d, J = 1
5.8Hz), 6.42 (1H, brs), 6.67 (1H, dt, J = 15.8, 6.2H
z), 7.58 (1H, dd, J = 8.8, 1.8Hz), 7.77-7.95 (4H,
m), 8.12 (1H, brs), 8.41 (1H, s). 4-[[2- (N'-tert-butoxycarbonylhydrazino) -2-oxoethyl] (6-chloro-naphthalene-2-sulfonyl) To a solution of methyl [amino] -2-butenoate (500 mg) in THF (25 ml) was added potassium-tert-butoxide (22 mg), and the mixture was stirred at 70 ° C for 15 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate.
The extract was washed with water and brine, dried and concentrated to give the colorless amorphous title compound (500 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.79 (1H, dd, J = 1
6.4, 4.8Hz), 2.92 (1H, dd, J = 16.4, 8.4Hz), 3.15 (1
H, dd, J = 12.4, 3.2Hz), 3.49 (1H, d, J = 16.6Hz), 3.7
3 (3H, s), 3.92 (1H, brd, J = 12.4Hz), 4.11 (1H, m),
4.22 (1H, d, J = 16.6Hz), 6.57 (1H, brs), 7.61 (1H,
dd, J = 8.8, 1.8Hz), 7.77 (1H, dd, J = 8.8, 1.8Hz),
7.90-8.00 (3H, m), 8.34 (1H, s). IR (KBr): 1738, 1682, 1370, 1350, 1242, 1165 cm ^-1 . Reference Example 46 Methyl 1-amino-4-[(6- Chloro-2-naphthyl) sulfoni
1- (tert-butoxycarbonylamino) -4-[(6-chloro-2-naphthyl) sulfonyl] -6 -oxo-2-piperazine acetate methyl (500 mg) 4N hydrochloric acid ethyl acetate solution (10 ml)
Was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated, an aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with dichloromethane.
I got ¹ H-NMR (CDCl ₃ ) δ: 2.80 (1H, dd, J = 16.4, 8.4 Hz),
2.93 (1H, dd, J = 16.4, 6.0Hz), 3.07 (1H, dd, J = 12.
4, 3.2Hz), 3.47 (1H, d, J = 16.2Hz), 3.72 (3H, s),
3.85 (1H, m), 3.99 (1H, m), 4.15 (1H, dd, J = 16.2,
1.6Hz), 4.20 (2H, brs), 7.61 (1H, dd, J = 8.8, 1.8H
z), 7.78 (1H, dd, J = 8.8, 1.8Hz), 7.90-8.00 (3H, m),
8.34 (1H, s). Reference Example 47 Methyl 1- (tert-butoxycarbonylamino) -6-oxo-
4- (4-vinyl-benzenesulfonyl) - 2-piperazine A cetearyl
In the same manner as in Reference Example 45, the title compound was obtained as colorless crystals from 4-vinylbenzenesulfonylglycine-tert-butyl ester. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.70-3.00 (2H,
m), 3.09 (1H, dd, J = 12.8, 3.2Hz), 3.42 (1H, d, J = 1
6.4Hz), 3.74 (3H, s), 3.79 (1H, m), 4.05-4.20 (2H,
m), 5.48 (1H, d, J = 11.0Hz), 5.92 (1H, d, J = 17.6H
z), 6.60 (1H, brs), 6.77 (1H, dd, J = 17.6, 11.0Hz),
7.57 (2H, d, J = 8.6Hz), 7.73 (2H, d, J = 8.6Hz). Reference Example 48 Methyl 1-amino-6-oxo-4- (4-vinylbenzenesulfo
Nyl) -2-piperazine acetate In the same manner as in Reference Example 46, methyl 1- (tert-butoxycarbonylamino) -6-oxo-4- (4-vinylbenzenesulfonyl) -2-piperazine acetate (11.66 g) The title compound (8.89 g) was obtained as a colorless syrup. ¹ H-NMR (CDCl ₃ ) δ: 2.70-3.00 (2H, m), 3.02 (1H, d
d, J = 12.8, 3.8Hz), 3.41 (1H, d, J = 16.0Hz), 3.73 (3
H, s), 3.75 (1H, m), 3.93-4.20 (2H, m), 4.22 (2H,
s), 5.48 (1H, d, J = 11.0Hz), 5.91 (1H, d, J = 17.6H
z), 6.76 (1H, dd, J = 17.6, 11.0Hz), 7.57 (2H, d, J =
8.4Hz), 7.73 (2H, d, J = 8.4Hz).

Example 1 6-Chloro-N-methyl-N- (2- {2- [1- (4 -pyridyl) -4-piperi
Jiniru] hydrazino} -2-oxoethyl) -2-naphthoquinone Tarensuruhon
A solution of amide 1- (4-pyridyl) -4-piperidone (3.52 g) and hydrazine hydrate (1.25 g) in ethanol (50 ml) was stirred at room temperature for 15 hours. The reaction solution was concentrated, and the obtained residue was crystallized from ether to give colorless crystals of [1- (4-pyridyl) -4-piperidinylidene] hydrazine (3.51 g). ¹ H-NMR (CDCl ₃ ) δ: 2.50 (2H, t, J = 6.2Hz), 2.61 (2
H, t, J = 6.2Hz), 3.54 (2H, t, J = 6.2Hz), 3.62 (2H,
t, J = 6.2Hz), 4.98 (2H, br), 6.60 (2H, d, J = 6.6Hz),
8.26 (2H, d, J = 6.6Hz). [1- (4-pyridyl) -4-piperidinylidene] hydrazine (1.9
0 g) and 1- (tert-butoxycarbonyl) sarcosine
To a solution of (1.90 g) in DMF (40 ml) was added WSC (2.30 g), and the mixture was stirred at room temperature for 15 hours. Aqueous sodium bicarbonate was added to the residue obtained by concentrating the reaction solution, and the mixture was extracted with ethyl acetate, dried and concentrated. The resulting residue was subjected to silica gel column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 30: 1). And purified as colorless crystals of 1- [(tert-
(Butoxycarbonyl) sarcosinyl] -2- [1- (4-pyridyl)
[-4-Piperidinylidene] hydrazine (1.0 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.45-2.80 (4H,
m), 2.90-3.00 (3H, m), 3.50-3.70 (4H, m), 3.90 (2H
x3 / 5, s), 4.30 (2Hx1 / 5, s), 4.36 (2Hx1 / 5, s), 6.62
(2H, d, J = 6.6Hz), 8.29 (2H, d, J = 6.6Hz). 1-[(tert-butoxycarbonyl) sarcosinyl] obtained
-2- [1- (4-pyridyl) -4-piperidinylidene] hydrazine
(1.0 g) was dissolved in methanol (20 ml), acetic acid (665 mg) was added under ice-cooling, followed by sodium cyanoborohydride (261 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried and concentrated to give a colorless oil, 1- [
(tert-Butoxycarbonyl) sarcosinyl] -2- [1- (4-pyridyl) -4-piperidinyl] hydrazine (1.0 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (2H, m), 1.47 (9H, s), 1.9
0 (2H, m), 2.93 (2H, m), 2.96 (3H, s), 3.11 (1H,
m), 3.81 (2H, m), 3.88 (2H, s), 4.55 (1H, brs), 6.
65 (2H, d, J = 6.6Hz), 7.70 (1H, br), 8.25 (2H, d, J
= 6.6Hz). 1- [(tert-butoxycarbonyl) sarcosinyl] -2- [1- (4
[Pyridyl) -4-piperidinyl] hydrazine (1.0 g) in methanol (12 ml), 4N hydrochloric acid in ethyl acetate (6 ml)
Was added and stirred at room temperature for 30 minutes. To the residue obtained by concentrating the reaction solution was added aqueous sodium bicarbonate, extracted with dichloromethane, dried and concentrated to give a colorless solid, 1-methylaminoacetyl-2- [1-
(4-Pyridyl) -4-piperidinyl] hydrazine (1.04 g) was obtained. The obtained 1-methylaminoacetyl-2- [1- (4-pyridyl) -4-piperidinyl] hydrazine trihydrochloride (200 mg)
To a solution of dichloromethane (15 ml) and 10% aqueous sodium carbonate solution (15 ml) at 0 ° C. with 6-chloronaphthalene-2.
-Sulfonyl chloride (150 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried,
Concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 20: 1) to give the title compound (108 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (2H, m), 1.94 (2H, m), 2.8
8 (3H, s), 2.98 (2H, m), 3.15 (1H, m), 3.74 (2H,
s), 3.83 (2H, m), 4.57 (1H, brs), 6.67 (2H, d, J =
6.6Hz), 7.61 (1H, dd, J = 1.8, 8.8Hz), 7.79 (1H, dd,
J = 1.8, 8.8Hz), 7.90-8.05 (4H, m), 8.26 (2H, d, J =
6.6Hz), 8.36 (1H, s).

Example 2 6-chloro-N-methyl-N- (2- {1-methyl-2- [1- (4-pyridyl)
-4-piperidinyl] hydrazino} -2-oxoethyl ) -2-naph
Talenesulfonamide In the same manner as in Example 1, colorless crystals of the title compound (204) were obtained using methylhydrazine instead of hydrazine hydrate.
mg). ¹ H-NMR (CDCl ₃ ) δ: 1.48 (2H, m), 1.83 (2H, m), 2.9
1 (2H, m), 2.93 (3Hx4 / 5, s), 3.08 (3Hx4 / 5, s), 3.2
1 (1H, m), 3.30 (3Hx1 / 5, s), 3.50 (3Hx1 / 5, s), 3.8
4 (2H, m), 4.02 (2Hx1 / 5, s), 4.34 (2Hx4 / 5, s), 6.6
7 (2H, d, J = 6.6Hz), 7.52 (1H, dd, J = 1.8, 8.8Hz),
7.80-7.96 (4H, m), 8.29 (2H, d, J = 6.6Hz), 8.39 (1
H, s).

Example 3 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridiyl)
L) -4-Piperidinylideneamino] -2-piperazinone 1- (tert-butoxycarbonylamino) -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (575 mg) in methanol (4 ml) 4N hydrochloric acid ethyl acetate solution (4ml)
Was added and stirred at room temperature for 30 minutes. Aqueous sodium bicarbonate was added to the residue obtained by concentrating the reaction solution, extracted with dichloromethane, dried and concentrated to give 1-amino-4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone as a colorless solid. Obtained. 1- obtained
Amino-4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone and 1- (4-pyridyl) -4-piperidone (237 m
g) in ethanol (30 ml)
While dehydrating using Soxhlet filled with 4A, 24
Reflux for hours. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1), and crystallized from ether to give the title compound (265 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (2H, m), 2.61 (2H, m), 3.4
3 (2H, m), 3.50-3.70 (6H, m), 3.88 (2H, s), 6.63
(2H, d, J = 6.4Hz), 7.62 (1H, dd, J = 1.8, 8.8Hz), 7.8
2 (1H, dd, J = 1.8, 8.8Hz), 7.90-8.00 (3H, m), 8.29
(2H, d, J = 6.4Hz), 8.39 (1H, s). IR (KBr): 1651, 1597, 1346, 1161 cm ^-1 .

Example 4 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridiyl)
L) -4-piperidinylamino] -2-piperazinone 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylideneamino] -2-piperazinone ( 120
mg) in trifluoroacetic acid (1 ml), triethylsilane (60 mg) was added, and the mixture was stirred at 50 ° C for 4 hours. The reaction solution was concentrated, an ice-cooled 1N aqueous sodium hydroxide solution was added to the residue, extracted with dichloromethane, dried and concentrated. The obtained residue was subjected to column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 20:
Purification in 1) and crystallization from acetone gave the title compound (88 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.42
(2H, m), 1.74 (2H, m), 2.85 (2H, m), 3.15 (1H,
m), 3.46 (2H, m), 3.61 (2H, m), 3.78 (2H, m), 3.86
(2H, s), 5.07 (1H, brs), 6.62 (2H, d, J = 6.2Hz),
7.62 (1H, dd, J = 1.8, 8.8Hz), 7.80 (1H, dd, J = 1.8,
8.8Hz), 7.90-8.00 (3H, m), 8.24 (2H, d, J = 6.2Hz),
8.38 (1H, s) .IR (KBr): 1651, 1597, 1348, 1163 cm ^-1 .

Example 5 4- (7-Chloro-2H-benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4 Piperijiniri Den'amino] -2-piperazinone Example 3 In the same manner as, 1-(tert-butoxycarbonylamino) -4- (7-chloro -2H- benzopyran-3-sulfonyl) -
Colorless crystals of the title compound from 2-piperazinone (1.45 g)
(700 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.40 (2H, m), 2.67 (2H, m), 3.5
5 (2H, m), 3.67 (2H, m), 3.71 (4H, s), 3.97 (2H,
s), 4.90 (2H, s), 6.67 (2H, d, J = 6.6Hz), 6.94 (1H,
d, J = 2.0Hz), 7.01 (1H, dd, J = 2.0, 8.0Hz), 7.15 (1
H, d, J = 8.0Hz), 7.31 (1H, s), 8.30 (2H, d, J = 6.6H
z) .IR (KBr): 1651, 1599, 1348, 1325, 1155 cm ^-1 .

Example 6 4- (7-chloro-2H-benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4-piperidinylamino ] -2-piperazinone In a similar manner to Example 4, 4- (7-chloro-2H-benzopyran-3-sulfonyl) -1- [1- (4-pyridyl) -4- Piperidinylideneamino] -2-piperazinone (500 mg) gave the title compound (405 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (2H, m),
1.89 (2H, m), 2.91 (2H,
m), 3.24 (1H, m), 3.55-3.
70 (4H, m), 3.83 (2H, m),
3.96 (2H, s), 4.89 (2H, s)
s), 5.16 (1H, brs), 6.64
(2H, d, J = 6.6 Hz), 6.93 (1
H, d, J = 2.0 Hz), 7.00 (1H,
dd, J = 2.0, 8.0 Hz), 7.14
(1H, d, J = 8.0 Hz), 7.30 (1
H, s), 8.25 (2H, d, J = 6.6)
Hz).

[0080] Example 7 N- [4- (7- chloro -2H- benzopyran-3 scan Ruhoni
Ru) -2-oxo-1-piperazinyl] -N- [ 1- (4-pyridyl) -4-
Piperidinyl] formamide 4- (7-chloro -2H- benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4-piperidinylamino] -2-piperazinone (10
(0 mg) in formic acid (4 ml) was refluxed for 15 hours. The residue obtained by concentrating the reaction solution was dissolved in dichloromethane, washed with a 1N aqueous sodium hydroxide solution, dried and concentrated. The obtained residue was crystallized from dichloromethane / ether to give the title compound (91 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.60-2.20 (4H, m), 2.90 (2H,
m), 3.60-4.10 (9H, m), 4.89 (2Hx1 / 2, d, J = 1.0Hz),
4.91 (2Hx1 / 2, d, J = 1.0Hz), 6.65 (2H, m), 6.92 (1H,
m), 6.95-7.04 (1H, m), 7.14 (1Hx1 / 2, d, J = 8.4Hz),
7.15 (1Hx1 / 2, d, J = 8.2Hz), 7.30 (1Hx1 / 2, s), 7.33
(1Hx1 / 2, s), 8.05 (1Hx1 / 2, s), 8.22 (1Hx1 / 2, s),
8.24-8.34 (2H, m) .IR (KBr): 1698, 1676, 1599, 1151 cm ^-1 .

Example 8 N- [4- (7-chloro-2H-benzopyran-3-sulfonyl) -2-o
Kiso - 1-piperazinyl] -N- [1- (4- pyridyl) -4-piperidyl
Nil] acetamide hydrochloride 4- (7-chloro-2H-benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4-piperidinylamino] -2-piperazinone (95
mg) in acetic anhydride (4 ml) was stirred at 80 ° C for 10 hours. To the residue obtained by concentrating the reaction solution was added a 1N aqueous solution of sodium hydroxide, and the mixture was extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate and brine, dried and concentrated to give N- [(7-
Chloro-2H-benzopyran-3-sulfonyl) -2-oxo-1-piperazinyl] -N- [1- (4-pyridyl) -4-piperidinyl] acetamide was obtained. The obtained free compound was dissolved in ethyl acetate, and a precipitate formed by adding an ethyl acetate solution of hydrochloric acid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (90 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-2.20 (7H, m), 3.05-4.05
(8H, m), 4.20-4.50 (3H, m), 5.00 (2H, s), 7.00-7.2
0 (4H, m), 7.40-7.55 (2H, m), 8.21 (2H, d, J = 6.6H
z).

Example 9 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridiyl)
Ru) -4-Piperidinylamino] -2-piperazinone hydrochloride 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylamino] -2- Piperazinone (500 mg)
The suspension was dissolved in methanol (20 ml) by adding a 4N solution of hydrochloric acid in ethyl acetate (1 ml), and the solution was concentrated. Ethanol was added to the residue for crystallization, which was collected by filtration and dried to give the title compound as a colorless solid (526 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.30 (2H, m), 1.60-1.75
(2H, m), 3.00-3.60 (8H, m), 3.77 (2H, s), 3.90-4.0
5 (2H, m), 7.13 (2H, d, J = 7.6Hz), 7.76 (1H, dd, J =
1.8, 8.8Hz), 7.91 (1H, dd, J = 1.8, 8.8Hz), 8.15-8.2
5 (3H, m), 8.28-8.33 (2H, m), 8.61 (1H, s).

Example 10 1- [1- (4-Pyridyl) -4-piperidinylideneamino] -4- (4-
Binirufu Enirusuruhoniru) -2 in piperazinone Example 3 In the same manner as, 1-(tert-butoxycarbonylamino) -4- (4-vinylphenyl) -2- piperazinone (2.1 g) from the title compound of colorless crystals (1.4 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.29 (2H, t, J = 5.8Hz), 2.63 (2
H, t, J = 5.8Hz), 3.43-3.55 (4H, m), 3.60-3.70 (4H,
m), 3.81 (2H, s), 5.49 (1H, d, J = 11.0Hz), 5.93 (1
H, d, J = 17.6Hz), 6.66 (2H, d, J = 6.6Hz), 6.78 (1H,
dd, J = 11.0, 17.6Hz), 7.59 (2H, d, J = 8.6Hz), 7.77
(2H, d, J = 8.6Hz), 8.30 (2H, d, J = 6.6Hz).

Example 11 1- [1- (4-Pyridyl) -4-piperidinylamino] -4- (4-vinyl
Rufeni Rusuruhoniru) -2-piperazinone 1- [1- (4-pyridyl) -4-piperidone Gini isopropylidene amino] -4- (4-
(Vinylphenylsulfonyl) -2-piperazinone (200 mg)
Was dissolved in methanol (10 ml), and acetic acid (110 m
g), followed by sodium cyanoborohydride (5
7 mg) and stirred at room temperature for 30 minutes. The reaction solution is concentrated, the residue is dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried and concentrated, and then subjected to column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 2%).
0: 1) and purified as a colorless amorphous title compound
(150 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (2H, m), 1.80 (2H, m), 2.8
8 (2H, m), 3.17 (1H, m), 3.37 (2H, m), 3.60 (2H, m
m), 3.80 (2H, s), 3.82 (2H, m), 5.08 (1H, d, J = 4.8H
z), 5.49 (1H, d, J = 11.0Hz), 5.92 (1H, d, J = 17.6H
z), 6.63 (2H, d, J = 6.6Hz), 6.77 (1H, dd, J = 11.0, 1
7.6Hz), 7.58 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 8.6H)
z), 8.25 (2H, d, J = 6.6Hz).

Example 12 1- (1-acetimidoyl-4-piperidinylamino) -4- (6-
Kuroronafuta Ren-2-sulfonyl) -2-piperazinone hydrochloride
To a salt 1- [1- (tert-butoxycarbonyl) -4-piperidinylamino] -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (300 mg) was added a 4N hydrochloric acid ethyl acetate solution (10 ml). ) And stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain crude crystals of 4- (6-chloronaphthalene-2-sulfonyl) -1- (4-piperidinylamino) -2-piperazinone hydrochloride. Got
4- (6-chloronaphthalene-2-sulfonyl) -1- (4-piperidinylamino) -2-piperazinone hydrochloride, triethylamine
Ethyl acetimidate (712 mg) was added to a solution of (1.16 g) in methanol (15 ml), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with a 1N aqueous sodium hydroxide solution, dried and concentrated. The obtained residue was dissolved in ethyl acetate, and the hydrochloride produced by the addition of hydrochloric acid in ethyl acetate was collected by filtration and dried to give the title compound as a colorless solid (243 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (2H, m), 1.68 (2H, m),
2.23 (3H, s), 3.00-3.23 (3H, m), 3.43 (4H, s), 3.65
(1H, m), 3.75 (2H, s), 3.91 (2H, m), 4.05 (1H,
m), 7.75 (1H, dd, J = 2.0, 8.8Hz), 7.90 (1H, dd, J =
2.0, 8.8Hz), 8.19 (1H, d, J = 8.8Hz), 8.25-8.33 (2H,
m), 8.60 (1H, s), 8.71 (1H, s), 9.29 (1H, s).

Example 13 1- [1- (2-Amino-4-pyrimidinyl) -4-piperidinylidene
Amino] -4- (6-chloronaphthalene-2-sulfonyl) -2-pipe
Radinone In the same manner as in Example 3, 1-amino-4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (320 mg) and
1- (2-amino-4-pyrimidinyl) -4-piperidone (173 mg)
1-butanol (30 ml) solution to molecular sieves 4
While dehydrating using a Soxhlet filled with A, 18
Reflux for hours. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1), and crystallized from ethyl acetate and ether to give the title compound as colorless crystals (185
mg). ¹ H-NMR (CDCl ₃ ) δ: 2.14-2.20 (2H, m), 2.53-2.59 (2
H, m), 3.50-3.70 (6H, m), 3.76-3.82 (2H, m), 3.87
(2H, s), 4.69 (2H, brs), 5.96 (1H, d, J = 5.8Hz), 7.
62 (1H, dd, J = 8.8, 1.8Hz), 7.82 (1H, dd, J = 8.8, 1.
8Hz), 7.91 (1H, d, J = 5.8Hz), 7.95 (1H, d, J = 1.8Hz),
7.95 (2H, d, J = 8.8Hz), 8.38 (1H, d, J = 1.8Hz). IR (KBr): 1660, 1590, 1550, 1490, 1460, 1450 cm ^-1 .

Example 14 1- [1- (2-Amino-4-pyrimidinyl) -4-piperidinylamide
No] -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazi
In the same manner as in Example 4, 1- [1- (2-amino-4-pyrimidinyl) -4-piperidinylideneamino] -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (120 mg) ) The title compound (61 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.68-1.78 (2
H, m), 2.76-2.90 (2H, m), 3.02-3.22 (1H, m), 3.41-
3.47 (2H, m), 3.57-3.62 (2H, m), 3.85 (2H, s), 4.17
-4.24 (2H, m), 4.62 (2H, brs), 5.06 (1H, d, J = 4.8H
z), 5.92 (1H, d, J = 6.4Hz), 7.62 (1H, dd, J = 8.8, 1.8
Hz), 7.80 (1H, dd, J = 8.8, 1.8Hz), 7.86 (1H, d, J =
6.4Hz), 7.95 (1H, d, J = 1.8Hz), 7.95 (2H, d, J = 8.8H)
z), 8.37 (1H, d, J = 1.8Hz) .IR (KBr): 1655, 1588, 1549, 1495, 1449 cm ^-1

Example 15 4- (8-Chloro-2,3-dihydrobenzo [b] oxepin-4-sul
Fonyl) -1- [1- (4-pyridyl ) -4-piperidinylamino] -2-
Piperazinone 1- [1- (4-Pyridyl) -4-piperidinylamino] -2-piperazinone trihydrochloride (385 mg) obtained in Reference Example 13 in dichloromethane (15 ml) and 10% aqueous sodium carbonate solution ( 1
5 ml) at 0 ° C with 8-chloro-2,3-dihydrobenzo
[b] Oxepin-4-sulfonyl chloride (307 mg) was added, and the mixture was stirred at room temperature for 3 hours. The organic layer was separated, washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol containing 10% ammonia water = 15: 1), and crystallized from ethanol and ether to give the title compound (298 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.38-1.57 (2H, m), 1.82-1.97 (2
H, m), 2.87-3.00 (4H, m), 3.15-3.35 (1H, m), 3.57-
3.66 (4H, m), 3.82-3.89 (2H, m), 3.94 (2H, s), 4.31
(2H, t, J = 4.6Hz), 5.17 (1H, d, J = 4.8Hz), 6.66 (2
H, d, J = 6.6Hz), 7.05 (1H, d, J = 2.2Hz), 7.07 (1H,
(dd, J = 7.8, 2.2Hz), 7.28 (1H, d, J = 7.8Hz), 7.39
(1H, s), 8.25 (2H, d, J = 6.6Hz) .IR (KBr): 3280, 2928, 1653, 1599, 1557, 1543, 151
4, 1483, 1410 cm ^-1

Example 16 4- (6-bromonaphthalene-2-sulfonyl) -1- [1- (4-pyridiyl)
L ) -4-Piperidinylamino] -2-piperazinone In the same manner as in Example 15, 6-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride was replaced by 6
Using -bromonaphthalene-2-sulfonyl chloride (101 mg), the title compound (83 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.31-1.47 (2H, m), 1.72-1.77 (2
H, m), 2.76-2.89 (2H, m), 3.02-3.22 (1H, m), 3.43-
3.48 (2H, m), 3.57-3.63 (2H, m), 3.70-3.80 (2H, m),
3.87 (2H, s), 5.07 (1H, d, J = 4.4Hz), 6.61 (2H, d,
J = 6.2Hz), 7.75 (1H, dd, J = 8.8, 1.8Hz), 7.80 (1H,
(dd, J = 8.8, 1.8Hz), 7.89 (1H, d, J = 8.8Hz), 7.94
(1H, d, J = 8.8Hz), 8.14 (1H, d, J = 1.8Hz), 8.25 (2
H, d, J = 6.2Hz), 8.36 (1H, d, J = 1.8Hz). IR (KBr): 2928, 1651, 1595, 1539, 1514, 1454, 1422
cm ^-1

Example 17 4- [2 (E)-(4-chlorophenyl) ethenesulfonyl] -1- [1-
(4-Hoon lysyl) -4-in-piperidinylamino] -2-piperazinone Example 15 In a manner analogous to that of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride 2 instead of Lido
(E)-(4-chlorophenyl) ethenesulfonyl chloride (22
3 mg) to give the title compound (8 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.37-1.56 (2H, m), 1.84-1.91 (2
H, m), 2.83-2.97 (2H, m), 3.13-3.30 (1H, m), 3.53-
3.58 (2H, m), 3.63-3.68 (2H, m), 3.79-3.86 (2H, m),
3.95 (2H, s), 5.10-5.25 (1H, br), 6.66 (2H, brs),
6.67 (1H, d, J = 15.4Hz), 7.41 (2H, d, J = 9.4Hz),
7.46 (2H, d, J = 9.4Hz), 7.50 (1H, d, J = 15.4Hz), 8.
25 (2H, brs). IR (KBr): 2924, 1645, 1541, 1489, 1456, 1422 cm ^-1

[0091] EXAMPLE 18 4- (5-Chloro-3- main Chirubenzo [b] thiophene-2-sulfonyl
) -1- [1- (4-pyridyl) -4-piperidinylamino] -2-pipe
Radinone In the same manner as in Example 15, 5-chloro-3-methylbenzo was used instead of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride.
[b] The title compound (158 mg) was obtained as colorless crystals using thiophen-2-sulfonyl chloride (149 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.34-1.51 (2H, m), 1.75-1.82 (2
H, m), 2.72 (3H, s), 2.77-2.90 (2H, m), 3.10-3.28
(1H, m), 3.54-3.65 (4H, m), 3.74-3.81 (2H, m), 3.98
(2H, s), 5.11 (1H, d, J = 4.8Hz), 6.62 (2H, d, J = 6.6
Hz), 7.51 (1H, dd, J = 8.8, 2.2Hz), 7.79 (1H, d, J
= 8.8Hz), 7.84 (1H, d, J = 2.2Hz), 8.25 (2H, d, J = 6.6
Hz). IR (KBr): 2924, 1655, 1649, 1642, 1597, 1545, 151
2, 1422 cm ^-1

Example 19 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridiyl)
L) -4-Piperidinylamino] -2-piperazinone Example 15
In the same manner as above, 6-chloronaphthalene-2-sulfonyl chloride (4.75 g) was used instead of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride to give the title compound as colorless crystals (4.7 g). 5.82 g) were obtained.

Example 20 4- (2-acetamido-4-methylthiazole-5-sulfonyl) -1
- [1- (4-pyridyl) -4 Piperi Jiniruamino] -2- piperazine
In the same manner as in Example 15, 2-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride was replaced with 2
Colorless amorphous title compound using 5-acetamide-4-methylthiazole-5-sulfonyl chloride (105 mg)
(58 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (2H, m), 1.86 (2H, m), 2.3
2 (3H, s), 2.55 (3H, s), 2.92 (2H, m), 3.10-3.35
(2H, m), 3.52 (2H, m), 3.62 (2H, m), 3.86 (2H, m),
3.90 (2H, s), 5.20 (1H, d, J = 4.4Hz), 6.66 (2H, d,
J = 6.6Hz), 8.28 (2H, d, J = 6.6Hz).

Example 21 4- (9-Chloro-2,3-dihydrobenzo [b] oxepin-4-sul
Fonyl) -1- [1- (4-pyridyl ) -4-piperidinylamino] -2-
In a similar manner to piperazinone Example 15, instead of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride 9
-Chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride (304 mg) was used to give the title compound (31) as colorless crystals.
2 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.38-1.57 (2H,
m), 1.85-1.92 (2H, m), 2.85-2.99 (2H, m), 3.02 (2H,
t, J = 4.8Hz), 3.18-3.30 (1H, m), 3.57-3.66 (4H, m),
3.81-3.88 (2H, m), 3.95 (2H, s), 4.41 (2H, t, J =
4.8Hz), 5.16 (1H, d, J = 4.8Hz), 6.65 (2H, d, J = 6.6H)
z), 7.03 (1H, t, J = 8.0Hz), 7.28 (1H, dd, J = 8.0,
1.8Hz), 7.42 (1H, s), 7.45 (1H, dd, J = 8.0, 1.8H
z), 8.26 (2H, d, J = 6.6Hz) .IR (KBr): 2942, 1651, 1597, 1539, 1510, 1472, 144
3, 1418 cm ^-1

Example 22 4- (5-chlorobenzo [b] furan-2-sulfonyl) -1- [1- (4-
Pyridyl) -4 Piperijinirua amino] -2 in piperazinone Example 15 by the same process as 5 instead of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride
-Chlorobenzo [b] furan-2-sulfonyl chloride (201 m
The title compound (97 mg) was obtained as colorless crystals using g). ¹ H-NMR (CDCl ₃ ) δ: 1.43-1.62 (2H, m), 1.87-1.94 (2
H, m), 2.87-3.02 (2H, m), 3.10-3.35 (1H, m), 3.72-
3.77 (2H, m), 3.83-3.89 (2H, m), 3.97-4.02 (2H, m),
4.41 (2H, s), 5.19 (1H, d, J = 4.8Hz), 6.66 (2H, d,
J = 6.6Hz), 6.89 (1H, s), 6.93 (1H, d, J = 8.8Hz), 7.
08 (1H, d, J = 2.2Hz), 7.09 (1H, dd, J = 8.8, 2.2Hz),
8.26 (2H, d, J = 6.6Hz). IR (KBr): 1640, 1601, 1514, 1476, 1449, 1416 cm ^-1

Example 23 4- (6-chlorobenzo [b] thiophen-2-sulfonyl) -1- [1-
(4-pyridyl) -4-piperidin arylamino] -2 in piperazinone Example 15 by the same process as in place of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride 6
-Chlorobenzo [b] thiophen-2-sulfonyl chloride (2
94 mg) to give the title compound (321 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.32-1.50 (2H, m), 1.73-1.82 (2
H, m), 2.80-2.93 (2H, m), 3.05-3.22 (1H, m), 3.49-
3.62 (4H, m), 3.77-3.83 (2H, m), 3.90 (2H, s), 5.07
(1H, d, J = 4.8Hz), 6.63 (2H, d, J = 6.6Hz), 7.51 (1
H, dd, J = 8.8, 1.8Hz), 7.93 (1H, d, J = 1.8Hz), 8.1
7 (1H, d, J = 8.8Hz), 8.25 (1H, s), 8.25 (2H, d, J =
6.6Hz). IR (KBr): 1651, 1597, 1543, 1512, 1478, 1449, 1422
cm ^-1

Example 24 4- (6- Bromonaphthalene -2-sulfonyl) -1- [1- (4-pyridiyl)
L) -4-Piperidinylamino] -2-piperazinone dihydrochloride In the same manner as in Example 9, 4- (6-bromonaphthalene-2-sulfonyl) -1- [1- (4-pyridyl)- 4-piperidinylamino]-
2-piperazinone (1.10 g) Title compound as a colorless solid
(1.26 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.30 (2H, m), 1.65-1.71
(2H, m), 3.07-3.20 (3H, m), 3.39-3.50 (4H, m), 3.78
(2H, s), 3.96-4.02 (2H, m), 5.83 (2H, brs), 7.14 (2
H, d, J = 7.2Hz), 7.87 (1H, dd, J = 8.4, 2.2Hz), 7.91
(1H, dd, J = 8.4, 2.2Hz), 8.18-8.25 (4H, m), 8.46
(1H, s), 8.61 (1H, s), 13.61 (1H, brs).

Example 25 4- (4-chlorobenzenesulfonyl) -1- [1- (4-pyridyl) -4
- Piperi Jiniruamino] -2 in piperazinone Example 15 In a manner analogous to that of 8-chloro-2,3-dihydrobenzo [b] 4 instead of oxepin-4-sulfonyl chloride
Using -chlorobenzenesulfonyl chloride (91 mg), the title compound (58 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.54 (2H, m), 1.80-1.85 (2
H, m), 2.85-2.98 (2H, m), 3.08-3.25 (1H, m), 3.36-
3.41 (2H, m), 3.58-3.63 (2H, m), 3.79 (2H, s), 3.7
9-3.87 (2H, m), 5.09 (1H, d, J = 4.4Hz), 6.65 (2H,
d, J = 6.4Hz), 7.57 (2H, d, J = 8.6Hz), 7.75 (2H, d, J
= 8.6Hz), 8.25 (2H, d, J = 6.4Hz) .IR (KBr): 2920, 1655, 1597, 1540, 1512, 1480, 1425
cm ^-1 .

Example 26 4- (4-bromobenzenesulfonyl) -1- [1- (4-pyridyl) -4
- Piperi Jiniruamino] -2 in piperazinone Example 15 In a manner analogous to that of 8-chloro-2,3-dihydrobenzo [b] 4 instead of oxepin-4-sulfonyl chloride
-Bromobenzenesulfonyl chloride (112 mg) was used to give the title compound (74 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.33-1.53 (2H, m), 1.78-1.85 (2
H, m), 2.83-2.96 (2H, m), 3.05-3.28 (1H, m), 3.35-
3.41 (2H, m), 3.58-3.63 (2H, m), 3.79 (2H, s), 3.7
9-3.86 (2H, m), 5.09 (1H, d, J = 4.4Hz), 6.64 (2H,
d, J = 5.8Hz), 7.67 (2H, d, J = 8.6Hz), 7.74 (2H, d, J
= 8.6Hz), 8.25 (2H, d, J = 5.8Hz) .IR (KBr): 2920, 1660, 1650, 1600, 1575, 1545, 151
0, 1425 cm ^-1 .

Example 27 4- (6-Chloro-1H-indene-2-sulfonyl) -1- [1- (4-pyr
Jill) -4 Piperijiniruami Bruno] -2 in piperazinone Example 15 by the same process as in place of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride 6
-Chloro-1H-indene-2-sulfonyl chloride (249 mg)
Was used to give the title compound (14 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.65 (2H, m), 1.80-1.87 (2
H, m), 2.81-2.93 (2H, m), 3.10-3.30 (1H, m), 3.55-
3.68 (4H, m), 3.75 (2H, s), 3.75-3.84 (2H, m), 4.0
7 (2H, s), 5.12-5.20 (1H, br), 6.63 (2H, d, J = 6.2H
z), 7.32-7.59 (4H, m), 8.25 (2H, d, J = 6.2Hz) .IR (KBr): 2932, 1651, 1597, 1545, 1512, 1456, 1420
cm ^-1 .

Example 28 4- (5-chlorothieno [3,2-b] pyridine-2- sulfonyl) -1-
[1- (4-pyridyl) -4-piperazinyl Rijiniruamino] -2- piperazino
In the same manner as in Example 15, 5-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride was replaced with 5
-Chlorothieno [3,2-b] pyridine-2-sulfonyl chloride
(203 mg) to give the title compound (107 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.55 (2H, m), 1.72-1.84 (2
H, m), 2.83-2.96 (2H, m), 3.10-3.30 (1H, m), 3.58-
3.63 (2H, m), 3.71-3.78 (2H, m), 3.89-3.94 (2H, m
m), 4.16 (2H, s), 5.13 (1H, d, J = 4.4Hz), 6.64 (2H,
d, J = 5.4Hz), 7.43 (1H, d, J = 8.4Hz), 8.20 (1H, dd,
J = 8.4, 1.0Hz), 8.25 (2H, d, J = 5.4Hz), 8.25 (1H,
d, J = 1.0Hz). IR (KBr): 3100, 2940, 1651, 1599, 1564, 1532, 151
4, 1422 cm ^-1 .

Example 29 4- (6-Chlorothieno [2,3-b] pyridine-2- sulfonyl) -1-
[1- (4-pyridyl) -4-piperazinyl Rijiniruamino] -2- piperazino
In the same manner as in Example 15, 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride was replaced with 6
-Chlorothieno [2,3-b] pyridine-2-sulfonyl chloride
(240 mg) to give the title compound (176 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.45-1.60 (2H, m), 1.85-1.95 (2
H, m), 3.16-3.40 (3H, m), 3.46-3.64 (4H, m), 3.90
(2H, s), 3.96-4.03 (2H, m), 6.83 (2H, d, J = 6.8Hz),
7.52 (1H, d, J = 8.8 Hz), 8.26 (2H, d, J = 6.8 Hz),
8.32 (1H, s), 8.45 (1H, d, J = 8.8Hz) .IR (KBr): 1676, 1645, 1545, 1468, 1422 cm ^-1 .

Example 30 4- [2 (E)-(4-bromophenyl) ethenesulfonyl] -1- [1-
(4-Hoon lysyl) -4-in-piperidinylamino] -2-piperazinone Example 15 In a manner analogous to that of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride 2 instead of Lido
(E)-(4-bromophenyl) ethenesulfonyl chloride (15
0 mg) to give the title compound (143 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (2H, m), 1.87 (2H, m), 2.8
9 (2H, m), 3.22 (1H, m), 3.58 (2H, m), 3.64 (2H,
m), 3.81 (2H, m), 3.95 (2H, s), 5.15 (1H, d, J = 4.6H
z), 6.63 (2H, d, J = 6.6Hz), 6.67 (1H, d, J = 15.4Hz),
7.37 (2H, d, J = 8.4Hz), 7.48 (1H, d, J = 15.4Hz), 7.
58 (2H, d, J = 8.4Hz), 8.25 (2H, d, J = 6.6Hz).

Example 31 4- [2 (E)-(4-methoxyphenyl) ethenesulfonyl] -1- [1
-(4-Pyridyl) -4-piperidinylamino] -2-piperazino
In the same manner as in Example 15, 2-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride was replaced with 2
The title compound (146 mg) was obtained as colorless crystals using (E)-(4-methoxyphenyl) ethenesulfonyl chloride (121 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.49 (2H, m), 1.86 (2H, m), 2.8
8 (2H, m), 3.23 (1H, m), 3.54 (2H, m), 3.64 (2H, m
m), 3.82 (2H, m), 3.86 (3H, s), 3.95 (2H, s), 5.16
(1H, d, J = 4.6Hz), 6.52 (1H, d, J = 15.4Hz), 6.63 (2
H, d, J = 6.6Hz), 6.94 (2H, d, J = 8.8Hz), 7.46 (2H,
d, J = 8.8Hz), 7.49 (1H, d, J = 15.4Hz), 8.25 (2H, d,
J = 6.6Hz).

Example 32 4- [2 (E)-(4-methylphenyl) ethenesulfonyl] -1- [1-
(4-Hoon lysyl) -4-in-piperidinylamino] -2-piperazinone Example 15 In a manner analogous to that of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride 2 instead of Lido
(E)-(4-methylphenyl) ethenesulfonyl chloride (11
5 mg) to give the title compound (146 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.86 (2H, m), 2.4
1 (3H, s), 2.87 (2H, m), 3.21 (1H, m), 3.55 (2H,
m), 3.65 (2H, m), 3.80 (2H, m), 3.95 (2H, s), 5.16
(1H, d, J = 4.8Hz), 6.62 (1H, d, J = 15.4Hz), 6.63 (2
H, d, J = 6.6Hz), 7.24 (2H, d, J = 8.4Hz), 7.41 (2H,
d, J = 8.4Hz), 7.52 (1H, d, J = 15.4Hz), 8.25 (2H, d,
J = 6.6Hz).

Example 33 4- [2 (E)-(4-fluorophenyl) ethenesulfonyl] -1- [1
-(4-Pyridyl) -4-piperidinylamino] -2-piperazino
In the same manner as in Example 15, 2-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride was replaced with 2
The title compound (144 mg) was obtained as a colorless solid using (E)-(4-fluorophenyl) ethenesulfonyl chloride (115 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.50 (2H, m), 1.88 (2H, m), 2.9
0 (2H, m), 3.22 (1H, m), 3.58 (2H, m), 3.65 (2H,
m), 3.830 (2H, m), 3.95 (2H, s), 5.16 (1H, d, J = 4.8
Hz), 6.55-6.90 (3H, m), 7.14 (2H, t, J = 8.4Hz), 7.4
6-7.60 (3H, m), 8.25 (2H, d, J = 6.6Hz).

Example 34 4- [4- (2-ethoxyethoxy) benzenesulfonyl] -1- [1-
(4-pyridyl) -4-piperidinylamino] -2-in-piperazinone Example 15 In a manner analogous to that of 8-chloro-2,3-dihydrobenzo [b] 4 instead of oxepin-4-sulfonyl chloride
-(2-ethoxyethoxy) benzenesulfonyl chloride (2
50 mg) to give the title compound as a colorless syrup (340 mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0Hz), 1.45 (2
H, m), 1.80 (2H, m), 2.88 (2H, s), 3.17 (1H, m),
3.32 (2H, m), 3.50-3.66 (4H, m), 3.70-3.90 (6H,
m), 4.19 (2H, m), 5.09 (1H, d, J = 5.2Hz), 6.64 (2H,
d, J = 6.6Hz), 7.06 (2H, d, J = 8.8Hz), 7.72 (2H, d,
J = 8.8Hz), 8.24 (2H, d, J = 6.6Hz).

Example 35 4- (7-Bromo-2H-benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4-piperidinylamino ] -2-piperazinone (Method A) In the same manner as in Example 15, 7-bromo was used instead of 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride. -2H-benzopyran-3-sulfonyl chloride (1.61 g) to give the title compound as colorless crystals (1.51 g)
I got (Method B) 4- (7-bromo-2H-benzopyran-3-sulfonyl) -1- (4-piperidinylamino) -2-piperazinone (4
A mixture of 71 mg), 4-chloropyridine hydrochloride (225 mg), triethylamine (405 mg) and ethanol (20 ml) was reacted in a sealed tube at 150 ° C. for 18 hours. The reaction solution was concentrated, and the residue was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with dichloromethane. The extract was washed with water and brine, dried, concentrated, and the residue obtained was purified by silica gel column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 12: 1) to obtain a mixture of ethanol and diethyl ether. The mixture was crystallized to give the title compound (156 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.38-1.58 (2H, m), 1.84-1.92 (2
H, m), 2.84-2.97 (2H, m), 3.15-3.35 (1H, m), 3.60-
3.67 (4H, m), 3.77-3.80 (2H, m), 3.97 (2H, s), 4.8
8 (2H, s), 5.16 (1H, d, J = 4.8Hz), 6.64 (2H, d, J =
6.2Hz), 7.07 (1H, d, J = 8.0Hz), 7.10 (1H, d, J = 1.8H)
z), 7.17 (1H, dd, J = 8.0, 1.8Hz), 7.28 (1H, s), 8.2
6 (2H, brs). IR (KBr): 2920, 1651, 1597, 1545, 1514, 1480, 1420
cm ^-1 .

Example 36 4- (7-Bromo-2H-benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4-piperidinylamino ] -2-piperazinone disalt
Salt 4- (7-bromo -2H- benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4-piperidinylamino] -2-piperazinone (600
mg)) in methanol (20 ml) was dissolved by adding 4N hydrochloric acid in ethyl acetate (1 ml), and the solution was concentrated. The residue was crystallized from a mixture of ethanol and ethyl acetate, filtered and dried to give the title compound as a colorless solid (596 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.43 (2H, m), 1.82-1.90
(2H, m), 3.10-3.43 (3H, m), 3.55 (4H, brs), 3.86
(2H, s), 4.20-4.60 (2H, br), 4.99 (2H, s), 7.16-7.
28 (4H, m), 7.41 (1H, d, J = 8.0Hz), 7.49 (1H, s), 8.
17-8.24 (2H, m), 13.42-13.62 (1H, br) .IR (KBr): 3080, 2946, 1645, 1595, 1549, 1481, 145
6, 1416 cm ^-1 .

Example 37 1- (1-acetimidoyl-4-piperidinylamino) -4- (7-
Bromo -2H- benzopyran-3 sul Honiru) -2- piperazino
Emissions dihydrochloride 4- (7-bromo -2H- benzopyran-3-sulfonyl) -1- (4-piperidinylamino) -2-piperazinone (104 mg) and methanol triethylamine (334 mg) (10 ml) Ethyl acetimidate hydrochloride (272 mg) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with a 1 N aqueous solution of sodium hydroxide and brine, dried and concentrated. The obtained residue was suspended in ethyl acetate, and the hydrochloride produced by the addition of 4N hydrochloric acid in ethyl acetate was filtered and dried to give the title compound as a colorless solid (243
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.35-1.50 (2H, m), 1.80-1.87
(2H, m), 2.26 (3H, s), 3.15-3.97 (13H, m), 4.98 (2
H, s), 7.20-7.27 (2H, m), 7.41 (1H, d, J = 8.2Hz),
7.49 (1H, s), 8.64 (1H, s), 9.20 (1H, s) .IR (KBr): 3140, 1671, 1627, 1597, 1557, 1481, 1416
cm ^-1 .

Example 38 4- (6-Chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4
- pyridyl) -4-piperidinyl] amino} -2-piperazino emissions (A Method) 1 obtained in Reference Example 11 - {[1- (tert- butoxycarbonyl) piperidinyl] amino} -4- (6-chloronaphthalene 2-sulfonyl) -2-piperazinone (1.90 g), methyl iodide (10 ml), potassium carbonate (600 mg) and DMF (5
0 ml) was stirred at 50 ° C. for 15 hours. Water was added to the residue obtained by concentrating the reaction solution, extracted with ethyl acetate, dried and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). A colorless amorphous 1-{[1- (tert-butoxycarbonyl) piperidinyl] methylamino} -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (1.63 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (2H, m), 1.43 (9H, s), 1.6
0 (1H, m), 1.75 (1H, m), 2.69 (3H, s), 2.69 (2H,
m), 3.30-3.65 (5H, m), 3.73 (2H, m), 3.99 (2H, m),
7.61 (1H, dd, J = 1.8, 8.8Hz), 7.79 (1H, dd, J = 1.8,
8.8Hz), 7.90-7.98 (3H, m), 8.35 (1H, s). 1-{[1- (tert-butoxycarbonyl) piperidinyl] methylamino} -4- (6-chloronaphthalene-2-sulfonyl) Methanol (10 ml) and 4N hydrochloric acid ethyl acetate solution (15 ml) were added to 2-piperazinone (1.63 g), and the mixture was stirred at room temperature for 30 minutes. 4-Chloropyridine hydrochloride (950 mg), triethylamine (3.8 g) and ethanol (100 ml) were added to the residue obtained by concentrating the reaction solution, and the mixture was reacted at 150 ° C. for 15 hours in a sealed tube. The reaction solution was concentrated, 1N aqueous sodium hydroxide solution was added to the residue, extracted with dichloromethane, dried and concentrated. The obtained residue was purified by column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1), and crystallized from ether to give the title compound (794 mg) as colorless crystals. (Method B) 1- {Methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone dihydrochloride (1.35 g) obtained in Reference Example 16 in dichloromethane (50 ml) and 10% To a solution of an aqueous sodium carbonate solution (50 ml) was added 6-chloronaphthalene-2-sulfonyl chloride (1.34 g) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1), and crystallized from ether to give the title compound (1.56 g) as colorless crystals. (Method C) 4- (6-chloronaphthalene-2-sulfonyl) -1- [1-
(4-pyridyl) -4-piperidinylamino] -2-piperazinone
(90 mg) was dissolved in a 37% aqueous formaldehyde solution (2.9 ml) and formic acid (1.4 ml) and refluxed for 15 hours. After cooling, the reaction solution was made alkaline by adding a 1N aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The obtained residue was subjected to column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 20:
Purification in 1) gave the title compound (38 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (2H, m), 1.60 (1H, m), 1.8
6 (1H, m), 2.71 (3H, s), 2.81 (2H, m), 3.30-3.90
(9H, m), 6.59 (2H, d, J = 6.6Hz), 7.62 (1H, dd, J = 2.
0, 8.8Hz), 7.80 (1H, dd, J = 1.8, 8.8Hz), 7.90-8.00
(3H, m), 8.24 (2H, d, J = 6.6Hz), 8.36 (1H, s).

Example 39 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4
- pyridyl) -4-piperidinyl] amino} -2-piperazino emissions salt
Salt 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4
-Pyridyl) -4-piperidinyl] amino} -2-piperazinone
To a suspension of (500 mg) in methanol (20 ml) was added and dissolved 4N hydrochloric acid in ethyl acetate solution (1 ml), and the solution was concentrated. The residue was crystallized from ethanol / ether, collected by filtration and dried to give the title compound (526 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.14 (2H, m), 1.60 (1H, m),
1.81 (1H, m), 2.53 (3H, s), 2.95-3.60 (7H, m), 3.73
(2H, m), 3.99 (2H, m), 7.09 (2H, d, J = 7.8Hz), 7.7
6 (1H, dd, J = 2.0, 8.8Hz), 7.91 (1H, dd, J = 1.4, 8.8
Hz), 8.15-8.35 (5H, m), 8.61 (1H, s).

Example 40 1-[(1-acetimidoyl-4-piperidinyl) methylamido
Roh] -4- (6-chloronaphthalene-2-sul Honiru) -2- piperazine
Nonhydrochloride 1-{[1- (tert-butoxycarbonyl) piperidinyl] methylamino} -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (106) obtained in Example 38 (Method A) mg) in methanol (3 ml), 4N hydrochloric acid in ethyl acetate (5 ml)
Was added and stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution was dissolved in methanol (8 ml), triethylamine (400 mg) and ethylacetimidate hydrochloride (245 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with a 1N aqueous sodium hydroxide solution and brine, dried and concentrated.
The obtained residue was suspended in ethyl acetate, and the hydrochloride generated by adding a 4N hydrochloric acid-ethyl acetate solution was collected by filtration and dried to give the title compound (87 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (2H, m), 1.56 (1H, m),
1.80 (1H, m), 2.21 (3H, s), 2.95-3.70 (10H, m), 3.7
1 (2H, s), 3.93 (2H, m), 7.74 (1H, dd, J = 2.0, 8.8H
z), 7.89 (1H, d, J = 8.8Hz), 8.20 (1H, d, J = 8.8Hz),
8.25-8.32 (2H, m), 8.61 (2H, brs), 9.20 (1H, br).

Example 41 4- (6-bromonaphthalene-2-sulfonyl) -1- {methyl [1- (4
-Pyridyl) -4-piperidinyl] amino} -2-piperazinone (Method A) In the same manner as in Example 38 (Method B), 6-bromonaphthalene-2- was used instead of 6-chloronaphthalene-2-sulfonyl chloride. The title compound (210 mg) was obtained as colorless crystals using sulfonyl chloride (254 mg). (Method B) In the same manner as in Example 38 (Method C), 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-
4- (6-) instead of piperidinylamino] -2-piperazinone
Bromonaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4
-Piperidinylamino] -2-piperazinone (1.4 g) was used to give the title compound (862 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.85-1.95 (2
H, m), 2.71 (3H, s), 2.71-2.92 (2H, m), 3.30-3.90
(9H, m), 6.59 (2H, d, J = 6.6Hz), 7.75 (1H, dd, J =
8.8, 1.8Hz), 7.81 (1H, dd, J = 8.8, 1.8Hz), 7.89 (1
H, d, J = 8.8Hz), 7.94 (1H, d, J = 8.8Hz), 8.15 (1H,
d, J = 1.8Hz), 8.24 (2H, d, J = 6.6Hz), 8.36 (1H, d,
J = 1.8Hz). IR (KBr): 2949, 1667, 1597, 1543, 1512, 1456, 1417
cm ^-1 .

Example 42 4- (7-Bromo-2H-benzopyran-3-sulfonyl) -1- {methyl
[1- (4-pyridyl) -4-piperidinyl] amino} -2-pipera
Zinone (Method A) In the same manner as in Example 38 (Method B), instead of 6-chloronaphthalene-2-sulfonyl chloride, 7-bromo-
The title compound (230 mg) was obtained as colorless crystals using 2H-benzopyran-3-sulfonyl chloride (308 mg). (Method B) In the same manner as in Example 38 (Method C), 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-
Piperidinylamino] -2-piperazinone instead of 4- (7-
Bromo-2H-benzopyran-3-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylamino] -2-piperazinone (1.5 g)
Was used to obtain the title compound (890 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.52 (2H, m), 1.80-2.00 (2
H, m), 2.82 (3H, s), 2.87 (2H, m), 3.40-3.70 (5H,
m), 3.79-3.87 (2H, m), 3.87 (2H, d, J = 3.0Hz), 4.88
(1H, d, J = 1.2Hz), 6.63 (2H, d, J = 6.6Hz), 7.07 (1H,
d, J = 8.0Hz), 7.11 (1H, d, J = 1.4Hz), 7.17 (1H, dd,
J = 8.0, 1.4Hz), 7.28 (1H, d, J = 1.2Hz), 8.25 (2H, d,
J = 6.6Hz) .IR (KBr): 2955, 1669, 1597, 1510, 1480, 1416 cm ^-1 .

Example 43 4- (6-chloronaphthalene-2-sulfonyl) -1- {ethyl [1- (4
- pyridyl) -4-piperidinyl] amino} -2-piperazino emissions (A method) Example 38 (A method) and the same method, 1- [1- (te
rt-butoxycarbonyl) -4-piperidinylamino] -4- (6-
(Chloronaphthalene-2-sulfonyl) -2-piperazinone (1.5
7 g) and methyl iodide instead of ethyl iodide (4.68 g)
Was used to obtain the title compound (370 mg) as colorless crystals. (Method B) 4- (6-chloronaphthalene-2-sulfonyl) -1- [1-
(4-pyridyl) -4-piperidinylamino] -2-piperazinone
(14 g) was dissolved in acetic acid (160 ml), sodium borohydride (11.36 g) was added little by little while maintaining the reaction solution at 20 ° C., and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and the residue was made alkaline by adding an aqueous sodium hydroxide solution, extracted with dichloromethane, dried and concentrated. The obtained residue was crystallized from ethanol to give the title compound (12.96 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.2Hz), 1.25-1.4
2 (2H, m), 1.57-1.70 (1H, m), 1.90-1.95 (1H, m),
2.68-2.92 (3H, m), 3.21-3.47 (6H, m), 3.65-3.83 (4
H, m), 6.59 (2H, d, J = 6.2Hz), 7.63 (1H, dd, J = 8.
8, 1.8Hz), 7.81 (1H, dd, J = 8.8, 1.8Hz), 7.96 (2H,
d, J = 8.8Hz), 7.96 (1H, d, J = 8.8Hz), 8.25 (2H,
d, J = 6.2Hz), 8.37 (1H, d, J = 1.8Hz). IR (KBr): 2973, 1669, 1597, 1510, 1456, 1416 cm ^-1 .

Example 44 4- (6-Chloronaphthalene-2-sulfonyl) -1- (n-propyl )
[1- (4-pyridyl) -4-piperidyl sulfonyl] amino} -2-piperazino
In the same manner as in Non- Example 38 (Method A), colorless crystals of the title compound (58 mg) were obtained using n-propyl iodide (1.70 g) instead of methyl iodide. ¹ H-NMR (CDCl ₃ ) δ: 0.84
(3H, t, J = 7.4Hz), 1.21-1.40 (4H, m), 1.55-1.70 (1
H, m), 1.89-1.96 (1H, m), 2.64-2.86 (3H, m), 3.16-
3.50 (6H, m), 3.67-3.90 (4H, m), 6.59 (2H, d, J = 6.
2Hz), 7.63 (1H, dd, J = 8.8, 2.2Hz), 7.81 (1H, dd,
J = 8.8, 1.4Hz), 7.94-7.98 (3H, m), 8.24 (2H, d, J =
6.2Hz), 8.36 (1H, s) .IR (KBr): 2924, 1667, 1595, 1539, 1507, 1450 cm ^-1 .

Example 45 1- {Allyl [1- (4-pyridyl) -4-piperidinyl] amino} -4-
In (6-chloronaphthalene-2-sulfonyl) -2-piperazino emissions Example 38 (A method) and the same method, 1- [1- (tert- butoxycarbonyl) -4-piperidinylamino] -4- The title compound (69 mg) was obtained as colorless crystals using (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (390 mg) and allyl bromide (2 ml) instead of methyl iodide. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (2H, m), 1.60 (1H, m), 1.9
0 (1H, m), 2.75 (2H, s), 3.10-3.95 (11H, m), 5.00-
5.20 (2H, m), 5.75 (1H, m), 6.58 (2H, d, J = 6.6Hz),
7.62 (1H, dd, J = 1.8, 8.8Hz), 7.79 (1H, dd, J = 1.8,
8.8Hz), 7.90-8.00 (3H, m), 8.24 (2H, d, J = 6.6Hz),
8.35 (1H, s).

Example 46 4- (6-bromonaphthalene-2-sulfonyl) -1- {methyl [1- (4
- pyridyl) -4-piperidinyl] amino} -2-piperazino emissions salt
In the same manner as in Example 39, 4- (6-chloronaphthalene-2-
Sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone instead of 4- (6-bromonaphthalene-2-sulfonyl) -1- {methyl [1- ( 4-Pyridyl) -4-piperidinyl] amino} -2-piperazinone (862 mg) was used to obtain the title compound (920 mg) as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.08 (2H, m), 1.63 (1H, m), 1.
80 (1H, m), 2.53 (3H, s), 2.95-3.55 (7H, m), 3.73
(2H, m), 3.80-4.10 (2H, m), 7.09 (2H, d, J = 7.0Hz),
7.80-7.95 (2H, m), 8.13-8.25 (4H, m), 8.46 (1H,
d, J = 1.8Hz), 8.60 (1H, s).

Example 47 4- (7-Bromo-2H-benzopyran-3-sulfonyl) -1- {methyl
[1- (4-pyridyl) -4-piperidinyl] amino} -2-pipera
Dinone hydrochloride In the same manner as in Example 39, 4- (6-chloronaphthalene-2-
4- (7-bromo-2H-) instead of sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone
The title compound was obtained as colorless crystals using benzopyran-3-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone.

Example 48 N- [4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1-
Piperazinyl] -2- [1- (4-pyridyl) -4-piperidinyl] a
2- [1- (tert-butoxycarbonyl) obtained in Cetamide Reference Example 20
4-Piperidinyl] -N- [4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1-piperazinyl] acetamide (210 mg) in methanol (2 ml), 4N hydrochloric acid in ethyl acetate (5 m
l) was added and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution was 4-chloropyridine hydrochloride (168 mg),
Triethylamine (452 mg) and ethanol (12 ml) were added, and the mixture was reacted at 150 ° C. for 15 hours in a sealed tube. The reaction solution was concentrated, and a 1 N aqueous solution of sodium hydroxide was added to the residue.
The mixture was extracted with dichloromethane, dried and concentrated. The obtained residue is subjected to column chromatography (dichloromethane: 10).
% Methanol solution containing 20% ammonia water = 20: 1) and crystallized from ether to give the title compound as colorless crystals
(354 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (2H, m), 1.83 (2H, m), 2.0
5 (1H, m), 2.10 (2H, s), 2.87 (2H, m), 3.54 (2H,
m), 3.70 (2H, m), 3.83 (2H, m), 3.90 (2H, s), 6.57
(2H, d, J = 6.4Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.7
8 (1H, dd, J = 1.8, 8.8Hz), 7.85-7.97 (3H, m), 8.14
(2H, d, J = 6.4Hz), 8.35 (1H, s).

Example 49 2- (1-acetimidoyl-4-piperidinyl) -N- [4- (6 -chloro
Ronafuta Ren-2-sulfonyl) -2-oxo-1-piperazinyl
2-Acetamide dihydrochloride 2- [1- (tert-butoxycarbonyl) obtained in Reference Example 20
4-Piperidinyl] -N- [4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1-piperazinyl] acetamide (210 mg) in methanol (2 ml), 4N hydrochloric acid in ethyl acetate (5 m
l) was added and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution was dissolved in methanol (15 ml), triethylamine (400 mg) and ethylacetimidate hydrochloride (271 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with a 1N aqueous sodium hydroxide solution and brine, dried and concentrated. The obtained residue was suspended in ethyl acetate, and the hydrochloride produced by the addition of 4N hydrochloric acid in ethyl acetate was collected by filtration and dried to give the title compound (8 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.21 (2H, m), 1.77 (2H, m), 1.
90-2.10 (3H, m), 2.22 (3H, s), 3.00-4.30 (10H, m),
7.72 (1H, dd, J = 1.8, 8.8Hz), 7.87 (1H, dd, J = 1.8,
8.8Hz), 8.10-8.30 (3H, m), 8.48 (1H, s), 8.56 (1H,
s), 9.06 (1H, s), 10.28 (1H, s).

Example 50 4-[(6-Chloro-2-naphthyl) sulfonyl] -6-methyl-1-[[1
-( 4-Pyridinyl) -4-piperidinyl] amino] -2-piperazi
Non dihydrochloride tert-butyl 3-methyl-5-oxo-4-[[1- (4-pyridinyl)
To a solution of (-4-piperidinyl) amino] -1-piperazinecarboxylate (1.1 g) in toluene (11 ml) was added dropwise trifluoroacetic acid (11 ml), the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (11 ml) and a 10% aqueous sodium carbonate solution (11 ml), 6-chloronaphthalene-2-sulfonyl chloride (0.90 g) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The organic layer was separated, washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol containing 10% ammonia water = 10: 1), and 4-[(6
-Chloro-2-naphthyl) sulfonyl] -6-methyl-1-[[1- (4-
Pyridinyl) -4-piperidinyl] amino] -2-piperazinone (1.1 g) was obtained. This product was dissolved in methanol (5 ml), 4N hydrochloric acid in ethyl acetate (1.3 ml) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate / methanol, collected by filtration and dried to give the title compound (1.1 g) as a colorless crystalline powder. ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ: 1.10-1.38 (2H, m), 1.23 (3
H, d, J = 6.4 Hz), 1.62-1.88 (2H, m), 3.00-3.70 (7
H, m), 3.86 (1H, d, J = 15.8 Hz), 3.90-4.12 (2H,
m), 7.14 (2H, d, J = 6.8 Hz), 7.75 (1H, dd, J = 2.
2, 8.8 Hz), 7.90 (1H, dd, J = 1.8, 8.8 Hz), 8.10-8.
36 (5H, m), 8.60 (1H, s).

Example 51 4-[(6-Chloro-2-naphthyl) sulfonyl] -6-methyl-1- [me
Tyl [1- (4-pyridinyl) -4-piperidinyl] amino] -2-pi
Perazinone 4-[(6-chloro-2-naphthyl) sulfonyl] -6-methyl-1-[[1
-(4-Pyridinyl) -4-piperidinyl] amino] -2-piperazinone dihydrochloride (0.63 g) was dissolved in methylene chloride (20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), and the layers were separated. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure,
[(6-chloro-2-naphthyl) sulfonyl] -6-methyl-1-[[1-
(4-Pyridinyl) -4-piperidinyl] amino] -2-piperazinone was obtained. Use this product in a 37% formaldehyde aqueous solution (8.0 m
l) and formic acid (4.1 ml) and refluxed for 2 hours.
After cooling, the reaction solution was made alkaline by adding a 1N aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give the title compound (370 mg) as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-1.30 (2H, m), 1.23 (3H,
d, J = 5.8 Hz), 1.30-1.70 (1H, m), 1.75-2.00 (1H,
m), 2.35-4.00 (13H, m), 6.60-6.82 (2H, m), 7.76 (1
H, dd, J = 1.8, 8.8 Hz), 7.90 (1H, dd, J = 1.8, 8.
8 Hz), 8.11 (2H, d, J = 6.2 Hz), 8.20 (1H, d, J =
(8.8 Hz), 8.24-8.36 (2H, m), 8.60 (1H, s).

Example 52 4-[(6-Chloro-2-naphthyl) sulfonyl] -6-methyl-1- [meth]
Tyl [1- (4-pyridinyl) -4-piperidinyl] amino] -2-pi
Perazinone hydrochloride 4-[(6-chloro-2-naphthyl) sulfonyl] -6-methyl-1- [methyl [1- (4-pyridinyl) -4-piperidinyl] amino] -2-piperazinone (0.34 g) It was dissolved in ethanol (2 ml), and 4N hydrochloric acid in ethyl acetate (0.24 ml), ethyl acetate (20 ml) and diethyl ether (30 ml) were added.
The precipitated powder was collected by filtration and dried to give the title compound (0.37 g) as a colorless amorphous powder. ¹ H-NMR (CD ₃ OD) δ: 1.15-1.50 (2H, m), 1.37 (3H, d,
J = 6.4 Hz), 1.60-1.90 (1H, m), 1.95-2.25 (1H, m),
2.61, 2.87 (total 3H, s for each), 2.90-4.40 (10H,
m), 7.00-7.18 (2H, m), 7.66 (1H, dd, J = 2.0, 8.8
Hz), 7.87 (1H, dd, J = 1.8, 8.8 Hz), 8.00-8.18 (5
H, m), 8.48 (1H, s).

Example 53 Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -6-oxo
So-1-[ [1- (4-pyridinyl) -4-piperidinyl] amino ] -2-
Piperazine carboxylate dihydrochloride 1- (tert-butyl) 3-methyl 5-oxo-4-[[1- (4-pyridinyl) -4-piperidinyl] amino] -1,3-piperazine dicarboxylate (0.36 g ) Was added dropwise to a toluene solution of (3.6 ml), and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was diluted with dichloromethane (3.6
ml) and a 10% aqueous sodium carbonate solution (3.6 ml), 6-chloronaphthalene-2-sulfonyl chloride (0.26 g) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The organic layer was separated, washed with brine, dried and concentrated. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol containing 10% ammonia water = 10: 1).
And purified with methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -6-oxo-1-[[1- (4-pyridinyl) -4-piperidinyl] amino] -2-piperazinecarboxylate ( 0.34 g)
I got This product was dissolved in methanol (5 ml), 4N hydrochloric acid in ethyl acetate (0.38 ml) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate / methanol,
Filter and dry to give the title compound as a colorless crystalline powder (0.12
g) was obtained. ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ: 1.10-1.40 (2H, m), 1.67-1.
90 (2H, m), 3.00-3.40 (4H, m), 3.60 (1H, d, J = 16.
2 Hz), 3.69 (3H, s), 3.87-4.12 (4H, m), 4.32-4.43
(1H, m), 7.13 (2H, d, J = 7.6 Hz), 7.75 (1H, dd, J
= 2.2, 8.8 Hz), 7.87 (1H, dd, J = 1.6, 8.8 Hz),
8.10-8.34 (5H, m), 8.60 (1H, s).

Example 54 Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
[1- (4-pyridinyl) -4-piperidinyl] amino] -6-oxo
So-2-piperazinecarboxylate hydrochloride methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -6-oxo-1-[[1- (4-pyridinyl) -4-piperidinyl] amino] -2-
Piperazine carboxylate dihydrochloride (0.26 g) was dissolved in methylene chloride (20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), and the layers were separated. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -6-oxo-1-[[1- (4-pyridinyl) -4-piperidinyl ] Amino] -2-piperazine carboxylate was obtained. This product was dissolved in 37% aqueous formaldehyde solution (3.1 ml) and formic acid (1.6 ml) and refluxed for 2 hours. After cooling, the reaction mixture was made alkaline by adding saturated aqueous sodium hydrogen carbonate, extracted with dichloromethane, dried and concentrated. The resulting residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give pale yellow oily methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (4-Pyridinyl) -4-piperidinyl] amino] -6-oxo-2-piperazinecarboxylate was obtained. Dissolve the product in methanol (2 ml) and add 4N hydrochloric acid in ethyl acetate
(0.15 ml), concentrated under reduced pressure, and dried to give the title compound (0.15 g) as a colorless amorphous powder. ¹ H-NMR (CD ₃ OD) δ: 1.20-1.50 (2H, m), 1.70-2.12 (2
H, m), 2.85-3.70 (5H, m), 2.94 (3H, s), 3.74 (3H,
s), 3.90-4.50 (5H, m), 7.07 (2H, d, J = 7.6 Hz),
7.66 (1H, dd, J = 2.2, 8.8 Hz), 7.84 (1H, dd, J =
1.6, 8.8 Hz), 7.98-8.18 (5H, m), 8.47 (1H, s).

Example 55 1- (2-Chloroethyl) -4- [4- [4- (6-chloronaphthalene chloride)
2-scan Ruhoniru) -2-oxo-1-piperazinyl amino] - 1-Pi
Peridinyl] pyridinium 1-amino-4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (33.98 g) and 1- (4-pyridyl) -4-piperidone (18.50 g) in ethanol (1 l) The 1,2-dichloroethane (300 ml) solution was refluxed for 3 days while dehydrating using a Soxhlet filled with Molecular Sieves 4A. After removing the insoluble matter by filtration, the residue obtained by concentrating the reaction solution was dissolved in methanol (1 l), acetic acid (33.82 g) was added under ice-cooling, and then sodium cyanoborohydride (17.06 g) was added. ) Was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated, the residue is dissolved in dichloromethane, washed with aqueous sodium bicarbonate and brine, dried, concentrated, and silica gel column chromatography (dichloromethane: methanol = 20: 1 to dichloromethane: methanol: triethylamine = 40: 2: 1). ) And basic silica gel column chromatography (tetrahydrofuran to methanol) to give a colorless amorphous title compound (30
g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.14-1.20 (2H, m), 1.65-1.73
(2H, m), 2.39-2.59 (2H, m), 3.17-3.24 (3H, m), 3.43
(4H, m), 3.76 (2H, s), 4.01-4.07 (2H, m), 4.50 (2
H, m), 5.61 (1H, m), 7.22 (2H, d, J = 8.0Hz), 7.75
(1H, d, J = 8.8Hz), 7.90 (1H, d, J = 9.2Hz), 8.20 (1H,
d, J = 9.2Hz), 8.22-8.28 (4H, m), 8.62 (1H, s).

Example 56 N- [4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1-
Piperazinyl] -1- (4-pyrid) -4- piperidinecarboxamide key
Samide 1- (4-pyridinyl) -4-piperidinecarboxylic acid (103 mg),
To a solution of HOBt (153 mg) in DMF (25 ml) was added WSC (192 m
g) was added at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. 1-Amino-4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (170 mg) obtained in Example 3 was added to the reaction solution, and the mixture was stirred at room temperature for 2 days. The residue obtained by concentrating the reaction solution is partitioned by adding dichloromethane and aqueous sodium bicarbonate, the organic layer is washed with saturated aqueous sodium bicarbonate, dried and concentrated, and the residue obtained is subjected to basic silica gel column chromatography (dichloromethane to dichloromethane).
Purified with dichloromethane: methanol = 20: 1),
Crystallization from ethyl acetate / methanol gave the title compound (115 mg) as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.78-1.98 (4H, m), 2.40-2.47 (1
H, m), 2.86-2.98 (2H, m), 3.52-3.57 (2H, m), 3.69-
3.74 (2H, m), 3.84-3.88 (4H, m), 6.62 (2H, dd, J =
1.5, 5.1Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.78 (1
H, dd, J = 1.8, 8.6Hz), 7.92-7.96 (3H, m), 8.02 (1H,
br s), 8.22 (2H, dd, J = 1.4, 5.2Hz), 8.35 (1H, d,
J = 1.2Hz).

Example 57 4- (7-bromo-2,2-dimethyl-2H-benzopyran-3-sulfo
Nil) -1- [1- (4-pyridyl) -4-piperidinylamino] -2-pi
Perazinone In the same manner as in Example 15, 8-chloro-2,3-dihydrobenzo [b] oxepin-4-sulfonyl chloride was replaced with 7
-Bromo-2,2-dimethyl-2H-benzopyran-3-sulfonyl chloride (0.51 g) using colorless crystals of the title compound (0.36 g).
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.57 (2H, m), 1.62 (6H, s),
1.86-1.94 (2H, m), 2.87-3.00 (2H, m), 3.20-3.35
(1H, m), 3.63 (4H, br s), 3.81-3.89 (2H, m), 3.96
(2H, s), 5.18 (1H, d, J = 5.2Hz), 6.65 (2H, d, J = 6.6
Hz), 7.05-7.16 (3H, m), 7.38 (1H, s), 8.26 (2H, d,
J = 6.6Hz) .IR (KBr): 2940, 1651, 1595, 1560, 1539, 1514, 148
0, 1416 cm ^-1 .

Example 58 4- (7-Bromo-2,2-dimethyl-2H-benzopyran-3-sulfo
Yl) - 1- {methyl [1- (4-pyridyl) -4-piperidin le] ami
Roh} -2 Pipera in Zinon Example 38 (C method) In a manner analogous to that of 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylamino 4- (7-bromo-2,
2-dimethyl-2H-benzopyran-3-sulfonyl) -1- [1- (4-
Pyridyl) -4-piperidinylamino] -2-piperazinone (15
0 mg) to give the title compound (78 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.60 (2H, m), 1.62 (6H,
s), 1.80-2.00 (2H, m), 2.83 (3H, s), 2.83-2.96 (2
H, m), 3.40-3.70 (5H, m), 3.80-3.95 (4H, m), 6.65
(2H, d, J = 6.6Hz), 7.05-7.16 (3H, m), 7.38 (1H, s),
8.25 (2H, d, J = 6.6Hz) .IR (KBr): 2926, 1667, 1597, 1560, 1512, 1480, 1416
cm ^-1 .

Example 59 4- (6-bromonaphthalene-2-sulfonyl) -1- {ethyl [1- (4
- pyridyl) -4-piperidinyl] amino} -2-piperazino in emissions Example 43 In a manner analogous to that of the title compound as colorless crystals (22
6 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.2Hz), 1.28-1.4
6 (2H, m), 1.60-1.66 (1H, m), 1.89-1.95 (1H, m),
2.67-2.96 (3H, m), 3.21-3.46 (6H, m), 3.66-3.91 (4
H, m), 6.59 (2H, d, J = 6.6Hz), 7.75 (1H, dd, J = 8.
8, 1.8Hz), 7.81 (1H, dd, J = 8.8, 2.0Hz), 7.89 (1H,
d, J = 8.8Hz), 7.95 (1H, d, J = 8.8Hz), 8.14 (1H,
s), 8.25 (2H, d, J = 6.6Hz), 8.35 (1H, s) .IR (KBr): 2969, 1667, 1595, 1510, 1454, 1416 cm ^-1 .

Example 60 4- (6-chloronaphthalene-2-sulfonyl) -1- {ethyl [1- (4
- pyridyl) -4-piperidinyl] amino} -2-piperazino emissions salt
In the same manner as in Example 39, 4- (6-chloronaphthalene-2-
The title compound (3.04 g) was obtained as colorless crystals using (sulfonyl) -1- {ethyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (2.89 g). ¹ H-NMR (DMSO-d ₆ ) δ: 0.81 (3H, t, J = 7.0Hz), 1.05-
1.30 (2H, m), 1.64-1.71 (1H, m), 1.86-1.92 (1H, m),
2.68-2.84 (1H, m), 2.97-3.15 (3H, m), 3.34-3.41
(6H, m), 3.79 (1H, s), 3.94-4.12 (2H, m), 7.11 (2
H, d, J = 7.6Hz), 7.76 (1H, dd, J = 8.8, 2.0Hz), 7.92
(1H, dd, J = 8.8, 2.0Hz), 8.19-8.33 (4H, m), 8.63 (1
H, s), 13.52 (1 H, br s).

Example 61 Ethyl {[4- (6-chloronaphthalene-2-sulfonyl) -2-o
Kiso -1-piperazinyl] [1- (4-pyridyl) -4-piperidyl two
L] amino} acetate 1-{[1- (tert-butoxycarbonyl) piperidinyl] amino} -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (523 mg) obtained in Reference Example 11; Ethyl iodoacetate (2.14 g), potassium carbonate (166 mg) and 1-methyl-
A mixture of 2-pyrrolidone (10 ml) was added under argon atmosphere for 8 hours.
Stirred at 0 ° C. for 40 hours. Water was added to the residue obtained by concentrating the reaction solution, extracted with ethyl acetate, dried and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: acetone = 2: 1) to be colorless. Crystalline ethyl {[1- (tert-butoxycarbonyl) -4-piperidinyl] [4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1
[Piperazinyl] amino} acetate (479 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2Hz), 1.19-1.4
0 (2H, m), 1.44 (9H, s), 1.57-1.80 (2H, m), 2.58-
2.71 (2H, m), 3.05-3.30 (1H, br), 3.35-4.15 (12H,
m), 7.61 (1H, dd, J = 8.8, 1.8Hz), 7.78 (1H, dd, J
= 8.8, 1.8Hz), 7.94 (1H, d, J = 1.8Hz), 7.95 (1H, d,
J = 8.8Hz), 8.34 (1H, d, J = 1.8Hz). IR (KBr): 2980, 2920, 1746, 1688, 1454, 1420 cm ^-1 . Hereinafter, the same as Example 38 (Method A) By the way, ethyl
{[1- (tert-butoxycarbonyl) -4-piperidinyl] [4- (6
-Chloronaphthalene-2-sulfonyl) -2-oxo-1-piperazinyl] amino} acetate (450 mg) gave the title compound (80 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.2Hz), 1.39-1.4
9 (2H, m), 1.60-1.67 (1H, m), 1.85-1.92 (1H, m),
2.69-2.88 (3H, m), 3.08-3.19 (1H, m), 3.50-4.13 (1
2H, m), 6.60 (2H, d, J = 6.6Hz), 7.62 (1H, dd, J = 8.
8, 1.8Hz), 7.80 (1H, dd, J = 8.8, 1.8Hz), 7.93-7.98
(3H, m), 8.25 (2H, d, J = 6.6Hz), 8.35 (1H, s) .IR (KBr): 2940, 1744, 1653, 1595, 1541, 1348, 1165
cm ^-1 .

Example 62 4- (6-Chloronaphthalene-2-sulfonyl) -1- {methyl [1-
(2,3,5,6-tetrafluoro-4-pyridyl) -4-piperidini
Le] amino} -2-piperazinone obtained in Reference Example 21 4- (6-chloronaphthalene-2-sulfonyl) -1- [methyl (4-piperidinyl) amino] -2-piperazinone hydrochloride (236 mg) , Pentafluoropyridine (16
9 mg), triethylamine (202 mg) and DMF (8 ml)
Was added and reacted at 100 ° C. for 2 hours under an argon atmosphere. The reaction solution was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, extracted with dichloromethane, dried and concentrated.
The obtained residue was crystallized from diethyl ether to give the title compound (208 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.50 (2H, m), 1.59-2.02 (2
H, m), 2.72 (3H, s), 3.00-3.25 (2H, m), 3.35-3.75
(7H, m), 3.77 (2H, s), 7.61 (1H, dd, J = 8.8,1.8H
z), 7.80 (1H, dd, J = 8.8, 1.8Hz), 7.93-7.97 (3H,
m), 8.36 (1H, d, J = 1.8Hz) .IR (KBr): 2930, 2855, 1667, 1638, 1532, 1476, 1418
cm ^-1 .

Example 63 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (2
-Methyl-4-pyridyl) -4-piperidinyl] amino} -2-pipe
Rajinon obtained in Reference Example 21 4- (6-chloronaphthalene-2-sulfonyl) -1- in the methyl (4-piperidinyl) amino] -2-piperazinone hydrochloride (945 mg), 4-chloro-2- Picolin (510 m
g), triethylamine (1.21 g) and ethanol (2
0 ml) and reacted at 150 ° C. for 8 hours in a sealed tube. The reaction solution was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, extracted with dichloromethane, dried and concentrated. The obtained residue is subjected to column chromatography (dichloromethane:
Purification was performed using methanol containing 10% ammonia water (15: 1), and the mixture was crystallized from ethyl acetate-ethanol to give the title compound (764 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.45 (2H, m), 1.78-2.05 (2
H, m), 2.67 (3H, s), 2.72 (3H, s), 3.05-3.17 (2H,
m), 3.25-3.55 (4H, m), 3.65-4.00 (5H, m), 6.54 (1
H, d, J = 1.8Hz), 6.66 (1H, dd, J = 7.2, 1.8Hz), 7.62
(1H, dd, J = 8.8,1.6Hz), 7.80 (1H, dd, J = 8.8, 1.6
Hz), 7.96 (2H, d, J = 8.8Hz), 7.96 (1H, d, J = 1.6H
z), 8.02 (1H, d, J = 7.2Hz), 8.36 (1H, s) .IR (KBr): 2894, 1642, 1611, 1541, 1456, 1416 cm ^-1 .

Example 64 4- (6-Chloronaphthalene-2-sulfonyl) -1- {methyl [1- (2
-Methyl-4-pyridyl) -4-piperidinyl] amino} -2-pipe
Radidinone hydrochloride In the same manner as in Example 39, 4- (6-chloronaphthalene-2-
The title compound (493 mg) was obtained as colorless crystals from (sulfonyl) -1- {methyl [1- (2-methyl-4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (528 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.28-1.46 (2H, m), 1.80-2.05
(2H, m), 2.68 (3H, s), 2.72 (3H, s), 3.06-3.19 (2H,
m), 3.30-3.60 (4H, m), 3.64-4.02 (5H, m), 6.56 (1
H, s), 6.63-6.68 (1H, m), 7.63 (1H, dd, J = 8.8, 2.
0Hz), 7.81 (1H, dd, J = 8.8, 1.8Hz), 7.97 (2H, d, J
= 8.8Hz), 7.97 (1H, d, J = 2.0 Hz), 7.99-8.04 (1H,
m), 8.37 (1H, s), 15.40 (1H, br s) .IR (KBr): 3054, 2921, 1642, 1611, 1541, 1456, 1418
cm ^-1 .

Example 65 4- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-ethyl
Le-4-pyridyl) -4-piperidyl sulfonyl] methylamino} -2-piperazinyl
The title compound (135 mg) as colorless crystals was obtained in the same manner as in Example 63 of radinone and using 4-bromo-2-ethylpyridine (186 mg) instead of 4-chloro-2-picoline. ¹ H-NMR (CDCl ₃ ) δ: 1.23-1.40 (2H, m), 1.27 (3H, t,
J = 7.6Hz), 1.55-1.70 (1H, m), 1.80-1.95 (1H, m),
2.70 (2H, q, J = 7.6Hz), 2.71 (3H, s), 2.71-2.90 (2
H, m), 3.35-3.90 (9H, m), 6.45 (1H, dd, J = 5.8, 2.6
Hz), 6.49 (1H, d, J = 2.6Hz), 7.62 (1H, dd, J = 8.8,
2.0Hz), 7.80 (1H, dd, J = 8.8, 2.0Hz), 7.95 (2H, d,
J = 8.8Hz), 7.95 (1H, d, J = 2.0Hz), 8.18 (1H, d, J
= 5.8Hz), 8.36 (1H, d, J = 2.0Hz) .IR (KBr): 2922, 1667, 1597, 1547, 1495, 1454, 1416
cm ^-1 .

Example 66 1-{[1- (2-Amino-4-pyridyl) -4-piperidinyl] methyl
Arylamino} -4- (6-Kuroronafu array type 2-sulfonyl) -2-Hoon
Perazinone In the same manner as in Example 63, colorless crystals of the title compound (78 mg) were obtained using 2-amino-4-chloropyridine (129 mg) instead of 4-chloro-2-picoline. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.38 (2H, m), 1.55-1.90
(2H, m), 2.65-2.82 (2H, m), 2.70 (3H, s), 3.37-3.78
(9H, m), 4.26 (2H, br s), 5.79 (1H, d, J = 2.2Hz),
6.12 (1H, dd, J = 6.2, 2.2Hz), 7.62 (1H, dd, J = 8.8,
2.0Hz), 7.78 (1H, d, J = 6.2Hz), 7.81 (1H, dd, J = 8.
8, 2.0Hz), 7.95 (2H, d, J = 8.8Hz), 7.96 (1H, d, J
= 2.0Hz), 8.37 (1H, s) .IR (KBr): 2951, 1661, 1603, 1541, 1507, 1495, 145
6, 1417 cm ^-1 .

Example 67 4- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-hydrido
Rokishime chill-4-pyridyl) -4-piperidinyl] Mechiruami
{} -2-Piperazinone In the same manner as in Example 63, (4-chloro-2-pyridyl) methanol (287 mg) was used instead of 4-chloro-2-picoline to give the title compound as colorless crystals (240 mg ) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.56-1.78 (1
H, m), 1.82-2.00 (1H, m), 2.71 (3H, s), 2.80-2.98
(2H, m), 3.32-3.88 (10H, m), 4.65 (2H, s), 6.54-6.
56 (2H, m), 7.63 (1H, dd, J = 8.8, 2.0Hz), 7.81 (1
H, dd, J = 8.8, 2.0Hz), 7.96 (2H, d, J = 8.8Hz), 7.9
6 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 5.4Hz), 8.36
(1H, d, J = 2.0 Hz). IR (KBr): 2930, 1663, 1601, 1541, 1491, 1456, 1418
cm ^-1 .

Example 68 4- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-hydr
Rokishime chill-4-pyridyl) -4-piperidinyl] Mechiruami
{} -2-Piperazinone hydrochloride In the same manner as in Example 39, 4- (6-chloronaphthalene-2-
Sulfonyl) -1- {methyl [1- (2-hydroxymethyl-4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (240 m
g) to give the title compound (255 mg) as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.02-1.20 (2H, m), 1.62-1.85
(2H, m), 2.54 (3H, s), 3.00-3.41 (7H, m), 3.74 (2H,
s), 3.90-4.10 (2H, m), 4.61 (2H, s), 6.19 (1H, br
s), 7.01-7.08 (2H, m), 7.77 (1H, dd, J = 8.8, 2.0H
z), 7.92 (1H, dd, J = 8.8, 1.8Hz), 8.11 (1H, t, J =
6.0Hz), 8.22 (1H, d, J = 8.8Hz), 8.31 (1H, d, J = 2.
0 Hz), 8.31 (1H, d, J = 8.8Hz), 8.63 (1H, s), 13.44
(1H, br s). IR (KBr): 3150, 1680, 1645, 1590, 1545, 1460 cm ^-1 .

Example 69 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (3
-Methyl-4-pyridyl) -4-piperidinyl] amino} -2-pipe
The title compound (98 mg) as colorless crystals was obtained in the same manner as in the case of radinone Example 63, except that 4-chloro-3-picoline hydrochloride (328 mg) was used instead of 4-chloro-2-picoline. ¹ H-NMR (CDCl ₃ ) δ: 1.36-1.55 (2H, m), 1.69-1.95 (2
H, m), 2.20 (3H, s), 2.56-2.69 (2H, m), 2.73 (3H,
s), 3.15-3.27 (2H, m), 3.38-3.60 (5H, m), 3.77 (2
H, s), 6.72 (1H, d, J = 5.6Hz), 7.61 (1H, dd, J = 8.
8, 2.0Hz), 7.80 (1H, dd, J = 8.8, 1.8Hz), 7.93-7.97
(3H, m), 8.25 (1H, s), 8.27 (1H, d, J = 5.6Hz), 8.3
6 (1H, s). IR (KBr): 2953, 2922, 1667, 1588, 1493, 1456, 1418
cm ^-1 .

Example 70 4- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2,3-di
Methyl-4-pyridyl) -4-pin Perijiniru] methylamino} -2-
Piperazinone In the same manner as in Example 63, the title compound (156 mg) was obtained as colorless crystals using 4-chloro-2,3-dimethylpyridine (283 mg) instead of 4-chloro-2-picoline. ¹ H-NMR (CDCl ₃ ) δ: 1.37-1.57 (2H, m), 1.68-1.76
(H, m), 1.87-1.97 (1H, m), 2.13 (3H, s), 2.49 (3H,
s), 2.54-2.67 (2H, m), 2.73 (3h, s), 3.06-3.20 (2
H, m), 3.36-3.56 (5H, m), 3.77 (2H, s), 6.67 (1H,
d, J = 6.0Hz), 7.61 (1H, dd, J = 8.8, 2.0Hz), 7.81 (1
H, dd, J = 8.8, 2.0Hz), 7.93-7.97 (3H, m), 8.19 (1
H, d, J = 6.0Hz), 8.36 (1H, s) .IR (KBr): 2951, 1624, 1580, 1476, 1456, 1418 cm ^-1 .

Example 71 4- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2,6-di
Methyl-4-pyridyl) -4-pin Perijiniru] methylamino} -2-
Piperazinone hydrochloride In the same manner as in Example 63 and Example 39, 4-chloro-2
-The title compound (187 mg) as colorless crystals using 4-chloro-2,6-dimethylpyridine hydrochloride (356 mg) instead of -picoline
I got ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.21 (2H, m), 1.60-1.90
(2H, m), 2.42 (6H, s), 2.53 (3H, s), 3.00-3.40 (4H,
m), 3.73 (2H, s), 3.90-4.25 (5H, m), 6.90 (2H, s),
7.76 (1H, dd, J = 8.8, 2.0Hz), 7.92 (1H, dd, J = 8.
8, 1.8Hz), 8.22 (1H, d, J = 8.8Hz), 8.29-8.33 (2H,
m), 8.63 (1H, s), 13.32 (1H, br s) .IR (KBr): 3393,
2928, 1636, 1539, 1456, 1418 cm ^-1 .

Example 72 4- (6-Chloronaphthalene-2-sulfonyl) -1- {[1- (2-ethoxy
Kishikaru Boniru-4-pyridyl) -4-piperidinyl] Mechirua
Mino} -2-piperazinone In the same manner as in Example 63, methyl 4-chloropyridine-2-carboxylate hydrochloride (2
08 mg) to give the title compound (57 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.40 (2H,
m), 1.44 (3H, t, J = 7.2H
z), 1.60-1.72 (1H, m), 1.
83-1.95 (1H, m), 2.72 (3
H, s), 2.75-2.97 (2H, m),
3.32-3.62 (5H, m), 3.70-
3.92 (4H, m), 4.45 (2H,
q, J = 7.2 Hz), 6.70 (1H, d
d, J = 6.0, 2.8 Hz), 7.51 (1
H, d, J = 2.8 Hz), 7.63 (1
H, dd, J = 8.8, 1.8 Hz), 7.
81 (1H, dd, J = 8.8, 1.8H
z), 7.94-7.98 (3H, m), 8.
35-8.37 (2H, m). IR (KBr): 2932, 1715, 166
7, 1595, 1541, 1495, 145
4, 1418 cm ^-1 .

Example 73 4- (6-chloronaphthalene- 2-sulfonyl) -1-{[1- (2-
Methoxycarbonyl-4-pyridyl) -4-piperidinyl] meth
Rua Mino} -2 in piperazinone Example 63 In a manner analogous to that of 4-chloro-2-picoline with 4-chloropyridine-2-carboxylate hydrochloride (1.08 g) instead of methanol instead of ethanol Was used to give the title compound (325 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.58-1.75 (1
H, m), 1.88-1.95 (1H, m), 2.72 (3H, s), 2.80-2.95
(2H, m), 3.39-3.62 (5H, m), 3.65-3.92 (4H, m), 3.9
8 (3H, s), 6.70 (1H, dd, J = 6.0, 2.8Hz), 7.51 (1H,
d, J = 2.8Hz), 7.63 (1H, dd, J = 8.8, 1.8Hz), 7.81
(1H, dd, J = 8.8, 1.8Hz), 7.94-7.98 (3H, m), 8.33-8.
36 (2H, m) .IR (KBr): 2926, 1725, 1669, 1597, 1543, 1497, 145
6, 1420 cm ^-1 .

Example 74 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4
- quinolinyl) -4-piperidinyl] amino} -2-piperazine obtained in non Reference Example 21 4- (6-chloronaphthalene-2-sulfonyl) -1- [methyl (4-piperidinyl) amino] -2-piperazinone Hydrochloride (236 mg) was added to 4-chloroquinoline (164 m
g), 4-dimethylaminopyridine (244 mg) and xylene (15 ml) were added, and the mixture was heated under reflux for 15 hours. The reaction solution was concentrated, and a 10% aqueous sodium carbonate solution was added to the residue.
The mixture was extracted with dichloromethane, dried and concentrated. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 15: 1), and diisopropyl ether-
Crystallization from isopropyl alcohol gave the title compound (46 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.53-1.73 (2H, m), 1.70-1.92 (1
H, m), 1.96-2.12 (1H, m), 2.77 (3H, s), 2.90-3.10
(2H, m), 3.33-3.77 (7H, m), 3.79 (2H, d, J = 4.8Hz),
6.81 (1H, d, J = 6.0Hz), 7.49-7.57 (1H, m), 7.61 (1
H, dd, J = 8.4, 2.2Hz), 7.70-7.83 (2H, m), 7.91-7.9
8 (4H, m), 8.27-8.33 (1H, m), 8.37 (1H, s), 8.62
(1H, d, J = 6.0Hz). IR (KBr): 2928, 1669, 1580, 1507, 1456, 1418 cm ^-1 .

Example 75 1-{[1- (2-Amino-4-pyridyl) -4-piperidinyl] methyl
Amino} -4- (6-Kuroronafutare emission-2-sulfonyl) -2-piperazinyl
Radinone hydrochloride In the same manner as in Example 39, 1-{[1- (2-amino-4-pyridyl) -4-piperidinyl] methylamino} -4- (6-chloronaphthalene-2-sulfonyl) -2 The title compound (224 mg) was obtained as colorless crystals from -piperazinone (200 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (2H, m), 1.54 (1H, m),
1.75 (1H, m), 2.52 (3H, s), 2.80-3.85 (11H, m), 5.9
5 (1H, s), 6.44 (1H, d, J = 7.2Hz), 7.17 (2H, brs),
7.60 (1H, dd, J = 5.8, 7.2Hz), 7.76 (1H, dd, J = 8.
8, 1.8Hz), 7.92 (1H, dd, J = 8.8, 2.0Hz), 8.21 (1H,
d, J = 8.8Hz), 8.30 (1H, d, J = 8.8Hz), 8.31 (1H, d,
J = 1.8Hz), 8.62 (1H, s), 12.25 (1H, brs).

Example 76 4- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-methyl
Arylamino-4-pyridyl) -4-pin Perijiniru] methylamino} -
2-Piperazinone In the same manner as in Example 63, 4-chloro-2-methylaminopyridine hydrochloride (223 m
The title compound (300 mg) was obtained as colorless crystals using g). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (2H, m), 1.62 (1H, m), 1.8
4 (1H, m), 2.71 (3H, s), 2.78 (2H, m), 2.87 (3H,
d, J = 5.2Hz), 3.30-3.90 (9H, m), 4.66 (1H, brq, J =
5.2Hz), 5.64 (1H, d, J = 2.2Hz), 6.07 (1H, dd, J = 6.
4, 2.2Hz), 7.62 (1H, dd, J = 8.8, 1.8Hz), 7.77 (1H,
d, J = 6.4Hz), 7.80 (1H, dd, J = 8.8, 1.8Hz), 7.90-
8.00 (3H, m), 8.35 (1H, s).

Embodiment 774- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-
Chilami No-4-pyridyl) -4-piperidinyl] methylami
No} -2-piperazinone In the same manner as in Example 63, 4-chloro-2-picoline was substituted for 4-chloro-2-picoline.
Instead, 4-chloro-2-dimethylaminopyridine hydrochloride (306
 mg) to give the title compound (130 mg) as a colorless solid.¹ H-NMR (CDCl_Three) δ: 1.32 (2H, m), 1.63 (1H, m), 1.8
6 (1H, m), 2.71 (3H, s), 2.80 (2H, m), 3.05 (6H,
s), 3.30-3.85 (9H, m), 5.75 (1H, d, J = 2.2Hz), 6.06
(1H, dd, J = 6.2, 2.2Hz), 7.61 (1H, dd, J = 8.8, 1.8H
z), 7.80 (1H, dd, J = 8.8, 1.8Hz), 7.88-8.00 (4H,
m), 8.35 (1H, s).

Example 78 4- (6-Chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridiyl)
L) -4-Piperidinylamino] -2-thioxopiperazine 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylamino] -2- Piperazinone (200 mg)
To a pyridine (10 ml) solution was added phosphorus pentasulfide (80 mg), and the mixture was stirred at 100 ° C. for 5 hours. The supernatant of the reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol containing 10% ammonia = 2).
0: 1) to give the title compound as a colorless solid (35 mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 1.51 (2H, m), 1.76 (2H, m), 2.8
2 (2H, m), 3.25 (1H, m), 3.58 (2H, m), 3.70-3.85
(4H, m), 4.36 (2H, s), 6.61 (2H, d, J = 6.6Hz), 6.73
(1H, d, J = 6.6Hz), 7.62 (1H, dd, J = 1.8, 8.8Hz), 7.8
1 (1H, dd, J = 1.8, 8.8Hz), 7.90-8.00 (3H, m), 8.26
(2H, d, J = 6.6Hz), 8.39 (1H, s) .IR (KBr): 1595, 1337, 1163 cm ^-1 .

Example 79 4- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (4-pyr
(Jill) -4-piperidinyl] (2,2,2-trifluoroethyl) a
Mino} -2-piperazinone In a similar manner to Example 43 (Method B), 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylamino] Using trifluoroacetic acid (5 ml) instead of -2-piperazinone (200 mg) and acetic acid, the title compound (37 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (2H, m),
1.64 (1H, m), 1.87 (1H, m), 2.76 (2H, m), 3.15 (1
H, m), 3.30-3.95 (9H, m), 4.04 (1H, d, J = 16.4Hz),
6.61 (2H, d, J = 6.6Hz), 7.63 (1H, dd, J = 1.8, 8.8Hz),
7.80 (1H, dd, J = 1.8, 8.8Hz), 7.90-8.00 (3H, m),
8.27 (2H, d, J = 6.6Hz), 8.37 (1H, s) .IR (KBr): 1669, 1597, 1348, 1273, 1161 cm ^-1 .

Example 80 4- (6-chloronaphthalene-2-sulfonyl) -1- {(2-methoxy
Ethyl) [1- (4-pyridyl) -4-piperidinyl] amino} -2-
Piperazinone In a similar manner to Example 43 (Method B), 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylamino] -2-piperazinone ( 200 mg) and methoxyacetic acid (4 ml) in place of acetic acid to give the title compound (1
23 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.36 (2H, m), 1.60 (1H, m), 1.9
0 (1H, m), 2.75 (2H, m), 3.09 (1H, m), 3.24 (3H,
s), 3.25-3.90 (11H, m), 3.91 (1H, d, J = 17.0Hz), 6.
58 (2H, d, J = 6.6Hz), 7.62 (1H, dd, J = 1.8, 8.8Hz),
7.81 (1H, dd, J = 1.8, 8.8Hz), 7.90-8.00 (3H, m), 8.
24 (2H, d, J = 6.6Hz), 8.36 (1H, s). IR (KBr): 1663, 1595, 1348, 1165 cm ^-1 .

Example 81 (3S) -3- (6-chloronaphthalene-2-sulfonylamino) -1-
[1- (4-pyridyl) -4-piperidinylideneamino] -2-pyrroli
Don (3S) -1-amino-3- (6-chloronaphthalene-2-sulfonylamino) -2-pyrrolidone (1.84 g) and 1- (4-pyridyl)-
A solution of 4-piperidone (560 mg) in ethanol (50 ml)
The mixture was refluxed for 15 hours while being dehydrated using a Soxhlet filled with Molecular Sieves 4A. The reaction solution was concentrated and crystallized from ethyl acetate to give the title compound (6
50 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.17 (1H, m),
2.38-2.70 (5H, m), 3.40-
3.80 (6H, m), 3.95 (1H, d
d, J = 8.4, 9.4 Hz), 6.68 (2
H, d, J = 6.6 Hz), 7.53 (1H,
dd, J = 1.8, 8.8 Hz), 7.80 −
8.00 (4H, m), 8.26 (2H,
d, J = 6.6 Hz), 8.46 (1H,
s).

[0155] Example 82 (3S) -3- (6- Chloro-2-sulfonyl Le
Amino) -1- [1- (4 -pyridyl) -4-piperidinylamino] -2-
Pyrrolidone (3S) -3- (6- chloronaphthalene-2-sulfonyl) -1-
[1- (4-Pyridyl) -4-piperidinylideneamino] -2-pyrrolidone (600 mg) was dissolved in methanol (40 ml), and acetic acid (761 mg) was added under ice-cooling. Sodium borohydride (300 mg) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, an aqueous solution of sodium carbonate was added to the residue, extracted with dichloromethane, dried, concentrated, purified by column chromatography (dichloromethane: methanol containing 10% aqueous ammonia = 20: 1), and crystallized from ethyl acetate. The title compound (576 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.82 (2H, m), 2.1
1 (1H, m), 2.58 (1H, m), 2.89 (2H, m), 3.17 (1H, m
m), 3.37-3.50 (2H, m), 3.70-3.85 (3H, m), 4.41 (1
H, br), 6.62 (2H, d, J = 6.6Hz), 7.57 (1H, dd, J = 2.
0, 8.8Hz), 7.90-7.96 (4H, m), 8.24 (2H, d, J = 6.6H
z), 8.46 (1H, s) .IR (KBr): 1696, 1601, 1514, 1327, 1157 cm ^-1 .

Example 83 (3S) -3- (6-Chloronaphthalene-2-sulfonylamino) -1-
{Methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-pi
Loridone (3S) -3- (6-chloronaphthalene-2-sulfonylamino) -1-
[1- (4-pyridyl) -4-piperidinylamino] -2-pyrrolidone
(400 mg) was dissolved in a 37% aqueous formaldehyde solution (11 ml) and formic acid (5 ml) and refluxed for 3 hours. After cooling, the reaction solution was made alkaline by adding an aqueous solution of sodium carbonate, extracted with dichloromethane, dried and concentrated. The residue was purified by column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1) and crystallized from dichloromethane to give the title compound as colorless crystals.
(180 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.49 (2H, m), 1.80 (2H, m), 2.1
0 (1H, m), 2.59 (1H, m), 2.67 (3H, s), 2.86 (2H,
m), 3.17 (1H, m), 3.30-3.40 (2H, m), 3.67 (1H, dd,
J = 7.8, 10.4Hz), 3.80 (2H, m), 6.61 (2H, d, J = 6.6H
z), 7.58 (1H, dd, J = 1.8, 8.8Hz), 7.90-8.00 (4H, m),
8.24 (2H, d, J = 6.6Hz), 8.46 (1H, s) .IR (KBr): 170
3, 1599, 1514, 1325, 1159 cm ^-1 .

Example 84 (3S) -3- [6-Chloronaphthalene-2-sulfonyl) methylamido
[No] -1- [1- (4-pyridyl) -4-piperidinylamino] -2 -pyro
Lidone (3S) -3- (6-chloronaphthalene-2-sulfonylamino) -1-
[1- (4-pyridyl) -4-piperidinylamino] -2-pyrrolidone
To a solution of (150 mg) in DMF (11 ml) was added dimethylformaldehyde dimethyl acetal (5 ml), and the mixture was stirred at 100 ° C for 2 hours. The reaction solution is concentrated, and the residue is purified by column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1) to give the title compound as a colorless solid
(100 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (2H, m), 1.84 (2H, m), 2.0
9 (1H, m), 2.42 (1H, m), 2.80 (3H, s), 2.90 (2H,
m), 3.17 (1H, m), 3.35-3.60 (2H, m), 3.81 (2H, m),
4.50 (1H, t, J = 5.2Hz), 4.90 (1H, t, J = 9.0Hz), 6.6
3 (2H, d, J = 6.6Hz), 7.54 (1H, dd, J = 2.0, 8.8Hz),
7.85-8.00 (4H, m), 8.25 (2H, d, J = 6.6Hz), 8.51 (1
H, s).

[0158] Example 85 (3R) -3- (6- chloro-naphthalene-2-sulfonyl) -1-
[1- (4-pyridyl) -4 Piperi Jiniruamino] in the same manner as 2-pyrrolidone Example 82, the title compound was obtained as colorless crystals using (3R) body in place of (3S) body. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (2H, m),
1.82 (2H, m), 2.11 (1H,
m), 2.58 (1H, m), 2.89 (2
H, m), 3.17 (1H, m), 3.37
-3.50 (2H, m), 3.70-3.85
(3H, m), 4.41 (1H, br),
6.62 (2H, d, J = 6.6 Hz);
57 (1H, dd, J = 2.0, 8.8H
z), 7.90-7.96 (4H, m), 8.
24 (2H, d, J = 6.6 Hz), 8.46
(1H, s). IR (KBr): 1682, 1599, 151
4, 1329, 1159 cm ^-1 .

[0159] Example 86 (3S) -3- (7- methoxyethanol naphthalene-2-sulfonyl
Arylamino) -1- [1- (4-pyridyl) -4 Piperi Jiniruamino -
2-pyrrolidone (3S) -3- (tert-butoxycarbonylamino) -1- [1- (4-pyridyl) -4-piperidinylamino] -2-pyrrolidone (220 mg)
To a methanol (10 ml) solution was added a 4N hydrochloric acid ethyl acetate solution (10 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, dichloromethane (20 ml) and triethylamine (700 mg) were added to the obtained residue, 7-methoxynaphthalene-2-sulfonyl chloride (150 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane, dried, concentrated and purified by column chromatography (dichloromethane: methanol containing 10% ammonia water = 20: 1) to give the title compound as a colorless amorphous (123 mg) I got ¹ H-NMR (CDCl ₃ ) δ: 1.43 (2H, m), 1.82 (2H, m), 2.1
0 (1H, m), 2.52 (1H, m), 2.89 (2H, m), 3.19 (1H, m
m), 3.30-3.50 (2H, m), 3.70-3.90 (3H, m), 3.94 (3
H, s), 4.40 (1H, br), 6.60 (2H, d, J = 6.6Hz), 7.24
(1H, d, J = 2.6Hz), 7.30 (1H, dd, J = 2.6, 9.0Hz), 7.74
(1H, dd, J = 1.8, 8.4Hz), 7.80 (1H, d, J = 9.0Hz), 7.
89 (1H, d, J = 8.4Hz), 8.22 (2H, d, J = 6.6Hz), 8.36
(1H, s). IR (KBr): 1696, 1599, 1510, 1325, 1256, 1217, 115
9, 1127 cm ^-1 .

Example 87 1- [1- (4-Pyridyl) -4-piperidinylamino]-(3S) -3- (4-
Like the vinyl-benzenesulfonylamino) -2-pyrrolidone Example 86, (3S) -3- (tert- butoxycarbonylamino) -1- [1- (4-pyridyl) -4-piperidinylamino] -
Using 2-pyrrolidone (220 mg) and 4-vinylbenzenesulfonyl chloride (105 mg), a colorless amorphous title compound (179 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.84 (2H, m), 2.1
0 (1H, m), 2.54 (1H, m), 2.91 (2H, m), 3.21 (1H, m
m), 3.38-3.50 (2H, m), 3.70-3.90 (3H, m), 4.44 (1
H, br), 5.45 (1H, d, J = 11.0Hz), 5.89 (1H, d, J = 17.
6Hz), 6.63 (2H, d, J = 6.6Hz), 6.76 (1H, dd, J = 11.0,
17.6Hz), 7.55 (2H, d, J = 8.4Hz), 7.88 (2H, d, J = 8.4
Hz), 8.25 (2H, d, J = 6.6Hz) .IR (KBr): 1703,1599, 1514, 1329, 1159 cm ^-1 .

Example 88 (3S) -3- (7-Bromo-2H-benzopyran-3 -sulfonylamido
ノ) -1- [1- (4-Pyridyl) -4-piperidinylamino] -2 -pyro
As in Ridon Example 86, (3S) -3- (tert-butoxycarbonylamino) -1- [1- (4-pyridyl) -4-piperidinylamino]-
2-pyrrolidone (220 mg) and 7-bromo-2H-benzopyran-3-
The colorless amorphous title compound (87 mg) was obtained using sulfonyl chloride (161 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.86 (2H, m), 2.0
7 (1H, m), 2.57 (1H, m), 2.94 (2H, m), 3.22 (1H, m
m), 3.35-3.55 (2H, m), 3.82 (2H, m), 4.00 (1H, dd,
J = 8.8, 9.8Hz), 4.35 (1H, br), 5.06 (2H, t, J = 1.5H
z), 6.65 (2H, d, J = 6.6Hz), 6.98-7.15 (3H, m), 7.28
(1H, s), 8.24 (2H, d, J = 6.6Hz) .IR (KBr): 1701, 1597, 1481, 1323, 1155, 1065 cm ^-1 .

Example 89 (3S) -3- (7-Chloronaphthalene-2-sulfonylamino) -1-
[1- (4-Pyridyl) -4-piperidinylamino] -2-pyrrolidone As in Example 86, (3S) -3- (tert-butoxycarbonylamino) -1- [1- (4-pyridyl) ) -4-Piperidinylamino]-
Colorless crystals of the title compound using 2-pyrrolidone (220 mg) and 7-chloronaphthalene-2-sulfonyl chloride (170 mg)
(88 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (2H, m),
1.83 (2H, m), 2.11 (1H,
m), 2.58 (1H, m), 2.92 (2
H, m), 3.19 (1H, m), 3.30
-3.50 (2H, m), 3.70-3.90
(3H, m), 4.40 (1H, br),
6.63 (2H, d, J = 6.6 Hz);
60 (1H, dd, J = 2.2, 8.8H
z), 7.83-8.02 (4H, m), 8.
24 (2H, d, J = 6.6 Hz), 8.39
(1H, s). IR (KBr): 1701, 1597, 154
0, 1319, 1157 cm ^-1 .

[0163] Example 90 (3S) -3- (4- chloro-styrene-beta (E) - sul Honi
Ruamino) -1- [1- (4-pyridyl) -4-piperidinylamino]-
Like the 2-pin pyrrolidone Example 86, (3S) -3- (tert- butoxycarbonylamino) -1- [1- (4-pyridyl) -4-piperidinylamino] -
Using 2-pyrrolidone (220 mg) and 4-chlorostyrene-β (E) -sulfonyl chloride (150 mg), a colorless amorphous title compound (161 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.86 (2H, m), 2.1
1 (1H, m), 2.60 (1H, m), 2.98 (2H, m), 3.24 (1H, m
m), 3.35-3.55 (2H, m), 3.82 (2H, m), 4.02 (1H, dd,
J = 8.4, 9.8Hz), 4.47 (1H, d, J = 5.2Hz), 6.63 (2H,
d, J = 6.6Hz), 6.91 (1H, d, J = 15.4Hz), 7.38 (2H, d, J
= 8.4Hz), 7.45 (2H, d, J = 8.4Hz), 7.48 (1H, d, J = 15.
4Hz), 8.24 (2H, d, J = 6.6Hz). IR (KBr): 1699, 1597, 1512, 1491, 1148 cm ^-1 .

Example 91 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (2-methyl
-4-pyridyl) -4-piperidin arylamino] -2-piperazinone Example 63 In a manner analogous to that of 4- (6-chloro-2-
4- (6-chloronaphthalene-2-) instead of sulfonyl) -1- [methyl (4-piperidinyl) amino] -2-piperazinone hydrochloride
Sulfonyl) -1- (4-piperidinylamino) -2-piperazinone dihydrochloride (495 mg) using colorless crystals of the title compound (320
mg). ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.38 (2H,
m), 1.63-1.69 (2H, m),
2.34 (3H, s), 2.64-2.78
(2H, m), 2.95-3.08 (1H,
m), 3.32-3.40 (2H, m),
48-3.53 (2H, m), 3.63-3.6
9 (2H, m), 3.76 (2H, s),
4.97 (2H, d, J = 4.8 Hz),
6.34-6.40 (2H, m), 7.52
(1H, dd, J = 8.8, 1.8 Hz),
7.71 (1H, dd, J = 8.8, 1.8
Hz), 7.85 (1H, d, J = 1.8H)
z), 7.85 (2H, d, J = 8.8H)
z), 8.05 (1H, d, J = 5.8H
z), 8.27 (1H, d, J = 1.8H
z). IR (KBr): 2930, 1655, 159
9, 1540, 1495, 1453, 1425
cm ^-1 .

Embodiment 924- (6-chloronaphthalene -2-sulfonyl) -1- [1- (2-
Methyl-4-pyridyl) -4-piperidinylamino] -2-pipera
Gino Dihydrochloride In the same manner as in Example 39, 4- (6-chloronaphthalene-2-
Sulfonyl) -1- [1- (2-methyl-4-pyridyl) -4-piperidi
Nylamino] -2-piperazinone (250 mg)
The title compound (277 mg) was obtained.¹ H-NMR (DMSO-d₆) δ: 1.10-1.30 (2H, m), 1.64-1.75
(2H, m), 2.44 (3H, s), 3.05-3.20 (3H, m), 3.44 (4H,
 s), 3.77 (2H, s), 3.94-4.01 (2H, m), 5.18 (2H, br
s), 6.99-7.03 (2H, m), 7.75 (1H, dd, J = 8.8, 2.0H
z), 7.91 (1H, dd, J = 8.8, 1.4Hz), 8.06-8.13 (1H,
m), 8.20 (1H, d, J = 8.8Hz), 8.28-8.32 (2H, m), 8.6
1 (1H, s), 13.50 (1H, brs) .IR (KBr): 3400, 2930, 1694, 1642, 1541, 1495, 1430
 cm^-1Example 934- (6-chloronaphthalene-2-sulfonyl) -1- [1- (3-pyridi
Ru) -4-Piperidinylideneamino] -2-piperazinone In the same manner as in Example 3, 1-amino-4- (6-chloronaphtha
(Len-2-sulfonyl) -2-piperazinone (510 mg) and 1
-(3-Pyridyl) -4-piperidone (260 mg) in toluene (20
 ml) The solution was refluxed for 7 hours. Cool the reaction to room temperature
The resulting crystals were collected by filtration and the title compound (480
mg).¹ H-NMR (CDCl_Three) δ: 2.25 (2H, t, J = 5.9Hz), 2.64
(2H, t, J = 5.8 Hz), 3.30 (2H, t, J = 5.8 Hz), 3.4
8-3.57 (4H, m), 3.65-3.71 (2H, m), 3.87 (2H, s), 7.
16-7.18 (2H, m), 7.62 (1H, dd, J = 1.8, 8.8 Hz),
7.82 (1H, dd, J = 1.9, 8.8 Hz), 7.93-7.98 (3H, m),
8.11 (1H, t, J = 3.0 Hz), 8.30 (1H, t, J = 1.8 Hz),
 8.38 (1H, d, J = 1.0 Hz). IR (KBr): 1661, 1346, 1163 cm^-1Example 944- (6-chloronaphthalene-2-sulfonyl) -1- [1- (3-pyridi
Ru) -4-piperidinylamino] -2-piperazinone In the same manner as in Example 11, 4- (6-chloronaphthalene-2-
Sulfonyl) -1- [1- (3-pyridyl) -4-piperidinylidenea
Mino] -2-piperazinone (420 mg) with cyanoborohydride
Reduction with sodium (53 mg) to give the title compound as colorless crystals
(330 mg) was obtained.¹ H-NMR (CDCl_Three) δ: 1.41-1.60 (2H, m), 1.73-1.98 (2
H, m), 2.68-2.81 (2H, m), 2.99-3.15 (1H, m), 3.45-
3.50 (2H, m), 3.58-3.66 (4H, m), 3.88 (2H, s), 5.1
2 (1H, d, J = 2.2 Hz), 7.13-7.15 (2H, m), 7.62 (1
H, dd, J = 2.2,8.8 Hz), 7.81 (1H, dd, J = 1.6, 8.6
 Hz), 7.93-7.97 (3H, m), 8.07 (1H, t, J = 2.9 Hz),
8.27 (1H, t, J = 1.8 Hz), 8.37 (1H, d, J = 1.6 H
z) .IR (KBr): 1651, 1346, 1163, 729, 698 cm^-1Example 954- (6-chloronaphthalene-2-sulfonyl) -1- {Methyl [1- (3
-Pyridyl) -4-piperidinyl] amino} -2-piperazino In In the same manner as in Method C of Example 38 and Example 39, 4-
(6-chloronaphthalene-2-sulfonyl) -1- [1- (3-pyridi
Ru) -4-Piperidinylamino] -2-piperazinone (280mg)
The title compound (220 mg) was obtained as colorless crystals.¹ H-NMR (DMSO-d₆) δ: 1.05-1.24 (2H, m), 1.51-1.59
(1H, m), 1.73-1.80 (1H, m), 2.54 (3H, s), 2.68-2.9
2 (2H, m), 3.17-3.88 (9H, m), 7.73-7.80 (2H, m), 7.
89-7.94 (2H, m), 8.13 (1H, d, J = 4.8 Hz), 8.21 (1
H, d, J = 8.8 Hz), 8.26-8.36 (3H, m), 8.62 (1H,
m). IR (KBr): 1690, 1557, 1343, 1155 cm^-1Example 964- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-meth
Kisimeti Ru-4-pyridyl) -4-piperidinyl] (methyl) a
Mino} -2-piperazinone In the same manner as in Example 63, 4-chloro-2-picoline was substituted for 4-chloro-2-picoline.
Instead, add 4-chloro-2-methoxymethylpyridine (0.27 g)
The title compound (230 mg) was obtained as colorless crystals by using the title compound.¹ H-NMR (CDCl_Three) δ: 1.33 (2H, m), 1.68 (1H, m), 1.8
5 (1H, m), 2.71 (3H, s), 2.81 (2H, m), 3.38-3.90
(9H, m), 3.47 (3H, s), 4.47 (2H, s), 6.50 (1H, dd,
 J = 6.1, 2.3Hz), 6.76 (1H, d, J = 3.0Hz), 7.63 (1H,
dd, J = 9.0, 2.0Hz), 7.81 (1H, dd, J = 6.6, 2.0Hz),
7.94-7.98 (3H, m), 8.20 (1H, d, J = 5.8Hz), 8.36 (1H,
 m) .IR (KBr): 1667, 1599, 1449, 1348, 1163, 1105, 731,
 696, 584 cm^-1Example 974- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-meth
Kisimeti Ru-4-pyridyl) -4-piperidinyl] (methyl) a
Mino} -2-piperazinone hydrochloride In the same manner as in Example 39, 4- (6-chloronaphthalene-2-
Sulfonyl) -1-{[1- (2-methoxymethyl-4-pyridyl) -4-
Piperidinyl] (methyl) amino} -2-piperazinone (200
 mg) to give the title compound (175 mg) as colorless crystals.¹ H-NMR (DMSO-d₆) δ: 1.10-1.15 (2H, m), 1.69-1.81
(2H, m), 2.53 (3H, s), 3.09-3.50 (7H, m), 3.72 (2H,
 br), 3.98-4.04 (5H, m), 4.52 (2H, s), 7.05 (1H, d,
 J = 8.0Hz), 7.11 (1H, s), 7.76 (1H, dd, J = 9.0, 2.
0Hz), 7.92 (1H, dd, J = 2.0, 8.8Hz), 8.19-8.23 (4H,
 m), 8.62 (1H, s) .IR (KBr): 1644, 1541, 1456, 1346, 1319, 1161, 113
6, 1105, 1078, 696, 667, 584 cm^-1Example 984- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-eth
Kisimeti Ru-4-pyridyl) -4-piperidinyl] (methyl) a
Mino} -2-piperazinone In the same manner as in Example 63, 4-chloro-2-picoline was substituted for 4-chloro-2-picoline.
Instead, add 4-chloro-2-ethoxymethylpyridine (0.55 g)
The title compound (505 mg) was obtained as a brown amorphous substance using
Obtained.¹ H-NMR (CDCl_Three) δ: 1.28 (3H, t, J = 7.0Hz), 1.38 (2
H, m), 1.68 (1H, m), 1.85-1.91 (1H, m), 2.71 (3H,
s), 2.80 (2H, m), 3.38-3.87 (9H, m), 3.62 (2H, q,
J = 7.0Hz), 4.51 (2H, s), 6.48 (1H, dd, J = 6.0, 2.8H
z), 6.79 (1H, d, J = 2.6Hz), 7.61 (1H, dd, J = 8.8,
2.2Hz), 7.81 (1H, dd, J = 8.8 and 1.8Hz), 7.93-7.97
(3H, m), 8.19 (1H, d, J = 6.2Hz), 8.36 (1H, d, J = 1.2H
z) .IR (KBr): 1669, 1599, 1456, 1348, 1163, 696 cm^-1Example 994- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-
Chilami Nomethyl-4-pyridyl) -4-piperidinyl] (meth H
Le) amino} -2-piperazinone In the same manner as in Example 63, 4-chloro-2-picoline was substituted for 4-chloro-2-picoline.
Instead, 4-chloro-2-dimethylaminomethylpyridine (530
 mg) to give the title compound as a brown amorphous (640 m
g) was obtained.¹ H-NMR (CDCl_Three) δ: 1.30-1.39 (2H, m), 1.61 (1H,
m), 1.84 (1H, m), 2.28 (6H, s), 2.71 (3H, s), 2.80
 (2H, m), 3.38-3.86 (13H, m), 6.48 (1H, dd, J = 6.1,
 2.7Hz), 6.76 (1H, d, J = 2.6Hz), 7.62 (1H, dd, J =
8.8 and 2.2Hz), 7.81 (1H, dd, J = 1.7 and 8.7Hz), 7.
93-7.98 (3H, m), 8.19 (1H, d, J = 5.8Hz), 8.36 (1H, d,
 J = 1.2Hz). IR (KBr): 1667, 1597, 1456, 1348, 1163, 1003, 733,
 696 cm^-1Example 1001-{[1- (2-acetylaminomethyl-4-pyridyl) -4-piperi
Dinyl] (methyl) amino} -4- (6-chloronaphthalene-2-
Sulfonyl) -2-piperazinone In the same manner as in Example 63, 4-chloro-2-picoline was substituted for 4-chloro-2-picoline.
Instead, 2-acetylaminomethyl-4-chloropyridine (185
 mg) to give the title compound (230 mg) as a brown powder.¹ H-NMR (CDCl_Three) δ: 1.30 (2H, m), 1.63 (1H, br), 1.
86 (1H, br), 2.05 (3H, s), 2.71 (3H, s), 2.80 (2H,
br), 3.38-3.77 (9H, m), 4.40 (2H, d, J = 4.8 Hz),
6.50-6.55 (2H, m), 6.74 (1H, m), 7.63 (1H, dd, J =
 1.8, 8.8 Hz), 7.81 (1H, dd, J = 1.8, 9.2 Hz), 7.9
3-7.98 (3H, m), 8.16 (1H, d, J = 5.8Hz), 8.37 (1H,
 m) .IR (KBr): 1665, 1599, 1348, 1163, 698, 667, 586 cm
^-1Example 1014- (6-chloronaphthalene-2-sulfonyl) -1- {[1- [2- (1-hi
Mud [Xy-1-methylethyl) -4-pyridyl] -4-piperidini
Ru] (Methyl) amino} -2-piperazinone In the same manner as in Example 63, 4-chloro-2-picoline was substituted for 4-chloro-2-picoline.
4-chloro-2- (1-hydroxy-1-methylethyl) instead
Title of brown amorphous substance using pyridine (257 mg)
The compound (220 mg) was obtained.¹ H-NMR (CDCl_Three) δ: 1.30-1.96 (4H, m), 1.50 (6H,
s), 2.72 (3H, s), 2.77-2.89 (2H, m), 3.37-3.84 (9
H, m), 5.18 (1H, br), 6.51 (1H, dd, J = 2.4 and6.0
 Hz), 6.65 (1H, d, J = 2.2 Hz), 7.62 (1H, dd, J =
2.0, 8.8 Hz), 7.80 (1H, dd, J = 1.6, 8.6 Hz), 7.93
-7.97 (3H, m), 8.16 (1H, d, J = 5.8 Hz), 8.36 (1H,
 d, J = 1.6 Hz) IR (KBr): 1667, 1599, 1493, 1456, 1348, 1319, 116
3, 1136, 1078, 993, 964, 729, 696, 667, 584 cm^-1Example 1024- (6-chloronaphthalene-2-sulfonyl) -1- {[1- (2-hid
Roxime Cyl-6-methyl-4-pi Lysyl) -4-piperidinyl]
(Methyl) amino} -2 -Piperazinone In the same manner as in Example 63, 4-chloro-2-picoline was substituted for 4-chloro-2-picoline.
Instead, 4-chloro-2-hydroxymethyl-6-methylpyridi
(236 mg) to give the title compound (240 mg) as a brown powder.
Obtained.¹ H-NMR (CDCl_Three) δ: 1.26-1.33 (2H, m), 1.70 (1H,
m), 1.84 (1H, m), 2.43 (3H, s), 2.71 (3H, s), 2.71
-2.87 (2H, m), 3.37-3.85 (10H, m), 4.59 (2H, s),
6.39 (2H, s), 7.63 (1H, dd, J = 2.0, 8.8 Hz), 7.80
 (1H, dd, J = 8.8,1.8 Hz), 7.93-7.98 (3H, m), 8.36
 (1H, s). IR (KBr): 1667, 1601, 1456, 1348, 1163, 1078, 731,
 698cm^-1Example 1031-{[1- (2-carbamoylmethyl-4-pyridyl) -4-piperidi
Nyl] (methyl) amino} -4- (6-chloronaphthalene-2-s
(Rufonyl) -2-piperazinone hydrochloride In the same manner as in Example 63 and Example 39, 4-chloro-2
-Instead of picoline, 2- (4-chloro-2-pyridinyl) ace
Title compound (105 mg) as brown powder using Tamide (188 mg)
 I got¹ H-NMR (CDCl_Three) δ: 1.14 (2H, m), 1.64 (1H, m), 1.8
2 (1H, m), 2.55 (3H, s), 3.11-4.05 (13H, m), 7.02
(1H, d, J = 7.0 Hz), 7.09 (1H, s), 7.29 (1H, s), 7.
74-7.79 (2H, m), 7.92 (1H, d, J = 8.4 Hz), 8.12-8.
33 (4H, m), 8.62 (1H, s) .IR (KBr): 1645, 1541, 1346, 1161, 698, 584 cm^-1Example 104Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1-
(2-hydroxymethyl-4-pyri Dinyl) -4-piperidinyl]
Amino] -6-oxo-2-piperazinecarboxylate disalt
Acid salt In the same manner as in Example 53, 1- (tert-butyl) 3-methyl
5-oxo-4-[[1- (4-pyridinyl) -4-piperidinyl] a
Mino] instead of 1,3-piperazinedicarboxylate
-(Tert-butyl) 3-methyl 4-[[1- (2-hydroxymethyl
-4-pyridinyl) -4-piperidinyl] amino] -5-oxo-1,3
-Use piperazine dicarboxylate (0.15g)
The title compound (0.13 g) was obtained as a colored crystalline powder.¹ H-NMR (DMSO-d₆) δ: 1.17-1.23 (2H, m), 1.78 (2H,
m), 3.11-3.33 (4H, m), 3.55-3.64 (3H, m), 3.69 (3H,
 s), 3.93-4.00 (4H, m), 4.37 (1H, m), 4.58 (2H, s),
 7.04-7.07 (2H, m), 7.75 (1H, dd, J = 2.2, 8.8 H
z), 7.88 (1H, dd, J = 1.8, 8.8 Hz), 8.07 (1H, t,
J = 6.2 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.28 (1H,
s), 8.30 (1H, d, J = 9.0 Hz), 8.61 (1H, s) .IR (KBr): 1748, 1669, 1645, 1539, 1348, 1240, 116
3, 1130, 1078 cm^-1Example 105Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1-
(2-hydroxymethyl-4-pi Ridinyl) -4-piperidinyl]
(Methyl) amino] -6-oxo-2-piperazinecarboxyle
Salt hydrochloride In the same manner as in Example 54, methyl 4-[(6-chloro-2-na
Fthyl) sulfonyl] -6-oxo-1-[[1- (4-pyridinyl) -4
-Piperidinyl] amino] -2-piperazinecarboxylate
Methyl 4-[(6-chloro-2-naphthyl) instead of dihydrochloride
Sulfonyl] -1-[[1- (2-hydroxymethyl-4-pyridini
Le) -4-Piperidinyl] amino] -6-oxo-2-piperazine
Table of colorless amorphous powder using ruboxylate (0.19 g)
The title compound (0.12 g) was obtained.¹ H-NMR (DMSO-d₆) δ: 1.14-1.30 (2H, m), 1.77-1.99
(2H, m), 2.86 (3H, s), 2.97-3.24 (4H, m), 3.44-3.60
 (2H, m), 3.71 (3H, s), 3.89-4.17 (4H, m), 4.30 (1
H, s), 4.57 (2H, s), 7.02-7.06 (2H, m), 7.75 (1H,
dd, J = 2.0, 8.6Hz), 7.87 (1H, dd, J = 1.8, 8.6 H
z), 8.08 (1H, m), 8.19 (1H, d, J = 9.2Hz), 8.28 (1
H, s), 8.30 (1H, d, J = 9.0 Hz), 8.60 (1H, s) .IR (KBr): 1748, 1669, 1645, 1539, 1454, 1404, 134
8, 1331, 1240, 1217, 1184, 1161, 1080, 964, 748, 5
92 cm^-1Example 106(+)-Methyl 4-[(6-chloro-2-naphthyl ) Sulfonyl] -1
-[M Tyl [1- (4-pyridinyl) -4-piperidinyl] amino] -6
-Oxo-2- Piperazine carboxylate Hydrochloride Methyl 4-[(6-chloro-2-naphthyl) sulfate obtained in Example 54
Ruphonyl] -1- [methyl [1- (4-pyridinyl) -4-piperidini
[Amino] -6-oxo-2-piperazinecarboxylate salt
Acid salt to chiral column (CHIRALPAK AD 50mmID x 500mmL)
Resolution by using (mobile phase: hexane / ethanol = 2
/ 8, flow rate: 70 ml / min, retention time: 19.42 minutes)
Fractions were concentrated. Dissolve this product in a small amount of methanol,
Add 4N hydrochloric acid / ethyl acetate, concentrate, dry and
The title compound (> 99.9% ee) as a light yellow powder with light
Obtained. Example 107(-)-Methyl 4-[(6-chloro-2-naphthyl ) Sulfonyl] -1
-[M Tyl [1- (4-pyridinyl) -4-piperidinyl] amino] -6
-Oxo-2- Piperazine carboxylate Hydrochloride Methyl 4-[(6-chloro-2-naphthyl) sulfate obtained in Example 54
Ruphonyl] -1- [methyl [1- (4-pyridinyl) -4-piperidini
[Amino] -6-oxo-2-piperazinecarboxylate salt
Acid salt to chiral column (CHIRALPAK AD 50mmID x 500mmL)
Resolution by using (mobile phase: hexane / ethanol = 2
/ 8, flow rate: 70 ml / min, retention time: 25.90 minutes)
Fractions were concentrated. Dissolve this product in a small amount of methanol,
Add 4N hydrochloric acid / ethyl acetate, concentrate, dry and
The title compound (99.4% ee) was obtained as a pale yellow powder having light properties.
Was. Example 108(+)-Methyl 4-[(6-chloro-2-naphthyl ) Sulfonyl] -6
-Oki So-1-[[1- (4-pyridinyl) -4-piperidinyl] amido
[No] -2-piperazinecarboxylate dihydrochloride Methyl 4-[(6-chloro-2-naphthyl) sulfate obtained in Example 53
Ruphonyl] -6-oxo-1-[[1- (4-pyridinyl) -4-piperidi
Nyl] amino] -2-piperazinecarboxylate dihydrochloride
Using a chiral column (CHIRALPAK AD 50mmID x 500mmL)
And optical resolution (mobile phase: hexane / ethanol = 1 /
9, Flow rate: 100 ml / min, retention time: 27.95 minutes)
The minute was concentrated. Dissolve the product in a small amount of methanol and add 4
Add normal hydrochloric acid / ethyl acetate, concentrate, dry and (+)
To give the title compound (> 99.9% ee) as a light yellow powder
Was. Example 109(-)-Methyl 4-[(6-chloro-2-naphthyl ) Sulfonyl] -6
-Oki So-1-[[1- (4-pyridinyl) -4-piperidinyl] amido
[No] -2-piperazinecarboxylate dihydrochloride Methyl 4-[(6-chloro-2-naphthyl) sulfate obtained in Example 53
Ruphonyl] -6-oxo-1-[[1- (4-pyridinyl) -4-piperidi
Nyl] amino] -2-piperazinecarboxylate dihydrochloride
Using a chiral column (CHIRALPAK AD 50mmID x 500mmL)
And optical resolution (mobile phase: hexane / ethanol = 1 /
9, Flow rate: 100 ml / min, retention time: 69.39 minutes)
The minute was concentrated. Dissolve the product in a small amount of methanol and add 4
Add normal hydrochloric acid / ethyl acetate, concentrate, dry and
The title compound (> 99.9% ee) as a light yellow powder with light
Obtained. Example 1104-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (4
-Pyridinyl) -4-piperidinyl] amino] -6-oxo-2-pi
Perazinecarbon acid Methyl 4-[(6-chloro-2-naphthyl) sulfate obtained in Example 54
Ruphonyl] -1- [methyl [1- (4-pyridinyl) -4-piperidini
[Amino] -6-oxo-2-piperazinecarboxylate salt
Acid salt (0.3 g), 2N aqueous sodium hydroxide solution (1.1 ml)
And a mixture of methanol (6.0 ml) at 40 ° C for 30 minutes.
Stirred. After cooling the reaction solution, the system was adjusted to pH 5 with 1N hydrochloric acid.
And concentrated under reduced pressure. The residue was collected on a CHP-20 column (water →
Purified with 30% acetonitrile aqueous solution containing 1% 1N hydrochloric acid)
The title compound (0.28 g) was obtained as a colorless powder.¹ H-NMR (CD_ThreeOD) δ: 1.18-1.50 (2H, m), 1.68-1.88
(1H, m), 1.90-2.12 (1H, m), 2.57 and 2.95 (total 3
H, s for each), 2.86-3.36 (3H, m), 3.40-3.64 (2H,
m), 3.96-4.30 (5H, m), 7.06 (2H, d, J = 7.6 Hz),
7.66 (1H, dd, J = 2.0, 8.6 Hz), 7.85 (1H, dd, J =
2.0, 8.6 Hz), 7.98-8.18 (5H, m), 8.48 (1H, s).4-[(6-chloro-2-naphthyl) sulfonyl] -6- (hydroxy
Methyl)- 1- [methyl [1- (4-pyridinyl) -4-piperidi Nil]
Amino] -2-pipe Radinone hydrochloride Methyl 4-[(6-chloro-2-naphthyl) sulfate obtained in Example 54
Ruphonyl] -1- [methyl [1- (4-pyridinyl) -4-piperidini
[Amino] -6-oxo-2-piperazinecarboxylate salt
Stir at 0 ° C in methanol solution (20 ml) of acid salt (0.3 g)
Below, add lithium borohydride (1.14 g) in three portions
I got it. After the reaction is completed, the system is replaced with 10% hydrochloric acid / methanol solution.
The solution was adjusted to pH 4 and concentrated under reduced pressure. Methyle chloride residue
Liquid and saturated sodium bicarbonate solution, and the organic layer is separated by magnesium sulfate.
After drying with a solvent, the mixture was concentrated under reduced pressure. Residue is CHP-20
Column (water → 30% acetonitrile containing 1% 1N hydrochloric acid)
Aqueous solution) to give the title compound as a colorless powder (0.12 g)
I got¹ H-NMR (CD_ThreeOD) δ: 1.20-1.50 (2H, m), 1.66-1.86
(1H, m), 2.00-2.14 (1H, m), 2.63 and 2.86 (total 3
H, s for each), 2.94-3.26 (3H, m), 3.28-4.36 (9H,
m), 7.00-7.18 (2H, m), 7.66 (1H, dd, J = 2.0, 8.8
Hz), 7.88 (1H, dd, J = 2.0, 8.8 Hz), 7.98-8.20 (5
H, m), 8.49 (1H, s). Example 1124-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (4
-Pyridinyl) -4-piperidinyl] amino] -6-oxo-2-pi
Perazine Carboki Samide hydrochloride Methyl 4-[(6-chloro-2-naphthyl) sulfate obtained in Example 54
Ruphonyl] -1- [methyl [1- (4-pyridinyl) -4-piperidini
[Amino] -6-oxo-2-piperazinecarboxylate salt
Acid salt (0.3 g) and 13% ammonia / methanol solution (3.5 m
l) was heated in a sealed tube at 90 ° C. for 2 days. After cooling the reaction system,
The reaction was concentrated under reduced pressure. The residue was purified on a CHP-20 column (water
→ 30% acetonitrile aqueous solution containing 1% 1N hydrochloric acid)
Purification gave the title compound (0.11 g) as a colorless powder.¹ H-NMR (CD_ThreeOD) δ: 1.18-1.54 (2H, m), 1.70-1.90
(1H, m), 1.92-2.12 (1H, m), 2.54 and 2.88 (total 3
H, s for each), 2.98-3.26 (2H, m), 3.36-4.34 (8H,
m), 7.08 (2H, d, J = 7.8 Hz), 7.66 (1H, dd, J = 1.
8, 8.8 Hz), 7.85 (1H, dd, J = 1.8, 8.8 Hz), 7.98-8.
18 (5H, m), 8.48 (1H, s). Example 1136- (aminomethyl) -4-[(6-chloro-2-naphthyl) sulfoni
Le] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
[No] -2-piperazinone dihydrochloride Triphenylphosphine (0.49 g), phthalimide (0.
Stir at 0 ° C to a mixture of 29 g) and methylene chloride (15 ml).
Below, diethyl azodicarboxylate (0.29 ml) was added, and 10
Stirred for minutes. To this solution, with stirring at 0 ° C., in Example 111
The resulting 4-[(6-chloro-2-naphthyl) sulfonyl] -6- (hydro
Xymethyl) -1- [methyl [1- (4-pyridinyl) -4-piperidi
Nyl] amino] -2-piperazinone hydrochloride (0.27 g)
A methylene solution (10 ml) was added, and the mixture was stirred at room temperature for 1 hour.
Was. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate, dried, and
Concentrated. Silica gel column chromatography of the residue
(Dichloromethane: methanol containing 10% ammonia water
= 10: 1) and purified as pale yellow powder 2-[(4-[(6-chloro
Ro-2-naphthyl) sulfonyl] -1- [methyl [1- (4-pyridini)
Le) -4-Piperidinyl] amino] -6-oxo-2-piperazini
M)]-1H-isoindole-1,3 (2H) -dione (0.28
g) was obtained.¹ H-NMR (CDCl_Three) δ: 1.20-2.10 (4H, m), 2.60-3.00
(5H, m), 3.10-4.40 (10H, m), 6.59 (2H, d, J = 6.6
Hz), 7.62 (1H, dd, J = 2.0, 8.8 Hz), 7.70-8.02 (8
H, m), 8.23 (2H, d, J = 5.8 Hz), 8.34 (1H, s). Then, the product, hydrazine monohydrate (0.072 ml) and d
A mixture of ethanol (8.4 ml) was heated to reflux for 3 hours.
After cooling the reaction solution, the insoluble matter was filtered, and the filtrate was concentrated under reduced pressure.
did. The residue is purified by silica gel column chromatography
Chloromethane: 10% ammonia water-containing methanol = 1
0: 1) and purified with 4N hydrochloric acid / ethyl acetate
By converting the compound to a salt, the title compound (0.17
g) was obtained.¹ H-NMR (CD_ThreeOD) δ: 1.20-1.60 (2H, m), 1.70-1.95
(1H, m), 2.00-2.30 (1H, m), 2.70 and 2.93 (total 3
H, s for each), 2.80-4.40 (12H, m), 7.04-7.22 (2H,
m), 7.68 (1H, dd, J = 2.0, 8.8 Hz), 7.90 (1H, dd,
J = 1.8, 8.8 Hz), 8.00-8.24 (5H, m), 8.53 (1H, s).N-[[4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
[1- (4-pyridinyl) -4-piperidinyl] amino] -6-oxo-
2-piperazini [Methyl] acetamide hydrochloride 6- (Aminomethyl) -4-[(6-chloro-2) obtained in Example 113
-Naphthyl) sulfonyl] -1- [methyl [1- (4-pyridinyl) -4
-Piperidinyl] amino] -2-piperazinone dihydrochloride (0.14 g), triethylamine (0.16 ml) and methyl chloride
Acetic anhydride (0.043) was added to a mixture of
ml) and stirred for 24 hours. Concentrate the reaction mixture under reduced pressure
The residue was purified with a CHP-20 column (water → 30% containing 1% 1N hydrochloric acid).
% Aqueous solution of acetonitrile) to give a colorless powder
Compound (0.12 g) was obtained.¹ H-NMR (CD_ThreeOD) δ: 1.20-1.58 (2H, m), 1.58-2.27
(2H, m), 2.02 (3H, s), 2.65 and 2.90 (total 3H, s f
or each), 2.90-4.40 (12H, m), 6.96-7.22 (2H, br),
7.66 (1H, d, J = 8.2 Hz), 7.88 (1H, d, J = 8.2 H
z), 7.98-8.22 (5H, m), 8.50 (1H, s).N-[[4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
[1- (4-pyridinyl) -4-piperidinyl] amino] -6-oxo-
2-piperazini Ru] methyl] (trifluo B) Methane sulfone
Amide hydrochloride 6- (Aminomethyl) -4-[(6-chloro-2) obtained in Example 113
-Naphthyl) sulfonyl] -1- [methyl [1- (4-pyridinyl) -4
-Piperidinyl] amino] -2-piperazinone dihydrochloride (0.11
g), 2,6-lutidine (0.19 ml), 4-dimethylaminopyri
-30 to a mixture of gin (5 mg) and methylene chloride (6 ml)
Under stirring at ℃, trifluoromethanesulfonic anhydride (0.10
 ml) and stirred for 1 hour. Wash the reaction solution with water,
After drying with magnesium acid, it was concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (dichloro
Methane: methanol containing 10% ammonia water = 10:
Purify in 1) to give the title compound (40 mg) as a pale yellow powder.
Obtained.¹ H-NMR (CD_ThreeOD) δ: 1.16-1.55 (2H, m), 1.60-1.90
(1H, m), 1.95-2.22 (1H, m), 2.63 and 2.87 (total 3
H, s for each), 3.00-4.40 (12H, m), 6.98-7.20 (2H,
m), 7.67 (1H, dd, J = 2.2, 8.8 Hz), 7.89 (1H, dd,
J = 1.6, 8.8 Hz), 7.96-8.20 (5H, m), 8.51 (1H, s).4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (4
-Pyridinyl) -4-piperidinyl] amino] -6- (4-morpholy
Nylcarbonyl) -2-piperazinone hydrochloride 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.22 g), mol
Holin (0.048 g), 1-hydroxy-1H-benzotriazo
To a mixture of alcohol monohydrate (0.085 g) and DMF (4.4 ml)
WSC (0.12 g) was added, and the mixture was stirred at room temperature for 18 hours. Reaction liquid
Was concentrated under reduced pressure, and then added to saturated aqueous sodium hydrogen carbonate and methylene chloride.
And separated. Dry the organic layer over magnesium sulfate
And concentrated under reduced pressure. The residue was collected on a CHP-20 column (water →
Purified with 30% acetonitrile aqueous solution containing 1% 1N hydrochloric acid)
The title compound (0.13 g) was obtained as a colorless powder.¹ H-NMR (CD_ThreeOD) δ: 1.20-1.60 (2H, m), 1.72-2.13
(2H, m), 2.62 and 2.85 (total 3H, s for each), 2.98
-4.30 (17H, m), 4.67 (1H, brs), 7.09 (2H, d, J = 7.
6 Hz), 7.65 (1H, dd, J = 2.0, 8.8 Hz), 7.78-7.90
Example 117. (1H, m), 7.98-8.18 (5H, m), 8.47 (1H, s).4-[(6-chloro-2-naphthyl) sulfonyl] -6-[(4-hydroxy
-1 -Piperidinyl) carbonyl] -1- [methyl [1- (4-pyri
Dinyl) -4-pi Peridinyl] amino] -2-piperazinone hydrochloride
salt 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
[No] -6-oxo-2-piperazinecarboxylic acid (0.20 g) and 4-
Example 11 using hydroxypiperidine (0.051 g)
In the same manner as in Example 6, the title compound (0.13
g) was obtained.¹ H-NMR (CD_ThreeOD) δ: 1.20-2.15 (8H, m), 2.62 and
2.85 (total 3H, s for each), 2.95-4.30 (14H, m),
4.60-4.85 (1H, m), 6.98-7.20 (2H, m), 7.58-7.72 (1
H, m), 7.74-7.92 (1H, m), 7.94-8.22 (5H, m), 8.46
(1H, s). Example 1184-[(6-chloro-2-naphthyl) sulfonyl] -6-[(4-methyl-1
-Piperazinyl) carbonyl -1- [methyl [1- (4-pyridini
Le) -4-piperi Dinyl] amino] -2-pi Perazinone dihydrochloride 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.18 g) and 1-
Using methyl piperidine (0.049 ml), Example 116
In the same manner, the title compound (0.15 g) was obtained as a yellow powder.
Obtained.¹ H-NMR (CD_ThreeOD) δ: 1.18-1.66 (2H, m), 1.74-2.14
(2H, m), 2.87 (3H, s), 2.97 (3H, s), 2.80-5.00 (18
H, m), 7.10 (2H, d, J = 7.4 Hz), 7.66 (1H, dd, J =
 1.8, 8.8 Hz), 7.78-7.96 (1H, br), 8.00-8.22 (5H,
m), 8.42-8.58 (1H, m).4-[(6-chloro-2-naphthyl) sulfonyl] -N- [2- (dimethyl
Amino) ethyl] -1- [methyl [1- (4-pyridinyl) -4-piperi
Dinyl] amino ] -6-Oxo-2-pipe Razinecarboxamide
Dihydrochloride 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.18 g) and N, N
-Using dimethylethylenediamine (0.035 ml)
By a method similar to that in Example 116, the title compound was obtained as a pale yellow powder.
 (0.17 g) was obtained.¹ H-NMR (CD_ThreeOD) δ: 1.20-1.62 (2H, m), 1.70-2.14
(2H, m), 2.89 (3H, s), 2.99 (3H, s), 3.00 (3H, s),
2.74-4.40 (14H, m), 7.08 (2H, d, J = 7.0 Hz), 7.66
 (1H, d, J = 8.4 Hz), 7.88 (1H, d, J = 8.4 Hz), 7.
98-8.22 (5H, m), 8.51 (1H, s). Example 120Ethyl 2-[[[4-[( 6-chloro-2-naphthyl) sulfonyl] -1-
[Methyl [1- (4-pyridinyl ) -4-Piperidinyl] a Mino] -6-
Oxo-2-piperazinyl] carbonyl] amino] acetate 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.18 g),
Synethylster hydrochloride (0.062 g), triethylamido
(0.12 ml), 1-hydroxy-1H-benzotriazole
WSC to a mixture of monohydrate (0.068 g) and DMF (4.4 ml)
(0.096 g) was added, and the mixture was stirred at room temperature for 18 hours. Reaction solution
After concentrating under reduced pressure, saturated aqueous sodium hydrogen carbonate and methylene chloride were used.
Separated. The organic layer is dried with magnesium sulfate,
Concentrated under reduced pressure. The residue was purified on a CHP-20 column (water → 1% 1
Purified with 30% acetonitrile aqueous solution containing normal hydrochloric acid)
The title compound (0.13 g) was obtained as a colorless powder.¹ H-NMR (CDCl_Three) δ: 1.29 (3H, t, J = 7.0 Hz), 1.00
-1.44 (2H, m), 1.46-1.78 (1H, m), 1.80-2.06 (1H,
m), 2.58-2.92 (5H, m), 3.24-3.90 (6H, m), 3.92-4.0
8 (3H, m), 4.10-4.28 (3H, m), 6.58 (2H, d, J = 6.4
 Hz), 7.54-7.84 (1H, m), 7.61 (1H, dd, J = 2.2, 8.
8 Hz), 7.78 (1H, dd, J = 1.8, 8.8 Hz), 7.86-8.00 (3
H, m), 8.23 (2H, d, J = 6.4 Hz), 8.35 (1H, s).4-[(6-chloro-2-naphthyl) sulfonyl] -N- [2- (ethyls
Ruphanyl) ethyl] -1- [methyl [1- (4-pyridinyl) ) -4-pi
Peridinyl] Mino] -6-oxo-2-piperazinecarboxa
Mido hydrochloride 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
[No] -6-oxo-2-piperazinecarboxylic acid (0.18 g) and 2-
Using (ethylthio) ethylamine hydrochloride (0.065 g)
By a method similar to that in Example 120, title of pale yellow powder
Compound (0.16 g) was obtained.¹ H-NMR (DMSO-d₆) δ: 0.96-1.36 (5H, m), 1.64-2.02
 (2H, m), 2.76 (3H, s), 2.35-4.30 (16H, m), 7.14
(2H, d, J = 7.0 Hz), 7.75 (1H, dd, J = 2.2, 8.8 H
z), 7.85 (1H, d, J = 8.8 Hz), 8.10-8.34 (5H, m),
8.38-8.52 (1H, m), 8.57 (1H, s). Example 1224-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (4
-Pyridinyl) -4-piperidinyl] amino] -6- (4-thiomol
(Holinylcarbonyl) -2-piperazinone hydrochloride 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.15 g)
As in Example 116 using omorpholine (0.041 ml)
The title compound (0.07 g) was obtained as a colorless powder by the method of
Was.¹ H-NMR (CD_ThreeOD) δ: 1.20-1.60 (2H, m), 1.70-2.12
(2H, m), 2.43-4.40 (21H, m), 6.98-7.18 (2H, m), 7.
65 (1H, d, J = 8.2 Hz), 7.84 (1H, d, J = 8.4Hz),
7.96-8.20 (5H, m), 8.47 (1H, s). Example 1234-[(6-chloro-2-naphthyl) sulfonyl] -6-[(1,1-dioxo
(Sid-4-thiomorpholinyl) Carbonyl] -1- [methyl [1- (4
-Pyridinyl) -4-piperidinyl] amine No] -2-piperazinone
Hydrochloride 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.15 g)
Omorpholine 1,1-dioxide trifluoroacetate (0.1
01 g) and in the same manner as in Example 120, colorless
The title compound (0.06 g) was obtained as a powder.¹ H-NMR (DMSO-d₆) δ: 1.00-1.40 (2H, m), 1.70-2.02
 (2H, m), 2.74 and 2.86 (total 3H, s for each), 2.
80-4.40 (18H, m), 7.12 (2H, d, J = 7.4 Hz), 7.75 (1
H, dd, J = 2.2, 8.8 Hz), 7.87 (1H, dd, J = 1.8, 8.
8 Hz), 8.10-8.36 (5H, m), 8.60 (1H, s). Example 1244-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (4
-Pyridinyl) -4-piperidinyl] amino] -6-[(1-oxide
-4-thiomol Holinyl) carbonyl] -2-piperazinone salt
Acid salt 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.17 g)
Omorpholine 1-oxide trifluoroacetate (0.107
g) in the same manner as in Example 120, using a colorless powder
The final title compound (0.10 g) was obtained.¹ H-NMR (DMSO-d₆) δ: 0.95-1.45 (2H, m), 1.70-2.05
 (2H, m), 2.20-4.80 (21H, m), 7.13 (2H, d, J = 7.2
 Hz), 7.68-7.82 (1H, m), 7.82-7.94 (1H, m), 8.10-8.
38 (5H, m), 8.59 (1H, s). Example 1252-[[[4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
[1 -(4-Pyridinyl) -4-piperidinyl] amino] -6-oxo-
2-piperazi Nyl] carbonyl] amino ] Acetic acid The ethyl 2-[[[4-[(6-chloro-2-naphne obtained in Example 120
Tyl) sulfonyl] -1- [methyl [1- (4-pyridinyl) -4-pipe
Ridinyl] amino] -6-oxo-2-piperazinyl] carboni
[Amino] acetate (0.18 g), 1N sodium hydroxide
(0.56 ml) and methanol (4.0 ml)
Stirred at 0 ° C. for 30 minutes. After cooling the reaction solution, 1N inside the system
The solution was adjusted to pH 5 with hydrochloric acid and concentrated under reduced pressure. Residue is CHP-20
Column (water → 25% acetonitrile containing 1% concentrated aqueous ammonia)
And purified by colorless powder to give the title compound (0.11
 g) was obtained.¹ H-NMR (CD_ThreeOD): δ 1.20-1.62 (2H, m), 1.68-1.90 (1
H, m), 1.90-2.10 (1H, m), 2.55 and 2.83 (total 3H,
s for each), 2.98-4.40 (12H, m), 7.09 (2H, d, J =
7.2 Hz), 7.66 (1H, dd, J = 2.2, 8.8 Hz), 7.86 (1H,
 dd, J = 1.8, 8.8 Hz), 7.98-8.18 (5H, m), 8.49 (1
H, s). Example 1261-[[4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
[1- (4-pyridinyl) -4-piperidinyl] amino] -6-oxo-
2-piperazini Le] carbonyl] -4-pi Peridine carboxylic acid 4-[(6-Chloro-2-naphthyl) sulfoni obtained in Example 110
L] -1- [Methyl [1- (4-pyridinyl) -4-piperidinyl] amido
No] -6-oxo-2-piperazinecarboxylic acid (0.18 g), ethi
Luisonipecotinate (0.068 ml), 1-hydroxy-1H-
Benzotriazole monohydrate (0.068 g) and DMF (4.4
ml), add WSC (0.096 g) and stir at room temperature for 18 hours.
Stirred. After concentrating the reaction solution under reduced pressure, saturated aqueous sodium hydrogen carbonate and
Liquid separation was performed with methylene chloride. The organic layer is magnesium sulfate
And concentrated under reduced pressure. Residue is CHP-20
(Water → 30% acetonitrile aqueous solution containing 1% 1N hydrochloric acid)
Liquid) and purified as a colorless powder of ethyl 1-[[4-[(6-chloro-2
-Naphthyl) sulfonyl] -1- [methyl [1- (4-pyridinyl) -4
-Piperidinyl] amino] -6-oxo-2-piperazinyl] cal
Bonyl] -4-piperidinecarboxylate was obtained. Next
In this product, 1N sodium hydroxide (1.14 ml) and
Stir the mixture of ethanol (4.0 ml) at 40 ° C for 30 minutes.
Was. After cooling the reaction solution, the inside of the system was adjusted to pH 5 with 1N hydrochloric acid,
Concentrated under reduced pressure. Residue was purified by CHP-20 column (water → 1%
25% acetonitrile aqueous solution containing concentrated ammonia water)
To give the title compound (0.07 g) as a colorless powder.¹ H-NMR (DMSO-d₆) δ: 0.95-2.00 (8H, m), 2.25-4.60
 (18H, m), 6.71 (2H, d, J = 6.2 Hz), 7.75 (1H, d,
J = 8.8 Hz), 7.85 (1H, d, J = 8.8 Hz), 8.09 (2H, d,
 J = 6.2 Hz), 8.18 (1H, d, J = 8.8 Hz), 8.30 (2H,
d, J = 8.8 Hz), 8.50-8.62 (1H, br).Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1-
(2-Methyl-4-pyridinyl) -4-piperidinyl] amino ] -6-
Oxo-2-pipe Razine carboxylate dihydrochloride 1- (tert-butyl) 3-methyl 4-[[1- (2-methyl-4-pyri
Dinyl) -4-piperidinyl] amino] -5-oxo-1,3-pipe
A solution of azine dicarboxylate (3.5 g) in toluene (1
Trifluoroacetic acid (17.5 ml) was added dropwise to
The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Residue, triet
Mixture of ruamine (10.9 ml) and dichloromethane (35 ml)
6-chloronaphthalene-2-sulfonyl chloride (2.
45 g) was added and the mixture was stirred at room temperature for 1 hour. Separate the organic layer,
After washing with saturated aqueous sodium hydrogen carbonate and brine, drying and concentration were performed.
The obtained residue is subjected to silica gel column chromatography.
(Dichloromethane: methanol containing 10% ammonia water
= 10: 1) and purified into 4N hydrochloric acid ethyl acetate solution
Hydrochloride to give the title compound (2.18 g) as a pale yellow powder.
Obtained.¹ H-NMR (DMSO-d₆+ D_TwoO) δ: 1.06-1.38 (2H, m), 1.66-
1.92 (2H, m), 2.42 (3H, s), 2.96-3.74 (8H, m), 3.8
6-4.10 (4H, m), 4.32-4.42 (1H, m), 6.94-7.08 (2H,
m), 7.75 (1H, dd, J = 1.8, 8.8 Hz), 7.87 (1H, dd,
J = 2.0, 8.8 Hz), 8.06 (1H, d, J = 7.2 Hz), 8.20
(1H, d, J = 8.8 Hz), 8.29 (2H, d, J = 9.2 Hz), 8.5
9 (1H, s). Example 128Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
Le [1- (2-Methyl-4-pyridinyl) -4-piperidinyl] ami
[No] -6-oxo-2-piperazinecarboxylate hydrochloride Methyl 4-[(6-chloro-2-naphthyl) obtained in Example 127
Sulfonyl] -1-[[1- (2-methyl-4-pyridinyl) -4-piperi
Dinyl] amino] -6-oxo-2-piperazinecarboxylate
Dihydrochloride (1.94 g) in methylene chloride (20 ml) and saturated
It was dissolved in aqueous sodium bicarbonate (20 ml) and separated. Organic layer of sulfuric acid
Dry over magnesium and concentrate under reduced pressure to give methyl
 4-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1- (2-methyl
Ru-4-pyridinyl) -4-piperidinyl] amino] -6-oxo-2
-Piperazine carboxylate was obtained. 37% of this product
To an aqueous solution of mualdehyde (25.2 ml) and formic acid (12.8 ml)
Dissolve and reflux for 2 hours. After cooling the reaction solution,
The solution is made alkaline by adding sodium bicarbonate and extracted with dichloromethane.
It was concentrated after drying. The residue was purified on a CHP-20 column (water → 1% 1
Purified with 30% acetonitrile aqueous solution containing normal hydrochloric acid)
4N hydrochloric acid in ethyl acetate solution (0.15 ml)
The title compound (1.67 g) was obtained as a colorless amorphous powder.¹ H-NMR (CD_ThreeOD) δ: 1.10-1.50 (2H, m), 1.65-1.90
(1H, m), 1.92-2.12 (1H, m), 2.47 (3H, s), 2.58 and
2.93 (total 3H, s for each), 2.85-4.50 (10H, m), 3.
74 (3H, s), 6.86-7.00 (2H, m), 7.66 (1H, dd, J =
2.2, 8.8 Hz), 7.84 (1H, dd, J = 1.8, 8.8 Hz), 7.93
 (1H, d, J = 8.4 Hz), 8.02-8.18 (3H, m), 8.48 (1H,
 s). Example 1294-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (2
-Methyl-4-pyridinyl)- 4-piperidinyl] amino] -6-o
Oxo-2-piperazinecarboxylic acid Methyl 4-[(6-chloro-2-naphthyl) obtained in Example 128
Sulfonyl] -1- [methyl [1- (2-methyl-4-pyridinyl) -4-
Piperidinyl] amino] -6-oxo-2-piperazinecarbox
Silate hydrochloride (0.22 g), 1N aqueous sodium hydroxide
Solution (1.4 ml) and methanol (4.0 ml) at 40 ° C
For 30 minutes. After cooling the reaction mixture, 1N hydrochloric acid
And the mixture was concentrated under reduced pressure. Residue is CHP-20
(Water → 25% acetonitrile containing 1% concentrated aqueous ammonia)
Aqueous solution) to give the title compound as a colorless powder (0.17 g)
I got¹ H-NMR (CD_ThreeOD) δ: 1.15-1.60 (2H, m), 1.65-2.10
(2H, m), 2.48 (3H, s), 2.95 (3H, s), 2.85-4.40 (10
H, m), 6.88-7.04 (2H, m), 7.66 (1H, dd, J = 2.0,
8.8 Hz), 7.85 (1H, dd, J = 1.8, 8.8 Hz), 7.88-8.00
 (1H, m), 8.04-8.20 (3H, m), 8.48 (1H, s).Methyl 1-[[1- (2- Methyl-4-pyridinyl) -4-piperidini
[Amino] -6-oxo-4-[(4-vinylphenyl) sul Honi
Ru] -2-Piperazinecarboxylate 1- (tert-butyl) 3-methyl 4-[[1- (2-methyl-4-pyri
Dinyl) -4-piperidinyl] amino] -5-oxo-1,3-pipe
Razine dicarboxylate (0.59 g) and 4-vinylben
As in Example 127, using zensulfonyl chloride
The title compound (0.25 g) was obtained as a pale yellow powder by the method of
Was.¹ H-NMR (CDCl_Three) δ: 1.22-1.54 (2H, m), 1.64-2.00
(2H, m), 2.44 (3H, s), 2.72-3.02 (2H, m), 3.04-3.30
 (2H, m), 3.55 (1H, d, J = 16.0 Hz), 3.78 (3H, s),
 3.64-4.34 (5H, m), 4.96 (1H, d, J = 2.8 Hz), 5.49
 (1H, d, J = 10.8 Hz), 5.92 (1H, d, J = 17.6 Hz),
6.40-6.58 (2H, m), 6.77 (1H, dd, J = 10.8, 17.6 H
z), 7.58 (2H, d, J = 8.4 Hz), 7.74 (2H, d, J = 8.4
 Hz), 8.14 (1H, d, J = 6.0 Hz).Methyl 1- [methyl [1- (2-methyl-4-pyridinyl) -4-pipe
[Lidinyl] amino] -6-oxo- 4-[(4-vinylphenyl )
Ruphonyl] -2-pipe Razine carboxylate Methyl 1-[[1- (2-methyl-4-pyridy) obtained in Example 130
Nil) -4-piperidinyl] amino] -6-oxo-4-[(4-vinyl
Phenyl) sulfonyl] -2-piperazinecarboxylate
(0.19 g), and in the same manner as in Example 128,
The title compound (0.55 g) was obtained as colorless crystals.¹ H-NMR (CDCl_Three) δ: 1.16-1.46 (2H, m), 1.55-1.75
(1H, m), 1.83-2.01 (1H, m), 2.43 (3H, s), 2.62 and
2.95 (total 3H, s for each), 2.67-2.90 (2H, m), 3.1
9 (1H, dd, J = 3.6, 12.4 Hz), 3.36-3.65 (1H, m),
3.57 (1H, d, J = 16.4 Hz), 3.78 (3H, s), 3.67-3.90
(3H, m), 3.97 (1H, d, J = 16.4 Hz), 4.05-4.20 (1H,
 m), 5.50 (1H, d, J = 10.8 Hz), 5.93 (1H, d, J = 1
7.6 Hz), 6.40-6.58 (2H, m), 6.78 (1H, dd, J = 10.8,
 17.6 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.73 (2H, d,
J = 8.6 Hz), 8.14 (1H, d, J = 5.8 Hz).4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (2
-Methyl-4-pyridinyl) -4-piperidinyl] amino] -6-o
Oxo-2-piperazinecarboxamide hydrochloride Methyl 4-[(6-chloro-2-naphthyl) obtained in Example 128
Sulfonyl] -1- [methyl [1- (2-methyl-4-pyridinyl) -4-
Piperidinyl] amino] -6-oxo-2-piperazinecarbox
As in Example 112 using sylate hydrochloride (0.19 g)
In the same manner, the title compound (0.075 g) was obtained as a colorless powder.
Obtained.¹ H-NMR (DMSO-d₆+ D_TwoO) δ: 0.95-1.25 (2H, m), 1.40-
1.90 (2H, m), 2.28 (3H, s), 2.30-4.10 (13H, m), 6.
46-6.66 (2H, m), 7.24-7.38 (1H, m), 7.48-7.68 (1H,
 m), 7.77 (1H, dd, J = 1.8, 8.8 Hz), 7.80-7.92 (1
H, m), 7.98 (1H, d, J = 6.0 Hz), 8.19 (1H, d, J =
Example 133: 8.8 Hz), 8.24-8.36 (2H, m), 8.57 (1H, s).4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl [1- (2
-Methyl-4-pyridinyl)- 4-piperidinyl] amino] -6-[(1
-Oxide-4-thiomorpholinyl) ca Rubonil] -2-pipera
Zinone hydrochloride 4-[(6-chloro-2-naphthyl) sulfoni obtained in Example 129
] -1- [methyl [1- (2-methyl-4-pyridinyl) -4-piperidi
Nyl] amino] -6-oxo-2-piperazinecarboxylic acid (0.25
 g) and thiomorpholine 1-oxide trifluoroacetic acid
Using a salt (0.132 g), in the same manner as in Example 120.
The title compound (0.15 g) was obtained as a colorless powder.¹ H-NMR (DMSO-d₆) δ: 0.95-1.43 (2H, m), 1.70-2.05
 (2H, m), 2.43 (3H, s), 2.25-4.80 (21H, m), 6.92-
7.10 (2H, m), 7.68-7.82 (1H, m), 7.82-7.96 (1H,
m), 8.02-8.14 (1H, m), 8.14-8.36 (3H, m), 8.58 (1
H, s). Example 1341- {Methyl [1- (4-pyridinyl) -4-piperidinyl] amino}-
4- (4 -Vinylbenzenesulfonyl ) -2-Piperazinone 1-{[1- (4-pyridinyl) -4-piperidinyl] amino} -4- (4-
(Vinylbenzenesulfonyl) -2-piperazinone (180 mg)
37% formaldehyde aqueous solution (11 ml) and formic acid (5
 ml) and refluxed for 2 hours. After cooling the reaction solution,
Add an aqueous sodium hydroxide solution to make it alkaline,
Extracted with dichloromethane, dried and concentrated. Residue column
Chromatography (dichloromethane: 10% ammonia
Purified with water-containing methanol = 20: 1), ether
To give the title compound as colorless crystals (139 mg, 75%)
I got¹ H-NMR (CDCl_Three) δ: 1.36 (2H, m), 1.70 (1H, m), 1.9
0 (1H, m), 2.73 (3H, s), 2.84 (2H, m), 3.20-3.90
(9H, m), 5.49 (1H, d, J = 11.0Hz), 5.92 (1H, d, J = 17.
6Hz), 6.62 (2H, d, J = 6.6Hz), 6.78 (1H, dd, J = 11.0,
 17.6Hz), 7.59 (2H, d, J = 8.2Hz), 7.76 (2H, d, J = 8.
2Hz), 8.24 (2H, d, J = 6.6Hz) .IR (KBr): 1669, 1593, 1507, 1350, 1167 cm^-1Example 135Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1-
(4-pyridinyl) -4-piperidi Nyl] amino] -6-oki S-2-
Piperazine acetate Methyl 1-amino-4-[(6-chloro-2) obtained in Reference Example 46
-Naphthyl) sulfonyl] -6-oxo-2-piperazineacete
(500 mg) and 1- (4-pyridinyl) -4-piperidinone
(240 mg) in ethanol (25 ml) was heated to reflux overnight.
Was. The reaction solution is concentrated under reduced pressure, and the resulting residue is
Acetic acid (0.60 g) and silica gel under ice-cooling.
Add sodium borohydride (120 mg) and add at room temperature
Stir for 2 hours. The reaction solution is concentrated under reduced pressure, and the residue is distilled.
Separate with dichloromethane (100 ml) and saturated aqueous sodium bicarbonate (100 ml).
Liquid. The organic layer was washed with water and saline, then dried and concentrated.
Shrank. The obtained residue is subjected to silica gel column chromatography.
Fee (dichloromethane: 10% ammonia water-containing meta
(Nol = 20: 1) to give the title compound as colorless crystals
(200 mg) was obtained.¹ H-NMR (CDCl_Three) δ: 1.43 (2H, m), 1.73 (2H, m), 2.6
5-3.20 (5H, m), 3.48 (1H, d, J = 16.0Hz), 3.70 (3H,
s), 3.60-4.00 (3H, m), 4.16 (1H, d, J = 16.0Hz), 4.8
3 (1H, d, J = 4.8Hz), 6.60 (2H, d, J = 6.6Hz), 7.62 (1
H, dd, J = 1.8, 8.8Hz), 7.79 (1H, dd, J = 1.8, 8.8Hz),
 7.90-8.00 (3H, m), 8.23 (2H, d, J = 6.6Hz), 8.36 (1
H, s). Example 136Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
Le [1- (4-pyridinyl) -4-piperidinyl] amino] -6-oxo
So-2-piperazine acetate Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1-
(4-pyridinyl) -4-piperidinyl] amino] -6-oxo-2-
Example 134 using piperazine acetate (100 mg)
The title compound (80 mg) was obtained as a colorless solid in the same manner as described above.
Was.¹ H-NMR (CDCl_Three) δ: 1.57 (2H, m), 1.93 (2H, m), 2.5
3-2.90 (4H, m), 2.84 (3H, s), 3.09 (1H, m), 3.69
(3H, s), 3.40-4.05 (5H, m), 6.58 (2H, d, J = 6.6Hz),
 7.62 (1H, dd, J = 1.8, 8.8Hz), 7.79 (1H, dd, J = 1.8,
 8.8Hz), 7.90-8.00 (3H, m), 8.23 (2H, d, J = 6.6Hz),
 8.35 (1H, s). Example 137Methyl 1-[[1- (2- Methyl-4-pyridinyl) -4-piperidini
[Amino] -6-oxo-4- (4-vinylbenzenesulfonyl)
-2-piperazine acetate Methyl 1-amino-6-oxo-4- (4-
(Vinylbenzenesulfonyl) -2-piperazine acetate
(1.06 g) and 1- (2-methyl-4-pyridinyl) -4-piperidinone
(0.57 g) and colorless in the same manner as in Example 135
The title compound (264 mg) was obtained as a solid.¹ H-NMR (CDCl_Three) δ: 1.47 (2H, m), 1.84 (2H, m), 2.5
0 (3H, s), 2.75-3.10 (5H, m), 3.20 (1H, m), 3.43
(1H, d, J = 16.0Hz), 3.71 (3H, s), 3.70-4.20 (5H,
m), 4.83 (1H, d, J = 4.8Hz), 5.50 (1H, d, J = 11.0Hz),
 5.93 (1H, d, J = 17.6Hz), 6.54 (1H, d, J = 2.6Hz), 6.
60 (1H, dd, J = 6.6, 2.6Hz), 6.81 (1H, dd, J = 17.6, 1
1.0Hz), 7.59 (2H, d, J = 8.4Hz), 7.75 (2H, d, J = 8.4H
z), 8.03 (1H, d, J = 6.6Hz) .IR (KBr): 1732, 1645, 1599, 1539, 1354, 1169 cm^-1 Example 138Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1-
(2-Methyl-4-pyridinyl) -4-piperidinyl] amino ] -6-
Oxo-2-pipe Razine acetate Methyl 1-amino-4-[(6-chloro-2) obtained in Reference Example 46
-Naphthyl) sulfonyl] -6-oxo-2-piperazineacete
(1.03 g), 1- (2-methyl-4-pyridinyl) -4-pipe
Lidinone (0.48 g) and acetic acid (0.15 g) were added to ethanol (25
 ml) and stirred at room temperature overnight. The reaction solution is
Concentrate and concentrate the residue in dichloromethane (100 ml) and saturated aqueous sodium bicarbonate
(100 ml). Wash the organic layer with water and saline
After cleaning, it was dried and concentrated. The residue obtained is methanol
Acetic acid (0.60 g) and shear under ice-cooling.
Add sodium borohydride (0.24 g) and terminate at room temperature.
Stirred at night. The reaction mixture was concentrated under reduced pressure, and the residue was
Separate with methane (100 ml) and saturated aqueous sodium bicarbonate (100 ml).
Was. The organic layer was washed with water and brine, dried and concentrated.
Was. The obtained residue is subjected to silica gel column chromatography.
ー (Dichloromethane: Methanol with 10% ammonia water
= 15: 1), ethyl acetate and diethyl ether
The title compound (0.64
 g) was obtained.¹ H-NMR (CDCl_Three) δ: 1.35-1.50 (2H, m), 1.60-1.80
(2H, m), 2.43 (3H, s), 2.69-3.20 (6H, m), 3.48 (1H,
 d, J = 16.0Hz), 3.78 (3H, s), 3.78-4.20 (5H, m), 4.8
2 (1H, d, J = 4.8Hz), 6.43-6.47 (2H, m), 7.62 (1H, d
d, J = 8.8, 1.6Hz), 7.79 (1H, dd, J = 8.8, 1.6Hz),
7.93-7.97 (3H, m), 8.13 (1H, d, J = 5.8Hz), 8.35
(1H, s) .IR (KBr): 2924, 1732, 1659, 1599, 1541, 1494, 1454,
 1416 cm^-1 Example 139Methyl 4-[(6-chloro-2-naphthyl) sulfonyl] -1- [methyl
Le [1- (2-Methyl-4-pyridinyl) -4-piperidinyl] ami
No] -6-oxo-2-piperazine acetate Methyl 4-[(6-chloro-2-naphthyl) obtained in Example 138
Sulfonyl] -1-[[1- (2-methyl-4-pyridinyl) -4-piperi
Dinyl] amino] -6-oxo-2-piperazine acetate (0.
30 g) with a 37% aqueous formaldehyde solution (6.5 ml) and
It was dissolved in formic acid (3.0 ml) and refluxed for 15 hours. reaction
After cooling the solution, add 1N aqueous sodium hydroxide and add
Make it luciferous, extract with dichloromethane, dry and concentrate
did. The obtained residue is crystallized from ethanol to be colorless
The title compound (95 mg) was obtained as crystals.¹ H-NMR (CDCl_Three) δ: 1.21-1.40 (2H, m), 1.53-1.65
(1H, m), 1.88-1.95 (1H, m), 2.43 (3H, s), 2.60-2.83
 (4H, m), 2.84 (3H, s), 3.02-3.20 (1H, m), 3.44-4.
04 (10H, m), 6.41-6.52 (2H, m), 7.62 (1H, dd, J =
8.8, 1.8Hz), 7.79 (1H, dd, J = 8.8, 1.8Hz), 7.94-7.9
8 (3H, m), 8.14 (1H, d, J = 5.4Hz), 8.35 (1H, s) .IR (KBr): 2953, 1732, 1667, 1599, 1543, 1494, 1456,
 1410 cm^-1 Example 1404-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1- (2-methyl
Le- 4-pyridinyl) -4-piperidinyl] amino] -6-oxo-2
-Piperazine Cetamide Methyl 4-[(6-chloro-2-naphthyl) obtained in Example 138
Sulfonyl] -1-[[1- (2-methyl-4-pyridinyl) -4-piperi
Dinyl] amino] -6-oxo-2-piperazine acetate (10
0 mg) and 13% ammonia / ethanol solution (6.0 ml)
Heated in a sealed tube at 90 ° C. for 6 hours. After cooling the reaction solution,
Concentrated down. The obtained residue is subjected to silica gel column chromatography.
Tomography (dichloromethane: 10% ammonia water included)
Purified with methanol with 15: 1), ethyl acetate and di
Crystallization from a mixture of ethyl ether to give colorless crystals
Compound (12 mg) was obtained.¹ H-NMR (CDCl_Three) δ: 1.26-1.57 (2H, m), 1.65-1.82
(2H, m), 2.42 (3H, s), 2.63-3.20 (6H, m), 3.40 (1H,
 d, J = 16.2Hz), 3.71-3.82 (2H, m), 3.95-4.08 (2H,
m), 4.26 (1H, d, J = 16.2Hz), 4.89 (1H, d, J = 5.2H
z), 5.51 (1H, brs), 5.88 (1H, brs), 6.42-6.47 (2H,
m), 7.62 (1H, dd, J = 8.8, 1.6Hz), 7.78 (1H, dd, J
= 8.8, 1.6Hz), 7.93-7.98 (3H, m), 8.12 (1H, d, J =
6.0Hz), 8.34 (1H, s) .IR (KBr): 3281, 3196, 2924, 1667, 1651, 1601, 1539,
 1495, 1454, 1416 cm^-1 Example 1414-[(6-chloro-2-naphthyl) sulfonyl] -1-[[1- (2-methyl
Le- 4-pyridinyl) -4-piperidinyl] amino] -6-oxo-2
-Piperazine vinegar acid Methyl 4-[(6-chloro-2-naphthyl) obtained in Example 138
Sulfonyl] -1-[[1- (2-methyl-4-pyridinyl) -4-piperi
Dinyl] amino] -6-oxo-2-piperazine acetate (1.
17 g), 2N aqueous sodium hydroxide solution (2.0 ml), meta
Mixture of ethanol (20 ml) and 1,4-dioxane (10 ml)
Was stirred at 40 ° C. for 2 hours. After cooling the reaction solution, add 1N hydrochloric acid
And concentrated under reduced pressure. Saturated saline solution for the residue
And extract with dichloromethane containing 10% methanol
After drying, it was concentrated. The residue obtained is ethanol and acetic acid
The title compound (1.
01 g) was obtained.¹ H-NMR (DMSO-d₆) δ: 1.09-1.35 (2H, m), 1.65-1.85
 (2H, m), 2.42 (3H, s), 2.50-2.79 (4H, m), 3.00-4.
10 (8H, m), 5.54 (1H, brs), 7.01-7.04 (2H, m), 7.7
5 (1H, dd, J = 8.8, 2.0Hz), 7.90 (1H, dd, J = 8.8,
2.0Hz), 8.09 (1H, d, J = 6.8Hz), 8.20 (1H, d, J = 8.8
Hz), 8.29-8.33 (1H, m), 8.61 (1H, s), 13.00-13.40
(1H, br) .IR (KBr): 3275, 3086, 2930, 1717, 1644, 1634, 1531,
 1493, 1454, 1420, 1404 cm^-1 Example 142｛[4- (6-chloronaphtha (Len-2-sulfonyl) -2-o
Xo-1-piperazinyl] [1- (4-pyridinyl) -4-piperidini
[Amino] acetonitrile 1-{[1- (tert-butoxycarbonyl) obtained in Reference Example 11
Ru) piperidinyl] amino} -4- (6-chloronaphthalene-2-s
(Ruphonyl) -2-piperazinone (5.23 g), iodoacetonit
Ril (10.00 g), potassium carbonate (1.66 g) and 1-methyl-2-
A mixed solution of pyrrolidinone (100 ml) was heated to 80 ° C under a nitrogen atmosphere.
For 15 hours and cooled. Saturated aqueous sodium bicarbonate was added to the reaction solution.
And extracted with ethyl acetate-tetrahydrofuran (1: 1)
The extract was dried and concentrated. The obtained residue is applied to a silica gel column.
Chromatography (hexane: acetone = 2: 1)
And purified from a mixture of ethyl acetate and diethyl ether.
Crystallized to form colorless crystals of [[1- (tert-butoxycarbonyl) pi
Peridinyl] [4- (6-chloronaphthalene-2-sulfonyl) -2
-Oxo-1-piperazinyl] amino} acetonitrile (0.80
g) was obtained.¹ H-NMR (CDCl_Three) δ: 1.18-1.38 (2H, m), 1.45 (9H,
s), 1.65-1.77 (2H, m), 2.61-2.74 (2H, m), 3.50-3.7
4 (5H, m), 3.78 (1H, d, J = 16.0Hz), 3.99-4.14 (3H,
m), 4.28 (1H, d, J = 16.0Hz), 7.61 (1H, dd, J = 8.8,
1.8Hz), 7.78 (1H, dd, J = 8.8, 1.8Hz), 7.95 (1H, d,
 J = 1.8Hz), 7.95 (2H, d, J = 8.8Hz), 8.35 (1H, s) .IR (KBr): 2980, 2260, 1676, 1630, 1480, 1455, 1420
cm^-1 The obtained {[1- (tert-butoxycarbonyl) piperidinyl]
 [4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1-
Piperazinyl] amino} acetonitrile (765 mg)
Knoll (10 ml), 4N hydrochloric acid in ethyl acetate (3 ml)
Was added and stirred at room temperature for 15 minutes. Concentrate the reaction mixture to obtain
4-bromopyridine hydrochloride (529 mg), N-ethyl
Ludisopropylamine (1.05 g) and ethanol (20 ml)
Was added and the mixture was refluxed for 2 days under an argon atmosphere. Reaction liquid
And 10% aqueous sodium carbonate solution was added to the residue.
The mixture was extracted with dichloromethane, dried and concentrated. Obtained residue
The residue is subjected to column chromatography (dichloromethane: 10
Purified with methanol containing 15% ammonia water = 15: 1)
And crystallized from a mixture of ethyl acetate and diethyl ether.
The title compound (62 mg) was obtained as colorless crystals.¹ H-NMR (CDCl_Three) δ: 1.33-1.48 (2H, m), 1.63-1.74 (1
H, m), 1.80-1.90 (1H, m), 2.70-2.88 (2H, s), 3.54-
3.92 (8H, m), 4.12 (1H, d, J = 16.0Hz), 4.31 (1H,
d, J = 16.0Hz), 6.62 (2H, d, J = 6.6Hz), 7.63 (1H, dd,
 J = 8.8, 1.8Hz), 7.81 (1H, dd, J = 8.8, 1.8Hz), 7.94-
7.99 (3H, m), 8.29 (2H, d, J = 6.6Hz), 8.37 (1H, s) .IR (KBr): 2940, 1669, 1595, 1508, 1454, 1416 cm^-1 Example 143Methyl {[4- (6-chloronaphthalene-2-sulfonyl) -2-o
Xo-1-piperazinyl] [1- (2-methyl-4-pyridinyl) -4-
Piperidinyl] amino} acetate In the same manner as in Example 38 (Method B), 6-chloronaphthale
Colorless crystals using 2--2-sulfonyl chloride (1.04 g).
The title compound (1.05 g) was obtained.¹ H-NMR (CDCl_Three) δ: 1.26-1.50 (2H, m), 1.61-1.67
(1H, m), 1.82-1.90 (1H, m), 2.45 (3H, s), 2.68-2.84
 (2H, m), 3.05-3.19 (1H, m), 3.50-4.12 (13H, m), 6.
42-6.48 (2H, m), 7.62 (1H, dd, J = 8.8, 2.0Hz), 7.8
0 (1H, dd, J = 8.8, 2.0Hz), 7.93-7.98 (3H, m), 8.16
 (1H, d, J = 5.8Hz), 8.36 (1H, s) .IR (KBr): 2953, 2922, 2851, 1748, 1667, 1599, 1543,
 1495, 1454, 1418 cm^-1 Example 144tert-butyl {[4- (6-chloronaphthalene- 2-sulfonyl)-
2-oxo-1-piperazinyl] [1- (2-methyl-4-pi (Rizinil)
-4-Piperidinyl] amino} acetate 1-amino-4- (6-chloronaphthalene-2 obtained in Example 3
-Sulfonyl) -2-piperazinone (544 mg), iodoacetic acid t
ert-butyl (2.14 g), potassium carbonate (166 mg) and 1-
Mixture of methyl-2-pyrrolidone (10 ml) in an argon atmosphere
The mixture was stirred at 80 ° C for 60 hours. After cooling the reaction solution,
, Extracted with dichloromethane, dried and concentrated.
The residue obtained is purified by silica gel column chromatography.
Purified with sun: acetone = 2: 1) to give colorless crystals tert
-Butyl {[4- (6-chloronaphthalene-2-sulfonyl) -2-o
[Oxo-1-piperazinyl] amino} acetate (294 mg) was obtained.
Was.¹ H-NMR (CDCl_Three) δ: 1.43 (9H, s), 3.40-3.45 (2H, m),
 3.46 (2H, d, J = 5.8Hz), 3.65- 3.71 (2H, m), 3.82
(2H, s), 5.34 (1H, t, J = 5.8Hz), 7.61 (1H, dd, J = 8.
8,1.8Hz), 7.79 (1H, dd, J = 8.8, 1.8Hz), 7.94 (1H,
 d, J = 1.8Hz), 8.35 (1H, s) .IR (KBr): 2978, 1732, 1661, 1495, 1456, 1424 cm^-1. The obtained tert-butyl {[4- (6-chloronaphthalene-2-sul
Honyl) -2-oxo-1-piperazinyl] amino} acetate
(250 mg) and 1- (2-methyl-4-pyridinyl) -4-piperidino
(209 mg) in acetic acid (6 ml)
Add sodium borohydride (233 mg) little by little,
For 2 days. After concentrating the reaction solution under reduced pressure, 1N water
Add an aqueous sodium oxide solution to make it alkaline, and add
It was extracted with dichloromethane, dried and concentrated. The resulting residue
Column chromatography (dichloromethane: 10%
Purified with methanol-containing methanol = 17: 1), vinegar
Crystallizes from a mixture of ethyl acetate and diethyl ether and is colorless
The title compound (155 mg) was obtained as crystals.¹ H-NMR (CDCl_Three) δ: 1.26-1.47 (2H, m), 1.37 (9H,
s), 1.55-1.68 (1H, m), 1.80-1.90 (1H, m), 2.44 (3H,
 s), 2.66-2.82 (2H, m), 3.08-3.22 (1H, m), 3.47-3.9
9 (10H, m), 6.43 (1H, dd, J = 5.8, 2.2Hz), 6.48 (1
H, d, J = 2.2Hz), 7.61 (1H, dd, J = 8.8, 1.8Hz), 7.
80 (1H, dd, J = 8.8, 1.8Hz), 7.92-7.97 (3H, m), 8.15
 (1H, d, J = 5.8Hz), 8.35 (1H, s) .IR (KBr): 2932, 1740, 1667, 1599, 1543, 1495, 1454,
 1418 cm^-1 Example 145{[4- (6-chloronaphthalene-2-sulfonyl)- 2-oxo-1-
Piperazinyl] [1- (2-methyl-4-pyridinyl) -4-pi Perigi
Nyl] amino} acetic acid The tert-butyl {[4- (6-chlorona) obtained in Example 144
Phthalene-2-sulfonyl) -2-oxo-1-piperazinyl] [1-
(2-Methyl-4-pyridinyl) -4-piperidinyl] amino} ace
Trif to a mixture of tate (135 mg) and toluene (1 ml)
Luoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 2 hours. Anti
The reaction solution is concentrated under reduced pressure, and the residue is concentrated on a CHP-20 column (water →
25% acetonitrile aqueous solution containing 1% concentrated ammonia water)
The title compound (75 mg) was obtained as a colorless powder.¹ H-NMR (DMSO-d₆) δ: 0.90-1.15 (2H, m), 1.20-1.3
5 (1H, m), 1.60-1.85 (1H, m), 2.31 (3H, s), 2.50-
2.72 (2H, m), 3.17-3.94 (11H, m), 6.48 (1H, dd, J
= 6.0, 2.0Hz), 6.58 (1H, d, J = 2.0Hz), 7.76 (1H, d
d, J = 9.0, 1.8Hz), 7.92 (1H, dd, J = 9.0, 1.8Hz),
8.01 (1H, d, J = 6.0Hz), 8.21 (1H, d, J = 9.0Hz), 8.2
8-8.32 (2H, m), 8.62 (1H, s) .IR (KBr): 3061, 2928, 1645, 1599, 1539, 1495, 1454,
 1418 cm^-1

Formulation Example 1 An FXa inhibitor (eg, a therapeutic agent for deep vein thrombosis, a therapeutic agent for cardiogenic cerebral infarction, etc.) containing a compound represented by the formula (I) or a salt thereof according to the present invention as an active ingredient is For example, it can be produced by the following formulation. After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule.

[0167] 2/3 of (1), (2), (3), (4) and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Formulation Example 2 After dissolving 50 mg of the compound obtained in Example 9 in 50 ml of Japanese Pharmacopoeia distilled water for injection, 10 ml of Japanese Pharmacopoeia distilled water was added.
The volume was 0 ml. The solution was filtered under sterile conditions, and then 1 ml each of the solution was taken, filled into an injection vial under sterile conditions, freeze-dried and sealed.

Experimental Example 1 (1) Human Activated Blood Coagulation Factor X (FXa) Inhibitory Effect Experimental method: 0.05M Tris-HCl buffer (pH 8.
3) 225 μl, 5 μl of sample (dissolve test compound in dimethyl sulfoxide) and human FXa (0.3 unit)
/ Ml) and reacted at 37 ° C. for 10 minutes, and then added 10 μl of substrate (3 mM, S-2765) and reacted at 37 ° C. for 10 minutes. Then, 50% aqueous acetic acid 2
After adding 5 μl to stop the reaction, the change in absorbance at 405 nm was measured with a spectrophotometer, and
% Inhibitory concentration (IC ₅₀ ) was determined.

(2) In Vitro Coagulation Time Measuring Method (2-1) Extrinsic Coagulation Time (PT) Measuring Method: Using PT-Test Wako (Wako Pure Chemical Industries), an automatic blood coagulation time measuring device (STA compact, DIAGNOSTICA) STAGO).
Human normal plasma (fresh human plasma FFP, Sekisui Chemical) 97μ
3 μl of the drug was added per liter, and preliminarily heated at 37 ° C. for 4 minutes. After adding 100 μl of a rabbit brain-derived tissue thromboplastin solution to 50 μl of the above plasma, the time until coagulation was measured. The drug was used by dissolving in dimethyl sulfoxide (DMSO). Coagulation time doubled concentration, DMSO instead of drug
Calculated based on the coagulation time when was added.

(2-2) Intrinsic Coagulation Time (APTT) Measurement Method: Using STA-APTT-LT (DIAGNOSTICA STAGO), an automatic blood coagulation time measurement device (STAcompact, DIAGNOSTICA STAG)
O). Human normal plasma (fresh human plasma FFP,
3 μl of the drug was added to 97 μl of Sekisui Chemical. Plasma 50 μl
Then, 50 μl of an active partial thromboplastin solution was added thereto, and preliminarily heated at 37 ° C. for 4 minutes. 20 mmol / l CaCl ₂ solution
50 μl was added and the time to coagulation was measured. Drug is D
Used dissolved in MSO. The clotting time doubled concentration was calculated based on the clotting time when DMSO was added instead of the drug.

(2-3) Thrombin clotting time (TT) measuring method: Automatic blood clotting time measuring device (Biomatic B10, Sarste
dt). Thrombin from human plasma (Sigm
a) was dissolved in distilled water to give 2.3 NIH units / ml. Human normal plasma (fresh human plasma FFP, Sekisui Chemical) 9
3 μl of the drug was added to 7 μl, and pre-warmed at 37 ° C. for 3 minutes.
For 100 μl of the above plasma, 200 μl of a thrombin solution was added,
The time to coagulation was measured. The drug was used after dissolving in DMSO. The clotting time doubled concentration was calculated based on the clotting time when DMSO was added instead of the drug.

(3) Ex vivo clotting time measurement method (mouse) (3-1) Intravenous administration: Male ICR mouse (25-35 g, Sl
c) was used. Pentobarbital (50 mg / kg, i.
p.) Under anesthesia, the drug was administered once from the tail vein at a volume of 5 ml / kg. Five minutes after administration, 0.3% sodium citrate (Citral, Yamanouchi Pharmaceutical) 1/10 volume was added from the abdominal aorta.
8 ml of blood was collected and centrifuged at 3000 rpm for 15 minutes to obtain plasma. After adding 100 μl of a rabbit brain-derived tissue thromboplastin solution to 50 μl of the above plasma, the time until coagulation was measured. The coagulation time was measured using PT-Test Wako (Wako Pure Chemical)
Automatic blood coagulation time measuring device (STA compact, DIAGNOSTICA
STAGO). The drug was used after being dissolved in physiological saline, and the control group was administered with physiological saline instead of the drug. The activity of the drug was indicated by the ratio (%) of the coagulation time of the drug administration group to the coagulation time of the control group. (3-2) Oral administration: Male ICR mouse (25-35 g, Slc)
It was used. 5 ml / k drug in mice fasted for more than 12 hours
Gavage was administered in a volume of g. One hour after administration, blood was collected from the abdominal aorta under anesthesia with pentobarbital (50 mg / kg, ip). The drug was used by suspending it in 0.5% methylcellulose, and the control group received 0.5% methylcellulose instead of the drug. Others were performed similarly to the above-mentioned experiment of intravenous administration.

(4) In vivo antithrombotic assay method (4-1) Rat arteriovenous shunt method: Umetsu et al. Method (Thromb. Haemostas., 39, 74-73, (1978)). Using a male SD rat (body weight 250-350 g) under pentobarbital (50 mg / kg, ip) anesthesia, an extracorporeal circuit of a polyethylene tube fitted with a silk thread between the left jugular vein and the right jugular vein It was created. To prevent blood coagulation, the tube was previously filled with physiological saline containing heparin (50 U / ml). The blood was circulated for 15 minutes, during which the wet weight of the thrombus attached to the silk thread was measured. The drug was administered orally or intravenously. In the case of oral administration, the drug was suspended in 0.5% methylcellulose and the experiment started.
The animals were dosed (5 ml / kg) under fasting hours before. The control group received 0.5% methylcellulose instead of the drug. In the case of intravenous administration, it was administered at a volume of 1 ml / kg from the tail vein 5 minutes before the start of blood circulation. The drug is dissolved in physiological saline and used.
The control group received physiological saline instead of the drug. The activity of the drug was calculated as the ratio (%) of the wet weight of the drug-administered group to the wet weight of the thrombus of the control group. (4-2) Rat abdominal vena cava partial ligation model Male Sprague-Dawley rat (250-400 g, CLEA Japan)
It was used. The abdominal vena cava thrombus model was used by modifying the method of Finkle et al. (Thromb. Haemostas., 79, 431-438, 1998). Pentobarbital (50mg / kg, ip)
After carefully exfoliating the abdominal vena cava under anesthesia, a thread was placed on the renal vein bifurcation of the abdominal vena cava and 1 cm downstream thereof, and all the branches in between were ligated. A balloon catheter (Fogarty 2F, Baxter) was inserted through the left femoral vein, and injury was caused three times with a balloon inflated with 200-300 ml of air between two threads. After removing the balloon catheter and tying the thread applied to the renal vein bifurcation together with a 26G needle, the needle was removed to create a partial ligation. Thirty minutes later, the other thread was tied, the thrombus formed between the two threads was carefully extracted, and the wet weight of the thrombus was measured using an analytical balance with a windshield (BP110S, Satorius). Further, 2 ml of blood was collected from the abdominal vena cava with 1/10 volume of 3.8% sodium citrate (Citral, Yamanouchi Pharmaceutical), and centrifuged at 3000 rpm for 10 minutes to obtain platelet poor plasma (PPP). The drug was administered orally or intravenously.
In the case of oral administration, the drug was suspended in 0.5% methylcellulose and administered 2 hours before the start of the experiment under fasting (5 ml / kg). The control group received 0.5% methylcellulose instead of the drug. In the case of intravenous administration, administration was performed at a volume of 1 ml / kg from the tail vein 5 minutes before the start of partial ligation. The drug was used after being dissolved in physiological saline, and the control group was administered with physiological saline instead of the drug. The activity of the drug (thrombus formation inhibition rate) was calculated as the ratio (%) of the wet weight of the drug administration group to the wet weight of the control group. (4-3) Rat deep vein thrombosis (DVT) model Male SD rats (body weight: 250 to 350 g) were used.
Under pentobarbital (50 mg / kg, ip) anesthesia,
A polyethylene tube was inserted into the left femoral vein. A silk thread (5 cm in length) connected to a guide wire in advance was inserted into the polyethylene tube, and filled with physiological saline containing heparin (50 U / ml) to prevent blood coagulation. After inserting a polyethylene tube until it reached the abdominal vena cava, the silk thread was left still in the abdominal vena cava using a guide wire. After standing for 30 minutes, heparin (200 U / kg) was intravenously administered via the tail vein. After exsanguination by cutting the brachial artery, the abdomen was opened to remove the silk thread, and the wet weight of the attached thrombus (including the weight of the silk thread) was measured. The drug was administered intravenously at a volume of 1 ml / kg from the tail vein 5 minutes before standing of the silk thread. The drug was used after being dissolved in physiological saline, and the control group was administered with physiological saline instead of the drug. The wet weight of the thrombus alone was calculated from (wet weight of thrombus attached to the silk thread)-(wet weight (11.6 ± 0.2 mg) measured by immersing the silk thread in venous blood collected with heparin). It indicates an IC ₅₀ in the test results in Table 1. This clearly shows that the compound of the present invention exhibits an excellent FXa inhibitory action.

[Table 1]  

[0175]

The compound (I) of the present invention or a salt thereof is
It has an excellent FXa inhibitory effect and has few side effects of bleeding,
It is also useful as an anticoagulant that can be absorbed orally, and is advantageously used for the prevention and treatment of various diseases caused by thrombus and infarction.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/553 A61K 31/553 A61P 7/02 A61P 7/02 9/10 9/10 43/00 111 43 / 00 111 123 123 C07D 401/12 C07D 401/12 401/14 401/14 405/14 405/14 409/14 409/14 411/14 411/14 413/14 413/14 417/14 417/14 495 / 04 105 495/04 105A F-term (reference) 4C063 AA01 AA03 AA05 BB02 BB07 BB09 CC12 CC34 CC62 CC79 DD10 DD12 DD14 DD29 EE01 4C071 AA01 BB01 CC01 CC21 DD12 EE13 FF06 HH01 HH13 JJ05 ACO4A01BC03A01 BC03A01A03A01 BC03 CB29 GA02 GA04 GA07 GA08 GA09 MA01 MA04 NA14 ZA15 ZA16 ZA36 ZA40 ZA54 ZA81 ZC02 ZC35

Claims (44)

[Claims] (1) Formula (1) [In the formula, R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ¹ and R ² each represent a hydrogen atom or an optionally substituted hydrocarbon group, The substituents of R ¹ and R ² or X ¹ and R ² may be bonded to each other to form an optionally substituted ring, and X ¹ and X ² may each be a bond or substituted A good alkylene group or an imino group which may be substituted, D represents an oxygen atom or a sulfur atom,
Represents a -N (R ³⁾ -Y- or -N = Y-, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group, Y good chain substituted Z represents (1) an amino group which may be substituted, (2) an imidoyl group which may be substituted, or (3) a substituted or unsubstituted cyclic group. Shows a good nitrogen-containing heterocyclic group. Or a salt thereof. 2. A prodrug of the compound according to claim 1 or a salt thereof. 3. The compound according to claim 1, wherein R is an optionally substituted hydrocarbon group. 4. The compound according to claim 1, wherein R is an optionally substituted heterocyclic group. 5. The compound according to claim 1, wherein R is an aryl group optionally substituted with a halogen atom or C _2-4 alkenyl. 6. The compound according to claim 1, wherein R is a naphthyl group optionally substituted with a halogen atom. 7. The compound according to claim 1, wherein R is a benzopyranyl group optionally substituted with a halogen atom. 8. R ¹ and R ² are bonded to each other to form —NX
Formula ¹ with ^1- CD-N- Wherein X ³ is an optionally substituted C _1-2 alkylene, X ⁴ is an optionally substituted C _1-3 alkylene,
Represents an oxygen atom or a sulfur atom. The compound according to claim 1, which forms a group represented by the formula: 9. R ¹ and R ² are bonded to each other to form —NX
Formula ¹ with ^1- CD-N- [In the formula, n is 1 or 2, m ″ is 1 or 2, R ⁸ is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, a substituted An optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted A thiocarbamoyl group or a sulfamoyl group which may be substituted, and D represents an oxygen atom or a sulfur atom.]. 10. R ¹ and R ² are bonded to each other to form —N—
With X ¹ -CD-N- [In the formula, n represents 1 or 2, and m represents 2 or 3. The compound according to claim 1, which forms a group represented by the formula: 11. The compound according to claim 10, wherein n = 1 and m = 2. 12. The substituent of X ¹ and R ² are bonded to each other to form a divalent group represented by —X ¹ —CD—N (R ² ) —. [In the formula, X ⁵ represents a bond or an optionally substituted methylene, X ⁶ represents an optionally substituted C _2-3 alkylene, and D represents an oxygen atom or a sulfur atom. The compound according to claim 1, which represents a group represented by the formula: 13. The substituent of X ¹ and R ² are bonded to each other to form a divalent group represented by —X ¹ —CD—N (R ² ) —. [In the formula, n ′ represents 0 or 1, and m ′ represents 2 or 3. ]
The compound according to claim 1, which represents a group represented by the formula: 14. The method according to claim 13, wherein n ′ = 0 and m ′ = 2.
A compound as described. 15. The compound according to claim 1, wherein R ¹ and R ² are each a hydrogen atom or an optionally substituted lower alkyl group. (16) an optionally substituted imino group represented by the formula -N
(R ⁴⁾ - wherein, R ⁴ is a hydrogen atom, a hydrocarbon which may be substituted hydrogen group or an acyl group] compound according to claim 1 is a group represented by. 17. The compound according to claim 1, wherein X ¹ is methylene. 18. The compound according to claim 1, wherein X ² is a bond. 19. The compound according to claim 1, wherein R ³ is a hydrogen atom, an optionally substituted lower alkyl group, formyl or an optionally substituted lower alkanoyl group. 20. The compound according to claim 1, wherein R ³ is a hydrogen atom or a lower alkyl group which may be substituted. 21. The compound according to claim 1, wherein Y is an optionally substituted cyclic hydrocarbon group. 22. The compound according to claim 1, wherein A is —N (R ³ ) —Y— and Y is phenylene which may be substituted. 23. The compound according to claim 1, wherein Y is an optionally substituted heterocyclic group. 24. The compound according to claim 1, wherein Y is an optionally substituted piperidine residue. 25. The compound according to claim 1, wherein Z is a nitrogen-containing heterocyclic group which may be substituted. 26. The compound according to claim 1, wherein D is an oxygen atom. 27. 4- (7-Chloro-2H-benzopyran-3-sulfonyl) -1- [1- (4-pyridyl) piperidin-4-ylamino] -2-
Piperazinone, 4- (6-chloronaphthalene-2-sulfonyl)-
1- [1- (4-pyridyl) piperidin-4-ylamino] -2-piperazinone, 4- (6-bromonaphthalene-2-sulfonyl) -1- [1-
(4-pyridyl) piperidin-4-ylamino] -2-piperazinone, 4- (7-bromo-2H-benzopyran-3-sulfonyl) -1- [1
-(4-pyridyl) piperidin-4-ylamino] -2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl
[1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4- (6-bromonaphthalene-2-sulfonyl) -1- {methyl [1- (4-pyridyl) piperidin-4- Yl] amino} -2-piperazinone, 4- (7-bromo-2H-benzopyran-3-sulfonyl) -1- {methyl [1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1- {ethyl [1- (4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (2-methyl-4-pyridyl) piperidin-4-yl] amino} -2-piperazinone, {[4- (6-chloronaphthalene-2-sulfonyl) -2-oxo-1 -Piperazinyl] [1-
(2-methyl-4-pyridyl) -4-piperidinyl] amino} acetic acid,
4- (6-chloronaphthalene-2-sulfonyl) -1-{[1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxylic acid, 4- (6-chloronaphthalene- 2-sulfonyl) -1-
{Methyl [1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxylic acid, 4- (6-chloronaphthalene
2-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazinecarboxamide, 4- (6-chloronaphthalene-2-sulfonyl)- 1- {methyl
[1- (2-Methyl-4-pyridyl) -4-piperidinyl] amino} -6-
Oxo-2-piperazinecarboxylic acid amide, 4- (6-chloronaphthalene-2-sulfonyl) -6-hydroxymethyl-1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone , 6-Aminomethyl-4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl]
Amino} -2-piperazinone, 6-acetylaminomethyl-4-
(6-chloronaphthalene-2-sulfonyl) -1- {methyl [1- (4-
Pyridyl) -4-piperidinyl] amino} -2-piperazinone, 4
-(6-chloronaphthalene-2-sulfonyl) -1-{[1- (4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazineacetic acid and 4- (6-chloronaphthalene-2- Sulfonyl) -1-{[1-
(2-methyl-4-pyridyl) -4-piperidinyl] amino} -6-oxo-2-piperazineacetic acid or a salt thereof. [28] a prodrug of the compound according to [27] or a salt thereof; 29. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof. 30. The composition according to claim 29, which is an anticoagulant. 31. The composition according to claim 29, which is an activated blood coagulation factor X inhibitor. 32. The composition according to claim 29, which is a prophylactic / therapeutic agent for myocardial infarction, cerebral thrombosis or deep vein thrombosis. 33. A compound of the formula (II): RSO ₂ Q wherein Q is a leaving group and the other symbols are as defined in claim 1. ]
Or a salt thereof and a compound of the formula (III): [The symbols in the formula are as defined in claim 1. Or a salt thereof; a compound represented by the formula (IV): [Wherein Q ¹ represents a leaving group, and the other symbols have the same meanings as in claim 1]. And a salt thereof, and a compound represented by the formula (V): [The symbols in the formula are as defined in claim 1. Or a salt thereof; a compound represented by the formula (VI): [The symbols in the formula are as defined in claim 1. And a salt thereof and a compound of the formula (VII): Wherein, A ¹ is Q ¹ -Y- or O = Y- indicates, Q ¹
Represents a leaving group, and the other symbols have the same meanings as in claim 1. Or a salt thereof;
Formula (VIII) [In the formula, Q ³ represents a hydrogen atom or a leaving group, and other symbols have the same meanings as in claim 1. And a salt thereof and a compound of the formula (IX): [In the formula, Q ⁴ represents a hydrogen atom or a leaving group, and the other symbols have the same meanings as in claim 1. The method for producing a compound or a salt thereof according to claim 1, wherein the compound or a salt thereof is reacted. 34. The formula: [Wherein, L ^1a and L ^2a each represent a hydrogen atom or an amino-protecting group, and indicate that R ^{1 ′} and R ^{2 ′} are bonded to each other to form an optionally substituted ring. Or that R ^{1 ′} is a hydrogen atom or an optionally substituted hydrocarbon group, and that the substituent of X ¹ and R ^{2 ′} are bonded to each other to form an optionally substituted ring. And other symbols have the same meanings as in claim 1. Or a salt thereof. 35. R ^{1 ′} and R ^{2 ′} are bonded to each other to form —N
With -X ¹ -CD-N- Wherein X ³ is an optionally substituted C _1-2 alkylene, X ⁴ is an optionally substituted C _1-3 alkylene,
Represents an oxygen atom or a sulfur atom. 35. The compound according to claim 34, which forms a group represented by the formula: 36. R ^{1 ′} and R ^{2 ′} are bonded to each other to form —N
With -X ¹ -CD-N- [In the formula, n is 1 or 2, m ″ is 1 or 2, R ⁸ is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, a substituted An optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted A thiocarbamoyl group or a sulfamoyl group which may be substituted, and D represents an oxygen atom or a sulfur atom.]. 37. R ^{1 ′} and R ^{2 ′} are bonded to each other to form —N
With -X ¹ -CD-N- [In the formula, n represents 1 or 2, and m represents 2 or 3. 35. The compound according to claim 34, which forms a group represented by the formula: 38. The compound according to claim 37, wherein n = 1 and m = 2. 39. The substituent of X ¹ and R ^{2 ′} are bonded to each other to form a divalent group represented by —X ¹ —CD—N (R ^{2 ′} ) — [In the formula, X ⁵ represents a bond or an optionally substituted methylene, X ⁶ represents an optionally substituted C _2-3 alkylene, and D represents an oxygen atom or a sulfur atom. 35. The compound according to claim 34, which represents a group represented by the formula: 40. The substituent of X ¹ and R ^{2 ′} are bonded to each other to form a divalent group represented by —X ¹ —CD—N (R ^{2 ′} ) —. [In the formula, n ′ represents 0 or 1, and m ′ represents 2 or 3. ]
35. The compound according to claim 34, which represents a group represented by the formula: 41. An apparatus according to claim 40, wherein n ′ = 0 and m ′ = 2.
A compound as described. 42. The formula: [Wherein R ^{1 ′} and R ^{2 ′} indicate that they are bonded to each other to form an optionally substituted ring,
^{1 ′} represents a hydrogen atom or an optionally substituted hydrocarbon group, and the substituent of X ¹ and R ^{2 ′} are bonded to each other to form an optionally substituted ring, The symbols have the same meaning as in claim 1. ] An enzyme inhibitor or receptor modulator comprising a compound having a divalent group represented by the following formula or a salt thereof. 43. The agent according to claim 42, which is an activated blood coagulation factor X inhibitor. 44. The agent according to claim 42, which is a prophylactic / therapeutic agent for myocardial infarction, cerebral thrombosis or deep vein thrombosis.