JPH11236372A - Sulfonamide derivative, its production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a specific inhibiting action against the activated blood coagulation factor X (hereinafter referred to FXa), effective on oral administration and useful for preventing and treating diseases caused by ischemia, thrombus or infarct as a safe medicine. SOLUTION: A compound of formula I (R<1> is a hydrocarbon group or a heterocyclic group; the ring A is a divalent nitrogen-containing heterocyclic group which may be substituted by one or more other groups; Y is a divalent hydrocarbon group or a divalent heterocyclic group; X is a binding hand or an alkylene; Z is an amino group substituted by a hydrocarbon group, an imidoyl group or the like; wherein when X and Z are the binding hand and a six- membered aromatic nitrogen-containing heterocyclic group, respectively, Y is a divalent hydrocarbon group or a divalent unsaturated heterocyclic group) or its salt, for example, 1-(6-chloronaphthalene-2-sulfonyl)-4-[4-(4-pyridyl)- benzoyl]piperazine. The compound of formula I is obtained, for example, by reacting a compound of the formula: R<1> SO2 Q (Q is a halogen) with a compound of formula II (the ring A is a nitrogen-containing heterocyclic group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to activated blood coagulation X.
The present invention relates to a novel sulfonamide derivative which has an anticoagulant effect by inhibiting factor (FXa) and is useful as a medicament, its production method and use.

[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. Heretofore, compounds having an FXa inhibitory action have been described in, for example, JP-A-5-208946,
O 96/16940, WO 96/40679 and W
O 96/10022.

[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 medicament which has a specific inhibitory effect on FXa, is effective by oral administration, and is safe for the prevention or treatment of diseases based on ischemia, thrombus or infarction. The present invention provides useful novel sulfonamide derivatives. The present inventors have conducted various studies and found that an amino group substituted with a divalent nitrogen-containing heterocyclic group between a sulfonyl group and a carbonyl group and a terminal hydrocarbon group,
Having an imidoyl group or a nitrogen-containing heterocyclic group,

Embedded image [Wherein, R ¹ represents a hydrocarbon group or a heterocyclic group, each of which may be substituted;

Embedded image X represents a divalent nitrogen-containing heterocyclic group which may be further substituted in addition to the group represented by Is a bond or an optionally substituted alkylene chain; Z is (1) an amino group substituted with an optionally substituted hydrocarbon group; (2) an imidoyl group optionally substituted; or (3) It represents a nitrogen-containing heterocyclic group which may be substituted.
Provided that X is a bond and Z may be substituted 6
When it is a membered aromatic nitrogen-containing heterocyclic group, Y is an optionally substituted divalent hydrocarbon group or divalent unsaturated heterocyclic group. (Hereinafter sometimes abbreviated as compound (I)) or a salt thereof 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 of a prophylactic / therapeutic agent for diseases based on thrombus or infarction, and based on these, completed the present invention.

That is, the present invention relates to (1) the compound (I) or a salt thereof, (2) the compound according to claim 1, wherein R ¹ is an optionally substituted hydrocarbon group, and (3) a compound wherein R ¹ is halogen. The compound according to the above (1), wherein the ring A is an aryl group optionally substituted with an atom;

Embedded image Wherein B is CH or a nitrogen atom, and m and n are 2 or 3
Is shown. (5) The compound according to (4), wherein B is a nitrogen atom, (6) the compound according to (4), wherein m and n are 2. And (7) the compound according to (1), wherein Y is a divalent aromatic heterocyclic group which may be substituted, and (8) the compound according to (1), wherein Y is a phenylene group which may be substituted. (9) The compound according to (1), wherein Y is an optionally substituted cyclohexylene group, and (10) the compound according to (1), wherein Z is an optionally substituted nitrogen-containing heterocyclic group. (11) the compound according to (1), wherein Z is an optionally substituted amidino group; (12) the compound according to (1), wherein Z is an optionally substituted guanidino group; 13) Z is (1) a mono- or an alkyl moiety optionally substituted with phenyl; -C _1-6 alkylamino, (2) guanidino, (3) formimidoyl amino, (4) acetimidoyl amino or (5) the piperidino (1) compounds described, (14) Z is formula -
N (R ")-C (R ') = NR or -C (R') = NR
Wherein R ″ is hydrogen or C _1-6 alkyl group, R is hydrogen, C _1-6 alkyl group, C _1-6 alkanoyl group or benzoyl group, R ′ is hydrogen, C _1-6 alkyl group Group, C
_1-6 alkanoyl group, benzoyl group, C _1-6 alkoxy group or C _1-6 alkyl group, amino group optionally having one or two substituents selected from C _1-6 alkanoyl group and benzoyl group (15) wherein Z is a group represented by the formula -NH-C (R ')
ＮＨNH or —C (R ′) ＝ NH wherein R ′ is a substituent 1-2 selected from a C _1-6 alkyl group or a C _1-6 alkyl group, a C _1-6 alkanoyl group and a benzoyl group. (1) a C _1-10 alkyl group, (2) C ₂₋ , a compound represented by the above (1), wherein R ¹ is a group represented by the following formula: ₆ alkenyl group, (3) C _2-6 alkynyl group, (4) C _6-14 aryl group or (5) 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom other than carbon atom. They each contain (i) a 5- to 6-membered aromatic monocyclic heterocyclic group, (ii) an 8- to 12-membered fused aromatic heterocyclic group, and (iii) a 3- to 8-membered saturated or unsaturated non-aromatic. A heterocyclic group selected from a group heterocyclic group,
The groups represented by (1) to (5) are each represented by (a) C
_1-6 alkoxy, halogen, C _1-6 alkyl, C _1-6 alkyl group optionally substituted with amino, hydroxy, cyano or amidino, (b) C _1-6 alkoxy, halogen, C _1-6 alkyl A C _6-14 aryl group optionally substituted with amino, hydroxy, cyano or amidino;
(C) each containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms,
(I) a 5- to 6-membered aromatic monocyclic heterocyclic group, (ii) an 8- to 12-membered fused aromatic heterocyclic group, each of which may be substituted by C _1-6 alkyl, C _1-6 alkanoyl or benzoyl. A heterocyclic group selected from a cyclic group and (iii) a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group, (d) C _1-6 alkyl, C _1-6 alkanoyl, benzoyl, halogenated _Optionally C _1-6 alkoxy-carbonyl, C _1-6
An amino group optionally substituted with alkylimidoyl, formimidoyl or amidino, (e) C _1-6 alkyl, C _1-6 alkanoyl, benzoyl or optionally halogenated C _1-6 alkoxy-carbonyl An imidyl group optionally substituted with (f) a C _1-6 alkyl, C _1-6 alkanoyl, benzoyl or an amidino group optionally substituted with an optionally halogenated C _1-6 alkoxy-carbonyl , (G) C _1-6 alkyl,
A hydroxy group optionally substituted with C _1-6 alkanoyl, benzoyl or optionally halogenated C _1-6 alkoxy-carbonyl, (h) a carboxyl group,
(I) a C _1-6 alkoxy-carbonyl group, (j) an amino optionally having one or two substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl as substituents, Having hydroxy, halogen, nitro, cyano, C _1-6 alkyl optionally substituted with 1 to 5 halogen atoms or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms _Optionally , a C _7-12 aryloxycarbonyl group, and (k) may have one or two substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl as substituents. Amino, hydroxy, halogen, nitro, cyano, C _1-6 alkyl optionally substituted with 1 to 5 halogen atoms or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms May have, C _{6 -10} aryl-C _1-4 alkoxy-carbonyl group, (l) halogen atom, (m) cyano group, (n) nitro group or (o) C _1-6 alkyl, C _3-6 cycloalkyl, C _{6- 10} aryl, C _7-11 aralkyl and heterocyclic group (the heterocyclic group contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (i) 5 to 6 Membered aromatic monocyclic heterocyclic group, (i
i) an 8- to 12-membered fused aromatic heterocyclic group; and (iii)
Selected from a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group), and a ring A may be substituted with a carbonyl group having one substituent.

Embedded image Wherein B is CH or a nitrogen atom, m and n each represent 2 or 3, and ring A is a group represented by the formula

Embedded image Group and formula represented by

Embedded image (A) carboxyl group, (b) C
_1-6 alkoxy-carbonyl group, (c) amino optionally having one or two substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl as substituents,
Hydroxy, halogen, nitro, cyano, 1
To five may have a C _1-6 alkoxy which may be substituted at C _1-6 alkyl or 1-5 halogen atoms substituted with a halogen atom, C _7-12
Amino, hydroxy, halogen, nitro, cyano which may have 1 to 2 substituents selected from aryloxycarbonyl group or (d) substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl ,
C optionally substituted with 1 to 5 halogen atoms
_1-6 alkyl or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms,
Y may be further substituted with a C _6-10 aryl-C _1-4 alkoxy-carbonyl group, and Y is (1) a linear C _1-10
An alkylene group, (2) a C _3-9 cycloalkylene group,
(3) a C _6-10 arylene group, (4) a C _7-10 aralkylene group, (5) a compound containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms.
A 6- or 6-membered divalent aromatic heterocyclic group or (6) a 5- or 6-membered divalent saturated or heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom; An unsaturated non-aromatic heterocyclic group, as defined in the above (1) to (6),
Each represents (a) a halogen atom, (b) a cyano group, (c) a C _1-6 alkyl group optionally substituted with halogen, amino, carboxyl or hydroxy, or (d) 1 to 5 X may be a bond or a linear C _1-6 alkylene which may be substituted with a C _1-6 alkoxy group which may be substituted with a halogen atom, and Z is (1) C _1-10 alkyl. An amino group optionally substituted with one or two substituents selected from a group and a C _6-14 aryl group, (2) a formula —N (R ″) — C (R ′) = NR or — C
(R ′) ＝ NR (wherein, R ″ represents hydrogen or a C _1-6 alkyl group, R represents hydrogen, a C _1-6 alkyl group, a C _1-6 alkanoyl group or a benzoyl group, R ′ Is hydrogen, C _1-6 alkyl group, C _1-6 alkanoyl group, benzoyl group, C
A substituent 1 to 1 selected from a _1-6 alkoxy group or a C _1-6 alkyl group, a C _1-6 alkanoyl group and a benzoyl group;
Represents an amino group which may have 2) or (3) 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to (3) carbon atoms And (a) a halogen atom, (b) an amino group,
(C) halogen, amino, carboxyl or hydroxy substituted optionally C _1-6 alkyl group, (d) carboxyl group, (e) C _1-6 alkoxy - carbonyl group, C ₁ as (f) substituent _-6 alkyl, C _1-6 alkanoyl and benzoyl, optionally having one or two substituents selected from amino, hydroxy, halogen,
Nitro, cyano, C _1-6 alkyl optionally substituted with 1 to 5 halogen atoms or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms , A C _7-12 aryloxycarbonyl group or (g) amino, hydroxy optionally having 1-2 substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl as substituents; Having halogen, nitro, cyano, C _1-6 alkyl optionally substituted with 1 to 5 halogen atoms or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms. The above (1), which is a 5- to 6-membered aromatic or non-aromatic monocyclic nitrogen-containing heterocyclic group which may be substituted with a C _6-10 aryl-C _1-4 alkoxy-carbonyl group. (17) 1- (6-chloronaphthalene-
2-sulfonyl) -4- [4- (4-pyridyl) -benzoyl] piperazine, 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (1H
-Imidazol-1-yl) benzoyl] piperazine, 1- (6-
Chloronaphthalene-2-sulfonyl) -4- [2- (4-pyridyl) -4
-Methyl-5-thiazolylcarbonyl] piperazine, 1- (tran
s-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine, 1- (6-chloronaphthalene-2-sulfonyl) -4- (tra
(ns-4-guanidinocyclohexane-1-ylcarbonyl) piperazine or a salt thereof, the compound according to the above (1), (18) a pharmaceutical composition comprising the compound (I) or a salt thereof, (19) the composition according to (18), which is an anticoagulant; (20) the composition according to (18), which is an activated blood coagulation factor X inhibitor;
1) Prevention of myocardial infarction, cerebral thrombosis or deep vein thrombosis
The composition according to the above (18), which is a therapeutic agent,

(22) Formula R ¹ SO ₂ Q (II) wherein Q is a halogen atom, and other symbols are as defined in the above (1). A compound (II) or a salt thereof represented by the formula

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

Embedded image [In the formula, ring A represents a nitrogen-containing heterocyclic group which may be further substituted, and other symbols have the same meanings as described in the above (1). A compound represented by the formula (IV):

Embedded image [The symbols in the formula have the same meanings as described in the above (1). A method for producing compound (I) or a salt thereof, which comprises reacting compound (V) or a salt thereof or a reactive derivative thereof represented by the formula:

Embedded image [The symbols in the formula have the same meanings as described in the above (1). (DI) or a salt thereof, and a compound represented by the formula R ¹⁰ OH, wherein R ¹⁰ represents a lower alkyl group. A compound represented by the formula (D-II) or a salt thereof:

Embedded image [The symbols in the formula are as defined above. A method for producing the compound (D-III) or a salt thereof represented by the formula (24):

Embedded image [The symbols in the formula have the same meanings as described in the above (23). (D-III) or a salt thereof represented by the formula

Embedded image [Wherein, R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group. ]
A compound represented by the formula (D-IV) or a salt thereof:

Embedded image [The symbols in the formula are as defined above. A method for producing the compound (DV) or a salt thereof represented by the formula:

Embedded image [In the formula, ring B represents an optionally substituted divalent non-aromatic heterocyclic group, and other symbols have the same meanings as described in the above (1). Or a salt thereof represented by the formula (EI):

Embedded image [In the formula, R ¹⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ¹⁵ represents a lower alkyl group, U represents an oxygen atom or a sulfur atom, V represents a hydrogen atom, Represents an optionally substituted hydrocarbon group or an amino group which may be substituted with an optionally substituted hydrocarbon group. A compound represented by the formula (E-III) or a salt thereof:

Embedded image [The symbols in the formula are as defined above. And a method for producing the compound (E-IV) or a salt thereof, and (26)
formula

Embedded image [Wherein, R ¹³ represents a hydrogen atom or a hydrocarbon group which may be substituted, and other symbols have the same meanings as described in the above (1). Or a salt thereof represented by the formula (E-II):

Embedded image [In the formula, R ¹⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ¹⁵ represents a lower alkyl group, U represents an oxygen atom or a sulfur atom, V represents a hydrogen atom, Represents an optionally substituted hydrocarbon group or an amino group which may be substituted with an optionally substituted hydrocarbon group. A compound represented by the formula (E-III) or a salt thereof:

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

In the above formula, R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group (preferably, an optionally substituted hydrocarbon group). R ¹
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 And C _1-10 alkyl groups such as nonyl (preferably C _1-6 alkyl). Examples of the alkenyl group include vinyl, allyl, isopropenyl, 2-methylallyl,
-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-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl C _{2 -6} alkenyl group 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 a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group and a cycloalkanedienyl 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 C _3-6 cycloalkenyl groups such as -yl and 1-cyclopenten-1-yl. The “cycloalkanedienyl group” includes, for example, C _4-6 such as 2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl and 2,5-cyclohexanedien-1-yl.
And cycloalkanedienyl groups. Examples of the `` aryl group '' as an example of a hydrocarbon group include a monocyclic or fused polycyclic aromatic hydrocarbon group, for example, phenyl,
C _6-14 aryl groups such as naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like are preferable, and phenyl, 1-naphthyl, 2-naphthyl and the like are particularly preferable.

The heterocyclic group of the "optionally substituted heterocyclic group" for R ¹ includes, for example, an oxygen atom, a sulfur atom, a nitrogen atom and the like as an atom (ring atom) constituting a ring system. An aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from the group consisting of a saturated or unsaturated heterocyclic group; And an aromatic heterocyclic group (aliphatic heterocyclic group). 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, furazanil, 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 fused aromatic heterocyclic groups such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like (for example, benzofuranyl, isobenzofuranyl, Benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl , Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinil, phenoxazinyl, phenothiazinyl Phenazinyl, phenoxathiinyl, thianthrenyl, Fenatorijiniru, Fenatororiniru, 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-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.
) Saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group). R ¹
As the substituents of the `` optionally substituted hydrocarbon group '' and the `` optionally substituted heterocyclic group '' represented by
For example, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, an aryl group which may be substituted, a cycloalkyl group or a cycloalkenyl group which may be substituted An optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted imidoyl group, an optionally substituted amidino group, an optionally substituted hydroxyl group, A thiol group, a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted, a halogen atom (for example, fluorine, chlorine, bromine, iodine and the like, preferably chlorine , Bromine and the like), a cyano group, a nitro group, an acyl group derived from sulfonic acid, an acyl group derived from carboxylic acid, and the like. 1 to 5 optional substituents these are at substitutable positions (preferably 1 to 3) may be substituted.

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, 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.), amino groups,
Examples thereof include a hydroxyl group, a cyano group, and an amidino group, and one or two of these optional substituents may be substituted at substitutable positions. Examples of the cycloalkyl group in the "optionally substituted cycloalkyl group" as a substituent include, for example, cyclopropyl, cyclobutyl, cyclopentyl,
And C _3-7 cycloalkyl groups such as cyclohexyl and cycloheptyl. 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 _3-6 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 methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
C ₁ such as n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, etc. _-6 alkyl and the like. 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 the substituent include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,
-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-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-C _2-6 alkenyl group hexenyl, etc. Is mentioned. 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 the substituent include ethynyl, 1-propynyl,
-Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl And C _2-6 alkynyl groups. 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, furazanil, 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 fused aromatic heterocyclic groups such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like (for example, benzofuranyl, isobenzofuranyl, Benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl , 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-triazolo [4,3- a ] pyridyl, 1, An 8- to 12-membered aromatic condensed heterocyclic group such as 2,4-triazolo [4,3- b ] pyridazinyl (preferably, the 5- or 6-membered aromatic monocyclic heterocyclic group is a benzene ring Or a heterocyclic ring condensed with
A heterocyclic ring in which two identical or different heterocyclic rings of a membered aromatic monocyclic heterocyclic group 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. ) Saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group).

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). An acyl group (eg, formyl, acetyl,
C _1-6 alkanoyl such as propionyl and pivaloyl, benzoyl and the like). As the substituent, "optionally substituted amino group", "optionally substituted imidoyl group", "optionally substituted amidino group",
Examples of the substituent in the “optionally substituted hydroxyl group” and the “optionally substituted thiol group” include a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, A C _1-6 alkyl group such as hexyl), an acyl group (C
_1-6 alkanoyl (eg, formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl, etc., optionally halogenated C _1-6 alkoxy-carbonyl (eg, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxy) Carbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), but the “amino group” in the “optionally substituted amino group” as a substituent may be substituted It may be substituted with an imidoyl group (for example, C _1-6 alkylimidoyl, formylimidoyl, amidino, etc.), and two substituents form a cyclic amino group together with a nitrogen atom. The cyclic amino group in such a case 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),
Aralkyl groups (for example, C _7-10 such as benzyl and phenethyl);
Aralkyl group, etc.), aryl group (for example, phenyl, 1-
Examples thereof include a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino such as 1-piperazinyl which may have a C _6-10 aryl group such as naphthyl and 2-naphthyl.

"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" refers to a carbamoyl group having one substituent on a nitrogen atom, such as a lower alkyl group (e.g., methyl,
A C _1-6 alkyl group such as ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), a cycloalkyl group (eg, cyclopropyl,
C such as cyclobutyl, cyclopentyl, cyclohexyl, etc.
_3-6 cycloalkyl group, etc.), aryl group (eg, C _6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl group (eg, C _7-10 aralkyl group such as benzyl, phenethyl and the like, preferably Is a phenyl-C _1-4 alkyl group and the like, and a heterocyclic group (for example, the same as the “heterocyclic group” as the substituent in the “optionally substituted hydrocarbon group” for R ¹ ) ) And the like.
The lower alkyl group, cycloalkyl group, aryl group, aralkyl group, and heterocyclic group may have a substituent, for example, a hydroxyl group, an amino group which may be substituted [the amino group Is, for example, 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, formyl, acetyl, propionyl, pivaloyl, etc.) Or C _1-6 alkanoyl, benzoyl or the like) as a substituent. ], A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, and a lower alkyl group optionally substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) And a lower alkoxy group which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). Examples of the lower alkyl group include a C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. , Ethyl and the like are preferred. Examples of the lower alkoxy group include C _1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and particularly methoxy, ethoxy and the like. Is preferred. Also,
These substituents may be the same or different and 1 or 2 to 3
(Preferably 1 or 2).

"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 (eg, 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, morpholinocarbonyl, 1-piperazinylcarbonyl and a lower alkyl group at the 4-position (for example, methyl, ethyl, propyl, isopropyl, butyl, t
A C _1-6 alkyl group such as butyl, pentyl, hexyl and the like; an aralkyl group (such as a C _7-10 aralkyl group such as benzyl and phenethyl); an aryl group (such as phenyl, 1-naphthyl and 2-naphthyl). And a 3- to 8-membered (preferably 5 to 6-membered) cyclic amino-carbonyl such as 1-piperazinylcarbonyl which may have a C _6-10 aryl group. Examples of the substituent of the “optionally substituted thiocarbamoyl 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 “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.

In the above formula, ring A represents a divalent nitrogen-containing heterocyclic group which may be further substituted. As the “divalent nitrogen-containing heterocyclic group” in the “optionally substituted divalent nitrogen-containing heterocyclic group” for ring A, a carbon atom is used as an atom (ring atom) constituting a ring system. And a divalent 6- to 8-membered nitrogen-containing nitrogen atom which contains at least one (preferably 1 or 2) nitrogen atom (s) and may further contain 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom. And heterocyclic groups. “Divalent 6- to 8-membered nitrogen-containing heterocyclic group” includes, for example, piperidinediyl (piperidine-
1,2-, 1,3- or 1,4-diyl), piperazinediyl (piperazine-1,2-, 1,3- or 1,4-
Diyl), morpholinediyl (morpholine-2,4- or 3,4-diyl), thiomorpholinediyl (thiomorpholine-2,4- or 3,4-diyl), etc. A 6-membered nitrogen-containing heterocyclic group such as homopiperidindiyl (homopiperidin-1,2-, 1,1
3- or 1,4-diyl), homopiperazinediyl (piperazine-1,2-, 1,3-, 1,4-, 1,5-,
Divalent 7-membered nitrogen-containing heterocyclic group containing 1 or 2 nitrogen atoms such as 1,6- or 1,7-diyl, for example, 1,4-diazacyclooctanediyl (1,4-diazacyclo) Octane-1,2-, 1,3-, 1,4-, 1,5-, 1,
6-, 1,7- or 1,8-diyl), 1,5-diazacyclooctanediyl (1,5-diazacyclooctane-1,2-, 1,3-, 1,4- or 1 , 5-diyl)
And a divalent 8-membered nitrogen-containing heterocyclic group containing 1 or 2 nitrogen atoms.

Examples of the substituent of the "divalent nitrogen-containing heterocyclic group" include a hydroxyl group, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group and an optionally substituted amino group. An optionally substituted lower alkyl group, 1 to 5 halogen atoms (eg, fluorine,
Chlorine, bromine, iodine, etc.), a lower alkoxy group which may be substituted with a carboxyl group which may be esterified, a carbamoyl group which may be substituted, and the like. These optional substituents can be substituted. May be substituted at 1 to 3 (preferably 1 to 2) positions.
Here, the substituent of the “optionally substituted amino group” includes 1 to 2 alkyl groups which may be substituted,
An optionally substituted carbamoyl group, an acyl group derived from sulfonic acid, an acyl group derived from carboxylic acid, and the like,
Examples of the “optionally substituted alkyl group”, “optionally substituted carbamoyl group”, “sulfonic acid-derived acyl group” and “carboxylic acid-derived acyl group” include the above-mentioned R ¹ `` Optionally substituted alkyl group '' as a substituent of the `` optionally substituted hydrocarbon group '', `` optionally substituted carbamoyl group '', `` sulfonic acid-derived acyl group '' and `` carboxylic acid-derived Examples of the "optionally substituted amino group" include the following (1) methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl. A lower (C _1-6 ) alkyl group such as tert-butyl, (2) mono- or di-lower (C
_1-6) alkylcarbamoyl group, (3) methanesulfonyl, C _1-6 alkylsulfonyl such as ethanesulfonyl,
(4) formyl, acetyl, propionyl, C _1-6 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 _1-6 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.), amino group, carboxyl group,
A hydroxyl group and the like can be mentioned, and these optional substituents may be substituted at 1 to 5 (preferably 1 or 2) at substitutable positions. The lower alkoxy group in the "optionally substituted lower alkoxy group optionally substituted with a halogen atom", for example methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec- butoxy, C _1, such as tert- butoxy _-6 alkoxy group and the like, and methoxy, ethoxy and the like are particularly preferable. The “optionally esterified carboxyl group” is the same as the optionally esterified carboxyl group as a substituent of the “optionally substituted hydrocarbon group” represented by R ¹ described above. Is mentioned. As the “optionally substituted carbamoyl group”, the same as the optionally substituted carbamoyl group as the substituent of the “optionally substituted hydrocarbon group” for R ¹ described above can be mentioned. Can be

As the ring A, for example,

Embedded image Wherein B is CH or a nitrogen atom, and m and n are 2 or 3
Is shown. And the like are preferred. In the above formula, B represents CH or a nitrogen atom. B is preferably a nitrogen atom. In the above formula, m and n represent 2 or 3. m and n are preferably 2. As the ring A, piperazinediyl (preferably piperazine-1,4-diyl) is most preferred.

In the above formula, Y is a divalent hydrocarbon group or a divalent heterocyclic group which may be substituted (a divalent hydrocarbon group or a divalent unsaturated heterocyclic group, more preferably , A divalent hydrocarbon group or a divalent aromatic heterocyclic group). Y is preferably a divalent hydrocarbon group or a divalent unsaturated heterocyclic group, each of which may be substituted, and each of which may be substituted, a divalent hydrocarbon group or a divalent aromatic group. A heterocyclic group is more preferable, and among them, a phenylene group, a cyclohexylene group or a divalent aromatic heterocyclic group, each of which may be substituted, is preferable. As the “divalent hydrocarbon group” of the “optionally substituted divalent hydrocarbon group” for Y, a saturated or unsaturated linear or cyclic divalent hydrocarbon group (preferably A saturated linear divalent hydrocarbon group, a saturated cyclic divalent hydrocarbon group or an unsaturated cyclic divalent hydrocarbon group, more preferably a saturated linear divalent hydrocarbon group. A hydrocarbon group, a saturated cyclic divalent hydrocarbon group or a divalent aromatic hydrocarbon group). Here, as the saturated linear divalent hydrocarbon group, a linear alkyl group (for example, methyl,
Ethyl, n-propyl, n-butyl, n-pentyl, n
A terminal hydrogen atom from a C _1-10 alkyl group (preferably C _1-6 alkyl, more preferably C _1-4 alkyl, etc.) such as -hexyl, n-heptyl, n-octyl, n-nonyl, etc. Examples of the removed groups (for example, linear C _1-6 alkylene such as methylene, ethylene, propylene, butylene, and pentylene, and preferably linear C _1-4 alkylene such as methylene and ethylene). Can be Here, as the unsaturated linear divalent hydrocarbon group, a linear alkenyl group (for example, vinyl, allyl,
-Propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl C _2-6 alkenyl group) and the like or straight chain alkynyl groups (e.g., ethynyl etc., 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-hexynyl, 5-C _2-6 hydrogen atoms of the terminal alkynyl groups, etc.) and the like hexynyl, etc. And linear C _2-6 alkenylene or C _2-6 alkynylene such as a group from which one has been removed. Here, as the saturated cyclic divalent hydrocarbon group, a cycloalkyl group (for example,
Any position (preferably, C _3-9 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, preferably C _5-7 cycloalkyl, more preferably cyclohexyl); Hydrogen atoms at different carbon atoms, more preferably at the furthest carbon atom)
A removed group (for example, C _5-7 cycloalkylene, preferably 1,4-cyclohexylene and the like) can be mentioned. 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 _3-6 cycloalkenyl group such as -1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc.), cycloalkanedienyl group (eg, 2,4-cyclopentanedien-1-ene) Yl, 2,4-cyclohexanediene-1
-Yl, a C _4-6 cycloalkanedienyl group such as 2,5-cyclohexanedien-1-yl and the like; an aryl group (for example, a C _6-10 aryl group such as phenyl and naphthyl, 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 substituent of the “optionally substituted divalent hydrocarbon group” represented by Y include the aforementioned A
The same substituents as the “bivalent nitrogen-containing heterocyclic group” represented by the ring are used. As the “divalent heterocyclic group” of the “optionally substituted divalent heterocyclic group” represented by Y,
As atoms (ring atoms) constituting the ring system, in addition to carbon atoms, at least one (preferably one or two) of 1 to 3 (preferably 1 to 2) heteroatoms selected from oxygen, sulfur and nitrogen atoms. Or three, more preferably one
Or 2), a 5- or 6-membered divalent aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like. Examples of the “divalent aromatic heterocyclic group” include, 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, 1,2,3
-Thiadiazole, 1,2,4-thiadiazole, 1,2,
5-thiadiazole, 1,3,4-thiadiazole, 1,
5, such as 2,3-triazole and 1,2,4-triazole
Two different ring atoms from two different ring atoms, such as 6-membered aromatic heterocycles and 6-membered aromatic heterocycles such as, for example, pyridine, pyridazine, pyrimidine, 1,2,4-triazine, 1,3,5-triazine, etc. Examples thereof include a divalent group obtained by removing a hydrogen atom. As the "divalent non-aromatic heterocyclic group", for example, a 5- to 6-membered saturated or unsaturated (preferably saturated) non-aromatic such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, etc. And a heterocyclic group (aliphatic heterocyclic group). Examples of the substituent of the “divalent heterocyclic group” represented by Y include the “divalent nitrogen-containing heterocyclic group” represented by the above-mentioned ring A.
The same substituents as described above are used. Y is preferably a divalent aromatic group which may be substituted.

In the above formula, Z represents an amino group substituted with an optionally substituted hydrocarbon group, an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. The amino group, imidoyl group or nitrogen-containing heterocyclic group is bonded to Y via a “bond or an optionally substituted alkylene chain” represented by X. Examples of the “alkylene chain” in the “optionally substituted alkylene chain” represented by X include linear lower (C _1-6 ) alkylenes such as methylene, ethylene, propylene, butylene, and pentylene. Among them, methylene,
C _1-4 alkylene such as ethylene is preferred. As the substituent of the “alkylene chain”, a lower alkyl group (for example, C _1-6 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like)
Alkyl, etc.), halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), hydroxyl groups, carboxyl groups which may be esterified (the above-mentioned "optionally substituted hydrocarbon groups" represented by R ¹⁾ Examples of the group include the same as the “carboxyl group which may be esterified”), and one or three of these optional substituents may be substituted at substitutable positions. As the “optionally substituted hydrocarbon group” as a substituent in the “optionally substituted hydrocarbon group (mono- or di-substituted) amino group” represented by Z, the above-mentioned R
Examples include the same as the “optionally substituted hydrocarbon group” shown in ¹ , but there are cases where two substituents form a cyclic amino group together with a nitrogen atom. Examples of the cyclic amino group in this case include 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino,
Piperazinyl and a lower alkyl group at the 4-position (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.),
Aralkyl groups (for example, C _7-10 such as benzyl and phenethyl);
Aralkyl group, etc.), aryl group (for example, phenyl, 1-
A 3- to 8-membered (preferably 5 to 6-membered) cyclic amino such as 1-piperazinyl which may have a C _6-10 aryl group such as naphthyl and 2-naphthyl, and the like; The amino group may have the same number of the same substituents as the above-mentioned “optionally substituted hydrocarbon group” for R ¹ . Further, the “optionally substituted hydrocarbon group” as a substituent in the “amino group substituted with an optionally substituted hydrocarbon group” represented by Z is a “substituted or imidoyl group”. When substituted, the “amino group substituted with an optionally substituted hydrocarbon group” represented by Z is an amino group substituted with “an optionally substituted imidoyl group” represented by Z described below. To form, for example, the formula -N (R ")-C
(R ′) = N—R wherein R ″ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R represents a hydrogen atom, an optionally substituted hydrocarbon group or a carboxylic acid-derived R ′ represents a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group derived from a carboxylic acid, an amino group which may be substituted or a hydroxyl group which may be substituted]. And the like are also included in the “amino group substituted with an optionally substituted hydrocarbon group” represented by Z. In the above formula, the “optionally substituted hydrocarbon group” represented by R, R ′ and R ″ includes the aforementioned R ¹
And the same as the "optionally substituted hydrocarbon group" represented by R, and the "carboxylic acid-derived acyl group" represented by R and R 'includes the "substituted substituted group" represented by R ¹ described above. As the substituent which the `` optionally substituted hydrocarbon group '' may have, the same as the `` acyl group derived from carboxylic acid '' may be mentioned, and as the `` optionally substituted hydroxyl group '' represented by R ′ Is the same as the “optionally substituted hydroxyl group” as the substituent which the “optionally substituted hydrocarbon group” represented by R ¹ may have, and R ′ As the “optionally substituted amino group” represented by the above, the “optionally substituted hydrocarbon group” which may be possessed by the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ R ¹ was like or the and also an amino group " Such as "optionally substituted hydrocarbon group" one or two have unprotected amino group represented the like. In the compound represented by the formula (I), a compound in which R is an acyl group derived from a carboxylic acid is represented by R
Are useful as prodrugs of compounds wherein is a hydrogen atom. As the “carboxylic acid-derived acyl group” represented by R, for example, the “carboxylic acid-derived acyl group” as a substituent which the “optionally substituted hydrocarbon group” represented by R ¹ may have The same as the “acyl group”, but the “carboxylic acid-derived acyl group” represented by R is
For example, a carboxyl group which may be esterified, such as a group represented by the formula -COOR '''(whereinR''' represents an optionally substituted hydrocarbon group), and the like. There may be. As the “optionally substituted hydrocarbon group” represented by R ″ ′, for example, those similar to the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ can be mentioned. Preferred examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ″ ′ include, for example, C _1-6 alkyl, C _2-6 alkenyl, C _2-6
3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryl-C _1-4 alkyl and the like. The "hydrocarbon group"
Examples of the substituents which may have, for example, the same number of the same substituents as the above-mentioned "optionally substituted hydrocarbon group" for R ¹ may have No. Examples of the group represented by the formula —COOR ′ ″ include a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, etc.), C _1-6 alkanoyl-C _1-6. Alkoxy-
Carbonyl group (eg, pivaloyloxymethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, acetoxy-tert-butoxycarbonyl, etc.), C _1-6 alkoxy-carbonyloxy-C _1-6 alkoxy-carbonyl group (eg, ethoxy Carbonyloxymethoxycarbonyl, etc.), 5-C _1-4 alkyl-2-oxo-dioxolen-4-yl-C _1-6 alkoxy-carbonyl group (eg, 5
-Methyl-2-oxo-dioxolen-4-ylmethoxycarbonyl) and the like. As the “amino group substituted with an optionally substituted hydrocarbon group” represented by Z, more specifically, for example, a mono- or an optionally substituted aryl group (preferably phenyl) or the like Di-lower (C _1-6 ) alkylamino groups (eg methylamino, ethylamino, benzylmethylamino,
Dimethylamino, diethylamino, diisobutylamino, diisopropylamino, N-ethyl-t-butylamino, benzylmethylamino), guanidino group, formimidoylamino group, acetimidoylamino group, piperidino group and the like. Examples of the "optionally substituted imidoyl group" for Z include, for example, a group represented by the formula -C
And a group represented by (R ′) = NR (the symbols in the formula have the same meanings as described above). 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). Examples include hydrogen, lower alkyl groups (eg, C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl), acyl groups (eg, C _1-6 alkanoyl groups such as formyl, acetyl, propionyl, pivaloyl). Benzoyl, etc.). Preferred examples of R ′ include hydrogen, a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl) and an acyl group (eg, formyl). , acetyl, propionyl, C _1-6 alkanoyl pivaloyl, benzoyl, etc.), amino which may be substituted (E.g., 1-2 of the same or different lower alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, C _1-6 alkyl groups isobutyl) or an acyl group (e.g. formyl, acetyl, propionyl, pivaloyl, etc. Amino group optionally substituted with C _1-6 alkanoyl, benzoyl, etc.), lower alkoxy group (eg, C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy) and the like. No. In the above formula, R ″ and R are preferably hydrogen or a lower alkyl group, and particularly preferably hydrogen. In the above formula, R ′ is preferably hydrogen, a lower alkyl group or an amino group which may be substituted, and among them, a lower alkyl group or an amino group which may be substituted is preferable. Amino groups (preferably, _aminos which may be substituted with C _1-4 alkyl) are preferable.

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, furazanil, 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 aromatic monocyclic nitrogen-containing heterocyclic group 5-6 membered. As the “non-aromatic nitrogen-containing heterocyclic group”, 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 the above-mentioned “divalent nitrogen-containing heterocyclic group” for the ring A are used. 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. However, when X is a bond and Z is a 6-membered nitrogen-containing heterocyclic group which may be substituted, Y may be a divalent hydrocarbon group or a divalent hydrocarbon group which may be substituted. It is preferably a saturated heterocyclic group. Preferred combinations of Y and Z include:
(1) Y is an optionally substituted divalent hydrocarbon group or a divalent heterocyclic group, and Z is an amino group substituted with an optionally substituted hydrocarbon group; An optionally substituted imidoyl group, an optionally substituted 5-membered aromatic nitrogen-containing heterocyclic group or an optionally substituted non-aromatic nitrogen-containing heterocyclic group (preferably an amino-substituted amino group) Group, an optionally substituted imidoyl group or an optionally substituted non-aromatic nitrogen-containing heterocyclic group, more preferably an amino group substituted with a hydrocarbon group or an optionally substituted imidoyl group). Case; (2) Z
Is an amino group substituted with an optionally substituted hydrocarbon group, an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group, and Y may be each substituted A divalent hydrocarbon group or a divalent unsaturated heterocyclic group (preferably each optionally substituted, a divalent hydrocarbon group or a divalent aromatic heterocyclic group, more preferably A phenylene group or a divalent aromatic heterocyclic group which may be substituted; (3)
Z is an optionally substituted 6-membered nitrogen-containing heterocyclic group, and Y is an optionally substituted divalent hydrocarbon group or divalent unsaturated heterocyclic group (preferably, A divalent hydrocarbon group or a divalent aromatic heterocyclic group which may be substituted, more preferably a phenylene group or a divalent aromatic heterocyclic group which may be substituted, respectively) (4) Y is a divalent saturated heterocyclic group, and Z is an amino group substituted with an optionally substituted hydrocarbon group, an imidoyl group optionally substituted, or an optionally substituted 5 Membered aromatic nitrogen-containing heterocyclic group or an optionally substituted non-aromatic nitrogen-containing heterocyclic group (preferably,
An amino group substituted with a hydrocarbon group, an imidoyl group optionally substituted or a non-aromatic nitrogen-containing heterocyclic group optionally substituted, more preferably an amino group substituted with a hydrocarbon group or substituted (5) an amino group substituted with an optionally substituted hydrocarbon group, an optionally substituted imidoyl group, or an optionally substituted 5-membered aromatic group; Group-containing nitrogen-containing heterocyclic group or an optionally substituted non-aromatic nitrogen-containing heterocyclic group (preferably an amino group substituted with a hydrocarbon group, an optionally substituted imidoyl group, or an optionally substituted A non-aromatic nitrogen-containing heterocyclic group, more preferably an amino group substituted with a hydrocarbon group or an optionally substituted imidoyl group), and Y is each optionally substituted. Or a divalent unsaturated heterocyclic group (preferably each of which may be substituted, a divalent hydrocarbon group or a divalent aromatic heterocyclic group, more preferably each of which may be substituted) Phenylene group or divalent aromatic heterocyclic group).

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, Potassium, magnesium, alkali metal salts such as calcium or alkaline earth metal salts, such as trimethylamine,
Organic salts such as salts with tertiary amines such as triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine and the like can be mentioned.

Compound (I) or a salt thereof can be produced, for example, by the following method. 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 formula

Embedded image [In the formula, Q represents a halogen atom, and the other symbols have the same meanings as described above. A compound (II) or a salt thereof represented by the formula

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 halogen atom. Examples of the halogen atom represented by Q include fluorine, chlorine, bromine, iodine and the like. This method is carried out by reacting compound (II) or a salt thereof with compound (III) or a salt thereof.
Alternatively, examples of the salt of (III) include an acid addition salt of the compound (I) with an acid which forms an acid addition salt.

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, for example, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide, sulfolane (tetramethylene sulfone), hexamethylphosphoramide, and water alone or in a mixed solvent Used as 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 hydrogen carbonate.
For example, triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N
Tertiary amines such as -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 is about -80 ° C to about 100 ° C, preferably about -5 ° C.
0 ° 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 72 hours, preferably about 15 hours.
Minutes to about 24 hours.

Method B formula

Embedded image [The symbols in the formula are as defined above. A compound represented by the formula (IV):

Embedded image [The symbols in the formula are as defined above. The compound (I) or a salt thereof can be produced by reacting the compound (V) or a salt thereof or a reactive derivative thereof represented by the following formula: This method comprises the step of reacting compound (IV) or a salt thereof with free acid (V) or a salt thereof (inorganic salt, organic salt, etc.) or a reactive derivative thereof (for example, acid halide, acid azide, acid anhydride,
Reaction with a mixed acid anhydride, active amide, active ester, active thioester, or the like. Examples of the salt of the compound (IV) 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 (V), 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, for example, 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, for example, acid chloride and acid bromide, and examples of the mixed acid anhydride include mono-C _1-4 alkyl carbonic acid mixed acid anhydrides (eg, free acid (V) and monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisopropyl carbonate). isobutyl carbonate, mono-tert- butyl carbonate, monobenzyl carbonate, mono (p- nitrobenzyl) carbonate, mixed acid anhydride with monoallyl carbonate), C _1-6 aliphatic carboxylic acid mixed acid anhydride (e.g., the free acid ( V) and mixed acid anhydrides of acetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, etc.), _C7-11 aromatic Mixed acid anhydrides of carboxylic acids (for example, mixed acid anhydrides of free acid (V) and benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc.), and mixed acid anhydrides of organic sulfonic acids (for example, Tansulfonic acid, ethanesulfonic acid, benzenesulfonic acid, mixed acid anhydrides with p-toluenesulfonic acid, etc., and the like as amides with nitrogen-containing heterocyclic compounds (for example, free acid (V) and pyrazole, Acid amides with imidazole, benzotriazole and the like, and these nitrogen-containing heterocyclic compounds are C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C _{1 -6} alkoxy (eg, methoxy, ethoxy,
Substituted with a halogen atom (eg, fluorine, chlorine, bromine, etc.), oxo, thioxo, C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, butylthio, etc.). May be used).

Examples of the active ester include organic phosphates (eg, diethoxy phosphate, diphenoxy phosphate, etc.), p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, and the like. 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 heterocyclic rings 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,
May be substituted with a propoxy, isopropoxy, butoxy, tert-butoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, etc.), a C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, butylthio, etc.) (Eg, 2-pyridylthiol ester, 2-benzothiazolylthiol ester) and the like. This reaction is generally performed in a solvent, and if necessary, a base or a condensing agent (for example, carbodiimides (DCC, W
SC, 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 was performed with compound (IV) 1
The amount of the compound (V) is about 1 to about 5 mol, preferably about 1 to about 2 mol, per mol. Reaction temperature is about -50 ° C
To about 150 ° C, preferably from about -20 ° C to about 10 ° C.
0 ° C. The reaction time varies depending on the type of compound (IV) or (V), the type of solvent and base, the reaction temperature, etc.
Usually about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours.

Method C formula

Embedded image [In the formula, T represents a halogen atom or —O—SO ₂ R ⁴ (R ⁴ represents a lower alkyl group which may be substituted with a halogen atom or a phenyl group which may have a substituent.)
Other symbols are as defined above. In the formula (VI), the halogen atom represented by T is
For example, fluorine, chlorine, bromine, iodine and the like can be mentioned. In the above formula, examples of the lower alkyl group represented by R ⁴ include methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, sec-butyl, tert-butyl, pentyl,
C _1-6 alkyl groups such as isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl 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 ⁴ include trichloromethyl, trifluoromethyl and the like. Examples of the substituent of the phenyl group represented by R ⁴ include a lower alkyl group (similar to the lower alkyl group represented by R ⁴ ) and a lower alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.) C _1-6 alkoxy group), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group,
A cyano group, a carboxyl group or the like is used.

This method is carried out by reacting compound (VI) with compound (VII). This reaction 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, isopropanol, butanol, tert-
Alcohols such as butanol, for example, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethers such as ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate, n-butyl acetate, for example, dichloromethane Halogenated hydrocarbons such as chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane, for example, hydrocarbons such as n-hexane, benzene and toluene; for example, formamide, N, N-dimethylformamide, N, N- Amides such as dimethylacetamide, for example, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, for example, nitriles such as acetonitrile, propionitrile, etc., as well as dimethyl sulfoxide, sulfolane, Xamethylphosphoramide,
Water or the like is used alone or as a mixed solvent.

This reaction may be carried out in the presence of a base, such as potassium hydride,
Alkali metal hydrides such as sodium hydride, for example, C1-C6 metal alkoxides such as lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, for example, hydroxide Inorganic bases such as lithium, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like, for example, triethylamine, tri (n-propyl) amine, tri (n-butyl)
Amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine,
N, N-dimethylaniline, N-methylpiperidine, N
Tertiary amines such as -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). Reaction temperature is about -30 ° C
To about 250C, preferably from about -10C to about 20C.
0 ° C. The reaction time varies depending on the type of the compound (VI) or (VII), the type of the solvent, the reaction temperature and the like.
Minutes to about 72 hours, preferably about 15 minutes to about 24 hours.
Time.

Method D formula

Embedded image [The symbols in the formula are as defined above. And a salt thereof with a compound represented by the formula: R ¹⁰ OH wherein R ¹⁰ represents a lower alkyl group. By reacting the compound (D-II) or a salt thereof represented by the formula

Embedded image [The symbols in the formula are as defined above. (D-III) or a salt thereof.
In the above formula, examples of the lower alkyl group represented by R ¹⁰ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl,
-Ethylpropyl, hexyl, isohexyl, 1,1-
Examples thereof include C _1-6 alkyl groups such as dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Among them, C _1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl are _exemplified. Alkyl groups are preferred. In this reaction, compound (D-1) and compound (DI)
Reacting with (I) to produce compound (D-III).
This reaction is usually performed in a solvent, and the compound (D-II)
In addition to the solvent itself, a solvent that does not inhibit the reaction is appropriately selected as a mixed solvent. Examples of such a solvent include ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, dimethoxyethane, ethylene glycol-dimethyl ether, and esters such as ethyl formate, ethyl acetate, and n-butyl acetate. Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene, and 1,2-dichloroethane; for example, hydrocarbons such as n-hexane, benzene, and toluene; for example, formamide, N, N-dimethylformamide; In addition to amides such as N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent. This reaction is generally performed in the presence of an acid or base catalyst. Examples of the acid catalyst include hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid and phosphoric acid, and organic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, and toluenesulfonic acid are used. Among them, hydrohalic acids such as hydrochloric acid and hydrobromic acid are used. Is preferred. As the base catalyst, a metal alkoxide of the compound (D-II) is used. As such a metal, an alkali metal such as sodium, potassium and lithium is preferably used. In the reaction, about 1 to about 10,000 mol of the compound (D-II) is added to 1 mol of the compound (DI),
Preferably about 1 to about 1000 moles are used. The amount of the catalyst is appropriately selected and used in the range of about 0.001 mol to a large excess with respect to 1 mol of the compound (DI). The reaction temperature is about -50 ° C to about 150 ° C, preferably -30 ° C.
C. to about 100.degree. The reaction time was determined using the compound (D-
The time is usually about 1 minute to about 96 hours, preferably about 30 minutes to about 48 hours, depending on the type of I) or (D-II), the type of solvent, the reaction temperature and the like. Next, the compound (D-III) has the formula

Embedded image [Wherein, R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group. ]
By reacting a compound (D-IV) or a salt thereof represented by the formula:

Embedded image [The symbols in the formula are as defined above. ] (DV) or a salt thereof can be produced. This method is performed by reacting compound (D-III) with compound (D-IV). 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, tricrene (trichloroethylene) and 1,2-dichloroethane, for example, n-hexane, benzene , Hydrocarbons such as toluene, for example, formamide,
In addition to amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide and the like are used alone or as a mixed solvent. The reaction is carried out with compound (D-III)
The compound (D-IV) is used in an amount of about 1 mol or more, usually a large excess, per 1 mol. The reaction temperature is about -50 ° C to about 150 ° C, preferably about -30 ° C to about 100 ° C. The reaction time is determined using compound (D-III) or (DI)
V) depends on the type, solvent type, reaction temperature, etc.
Usually about 15 minutes to about 120 hours, preferably about 30 minutes to about 96 hours. Method E formula

Embedded image [In the formula, ring B represents an optionally substituted divalent non-aromatic heterocyclic group, and the other symbols have the same meanings as described above. ]
And a salt thereof represented by the formula (EI):

Embedded image [In the formula, R ¹⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ¹⁵ represents a lower alkyl group, U represents an oxygen atom or a sulfur atom, V represents a hydrogen atom, Represents an optionally substituted hydrocarbon group or an amino group which may be substituted with an optionally substituted hydrocarbon group. By reacting the compound (E-III) or a salt thereof represented by the formula

Embedded image [The symbols in the formula are as defined above. ] Or a salt thereof. Also, the formula

Embedded image [In the formula, R ¹³ represents a hydrogen atom or a hydrocarbon group which may be substituted, and other symbols have the same meanings as described above. ]
Or a salt thereof with a compound (E-II)
-III) or a salt thereof to obtain a compound of the formula

Embedded image [The symbols in the formula are as defined above. ] (EV) or a salt thereof. In the formulas (EI) to (EV), the “optionally substituted divalent non-aromatic heterocyclic group” represented by ring B includes the “substituted substituted” represented by Y described above. And the optionally substituted divalent non-aromatic heterocyclic group exemplified as the "optionally divalent heterocyclic group", and the non-aromatic heterocyclic ring includes a 5- to 8-membered ring (Preferably 5-6
Is preferred, and a saturated heterocyclic ring is more preferred.
Examples of the “optionally substituted hydrocarbon group” represented by R ¹³ , R ¹⁴ and V include the same as the “optionally substituted hydrocarbon group” represented by R ¹ described above, As the “lower alkyl group” for R ¹⁵ , the same as the “lower alkyl group” for R ¹⁰ described above can be mentioned, and for the “optionally substituted hydrocarbon group” for V As the amino group optionally substituted with
And an amino group which may have one or two “optionally substituted hydrocarbon groups” represented by R ¹ described above. This reaction is carried out with compound (EI) or (E-II)
And compound (E-III). 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, and 1,2-dichloroethane; for example, n-hexane, benzene, and toluene Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone ,
For example, in addition to nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent. This reaction is usually performed in the presence of a base. As the base to be used, for example, trimethylamine,
Triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine,
Cyclohexyldimethylamine, pyridine, lutidine,
Tertiary amines such as γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine; alkali metal salts such as sodium hydrogen carbonate, potassium carbonate; potassium hydroxide, sodium hydroxide Alkali hydroxides; alkoxides such as sodium methoxide; and the like. In the reaction, about 1 to about 100 mol, preferably about 1 to about 50 mol, of compound (E-III) is used per 1 mol of compound (EI) or (E-II). Reaction temperature is about -30 ° C
To about 250C, preferably from about -10C to about 20C.
0 ° C. The reaction time was determined using the compounds (EI), (EI)
The time is usually about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours, depending on the type of I) or (E-III), the type of solvent, the reaction temperature and the like. Starting compound (II) used in the above-mentioned production methods A to E,
(III), (IV), (V) and (VI) can be produced by a method known per se or a method analogous thereto. Compounds (DI), (EI) and (E-II)
Can be produced by a method for producing compound (I) or a method analogous thereto. a) Method for producing compound (II) i)

Embedded image [The symbols in the formula are as defined above. In this method, compound (VIII) or a salt thereof (inorganic salt, organic salt, etc.)
By halogenating Compound (VIII)
Examples of the inorganic salt used include alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, etc.). Examples of the organic salt include trialkylamine salts (eg, trimethylamine salt, Triethylamine salts, tert-butyldimethylamine salts, diisopropylethylamine salts, etc.) and aromatic tertiary amine salts (eg, N, N-dimethylaniline salts, pyridine salts, quinoline salts, etc.) are used. Examples of the halogenating agent include phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphoryl chloride, phosphoryl bromide, thionyl chloride, and thionyl bromide. In the reaction, compound (VIII) and the halogenating agent may be reacted without solvent, but a solvent may be used if necessary. Such solvents include, for example, dioxane, tetrahydrofuran,
Ethers such as diethyl ether, diisopropyl ether and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and chlorobenzene; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide and the like are used alone or as a mixed solvent. The reaction is used in an amount of about 1 to about 100 mol, preferably about 1 to about 50 mol, per 1 mol of compound (VIII). The reaction temperature is about -30 ° C to about 25
0 ° C, preferably from about -20 ° C to about 200 ° C.
The reaction time varies depending on the type of compound (VIII) or halogenating agent, the type of solvent and the reaction temperature, but is usually about 1 minute to about 72 hours, preferably about 10 minutes to about 24 hours.

Ii)

Embedded image [In the formula, L ¹ represents a hydrogen atom or a leaving group, and the other symbols have the same meanings as described above. This method is a method for producing compound (II) by reacting compound (IX) with, for example, chlorine or bromine represented by Q ₂ in the presence of water. The leaving group for L ¹ includes, for example, -C
N, -C (= NH) NH 2 or the like is used. The reaction is usually performed in a solvent, and the solvent used in the above method C is preferably used. The reaction is carried out in an amount of about 1 to about 100 mol, preferably about 1 to about 30 mol, of chlorine or bromine per 1 mol of compound (IX). The reaction temperature is about -50 ° C to about 180
° C, preferably from about -30 ° C to about 120 ° C. As the method for producing sulfonyl chloride or sulfonyl bromide represented by the compound (II), a number of known methods are known. (II) can be produced.

B) Method for producing compound (III)

Embedded image [In the formula, L ² is a protecting group for an amino group, and other symbols are as defined above. In the formulas (X) and (XI), examples of the protecting group represented by L ² include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.), a benzyl group, and a tert-butyloxy group. Carbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group, phenylcarbonyl group, C _1-6 alkyloxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl and the like),
A _C7-10 aralkyl-carbonyl group (for example, benzylcarbonyl), a trityl group, an N, N-dimethylaminomethylene group and the like are used. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro groups and the like. In this method, first, compound (X)
And compound (V) or a reactive derivative thereof to produce compound (XI). The conditions described in Method B can be directly applied to the various conditions in this reaction. From the compound (XI) thus produced, the compound (III) can be produced by removing the protecting group. As a method for removing these protecting groups, 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.

C) Method for producing compound (IV)

Embedded image [In the formula, L ³ is a protecting group for an amino group, and other symbols are as defined above. In formulas (XII) and (XIII), the protecting group represented by L ³ is the same as the protecting group described for L ² in b).
In this method, compound (XIII) is produced by reacting compound (II) with compound (XII). For this reaction, the method described in Method A can be applied as it is. Manufactured compound (XII
Method for removing the protecting group of I) the method described in L ³ of the b) is used as it is.

D) Method for producing compound (V) i)

Embedded image [In the formula, Z ¹ represents an amino group substituted with an optionally substituted hydrocarbon group or a nitrogen-containing heterocyclic group optionally substituted, and R ⁵ represents a lower alkyl group or an optionally substituted benzyl group. The group and other symbols are as defined above. ] In the above formula, the substituent of the optionally substituted hydrocarbon group represented by Z ^1, substituted a substituent of an amino group, the substituent of an optionally substituted nitrogen-containing heterocyclic groups mentioned above Z The one described in is used as it is. As the lower alkyl group represented by R ⁵ , a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) and the like, and as a substituent of the optionally substituted benzyl group, lower alkyl group (e.g. methyl, ethyl, C _1-6 alkyl groups such as propyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy and the like C _1-6
An alkoxy group), a halogen atom (for example, fluorine, chlorine,
Bromine, etc.), and one or three of these optional substituents may be substituted at substitutable positions. In this method, compound (XIV) is reacted with compound (XV) to give compound (XV
I) to manufacture. This reaction condition is carried out by the method used in the above method C or a method analogous thereto.

Ii)

Embedded image [In the formula, Z ² represents a nitrogen-containing heterocyclic group which may be substituted, L ⁴ represents —B (R ⁶ ) ₂ (R ⁶ represents a hydroxyl group or a lower alkyl group.), —ZnT ² , and —CuT. ² (T ² represents a halogen atom) or —Sn (R ⁷ ) ₃ (R ⁷ represents a lower alkyl group); T ¹ represents a halogen atom or —O—SO ₂ R ⁴ ;
Other symbols are as defined above. In the above formula, as the substituent of the optionally substituted nitrogen-containing heterocyclic group represented by Z ² , the substituent represented by Z described above is directly applied. Examples of the lower alkyl group represented by R ⁶ and R ⁷ include C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl, and among them, methyl, ethyl and the like are preferable. T ¹ ,
Examples of the halogen atom represented by T ² include fluorine, chlorine, bromine, iodine and the like.

This reaction is usually carried out in a solvent in the presence of a suitable catalyst and, if necessary, in the presence of a base, and a solvent which 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, and 1,2-dichloroethane; for example, n-hexane, benzene, and toluene Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, and ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone ,
For example, in addition to nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.

As the catalyst used in this reaction, a palladium catalyst is preferably used, and for example, palladium chloride, palladium acetate, bis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium and the like are used. As the base, for example, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like are used. The reaction is carried out in an amount of about 0.5 to about 4 mol, preferably about 0.7, per 1 mol of compound (XVII).
To about 2 moles. The amount of the catalyst to be used is about 0.0001 to about 0.1 per 1 mol of compound (XVIII).
Is a mole. The reaction temperature is about -90 ° C to about 150 ° C,
Preferably it is about -70 ° C to about 100 ° C. The reaction time depends on the type of compound (XVII), (XVIII), type of solvent,
Depending on the reaction temperature, it usually ranges from about 15 minutes to about 48 minutes.
Hours, preferably from about 30 minutes to about 24 hours.

Iii)

Embedded image [In the formula, Z ³ represents an optionally substituted nitrogen-containing heterocyclic group, M represents an oxygen atom or a sulfur atom, T ³ represents a halogen atom, R ⁸ represents a hydrogen atom or a lower alkyl group, and other symbols Is as defined above. In the above formula, as the substituent of the optionally substituted nitrogen-containing heterocyclic group represented by Z ³ , the substituent represented by Z described above is used as it is. Examples of the lower alkyl group represented by R ⁸ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t
and C _1-6 alkyl groups such as ert-butyl. In this reaction, compound (XX) is reacted with compound (XXI) to produce compound (XXII). The reaction is usually performed in a solvent, and the solvent used in the above ii) can be directly applied as such a solvent. In the reaction, 1 to 5 mol, preferably 1 to 3 mol of compound (XXI) is used per 1 mol of compound (XX). The reaction temperature is from -30C to 150C, preferably from -10C to 120C. The reaction time varies depending on the type of the compound (XX) or (XXI), the type of the solvent, and the reaction temperature, but is usually 5 minutes to 48 hours, preferably 1 hour.
5 minutes to 24 hours.

Iv)

Embedded image [In the formula, T ⁴ represents a halogen atom, and other symbols have the same meanings as described above. In the above formula, as the halogen atom represented by T ⁴ , for example, chlorine, bromine and the like are used. In this reaction, compound (XXIV) is produced by reacting compound (XX) with compound (XXIII). This reaction is carried out in the same manner as in the above iii), or a method analogous thereto.

V)

Embedded image [In the formula, Z ⁴ represents a nitrogen-containing heterocyclic group which may have a substituent, R ⁹ represents a hydrogen atom or a lower alkyl group, and other symbols have the same meanings as described above. In the above formula, as the substituent of the nitrogen-containing heterocyclic group which may have a substituent represented by Z ⁴ , the substituent represented by Z is applicable as it is. As the lower alkyl group represented by R ⁹ , for example, a C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl is used. The reaction is usually performed in a solvent, and the solvent used in the above ii) can be directly applied as such a solvent.
The reaction is performed based on 1 mole of compound (XXV) and compound (XXVI).
About 0.8 to about 5 moles, preferably about 0.9 to about 3 moles
Is a mole. The reaction temperature and reaction time can be performed under the same conditions as in the above iv).

The compound (XV) prepared as described above
I), (XIX), (XXII), (XXIV) and (XXVII) are converted to the free acid as required. For example, when R ⁵ is a lower alkyl group, the reaction is carried out by hydrolysis with an acid or alkali. As the acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid and the like are preferably used. As the alkali, lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide and the like are used. In the case where R ⁵ is an optionally substituted benzyl group, in addition to the acid or alkali hydrolysis,
Free acid can also be produced by catalytic reduction (hydrogenolysis). A catalyst is used in the present catalytic reduction reaction. Raney nickel or the like is used. The present reduction reaction may be carried out under pressure if necessary. The pressure may be about 1 to about 50 atm, preferably about 1 to about 20 atm.
Atmospheric pressure. The reaction is generally performed in a solvent, and the solvent used in the above ii) can be applied as it is. The reaction temperature is about -10 ° C to about 150 ° C, preferably about -5 ° C to about 120 ° C. The reaction time varies depending on the type of compound, type of solvent, type of catalyst,
Usually about 15 minutes to about 72 hours, preferably about 30 minutes to about 24 hours.

When the 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. When the compound is obtained as a salt, a free form or other compound can be obtained according to a conventional method. It can also be converted to salt. The compound (I) thus obtained can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization, filtration, recrystallization,
Isolation and purification can be performed by using means such as column chromatography and thin-layer chromatography. The salt of 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. Can also. Further, the compound (I) or a salt thereof may be a hydrate, and both a hydrate and a non-hydrate are included in the scope of the present invention.

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, human, monkey, cat, pig, horse, Cow, mouse, rat, guinea pig,
Dogs, rabbits, etc.), for example, it is useful for the prevention or treatment of the following diseases, and is particularly preferably used for the prevention or treatment of cerebral infarction due to atrial fibrillation, deep vein thrombosis, and the like. Brain: cerebral infarction due to atrial fibrillation, 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 revascularization and stenosis after coronary intervention such as atherectomy, peripheral: deep vein thrombosis, pulmonary embolism, peripheral vascular disease, adult respiration Compulsive syndrome, chronic kidney disease (eg, diabetic nephropathy, chronic glomerulonephritis, IgA nephropathy, etc.), diabetic circulatory disorder,
Pain, neuropathy, thrombosis, etc .: Thrombocytopenia due to dialysis, thrombocytopenia during major surgery, arteriosclerosis, cancer metastasis, systemic inflammatory response syndrome (SIR)
S) or pancreatitis, pancreatic intravascular coagulation syndrome (DIC) occurring in patients with sepsis 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) or a salt thereof of the present invention can be administered orally or parenterally as it is or by mixing a pharmacologically acceptable carrier. The preparation of the present invention containing the compound (I) or a salt thereof may be administered orally in the form of tablets (including sugar-coated tablets, 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 the 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 formed into pills and granules. In such a 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 the excipient 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 lubricants 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 stearate 40, 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. 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 which are 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 to three divided doses. The preparation of the present invention may optionally contain a thrombolytic agent (eg, TP
A, heparin, urokinase, etc.), Alzheimer's therapeutic agents (eg, avan, karan, etc.), cholesterol therapeutic agents (eg, HMG-such as simvastatin, pravastatin, etc.)
CoA reductase inhibitors, etc.), TG lowering drugs (eg, clofibrate), AII antagonists (eg, bropress), antiplatelet drugs (eg, aspirin), Ca antagonists (eg, calslot, amlodipine) Alternatively, these pharmaceutical ingredients can be used in an appropriate amount.

[0048]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples. The range may be changed without departing from the range. Elution in column chromatography in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, silica gel 60F ₂₅₄ manufactured by Merck was used as a TLC plate, and a solvent used as an elution solvent in column chromatography was used as a developing solvent.
A UV detector was employed as a detection method. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh) also manufactured by Merck was used. IR spectrum is Shimadzu FT
-Measured in KBr using an IR-8100 spectrometer. NMR spectra were measured on a Gemini 200 spectrometer using tetramethylsilane as an internal or external reference and all δ values are given in ppm. 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 quint: quintet ABq: AB type quartet dd: double doublet m: doublet Multiplet br: broad brs: broad singlet J: coupling constant WSC: water-soluble carbodiimide

[0049]

EXAMPLES Reference Example 1 1-tert-butoxycarbonyl-4- (4-chloromethylbenzoyl) piperazine 4-chloromethylbenzoyl chloride (5.3 g) in THF (8 ml)
The solution was treated with 1-tert-butoxycarbonyl-piperazine (5.19
g) and triethylamine (2.82 g) in THF (16 ml) at 0 ° C.
And stirred at room temperature for 10 minutes. Concentrate the reaction,
The obtained solid residue was washed with water and ethyl acetate and then dried to obtain the title compound (9.44 g) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.30-3.80 (8H,
m), 4.61 (2H, s), 7.40 (2H, d, J = 8.4Hz), 7.46 (2
Reference example 2 TH of 1- (2-naphthalenesulfonyl) piperazine hydrochloride 2-naphthalenesulfonyl chloride (23 g, 101 mmol)
F (10 ml) solution was added to 1-formylpiperazine (11.4
g, 100 mmol) and triethylamine (15 g, 150 mmol) in TH
The mixture was added dropwise to an F (100 ml) solution, stirred at room temperature for 30 minutes, and then concentrated. The obtained residue was washed with water and diisopropyl ether, and dried under reduced pressure to obtain 1-formyl-4- (2-naphthalenesulfonyl) piperazine. ¹ H-NMR (CDCl ₃ ) δ: 3.00-3.20 (4H, m), 3.48 (2H,
t, J = 5.0Hz), 3.66 (2H, t, J = 5.0Hz), 7.58-7.77 (3
H, m), 7.90-8.02 (4H, m), 8.33 (1H, s) .IR (KBr): 1675, 1347, 1166 cm ^-1 .The obtained 1-formyl-4- (2-naphthalenesulfonyl) Ethanol (30 ml) and 1N hydrochloric acid (100 ml) were added to piperazine, and the mixture was refluxed for 5 hours. The reaction solution was concentrated, and the obtained residue was washed with ethyl acetate and dried under reduced pressure to obtain 1- (2-naphthalenesulfonyl) piperazine hydrochloride (43.3 g).

Reference Example 3 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride A solution of 1-tert-butoxycarbonyl-piperazine (1.0 g) in aqueous sodium hydrogen carbonate (10 ml) and ethyl acetate (10 ml) 6-chloronaphthalene-2-sulfonyl chloride (1.4 g)
Was added and stirred at room temperature for 1 hour. The resulting precipitate was dissolved in dichloromethane, the organic layer was separated, washed with water, dried and concentrated. The obtained residue is crystallized from diisopropyl ether to give colorless crystals of 1- (tert-butoxycarbonyl).
-4- (6-chloronaphthalene-2-sulfonyl) piperazine (2.0
2 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (9H, s), 3.04 (4H, m), 3.5
2 (4H, m), 7.58 (1H, dd, J = 2.2, 8.8Hz), 7.76 (1H,
dd, J = 1.8, 8.8Hz), 7.85-7.98 (3H, m), 8.31 (1H,
s) .IR (KBr): 1697, 1420, 1347, 1249, 1166 cm ^-1 .The obtained 1- (tert-butoxycarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine (2.0 g) Methano
(10 ml) and a 4N solution of hydrochloric acid in ethyl acetate (20 ml) were added.
The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the obtained residue was triturated with acetone and dried under reduced pressure to give the title compound.
(1.66 g) was obtained. Reference Example 4 1- (4-Chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine 4-Chloromethylbenzoyl chloride (3.02 g) was prepared by adding 1- (2-naphthalenesulfonyl) piperazine hydrochloride (5.0 g) to acetic acid. It was added to a solution of ethyl (60 ml) and a 10% aqueous sodium hydrogen carbonate solution (40 ml), and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with water and saturated brine, dried and concentrated.The residue obtained was washed with diisopropyl ether and dried under reduced pressure to give the title compound (4.945 g, 78%). Was. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (4H, brs), 3.40-3.95 (4H,
br), 4.56 (2H, s), 7.29 (2H, d, J = 8.2Hz), 7.39 (2
H, d, J = 8.2Hz), 7.60-7.78 (3H, m), 7.90-8.05 (3H,
m), 8.34 (1H, d, J = 1.8Hz).

Reference Example 5 1- (3-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine In the same manner as in Reference Example 4, 3-chloromethylbenzoyl chloride was used instead of 4-chloromethylbenzoyl chloride. And synthesized. ¹ H-NMR (CDCl ₃ ) δ: 3.11 (4H, brs), 3.40-4.00 (4H,
br), 4.54 (2H, s), 7.19-7.48 (4H, m), 7.58-7.78 (3
H, m), 7.90-8.05 (3H, m), 8.33 (1H, d, J = 1.8 Hz). Reference Example 6 1- (4-chloromethylbenzoyl) -4- (6-chloronaphthalene
2- (2-sulfonyl) piperazine 1- (2-naphthalenesulfonyl) in the same manner as in Reference Example 4.
1- (6-chloronaphthalene-2 instead of piperazine hydrochloride
-Sulfonyl) piperazine hydrochloride. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (4H, brs), 3.40-4.00 (4H,
br), 4.57 (2H, s), 7.30 (2H, d, J = 8.4Hz), 7.40 (2
H, d, J = 8.4Hz), 7.60 (1H, dd, J = 1.8, 8.6Hz), 7.76
(1H, dd, J = 1.8, 8.6Hz), 7.93 (2H, d, J = 8.6Hz), 7.9
5 (1H, d, J = 1.8Hz), 8.31 (1H, d, J = 1.8Hz) .IR (KBr): 1635, 1432, 1347, 1166 cm ^-1 .

Reference Example 7 1- (tert-butoxycarbonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine 1- (tert-butoxycarbonyl) -4- (4-chloromethylbenzoyl) piperazine (5.185 g), Potassium carbonate (2.114
g) and a mixture of diisopropylamine (15.45 g) in DMF (50 ml) was stirred at 100 ° C. for 10 hours. The reaction solution was concentrated, and the obtained residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated to give the title compound as a colorless solid (4.707 g). ¹ H-NMR (CDCl ₃ ) δ: 1.02 (12H, d, J = 6.6 Hz), 1.47 (9
H, s), 3.00 (2H, quint, J = 6.6Hz), 3.46 (4H, brs),
3.65 (2H, s), 3.30-3.80 (4H, brs), 7.31 (2H, d, J =
8.4 Hz), 7.43 (2H, d, J = 8.4 Hz). IR (KBr): 1699, 1629, 1421, 1245, 1168 cm ^-1 . Reference Example 8 1- (4-diisopropylaminomethylbenzoyl) piperazine) 1 -(tert-butoxycarbonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine (4.6 g) in ethyl acetate
(10 ml), trifluoroacetic acid (20 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in water, made alkaline with an aqueous sodium hydroxide solution, and extracted with dichloromethane. After drying, the residue obtained by concentration was triturated from hexane, filtered and dried to give the title compound.
(3.12 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (12H, d, J = 6.6 Hz), 2.88 (4
H, brs), 3.00 (2H, quint, J = 6.6Hz), 3.30-3.85 (4
H, brs), 3.65 (2H, s), 7.31 (2H, d, J = 8.0Hz), 7.42
(2H, d, J = 8.0Hz). IR (KBr): 3309, 1615, 1606, 1463, 1434, 1288
cm ^-1 .

Reference Example 9 1- (tert-butoxycarbonyl) -4- [4- (N-ethyl)
-tert-butylaminomethyl) benzoyl] piperazine Synthesized in the same manner as in Reference Example 7, using N-ethyl-tert-butylamine instead of diisopropylamine.
Colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.0 Hz), 1.10 (9
H, s), 1.47 (9H, s), 2.62 (2H, q, J = 7.0Hz), 3.45
(4H, brs), 3.30-3.90 (4H, brs), 3.69 (2H, s), 7.32
(2H, d, J = 8.0 Hz), 7.45 (2H, d, J = 8.0 Hz). IR (KBr): 1700, 1641, 1419, 1247, 1170, 1008 cm ^-1 .Reference Example 10 1- (tert -Butoxycarbonyl) -4- [4- (2,6-dimethylpiperidinomethyl) benzoyl] piperazine Synthesized in the same manner as in Reference Example 7, using 2,6-dimethylpiperidine instead of diisopropylamine. Pale yellow syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.2 Hz), 1.20-1.4
0 (4H, m), 1.47 (9H, s), 1.50-1.70 (2H, m), 2.48
(2H, m), 3.46 (4H, brs), 3.60 (4H, brs), 3.78 (2H,
s), 7.32 (2H, d, J = 8.0Hz), 7.44 (2H, d, J = 8.0Hz) .IR (Neat): 1699, 1639, 1419, 1247, 1172, 1008c
m ^-1 .

Reference Example 11 1- (tert-butoxycarbonyl) -4- [4- (2-diisopropylaminoethyl) benzoyl] piperazine 4- (2-diisopropylaminoethyl) benzoic acid (300 mg)
In DMF (10 ml) solution, 1,1-carbonyldiimidazole (215
mg) and stirred at room temperature for 15 minutes. Followed by 1-tert-
Butoxycarbonyl-piperazine (247 mg) was added, and the mixture was further stirred at room temperature for 4 hours. The reaction solution was concentrated, and the obtained residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated to give the title compound as a colorless oil (483 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.01 (12H, d, J = 6.6 Hz), 1.47 (9
H, s), 2.55-2.80 (4H, m), 3.05 (2H, quint, J = 6.6H
z), 3.30-3.90 (8H, m), 7.23 (2H, d, J = 8.2Hz), 7.32
(2H, d, J = 8.2 Hz). IR (Neat): 1700, 1644, 1419, 1245, 1170 cm ^-1 . Reference Example 12 1- (6-bromonaphthalene-2-sulfonyl) piperazine hydrochloride 1-tert To a solution of -butoxycarbonyl-piperazine (1.25 g) in aqueous sodium hydrogen carbonate solution (10 ml) and ethyl acetate (10 ml) was added 6-bromonaphthalene-2-sulfonyl chloride (2.05 g).
g) was added and stirred at room temperature for 1 hour. The resulting precipitate was dissolved in dichloromethane, the organic layer was separated, washed with water, dried and concentrated. The obtained residue is crystallized from diisopropyl ether to give colorless crystals of 1- (tert-butoxycarbonyl) -4- (6-bromonaphthalene-2-sulfonyl) piperazine.
(2.83 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (9H, s), 3.04 (4H, t, J = 5.
0Hz), 3.52 (4H, t, J = 5.0Hz), 7.65-7.95 (4H, m), 8.
11 (1H, s), 8.29 (1H, s) .IR (KBr): 1695, 1423, 1347, 1249, 1166 cm ^-1 .The obtained 1- (tert-butoxycarbonyl) -4- (6-bromo Naphthalene-2-sulfonyl) piperazine (2.80 g)
(10 ml) and 4N hydrochloric acid ethyl acetate solution (25 ml)
The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the obtained residue was triturated with acetone and dried under reduced pressure to give the title compound.
(2.358 g) was obtained.

Reference Example 13 4- (3-pyridyl) benzoic acid Ethyl 4-bromobenzoate (1.15 g), 3-pyridyldiethylborane (888 mg), dimethoxytetrakistriphenylphosphinepalladium (0) (500 mg) To a mixed solution of ethane (20 ml) was added a 2M aqueous sodium carbonate solution (5 ml),
Reflux for hours. Dilute the reaction solution with ethyl acetate, separate the organic layer, wash with water, extract with 1N hydrochloric acid, make the aqueous extract alkaline with aqueous sodium hydroxide, re-extract with ethyl acetate, dry and concentrate. This gave ethyl 4- (3-pyridyl) benzoate (2.14 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.0 Hz), 4.42 (2
H, q, J = 7.0Hz), 7.41 (1H, dd, J = 4.8, 8.2Hz), 7.66
(2H, d, J = 8.8Hz), 7.92 (1H, dt, J = 2.0, 8.2Hz), 8.1
6 (2H, d, J = 8.8Hz), 8.65 (1H, dd, J = 2.0, 4.8Hz),
8.89 (1H, d, J = 2.0 Hz). IR (Neat): 1716, 1274 cm ^-1 . A solution of the obtained ethyl 4- (3-pyridyl) benzoate (2.14 g) in ethanol (20 ml). 1N sodium hydroxide aqueous solution
(15 ml) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the obtained residue was dissolved in water, and 1N hydrochloric acid (15 m
The precipitate formed by adding l) was collected by filtration, washed with water, and dried to obtain the title compound (1.488 g). Reference Example 14 5- (4-pyridyl) -2-thiophenecarboxylic acid methyl 5-bromo-2-thiophenecarboxylate (884 mg),
Pyridylboronic acid (500 mg), tetrakistriphenylphosphine palladium (0) (250 mg) dimethoxyethane
(15 ml), a 2 M aqueous sodium carbonate solution (4 ml) was added to the mixed solution, and the mixture was refluxed for 15 hours. Dilute the reaction solution with ethyl acetate, separate the organic layer, wash with water, extract with 1 N hydrochloric acid,
The aqueous extraction solution was made alkaline with an aqueous sodium hydroxide solution, re-extracted with ethyl acetate, dried and concentrated to give a pale yellow solid methyl 5- (4-pyridyl) -2-thiophenecarboxylate (4
28 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 7.47 (1H, d, J = 4.
0Hz), 7.50 (2H, d, J = 6.2Hz), 7.80 (1H, d, J = 4.0H)
z), 8.65 (2H, d, J = 6.2 Hz) .IR (KBr): 1712, 1453, 1417, 1282, 1247 cm ^-1 .Methyl 5- (4-pyridyl) -2-thiophenecarboxylate obtained To a solution of (410 mg) in ethanol (20 ml) was added a 1N aqueous sodium hydroxide solution (4 ml), and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction solution was dissolved in water, 1N hydrochloric acid (4 ml) was added, the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (363 mg).

Reference Example 15 5- (4-pyridyl) -2-furancarboxylic acid methyl 5-bromo-2-furancarboxylate (820 mg), 4-pyridylboric acid (500 mg), tetrakistriphenylphosphine palladium (0 ) (250 mg) of dimethoxyethane (15 m
l) 2M aqueous sodium carbonate solution (4 ml) was added to the mixed solution,
Refluxed for 15 hours. Dilute the reaction solution with ethyl acetate, separate the organic layer, wash with water, extract with 1N hydrochloric acid, make the aqueous extract alkaline with aqueous sodium hydroxide, re-extract with ethyl acetate, dry and concentrate. Thus, methyl 5- (4-pyridyl) -2-furancarboxylate (126 mg) was obtained as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 6.96 (1H, d, J = 3.
8Hz), 7.27 (1H, d, J = 3.8Hz), 7.64 (2H, d, J = 6.2H)
z), 8.68 (2H, d, J = 6.2 Hz) .IR (KBr): 1727, 1608, 13.7, 1145 cm ^-1 .Methyl 5- (4-pyridyl) -2-furancarboxylate (1
To a solution of (00 mg) in ethanol (10 ml) was added a 1N aqueous sodium hydroxide solution (4 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and the resulting residue was dissolved in water.
(4 ml) was added, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (59 mg). Reference Example 16 4- (1H-imidazol-1-yl) benzoic acid ethyl 4-fluorobenzoate (8.4 g), imidazole (4.08
g) and potassium carbonate (20.7 g) in DMF (30 ml).
The mixture was stirred at 100 ° C. for 10 hours. The residue obtained by concentrating the solvent was dissolved in ethyl acetate, washed with water, dried and concentrated. Hexane was added to the obtained residue, and the insoluble matter was collected by filtration.
After washing with hexane and drying, a colorless solid ethyl 4- (1H-imidazol-1-yl) benzoate (1.74 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.2 Hz), 4.42 (2
H, q, J = 7.2Hz), 7.25 (1H, s), 7.36 (1H, t, J = 1.4H
z), 7.48 (2H, d, J = 8.8Hz), 7.95 (1H, s), 8.18 (2H,
d, J = 8.8Hz). Ethyl 4- (1H-imidazol-1-yl) benzoate obtained
To a solution of (1.73 g) in ethanol (18 ml) was added a 1N aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction solution was dissolved in water, 1N hydrochloric acid (10 ml) was added, and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.43 g). .

Reference Example 17 4- (1,2,4-triazol-1-yl) benzoic acid and 4- (1,2,4-triazol-1-yl) benzoic acid
(1,2,4-triazol-4-yl) benzoic acid ethyl 4-fluorobenzoate (8.4 g), triazole (4.14
g) and potassium carbonate (20.7 g) in DMF (30 ml).
The mixture was stirred at 100 ° C. for 3 hours. The solvent was concentrated, and the obtained residue was dissolved in dichloromethane, washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 → 20: 1) to give 4- (1,2,4-triazol-1-yl) as a colorless solid.
Ethyl benzoate (4.0 g) and ethyl 4- (1,2,4-triazol-4-yl) benzoate (369 mg) were obtained. Ethyl 4- (1,2,4-triazol-1-yl) benzoate: ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.0 Hz), 4.42 (2
H, q, J = 7.0Hz), 7.79 (2H, d, J = 8.8Hz), 8.15 (1H,
s), 8.20 (2H, d, J = 8.8Hz), 8.66 (1H, s) .IR (KBr): 1722, 1610, 1523, 1440, 1278, 1224, 1106
cm ^-1 .Ethyl 4- (1,2,4-triazol-4-yl) benzoate: ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.0 Hz), 4.44 (2
H, q, J = 7.0Hz), 7.49 (2H, d, J = 8.8Hz), 8.24 (2H,
d, J = 8.8Hz), 8.56 (2H, s) .IR (KBr): 1700, 1614, 1529, 1504, 1284, 1259, 124
^1, 1085 cm ^-1 . The obtained ethyl 4- (1,2,4-triazol-1-yl) benzoate (3.8 g) was dissolved in a solution of ethanol (20 ml) in THF (10 ml).
A normal aqueous sodium hydroxide solution (20 ml) was added, and the mixture was added at room temperature for 2 hours.
Allowed to stir for hours. The residue obtained by concentrating the reaction solution was dissolved in water, 1N hydrochloric acid (20 ml) was added, and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound 4- (1H-imidazole- 1-yl) benzoic acid (3.147 g) was obtained. Similarly, 4- (1,
To a solution of ethyl 2,4-triazol-4-yl) benzoate (365 mg) in ethanol (4 ml) -THF (4 ml) was added a 1N aqueous solution of sodium hydroxide (4 ml) and the mixture was stirred at room temperature for 2 hours It was allowed to stir. The reaction solution was concentrated and the resulting residue was dissolved in water.
(4 ml), and the resulting precipitate was collected by filtration, washed with water and dried, and the title compound 4- (1H-imidazol-4-yl) benzoic acid (27
5 mg). Reference Example 18 4- (4-pyridyl) -2-thiazolecarboxylic acid [4-bromoacetylpyridine hydrobromide (5.62 g), and a mixed solution of ethyl thiooxamate (2.66 g) in ethanol (80 ml) for 1 hour Reflux. The solvent was concentrated, and aqueous sodium bicarbonate and ethyl acetate were added to the obtained residue. The organic layer was separated, washed with water and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain ethyl 4- (4-pyridyl) -2-thiazolecarboxylate (2.64 g) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 6.5 Hz), 4.52 (2
H, q, J = 6.5Hz), 7.90 (2H, d, J = 6.2Hz), 8.02 (1H,
s), 8.71 (2H, d, J = 6.2 Hz). 1N hydroxylation was performed on a solution of the obtained ethyl 4- (4-pyridyl) -2-thiazolecarboxylate (1.5 g) in ethanol (10 ml). An aqueous sodium solution (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the obtained residue was dissolved in water.
The precipitate formed by adding normal hydrochloric acid (10 ml) was collected by filtration, washed with water, and dried to obtain the title compound (1.105 g).

Reference Example 19 A mixed solution of 2- (4-pyridyl) -4-thiazolecarboxylic acid thioisonicotinamide (5.0 g) and ethyl bromopyruvate (7.22 g) in ethanol (90 ml) was refluxed for 5 hours. . The solvent was concentrated, and aqueous sodium bicarbonate and ethyl acetate were added to the obtained residue. The organic layer was separated, washed with water and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give a light yellow solid.
Ethyl-(4-pyridyl) -4-thiazolecarboxylate (4.55 g)
I got ¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.0 Hz), 4.47 (2
H, q, J = 7.0Hz), 7.88 (2H, d, J = 6.2Hz), 8.28 (1H,
s), 8.75 (2H, d, J = 6.2Hz). 1N hydroxylation of a solution of the obtained ethyl 2- (4-pyridyl) -4-thiazolecarboxylate (1.5g) in ethanol (10ml). An aqueous sodium solution (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction solution was dissolved in water, 1N hydrochloric acid (10 ml) was added, and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.264 g). . Reference Example 20 Ethyl 4-methyl-2- (4-pyridyl) thiazole-5-carboxylate A mixture of thioisonicotinamide (2.76 g), ethyl 2-chloroacetoacetate (3.6 g), and ethanol (30 ml) was added to a mixture of 2 parts.
The mixture was refluxed for 0 hours. The solvent was distilled off, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was subjected to silica gel chromatography, and hexane-ethyl acetate (2: 1) was used.
To give the title compound as crystals (2.0 g, 40.3
%). ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2 Hz), 2.81 (3H,
s), 4.38 (2H, q, J = 7.2Hz), 7.81 (2H, d, J = 6.2Hz), 8.
73 (2H, d, J = 6.2Hz).

Reference Example 21 4-methyl-2- (4-pyridyl) thiazole-5-carboxylic acid ethyl 4-methyl-2- (4-pyridyl) thiazole-5-carboxylate (744 mg), 1N NaOH (4 ml) , A mixture of tetrahydrofuran-ethanol (1: 1, 6 ml) was stirred at room temperature for 1 hour.
After dilution with water, 1N hydrochloric acid (4 ml) was added to give the title compound as crystals (595 mg, 90.2%). ¹ H-NMR (DMSO-d ₆ ) δ: 2.71 (3H, s), 7.90 (2H, d, J = 5.
2.74), 8.74 (2H, d, J = 5.2Hz). Reference Example 22 Ethyl 2- (4-pyridyl) thiazole-5-carboxylate In the same manner as in Reference Example 20, thioisonicotinamide and 2-
The title compound was obtained as crystals from ethyl chloro-2-formylacetate. ¹ H-NMR (CDCl ₃ ) δ: (1.42, 3H, t, J = 7.2 Hz), 4.42 (2
H, q, J = 7.2Hz), 7.84 (2H, d, J = 6.4Hz), 8.50 (1H,
s), 8.76 (2H, d, J = 6.2Hz).

Reference Example 23 2- (4-pyridyl) thiazole-5-carboxylic acid The title compound was obtained as crystals in the same manner as in Reference Example 21. ¹ H-NMR (DMSO-d ₆ ) δ: 7.95 (2H, d, J = 6.2 Hz), 8.52 (1
H, s), 8.76 (2H, d, J = 6.2 Hz). Reference Example 24 Ethyl 4- (4-pyridyl) benzoate Ethyl 4-bromobenzoate (2.29 g), 4-pyridylboronic acid
(1.23 g), a mixture of 1M aqueous sodium hydrogen carbonate solution (30 ml) and 1,2-dimethoxyethane (40 ml) was added with tetrakis (triphenylphosphine) palladium (0.3 g), and the mixture was refluxed with stirring for 3 hours in a nitrogen stream. did. Water was added and extracted with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel chromatography, and eluted with hexane-ethyl acetate (2: 1) to give the title compound as crystals (1.15 g, 50.7%). ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 6.8 Hz), 4.41 (2H,
q, J = 6.8Hz), 7.54 (2H, d, J = 5.2Hz), 7.70 (2H, d, J =
8.8Hz), 8.16 (2H, d, J = 8.8Hz), 8.70 (2H, d, J = 5.2H)
z).

Reference Example 25 4- (4-pyridyl) benzoic acid Ethyl 4- (4-pyridyl) benzoate (1.0 g), 1N NaOH (8.8 m
l), a mixture of ethanol (8.8 ml) was stirred at room temperature for 1 hour. After dilution with water, 1N hydrochloric acid (8.8 ml) was added to give the title compound as crystals (0.76 g, 86.4%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.75 (2H, d, J = 6.2 Hz), 7.92 (2
H, d, J = 8.2 Hz), 8.07 (2H, d, J = 8.2 Hz), 8.68 (2H, d,
Reference Example 26 Methyl 6- (4-pyridyl) nicotinate In the same manner as in Reference Example 24, methyl 6-chloronicotinate and 4-
The title compound was obtained from pyridylboronic acid. ¹ H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 7.89 (1H, d, J = 8.0H
z), 7.94 (2H, d, J = 6.2Hz), 8.42 (1H, dd, J = 1.8, 8.0H
z), 8.77 (2H, d, J = 6.2Hz), 9.32 (1H d, J = 1.8Hz).

Reference Example 27 6- (4-Pyridyl) nicotinic acid The title compound was obtained as crystals in the same manner as in Reference Example 25. ¹ H-NMR (DMSO-d ₆ ) δ: 8.11 (2H, d, J = 6.0 Hz), 8.25 (1
H, d, J = 8.2Hz), 8.41 (1H, dd, J = 2.2, 8.2Hz), 8.75 (2
H, d, J = 6.0 Hz), 9.21 (1 H, d, J = 2.2 Hz) .Reference Example 28 4- (Diisopropylaminomethyl) -2-methoxybenzoic acid Methyl 2-methoxy-4-methylbenzoate (5.0 g), a mixture of N-bromosuccinimide (4.94 g), 2,2-azobis (isobutyronitrile) (0.23 g) and carbon tetrachloride (50 ml) was heated under reflux for 40 minutes. After cooling, the deposited precipitate was filtered off and the solvent was distilled off to obtain methyl 4-bromomethyl-2-methoxybenzoate as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.89 (3H, s), 3.93 (3H, s), 7.00
(2H, m), 7.77 (1H, d, J = 8.0 Hz) .Methyl 4-bromomethyl-2-methoxybenzoate (2.59 g), diisopropylamine (3.92 ml), potassium carbonate (1.38 g),
A mixture of dimethylformamide (30 ml) was stirred at 80 ° C. for 2 hours. Water was added and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. Residue in THF-EtOH
(1: 1, 30 ml) and 1N aqueous sodium hydroxide solution
(15 ml) and stirred at 80 ° C. for 20 minutes. After adding water and washing with ether, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off.
The residue was dissolved in THF, and the insoluble matter was removed by filtration. The filtrate was concentrated and crystallized from isopropyl ether to obtain the title compound (0.3 g). ¹ H-NMR (DMSO-d ₆ ) δ: 1.07 (12H, d, J = 6.6 Hz), 3.14 (1
H, m), 3.63 (1H, m), 3.82 (3H, s), 7.04 (1H, d, J = 7.6
Hz), 7.21 (1H, s), 7.62 (1H, d, J = 7.6Hz).

Reference Example 29 1- (tert-butoxycarbonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (tert-butoxycarbonyl) piperazine (3.72 g), Four-
Methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (4.4
g), DMF of triethylamine (2.5 g) and HOBt (2.7 g)
(60 ml), WSC hydrochloride (4.217 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, and dichloromethane and aqueous sodium bicarbonate were added to the residue. The organic layer was separated, washed with water and brine, and dried and concentrated. The obtained residue is subjected to silica gel chromatography (dichloromethane: methanol = 5).
Purification by 0: 1) gave the title compound (6.49 g) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.52 (3H, s), 3.5
0 (4H, m), 3.61 (4H, m), 7.77 (2H, d, J = 6.2Hz), 8.
72 (2H, d, J = 6.2 Hz). IR (KBr): 1688, 1626, 1418, 1244 cm ^-1 . Reference Example 30 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl ]
Piperazine dihydrochloride 1- (tert-butoxycarbonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine (6.40 g)
Then, add methanol (30 ml) and 4N hydrochloric acid in ethyl acetate (3 ml).
0 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the obtained residue was triturated with ether and dried under reduced pressure to obtain the title compound (5.8 g). ¹ H-NMR (DMSO-d ₆ ) δ: 2.09 (3H, s), 3.19 (4H, m),
3.79 (4H, m), 8.20-8.30 (2H, m), 8.90 (2H, d, J = 6.6
Hz), 9.45 (2H, brs). Reference Example 31 N, O-dimethyl-N- (1-tritylpiperidine-4-
Carbonyl) hydroxylamine 1-tritylpiperidine-4-carboxylic acid (7.0 g),
O, N-dimethylhydroxylamine hydrochloride (2.0 g),
Dichloromethane (70 ml) and triethylamine (2.
WSC (3.97 g) was added to the mixture at room temperature.
Stirred for hours. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed with water and dried (MgSO ₄ ). The solvent was distilled off, and the obtained crystals were washed with isopropyl ether (6.3 g). ¹ H-NMR (CDCl ₃ ) δ: 1.34-1.72 (4H, m), 2.00-2.20 (2
H, m), 2.54 (2H, m), 3.17 (3H, s), 3.21 (2H, m), 3.59
(3H, s), 7.12-7.48 (15H, m). Reference Example 32 N- (4-bromobenzyl) -N, N-diisopropylamine 4-bromobenzylbromide (5.0 g), N, N-diisopropylamine ( 7.85 ml), potassium carbonate (2.76 g)
And a mixture of dimethylformamide (50 ml) at 80 ° C
For 2 hours. Water was added and extracted with ether. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off to obtain the title compound (5.0 g). ¹ H-NMR (CDCl ₃ ) δ: 1.00 (12H, d, J = 6.6 Hz), 2.9
9 (2H, m), 3.57 (2H, s), 7.25 (2H, d, J = 8.8Hz), 7.40
(2H, d, J = 8.8 Hz). Reference Example 33 4- (4-diisopropylaminomethylbenzoyl)-
1-Tritylpiperidine A solution of N- (4-bromobenzyl) -N, N-diisopropylamine (2.3 g) in THF (10 ml) was added at -78.degree.
-BuLi (1.6 mmol / ml hexane solution, 3.8 ml) was added dropwise. After 10 minutes, N, O-dimethyl-N- (1-tritylpiperidine-4-carbonyl) hydroxylamine (1.5
g) in THF (20 ml) was added dropwise.
Stir for 30 minutes. An aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract is washed with water and dried (MgSO ₄ )
Thereafter, the solvent was distilled off to obtain the title compound (5.0 g). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 4.8 Hz), 1.02
(6H, d, J = 4.8Hz), 1.50 (2H, m), 1.83 (2H, m), 2.08 (2
H, m), 3.01 (2H, m), 3.08 (1H, m), 3.64 (2H, s), 7.12
-7.48 (17H, m), 7.81 (2H, d, J = 8.0 Hz). Reference Example 34 2- (6-tert-butoxycarbonylamino-3-pyridyl) -4-methyl-5-thiazolecarboxylic acid 6- tert-butoxycarbonylaminonicotinamide (1.
66g), phosphorus pentasulfide (2.33g) and THF (150m
The mixture of 1) was heated at reflux for 15 minutes. The insoluble material was removed by filtration and the solvent was distilled off. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract is washed with water and dried (MgSO ₄ )
Thereafter, the solvent was distilled off to obtain 6-tert-butoxycarbonylaminothionicotinamide as crystals. Filter the crystals,
Washed with ether (0.75 g). 6-tert-butoxycarbonylaminothionicotinamide (506 mg), ethyl 2-chloroacetoacetate (492 mg), sodium acetate (2 mg
A mixture of 52 mg) and ethanol (20 ml) was heated under reflux for 2 hours. An aqueous solution of sodium hydrogen carbonate and water were added, and the precipitated crystals were collected by filtration. Washing with water, ethanol and ether in that order gave ethyl 2- (6-tert-butoxycarbonylamino-3-pyridyl) -4-methyl-5-thiazolecarboxylate (200 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 6.2 Hz), 1.57
(9H, s), 2.77 (3H, s), 4.35 (2H, q, J = 6.2Hz), 8.09 (1
H, d, J = 8.8Hz), 8.20 (1H, dd, J = 2.2, 8.8Hz), 8.55 (1
H, brs), 8.89 (1H, d, J = 2.2 Hz). Ethyl 2- (2-tert-butoxycarbonylamino-5-pyridyl) -4-methyl-5-thiazolecarboxylate
(180 mg), 1 N NaOH (2 ml) and EtOH-T
A mixture of HF (2: 1, 6 ml) was stirred at 70 ° C. for 1 hour. 1N HCl (2 ml) was added to give the title compound (151 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.50 (9H, s), 2.67 (3H,
s), 7.94 (1H, d, J = 8.8Hz), 8.26 (1H, d, J = 8.8Hz), 8.
80 (1H, s). Reference Example 35 1-tert-butoxycarbonyl-4- (3,4-methylenedioxybenzenesulfonyl) piperazine 1-tert-butoxycarbonylpiperazine and 3,4
-The title compound was obtained from -methylenedioxybenzenesulfonyl chloride in the same manner as in Reference Example 12. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.97 (4H, m),
3.51 (4H, m), 6.09 (2H, s), 6.91 (1H, d, J = 8.2Hz), 7.
15 (1H, d, J = 2.1 Hz), 7.29 (1H, dd, J = 2.1, 8.2 Hz). Reference Example 36 4- (6-chloronaphthalene-2-sulfonyl) -1- [4- (2- Cyanoethyl) benzoyl] piperazine 4- (6-chloronaphthalene-2-sulfonyl) -1- [4- (2-cyano
[1-Ethenyl) benzoyl] piperazine (699 mg) was dissolved in pyridine (15 ml) and methanol (5 ml), and sodium borohydride (68 mg) was added. After stirring at 60 ° C. for 2 hours, the solvent was distilled off under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to give the title compound (450
mg). ¹ H-NMR (CDCl ₃ ) δ: 2.62 (2H, t, J = 7.2 Hz), 2.96 (2
(H, t, J = 7.2Hz), 3.09 (4H, brs), 3.71 (4H, br), 7.2
0-7.33 (4H, m), 7.59 (1H, dd, J = 8.9, 1.9Hz), 7.75
(1H, dd, J = 8.7, 1.7Hz), 7.89-7.97 (3H, m), 8.30 (1
H, s) .IR (KBr): 2247, 1636, 1433, 1348, 1161, 939, 735,
579 cm ^-1. Reference Example 37 1-(tert-butoxycarbonyl) -4- (4-chlorobenzoyl methanesulfonyl) piperazine 1-(tert-butoxycarbonyl) -4-tetrahydrofuran-methanesulfonyl piperazine (1.32 g) (10 1.6M n-butyllithium hexane solution at 0 ° C (6.25 ml)
Was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was cooled to -78 ° C, a solution of methyl 4-chlorobenzoate (853 mg) in tetrahydrofuran (5 ml) was added, and the mixture was stirred at the same temperature for 3 hours and heated to 0 ° C. Water (10 ml) was added to the reaction solution, and the mixture was acidified with a citric acid aqueous solution. The mixture was extracted with ether, and the organic layer was washed with brine, dried and concentrated, and then subjected to silica gel column chromatography (hexane / ethyl acetate = 2/2 / hexane).
Purification in 1) gave the title compound (790 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.31 (4H, m), 3.5
0 (4H, m), 4.54 (2H, s), 7.50 (2H, d, J = 8.8Hz), 7.
98 (2H, d, J = 8.8 Hz). IR (KBr): 1694, 1348, 1283, 1250, 1161 cm ^-1 . Reference Example 38 1- [2- (4-Chlorophenyl) ethynesulfonyl] piperazine hydrochloride 1 -(tert-Butoxycarbonyl) -4- (4-chlorobenzoylmethanesulfonyl) piperazine (640 mg), 2-chloro-1-methylpyridinium iodide (650 mg) in dichloromethane (8 ml) (4 ml) was added dropwise, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 1- (tert-butoxycarbonyl) -4- [2- (4-chlorophenyl) ethynesulfonyl] piperazine as a colorless solid. (521 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.22 (4H, m), 3.6
2 (4H, m), 7.40 (2H, d, J = 8.8Hz), 7.52 (2H, d, J =
IR (KBr): 2184, 1698, 1368, 1171 cm- ¹ . 1- (tert-butoxycarbonyl) -4- [2- (4-chlorophenyl) ethinsulfonyl] piperazine (500 mg) 4
The Boc group was removed with a normal hydrochloric acid ethyl acetate solution to give the title compound (380 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.34 (4H, m), 3.44 (4H, m),
7.62 (2H, d, J = 8.6Hz), 7.85 (2H, d, J = 8.6Hz), 9.34
Reference Example 39 1- (2H-benzopyran-3-sulfonyl) piperazine hydrochloride 1- (ethenesulfonyl) piperazine (1.38 g), salicylaldehyde (610 mg) and tert-butoxy potassium (16
A solution of 8 mg) in tert-butanol (20 ml) was refluxed for 4 days. The reaction solution was concentrated, and ethyl acetate was added. The organic layer was washed with water and brine, dried and concentrated, and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 1-colorless solid. (2H-benzopyran-3-sulfonyl) -4- (tert-butoxycarbonyl) piperazine (420 mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.21 (4H, m), 3.5
4 (4H, m), 4.88 (2H, s), 6.90 (1H, d, J = 7.6Hz), 6.
99 (1H, dt, J = 0.8, 7.6Hz), 7.16-7.36 (3H, m) .IR (KBr): 1698, 1628, 1605, 1161 cm ^-1 .The obtained 1- (2H-benzopyran-3 -Sulfonyl) -4- (tert-
The Boc group was removed with 4N hydrochloric acid in ethyl acetate using butoxycarbonyl) piperazine to give the title compound as a colorless solid. Reference Example 40 In the same manner as Reference Example 39, the following compounds were synthesized using various corresponding salicylaldehydes instead of salicylaldehyde. 1- (5-chloro-2H-benzopyran-3-sulfonyl) -4- (tert-
(Butoxycarbonyl) piperazine ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.22 (4H, m), 3.5
4 (4H, m), 4.85 (2H, d, J = 1.2Hz), 6.82 (1H, d, J =
8.2Hz), 7.04 (1H, dd, J = 1.2, 8.2Hz), 7.22 (1H, t,
J = 8.2Hz), 7.56 (1H, d, J = 1.2Hz) .IR (KBr): 1698, 1697, 1454, 1422, 1248, 1161 cm- ¹ . 1- (6-Chloro-2H-benzopyran-3 -Sulfonyl) -4- (tert-
(Butoxycarbonyl) piperazine ¹ H-NMR (CDCl ₃ ) δ: 1.
45 (9H, s), 3.21 (4H, m), 3.54 (4H, m), 4.87 (2H,
d, J = 1.0Hz), 6.84 (1H, d, J = 8.4Hz), 7.15-7.28 (3
H, m) .IR (KBr): 1696, 1630, 1480, 1406, 1343, 1329, 1155
cm ^-1 .1- (7-Chloro-2H-benzopyran-3-sulfonyl) -4- (tert-
(Butoxycarbonyl) piperazine ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.21 (4H, m), 3.5
4 (4H, m), 4.88 (2H, d, J = 1.2Hz), 6.92 (1H, d, J =
2.2Hz), 6.98 (1H, dd, J = 2.2, 8.2Hz), 7.11 (1H, d,
J = 8.2Hz), 7.21 (1H, s). IR (KBr): 1688, 1601, 1418, 1281, 1248, 1150 cm ^-1 . Reference Example 41 1- (5-chlorobenzofuran-2-sulfonyl) piperazine hydrochloride Salt 1- (chloromethanesulfonyl) -4-formylpiperazine
(2.26 g), 5-chlorosalicylaldehyde (1.56 g) and potassium carbonate (1.38 g) in DMF (30 ml)
Stirred at 48 ° C. for 48 hours. The reaction mixture was concentrated, and ethyl acetate was added. The organic layer was washed with water and brine, dried and concentrated, and purified by silica gel column chromatography (ethyl acetate) to give colorless crystals of 1- (5-chlorobenzofuran). 2-Sulfonyl) -4-formylpiperazine (406 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.34 (4H, m), 3.51 (2H, m), 3.6
8 (2H, m), 7.34 (1H, s), 7.45 (1H, dd, J = 1.8, 8.8H
z), 7.50 (1H, d, J = 8.8Hz), 7.68 (1H, d, J = 1.8Hz),
8.02 (1H, s) .Concentrated hydrochloric acid (1 ml) was added to a solution of 1- (5-chlorobenzofuran-2-sulfonyl) -4-formylpiperazine (405 mg) in ethanol (15 ml), and the mixture was refluxed for 30 minutes. I let it. The solvent was distilled off, and the obtained solid was washed with ethyl acetate and dried to give the title compound (312 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.22 (4H, m), 3.43 (4H, m),
7.62 (1H, dd, J = 2.2, 9.2Hz), 7.75 (1H, d, J = 1.0H
z), 7.85 (1H, dd, J = 1.0, 9.2Hz), 7.95 (1H, d, J = 2.
Reference Example 42 1- (6-chlorobenzofuran-2-sulfonyl) piperazine hydrochloride In the same manner as in Reference Example 41, 4-chlorosalicylaldehyde was used instead of 5-chlorosalicylaldehyde. And synthesized. ¹ H-NMR (DMSO-d ₆ ) δ: 3.20 (4H, m), 3.40 (4H, m),
7.50 (1H, m), 7.82 (1H, s), 7.88 (1H, d, J = 8.0H
z), 8.03 (1H, m), 9.09 (2H, brs).

Example 1 1- (4-Diisopropylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine 1- (4-Chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg), carbonic acid A solution of potassium (200 mg) and diisopropylamine (4 ml) in DMF (6 ml) was stirred at 100 ° C. for 10 hours. The residue obtained by concentrating the solvent was dissolved in ethyl acetate, washed with water and extracted with 1N hydrochloric acid. After making the aqueous extraction solution alkaline with aqueous sodium hydroxide solution,
The mixture was extracted with dichloromethane, dried and concentrated. The obtained residue is subjected to silica gel column chromatography (hexane:
Purify with ethyl acetate = 1: 2) to give the title compound (70 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.10 (4H, brs), 3.61 (2H, s),
3.71 (4H, brs), 7.21 (2H, d, J = 8.4Hz), 7.37 (2H, d,
J = 8.4Hz), 7.59-7.78 (3H, m), 7.90-8.04 (3H, m),
8.33 (1H, s). IR (KBr): 1637, 1457, 1424, 1283, 1166 cm ^-1 . Example 2 1- (2-Naphthalenesulfonyl) -4- (4-piperidinomethylbenzoyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (313 mg), piperidine (321 mg) in DMF (6 m
l) The solution was stirred at 70 ° C for 10 hours to give the title compound (353 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.65 (6H,
m), 2.34 (4H, m), 3.10
(4H, brs), 3.44 (2H, s),
3.73 (4H, brs), 7.22 (2H, brs)
d, J = 8.0 Hz), 7.31 (2H,
d, J = 8.0 Hz), 7.58-7.80 (3
H, m), 7.90-8.07 (3H, m),
8.33 (1H, s). IR (KBr): 1636, 1347, 116
6 cm ^-1 . Example 3 1- (2-Naphthalenesulfonyl) -4- (4-piperidinomethylbenzoyl) piperazine hydrochloride 1- (2-Naphthalenesulfonyl) -4- (4-piperidinomethylbenzoyl) piperazine (350 mg) )), 4N hydrochloric acid in ethyl acetate (5 ml) was added, and the resulting hydrochloride precipitate was collected by filtration to give the title compound (337 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.39 (1H, m), 1.70-2.00 (3H,
m), 2.20-2.40 (2H, m), 2.40-2.62 (2H, m), 3.10 (4
H, brs), 3.37-3.95 (6H, m), 4.08 (2H, d, J = 5.0Hz),
7.36 (2H, d, J = 8.2Hz), 7.60-7.80 (5H, m), 7.93-8.
06 (3H, m), 8.35 (1H, s), 12.47 (1H, brs). IR (KBr): 1636, 1347, 1166 cm ^-1 . Example 4 1- [4- (1H-imidazole- 1-ylmethyl) benzoyl] -4-
(2-Naphthalenesulfonyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (313 mg), imidazole (257 mg) DMF (6
ml) solution was stirred at 70 ° C for 10 hours to give the title compound (305 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 3.09 (4H, brs), 3.40-4.00 (4H,
br), 5.12 (2H, s), 6.88 (1H, s), 7.10 (1H, s), 7.1
3 (2H, d, J = 8.0Hz), 7.28 (2H, d, J = 8.0Hz), 7.53 (1H, s), 7.58-7.76 (3H, m), 7.90-8.04 (3H, m) ,
8.32 (1H, d, J = 1.6Hz). IR (KBr): 1633, 1432, 1347, 1284, 1166 cm ^-1 .

Example 5 1- [4- (1H-Imidazol-1-ylmethyl) benzoyl] -4-
(2-Naphthalenesulfonyl) piperazine hydrochloride 1- [4- (1H-imidazole-1-ylmethyl) benzoyl] -4-
4N Hydrochloric acid ethyl acetate solution (5 ml) was added to (2-naphthalenesulfonyl) piperazine (300 mg), and the resulting hydrochloride precipitate was collected by filtration to give the title compound (299 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.11 (4H, brs), 3.40-3.95 (4H,
m), 5.54 (2H, s), 7.07 (1H, s), 7.30-7.46 (5H, m),
7.60-7.78 (3H, m), 7.90-8.05 (3H, m), 8.33 (1H, s),
9.84 (1H, s). IR (KBr): 3400, 1631, 1440, 1347, 1284, 1164 cm ^-1 . Example 6 1- (4-Diethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine Performed In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (313 mg), diethylamine (276 mg) DMF
(6 ml) The solution was stirred at 70 ° C for 10 hours to give the title compound (326 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, t, J = 7.0Hz), 2.59 (4
(H, q, J = 7.0Hz), 3.11 (4H, brs), 3.54 (2H, s), 3.72
(4H, brs), 7.23 (2H, d, J = 8.0Hz), 7.33 (2H, d, J =
8.0Hz), 7.58-7.80 (3H, m), 7.90-8.05 (3H, m), 8.33
(1H, s). IR (KBr): 1635, 1428, 1347, 1282, 1166 cm ^-1 .

Example 7 1- (4-Diethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine hydrochloride 1- (4-Diethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (320 mg) To the mixture was added a 4N solution of hydrochloric acid in ethyl acetate (5 ml), and the resulting precipitate of hydrochloride was collected by filtration to give the title compound (268 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.41 (6H, t, J = 7.0Hz), 2.90-3.3
0 (8H, m), 3.40-4.00 (4H, m), 4.13 (2H, d, J = 5.6H
z), 7.37 (2H, d, J = 8.0Hz), 7.60-7.83 (5H, m), 7.92
8.07 (3H, m), 8.35 (1H, s), 12.47 (1H, brs) .IR (KBr): 3340, 1631, 1459, 1434, 1347, 1284, 1166
cm ^-1 . Example 8 1- (4-benzylmethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- ( 2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (105 mg), benzylmethylamine (100 mg)
(6 ml) was stirred at 70 ° C. for 10 hours to give the title compound (359 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.16 (3H, s), 3.09 (4H, brs),
3.49 (2H, s), 3.50 (2H, s), 3.70 (4H, brs), 7.18-7.
42 (9H, m), 7.58-7.80 (3H, m), 7.90-8.03 (3H, m),
8.33 (1H, s) .IR (KBr): 1639, 1428, 1347, 1283, 1166 cm ^-1 .

Example 9 1- (4-benzylmethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine hydrochloride 1- (4-benzylmethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (358 mg) was added 4N hydrochloric acid ethyl acetate solution (5 ml), and the resulting hydrochloride precipitate was collected by filtration to give the title compound (391 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.56 (3H, d, J = 4.4 Hz), 3.12 (4
H, brs), 3.40-4.16 (6H, m), 4.25-4.38 (2H, m), 7.30
-7.50 (5H, m), 7.50-7.80 (7H, m), 7.91-8.06 (3H,
m), 8.34 (1H, s), 12.82 (1H, brs) .IR (KBr): 3400, 1633, 1459, 1434, 1347, 1284, 1166
cm ^-1 . Example 10 1- (4-Dimethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2 -Naphthalenesulfonyl) piperazine (300 mg),
A 50% aqueous solution of dimethylamine (2 ml) in DMF (6 ml) was added
The mixture was stirred at 0 ° C for 1 hour to give the colorless amorphous title compound (42 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.22 (6H, s), 3.10 (4H, brs),
3.41 (2H, s), 3.40-4.00 (4H, br), 7.25 (2H, d, J = 8.
2Hz), 7.31 (2H, d, J = 8.2Hz), 7.60-7.80 (3H, m), 7.9
0-8.05 (3H, m), 8.33 (1H, d, J = 1.6Hz). IR (KBr): 1635, 1455, 1428, 1347, 1166 cm ^-1 .

Example 11 1- (4-Dimethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine hydrochloride 1- (4-dimethylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (42 To the resulting compound was added 4N hydrochloric acid ethyl acetate solution (1 ml), and the resulting hydrochloride precipitate was collected by filtration to give the title compound (40 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.22 (6H, d, J = 4.4 Hz), 3.12 (4
H, brs), 3.40-3.95 (4H, m), 4.14 (2H, d, J = 4.6Hz),
7.38 (2H, d, J = 8.2Hz), 7.60-7.80 (5H, m), 7.90-8.0
6 (3H, m), 8.34 (1H, s) .IR (KBr): 3354, 1633, 1463, 1436, 1347, 1284, 1166
cm ^-1. Example 12 1- (4-methylaminomethyl) -4- (2-naphthalenesulfonyl) piperazine the same method as in Example 1 1- (4-
(Chloromethylbenzoyl) -4- (2-naphthalenesulfonyl)
A solution of piperazine (600 mg), potassium carbonate (616 mg) and a 40% aqueous solution of methylamine (2 ml) in DMF (6 ml) was stirred at 50 ° C. for 1 hour to give the title compound as a colorless amorphous (473 mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.10 (4H, brs),
3.74 (2H, s), 3.40-3.95 (4H, br), 7.25 (2H, d, J = 8.
0Hz), 7.32 (2H, d, J = 8.0Hz), 7.58-7.78 (3H, m), 7.9
0-8.03 (3H, m), 8.33 (1H, s) .IR (KBr): 3322, 1635, 1430, 1347, 1166 cm ^-1 .

Example 13 1- (4-methylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine hydrochloride 1- (4-methylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (373 To the resulting compound was added 4N hydrochloric acid ethyl acetate solution (5 ml), and the resulting hydrochloride precipitate was collected by filtration to give the title compound (387 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 3.10 (4H, brs),
3.40-3.90 (4H, m), 4.05 (2H, s), 7.31 (2H, d, J = 7.8
Hz), 7.59 (2H, d, J = 7.8Hz), 7.60-7.78 (3H, m), 7.9
0-8.05 (3H, m), 8.33 (1H, s), 9.88 (2H, brs) .IR (KBr): 1635, 1461, 1434, 1347, 1284, 1166 cm ^-1 .Example 14 1- (4 -Diisobutylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (208 mg), diisobutylamine (292 mg)
The DMF (10 ml) solution was stirred at 100 ° C. for 5 hours to give the title compound (127 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.83 (12H, d, J = 6.6Hz), 1.74 (2
H, m), 2.05 (4H, d, J = 7.2Hz), 3.10 (4H, brs), 3.45
(2H, s), 3.40-3.90 (4H, br), 7.22 (2H, d, J = 8.2H
z), 7.33 (2H, d, J = 8.2Hz), 7.58-7.80 (3H, m), 7.90
-8.03 (3H, m), 8.33 (1H, s) .IR (KBr): 1635, 1455, 1428, 1349, 1283, 1168 cm ^-1 .

Example 15 1- [4- (N-ethyl-tert-butylamino) benzoyl] -4- (2-
Naphthalenesulfonyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (310 mg), N-ethyl-tert-butylamine (7
A solution of 57 mg) in DMF (10 ml) was stirred at 100 ° C. for 5 hours to give the title compound (127 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.0Hz), 1.08 (9
H, s), 2.59 (2H, q, J = 7.0Hz), 3.10 (4H, brs), 3.65
(2H, s), 3.40-3.90 (4H, br), 7.21 (2H, d, J = 8.2H
z), 7.40 (2H, d, J = 8.2Hz), 7.60-7.77 (3H, m), 7.90
-8.04 (3H, m), 8.33 (1H, d, J = 1.6Hz). IR (KBr): 1635, 1455, 1347, 1282, 1168 cm ^-1 . Example 16 1- [4- (2,6 -Dimethylpiperidinomethyl) benzoyl] -4-
(2-Naphthalenesulfonyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (209 mg), 2,6-dimethylpiperidine (256 m
A solution of g) in DMF (10 ml) was stirred at 100 ° C. for 8 hours to give the title compound as colorless crystals (61 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.2Hz), 1.20-1.4
0 (4H, m), 1.62 (2H, m), 2.46 (2H, s), 3.11 (4H, b
rs), 3.73 (2H, s), 3.50-3.90 (4H, br), 7.21 (2H, d,
J = 8.0Hz), 7.38 (2H, d, J = 8.0Hz), 7.60-7.80 (3H,
m), 7.90-8.04 (3H, m), 8.32 (1H, s) .IR (KBr): 1635, 1428, 1349, 1284, 1166 cm ^-1 .

Example 17 1- [4- (3,5-dimethylpiperidinomethyl) benzoyl] -4-
(2-Naphthalenesulfonyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (156 mg), 3,5-dimethylpiperidine (171 m
A solution of g) in DMF (10 ml) was stirred at 100 ° C. for 5 hours to give the title compound (170 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.56 (1H, m), 0.80 (6H, d, J = 6.
2Hz), 0.88 (1H, m), 1.35-1.80 (4H, m), 2.74 (2H,
m), 3.12 (4H, brs), 3.44 (2H, s), 3.75 (4H, brs),
7.23 (2H, d, J = 8.0Hz), 7.31 (2H, d, J = 8.0Hz), 7.60
-7.80 (3H, m), 7.90-8.05 (3H, m), 8.33 (1H, d, J =
IR (KBr): 1639, 1459, 1430, 1349, 1284, 1168 cm ^-1 . Example 18 1- (3-Diisopropylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine Example 1 In a similar manner to 1- (3-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (500 mg),
Potassium carbonate (500 mg), diisopropylamine (2 ml)
The DMF (10 ml) solution was stirred at 100 ° C. for 10 hours to obtain the colorless amorphous title compound (216 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.95 (12H, d, J = 6.6 Hz), 2.93 (2
H, quint, J = 6.6Hz), 3.10 (4H, brs), 3.58 (2H, s),
3.40-4.00 (4H, br), 7.08-7.44 (4H, m), 7.58-7.78
(3H, m), 7.90-8.04 (3H, m), 8.33 (1H, d, J = 1.8Hz). IR (KBr): 1635, 1349, 1168 cm ^-1 .

Example 19 1- (3-Diisopropylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine hydrochloride 1- (3-Diisopropylaminomethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (215 The resulting precipitate of hydrochloride was collected by filtration to obtain the title compound (219 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.48 (6H, d, J = 6.6Hz), 1.51 (6
H, d, J = 6.6Hz), 3.18 (4H, m), 3.40-3.90 (6H, m),
4.14 (2H, d, J = 5.6Hz), 7.33 (1H, d, J = 7.8Hz), 7.44
(1H, t, J = 7.8Hz), 7.58-7.80 (4H, m), 7.85-8.05 (4
H, m), 8.34 (1H, s), 11.74 (1H, brs). IR (KBr): 1633, 1461, 1430, 1347, 1286, 1166 cm ^-1 . Example 20 4- (2-naphthalenesulfonyl) 1- (3-piperidinomethylbenzoyl) piperazine In the same manner as in Example 1, 1- (3-chloromethylbenzoyl) -4- (2-naphthalenesulfonyl) piperazine (300 mg),
Potassium carbonate (313 mg), piperidine (321 mg) in DMF (10 m
l) The solution was stirred at 70 ° C for 3 hours to obtain a colorless amorphous title compound (256 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.65 (6H, m), 2.32 (4H,
m), 3.10 (4H, brs), 3.43 (2H, s), 3.40-4.00 (4H, b
r), 7.16 (1H, dt, J = 1.6, 7.2Hz), 7.24-7.39 (3H,
m), 7.60-7.80 (3H, m), 7.90-8.05 (3H, m), 8.33 (1
H, d, J = 1.6Hz) .IR (KBr): 1635, 1347, 1166 cm ^-1 .

Example 21 1- (6-Chloronaphthalene-2-sulfonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine In the same manner as in Example 1, 1- (4-chloromethylbenzoyl) -4 -(6-chloronaphthalene-2-sulfonyl) piperazine
(376 mg), a solution of potassium carbonate (250 mg), and diisopropylamine (2 ml) in DMF (20 ml) were stirred at 100 ° C. for 4 hours to obtain a colorless amorphous title compound (113 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.10 (4H, brs), 3.61 (2H, s),
3.70 (4H, brs), 7.21 (2H, d, J = 8.2Hz), 7.37 (2H, d,
J = 8.2Hz), 7.59 (1H, dd, J = 2.0, 8.4Hz), 7.75 (1H,
dd, J = 2.0, 8.4Hz), 7.92 (2H, d, J = 8.4Hz), 7.95 (1
H, d, J = 2.0 Hz), 8.30 (1H, d, J = 2.0 Hz). IR (KBr): 1637, 1347, 1166 cm ^-1 . Example 22 1- (6-chloronaphthalene-2-sulfonyl) ) -4- (4-Diisopropylaminomethylbenzoyl) piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine (110 mg) in 4N hydrochloric acid in ethyl acetate (5 ml) was added, and the resulting precipitate of hydrochloride was collected by filtration to give the title compound (113 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.50 (6H, d, J = 6.6 Hz), 1.52 (6
H, d, J = 6.6Hz), 3.12 (4H, brs), 3.40-3.90 (6H, m),
4.17 (2H, d, J = 5.4Hz), 7.36 (2H, d, J = 8.0Hz), 7.5
9 (1H, dd, J = 1.8, 8.8Hz), 7.77 (1H, dd, J = 1.8, 8.8
Hz), 7.88-8.00 (5H, m), 8.31 (1H, s), 11.73 (1H, b
rs) .IR (KBr): 3311, 1635, 1455, 1432, 1345, 1284, 1166
cm ^-1 .

Example 23 1- (6-Bromonaphthalene-2-sulfonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine 10% hydrogencarbonate of 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) 6-Bromonaphthalene-2-sulfonyl chloride (179 mg) was added to a sodium aqueous solution (10 ml) and ethyl acetate (15 ml) solution, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with water, and extracted with 1N hydrochloric acid. The aqueous extract was made alkaline with aqueous sodium hydroxide, extracted with dichloromethane, dried and concentrated.
The residue obtained by concentration was crystallized from ether to give the title compound (201 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.10 (4H, brs), 3.61 (2H, s),
3.71 (4H, brs), 7.20 (2H, d, J = 8.0Hz), 7.37 (2H, d,
J = 8.0Hz), 7.67-7.78 (2H, m), 7.85 (1H, d, J = 8.8H
z), 7.91 (1H, d, J = 8.6Hz), 8.12 (1H, s), 8.29 (1H,
s). IR (KBr): 1637, 1459, 1347, 1284, 1164 cm ^-1 Example 24 1- (4-diisopropylaminomethylbenzoyl) -4- (1-naphthalenesulfonyl) piperazine A method similar to that in Example 23. Then, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) was reacted with 1-naphthalenesulfonyl chloride (144 mg) to obtain a colorless amorphous title compound (181 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.20 (4H, brs), 3.61 (2H, s),
3.40-3.80 (4H, br), 7.21 (2H, d, J = 8.2Hz), 7.37 (2
H, d, J = 8.2Hz), 7.50-7.73 (3H, m), 7.96 (1H, m),
8.11 (1H, d, J = 8.4Hz), 8.21 (1H, d, J = 7.2Hz), 8.73
(1H, d, J = 7.4Hz). IR (KBr): 1635, 1428, 1349, 1162 cm ^-1 .

Example 25 1- (4-Diisopropylaminomethylbenzoyl) -4- (1-naphthalenesulfonyl) piperazine hydrochloride 1- (4-Diisopropylaminomethylbenzoyl) -4- (1-naphthalenesulfonyl) piperazine (181 The resulting hydrochloride precipitate was collected by filtration to give the title compound (180 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.51 (6H, d, J = 6.4 Hz), 1.53 (6
H, d, J = 6.4Hz), 3.21 (4H, brs), 3.40-3.90 (6H, m),
4.18 (2H, d, J = 5.6Hz), 7.37 (2H, d, J = 7.2Hz), 7.5
3-7.75 (3H, m), 7.85-8.00 (3H, m), 8.13 (1H, d, J =
8.0Hz), 8.22 (1H, d, J = 7.4Hz), 8.74 (1H, d, J = 8.2H
z), 11.73 (1H, brs). IR (KBr): 1635, 1436, 1284, 1162, 1137 cm ^-1 . Example 26 1- (4-diisopropylaminomethylbenzoyl) -4- (4-toluenesulfonyl) Piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) was reacted with 4-toluenesulfonyl chloride (122 mg) to give the title compound (141 mg) as colorless crystals. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (12H, d, J = 6.6Hz), 2.46 (3
H, s), 2.90-3.10 (6H, m), 3.63 (2H, s), 3.40-3.90
(4H, br), 7.23 (2H, d, J = 8.4Hz), 7.35 (2H, d, J = 8.
4Hz), 7.39 (2H, d, J = 8.4Hz), 7.63 (2H, d, J = 8.4H
z) .IR (KBr): 1640, 1428, 1351, 1168 cm ^-1 .

Example 27 1- (4-Bromobenzenesulfonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) ) And 6-bromobenzenesulfonyl chloride (149 mg) to give the title compound (190 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (12H, d, J = 66Hz), 2.85-3.1
0 (6H, m), 3.63 (2H, s), 3.45-3.85 (4H, br), 7.24
(2H, d, J = 8.4Hz), 7.40 (2H, d, J = 8.4Hz), 7.60 (2H, d, J = 8.4Hz)
d, J = 8.6Hz), 7.71 (2H, d, J = 8.6Hz). IR (KBr): 1635, 1428, 1361, 1248, 1168 cm ^-1 . Example 28 1- (benzylsulfonyl) -4- (4-Diisopropylaminomethylbenzoyl) piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) was reacted with benzylsulfonyl chloride (112 mg) to give colorless crystals. The compound (124 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (12H, d, J = 6.6Hz), 3.00 (2
H, quint, J = 6.6Hz), 3,09 (4H, brs), 3.64 (2H, s),
3.40-3.80 (4H, br), 4.25 (2H, s), 7.20-7.30 (3H,
m), 7.33-7.50 (6H, m) .IR (KBr): 1635, 1455, 1428, 1345, 1283, 1158 cm ^-1 .

Example 29 1- (4-Diisopropylaminomethylbenzoyl) -4- (6-methoxynaphthalene-2-sulfonyl) piperazine 1- (4-Diisopropylaminomethylbenzoyl) piperazine (200 mg) and 6-methoxynaphthalene-2-sulfonyl chloride (150 mg) were reacted to give the title compound (200 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.07 (4H, brs), 3.61 (2H, s),
3.40-3.95 (4H, br), 3.97 (3H, s), 7.16-7.40 (6H,
m), 7.68 (1H, dd, J = 1.8, 8.8Hz), 7.86 (2H, d, J = 8.
8Hz), 8.23 (1H, s). IR (KBr): 1633, 1347, 1264, 1162 cm ^-1 . Example 30 1- (4'-chlorobiphenyl-4-sulfonyl) -4- (4-diisopropylamino Methylbenzoyl) piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) was reacted with 4′-chlorobiphenyl-4-sulfonyl chloride (209 mg) to give colorless crystals. The title compound (270 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.98 (2
H, quint, J = 6.6Hz), 3.08 (4H, brs), 3.63 (2H, s),
3.72 (4H, brs), 7.24 (2H, d, J = 8.0Hz), 7.39 (2H, d,
J = 8.0Hz), 7.47 (2H, d, J = 8.8Hz), 7.56 (2H, d, J =
8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.81 (2H, d, J = 8.8H
z) .IR (KBr): 1637, 1427, 1351, 1283, 1168 cm ^-1 .

Example 31 1- [2 (E)-(4-chlorophenyl) ethenylsulfonyl] -4- (4
-Diisopropylaminomethylbenzoyl) piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) and 2 (E)-(4-
(Chlorophenyl) ethenylsulfonyl chloride (172 mg)
To give the colorless amorphous title compound (200 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (12H, d, J = 6.6 Hz), 2.99 (2
H, quint, J = 6.6Hz), 3.22 (4H, brs), 3.64 (2H, s),
3.75 (4H, brs), 6.63 (1H, d, J = 15.8Hz), 7.25-7.50
(9H, m). IR (KBr): 1635, 1434, 1347, 1154 cm ^-1 . Example 32 1- (4-Diisopropylaminomethylbenzoyl) -4- (7-methoxynaphthalene-2-sulfonyl) piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) was reacted with 7-methoxynaphthalene-2-sulfonyl chloride (203 mg) to give the title compound as colorless crystals (316 mg). ). ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.10 (4H, brs), 3.61 (2H, s),
3.72 (4H, brs), 3.96 (3H, s), 7.17-7.40 (6H, m), 7.
58 (1H, dd, J = 1.8, 8.8Hz), 7.83 (2H, d, J = 9.2Hz),
7.91 (1H, d, J = 8.8Hz), 8.20 (1H, s). IR (KBr): 1629, 1347, 1257, 1218, 1166 cm ^-1 .

Example 33 1- (7-Chloronaphthalene-2-sulfonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (150 mg) and 7-chloronaphthalene-2-sulfonyl chloride (142 mg) were reacted to give the title compound (200 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.10 (4H, brs), 3.62 (2H, s),
3.71 (4H, brs), 7.20 (2H, d, J = 8.0Hz), 7.37 (2H, d,
J = 8.0Hz), 7.62 (1H, dd, J = 1.8, 8.8Hz), 7.73 (1H,
dd, J = 1.8, 8.8Hz), 7.85-8.03 (3H, m), 8.23 (1H, s) IR (KBr): 1635, 1428, 1363, 1347, 1284, 1166 cm ^-1 . Example 34 1- (5-chloronaphthalene-2-sulfonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (150 mg) and 5-chloro Naphthalene-2-sulfonyl chloride (142 mg) was reacted to obtain the title compound (179 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.11 (4H, brs), 3.61 (2H, s),
3.71 (4H, brs), 7.21 (2H, d, J = 8.2Hz), 7.37 (2H, d,
J = 8.2Hz), 7.57 (1H, t, J = 8.0Hz), 7.78 (1H, d, J =
8.0Hz), 7.84 (1H, dd, J = 2.0, 8.8Hz), 7.91 (1H, d,
J = 8.0Hz), 8.33 (1H, d, J = 2.0Hz), 8.45 (1H, d, J = 8.8
Hz) .IR (KBr): 1635, 1426, 1361, 1332, 1284, 1166 cm ^-1 .

Example 35 1- (4-Diisopropylaminomethylbenzoyl) -4- [6-
(2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl] piperazine In the same manner as in Example 23, 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) and 6- (2,2 , 2-
Reaction with trichloroethoxycarbonylamino) naphthalene-2-sulfonyl chloride (289 mg) gave the title compound (303 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.09 (4H, brs), 3.61 (2H, s),
3.71 (4H, brs), 4.89 (2H, s), 7.21 (2H, d, J = 8.2H
z), 7.23 (1H, brs), 7.37 (2H, d, J = 8.2Hz), 7.56 (1
H, dd, J = 2.2, 8.8Hz), 7.72 (1H, dd, J = 2.0, 8.8Hz),
7.94 (1H, d, J = 8.8Hz), 7.95 (1H, d, J = 8.8Hz), 8.2
0 (1H, d, J = 2.2Hz), 8.27 (1H, d, J = 2.0Hz) .IR (KBr): 3241, 1747, 1616, 1558, 1347, 1210, 1164
. cm ^-1 Example 36 1- (4-diisopropylamino-methylbenzoyl) -4- (6-hydroxy-2-sulfonyl) piperazine 1- (4-diisopropylamino-methylbenzoyl) -4- (6-methoxy-naphthalene - 2-sulfonyl) piperazine (100 mg)
In CH ₂ Cl ₂ (6 ml) solution was added dropwise BBr ₃ in 3.5 MCH ₂ Cl ₂ solution (0.12 ml) at 0 ° C., and stirred for 1 hour at room temperature. Aqueous sodium bicarbonate was added to the reaction solution, the organic layer was separated, dried and concentrated to give the title compound as a colorless solid (91 mg). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (12H, d, J = 6.6 Hz), 2.97 (2
H, quint, J = 6.6Hz), 3.07 (4H, brs), 3.62 (2H, s),
3.72 (4H, brs), 7.08-7.26 (4H, m), 7.39 (2H, d, J =
7.8Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.69 (1H, d,
J = 8.8Hz), 7.79 (1H, d, J = 8.8Hz), 8.19 (1H, s) .IR (KBr): 3163 (br), 1610, 1465, 1438, 1347, 1284,
1162 cm ^-1 .

Example 37 1- (4-Diisopropylaminomethylbenzoyl) -4- (7-hydroxynaphthalene-2-sulfonyl) piperazine In the same manner as in Example 36, 1- (4-diisopropylaminomethylbenzoyl)- in CH ₂ Cl ₂ (6 ml) solution of 4- (7-methoxynaphthalene-2-sulfonyl) piperazine (0.99 mg), 0
At 0 ° C, a solution of BBr ₃ in 3.5 M CH ₂ Cl ₂ (0.18 ml) was added dropwise.
Stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added to the reaction solution, the organic layer was separated, dried and concentrated to give the title compound as a colorless solid (119 m
g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (12H, d,
J = 6.6 Hz), 2.80-3.10 (6H,
m), 3.30-3.75 (6H, m),
7.18-7.40 (6H, m), 7.48
(1H, d, J = 8.6 Hz), 7.93 (1
H, d, J = 9.0 Hz), 8.02 (1H,
d, J = 8.6 Hz), 8.17 (1H,
s), 10.18 (1H, brs). IR (KBr): 3100 (br), 162
7, 1587, 1442, 1345, 128
2, 1170 cm ^-1 . Example 38 1- (6-Aminonaphthalene-2-sulfonyl) -4- (4-diisopropylaminomethylbenzoyl) piperazine 1- (4-diisopropylaminomethylbenzoyl) -4- [6-
To a solution of (2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl] piperazine (125 mg) in acetic acid (3 ml) was added zinc dust (1.0 g), and the mixture was stirred at room temperature for 3 hours. The insolubles were filtered through celite, the filtrate was concentrated, and the residue was dissolved in 1N hydrochloric acid. The mixture was made alkaline with a 1N aqueous solution of sodium hydroxide, the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (92 mg) as a pale purple solid. ¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (12H, d, J = 6.6 Hz), 2.80-
3.10 (6H, m), 3.57 (4H, brs), 3.60 (2H, s), 5.95
(2H, s), 6.88 (1H, d, J = 2.0Hz), 7.07 (1H, dd, J = 2.
0, 8.8Hz), 7.23 (2H, d, J = 8.0Hz), 7.35 (2H, d, J =
8.0Hz), 7.47 (1H, dd, J = 1.6, 8.8Hz), 7.66 (1H, d, J
= 8.8Hz), 7.83 (1H, d, J = 8.8Hz), 8.08 (1H, d, J = 1.6
Hz) .IR (KBr): 1629, 1508, 1430, 1347, 1162 cm ^-1 .

Example 39 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (N-ethyl
-tert-butylaminomethyl) benzoyl] piperazine 1- (tert-butoxycarbonyl) -4- [4- (N-ethyl-tert-butylaminomethyl) benzoyl] piperazine (200 mg) in methanol (0.5 ml) 4N hydrochloric acid ethyl acetate solution (2
ml) and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated, and the obtained residue was dissolved in ethyl acetate (10 ml) and aqueous sodium bicarbonate (10 ml), and 6-chloronaphthalene-2-sulfonyl chloride (135
mg) was added and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with water, and extracted with 1N hydrochloric acid. The aqueous extract was made alkaline with aqueous sodium hydroxide, extracted with dichloromethane, dried and concentrated. The obtained residue was crystallized from ether / hexane to give the title compound (163 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.85 (6H, t, J = 7.0Hz), 1.08 (9
H, s), 2.59 (2H, q, J = 7.0Hz), 3.09 (4H, brs), 3.65
(2H, s), 3.72 (4H, brs), 7.21 (2H, d, J = 7.8Hz),
7.40 (2H, d, J = 7.8Hz), 7.60 (1H, d, J = 9.0Hz), 7.75
(1H, d, J = 9.0Hz), 7.90-7.97 (3H, m), 8.31 (1H, s). IR (KBr): 1637, 1457, 1430, 1349, 1284, 1166 cm ^-1 . 1- (6-bromonaphthalene-2-sulfonyl) -4- [4- (N-ethyl
-tert-butylaminomethyl) benzoyl] piperazine In the same manner as in Example 39, 1- (tert-butoxycarbonyl) -4- [4- (N-ethyl-tert-butylaminomethyl) benzoyl] piperazine (200 mg ) Was treated with hydrochloric acid and reacted with 6-bromonaphthalene-2-sulfonyl chloride (160 mg).
The title compound (166 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.85 (6H, t, J = 7.0Hz), 1.08 (9
H, s), 2.59 (2H, q, J = 7.0Hz), 3.10 (4H, brs), 3.65
(2H, s), 3.72 (4H, brs), 7.20 (2H, d, J = 8.2Hz),
7.39 (2H, d, J = 8.2Hz), 7.67-7.79 (2H, m), 7.85 (1
H, d, J = 8.8Hz), 7.91 (1H, d, J = 8.8Hz), 8.12 (1H,
s), 8.29 (1H, s) .IR (KBr): 1637, 1428, 1347, 1330, 1284, 1164 cm ^-1 .

Example 41 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (2,6-dimethylpiperidinomethyl) benzoyl] piperazine In the same manner as in Example 39, 1- ( tert-butoxycarbonyl) -4- [4- (2,6-dimethylpiperidinomethyl) benzoyl]
After treating piperazine (200 mg) with hydrochloric acid, 6-chloronaphthalene
Reaction with -2-sulfonyl chloride (132 mg) gave the title compound (40 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, t, J
= 6.2 Hz), 1.28 (4H, m), 1.
61 (2H, m), 2.45 (2H, m),
3.11 (4H, brs), 3.70 (4
H, brs), 3.73 (2H, s), 7.
21 (2H, d, J = 8.0 Hz), 7.39
(2H, d, J = 8.0 Hz), 7.59
(1H, dd, J = 2.0, 8.8 Hz),
7.75 (1H, dd, J = 1.8, 8.8H
z), 7.90-8.00 (3H, m), 8.
30 (1H, s). IR (KBr): 1635, 1455, 143
2, 1347, 1284, 1166 cm ^-1 . Example 42 1- (6-bromonaphthalene-2-sulfonyl) -4- [4- (2,6
-Dimethylpiperidinomethyl) benzoyl] piperazine In the same manner as in Example 39, 1- (tert-butoxycarbonyl) -4- [4- (2,6-dimethylpiperidinomethyl) benzoyl]
After treating piperazine (200 mg) with hydrochloric acid, 6-bromonaphthalene
Reaction with -2-sulfonyl chloride (155 mg) gave the title compound (47 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, t, J = 6.2Hz), 1.28 (4
H, m), 1.60 (2H, m), 2.46 (2H, m), 3.10 (4H, brs),
3.71 (4H, brs), 3.73 (2H, s), 7.21 (2H, d, J = 8.2H
z), 7.39 (2H, d, J = 8.2Hz), 7.67-7.80 (2H, m), 7.80
(1H, d, J = 9.0Hz), 7.91 (1H, d, J = 8.8Hz), 8.12 (1
H, s), 8.29 (1H, s) .IR (KBr): 1639, 1459, 1432, 1345, 1284, 1164 cm ^-1 .

Example 43 1- [4- (2-Diisopropylaminoethyl) benzoyl] -4-
(2-Naphthalenesulfonyl) piperazine In the same manner as in Example 39, 1- (tert-butoxycarbonyl) -4- [4- (2-diisopropylaminoethyl) benzoyl]
Piperazine (161 mg) was treated with hydrochloric acid, and then reacted with 2-naphthalenesulfonyl chloride (95 mg) to give the title compound (76 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (12H, d, J = 6.6Hz), 2.50-2.
74 (4H, m), 3.02 (2H, quint, J = 6.6Hz), 3.09 (4H, br
s), 3.70 (4H, brs), 7.16 (2H, d, J = 8.4Hz), 7.21 (2
H, d, J = 8.4Hz), 7.58-7.77 (3H, m), 7.90-8.04 (3H,
m), 8.33 (1H, s) IR (KBr): 1637, 1457, 1426, 1347, 1284, 1166 cm ^-1 . Example 44 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (2-Diisopropylaminoethyl) benzoyl] piperazine In the same manner as in Example 39, 1- (tert-butoxycarbonyl) -4- [4- (2-diisopropylaminoethyl) benzoyl]
After treating piperazine (161 mg) with hydrochloric acid, 6-chloronaphthalene
Reaction with 2-sulfonyl chloride (110 mg) gave the title compound (69 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.50-2.
75 (4H, m), 3.03 (2H, quint, J = 6.6Hz), 3.09 (4H, br
s), 3.70 (4H, brs), 7.16 (2H, d, J = 8.4Hz), 7.21 (2
H, d, J = 8.4Hz), 7.59 (1H, dd, J = 2.0, 8.8Hz), 7.75
(1H, dd, J = 1.6,8.8Hz), 7.92 (2H, d, J = 8.8Hz), 7.94
(1H, s), 8.29 (1H, s) .IR (KBr): 1635, 1455, 1428, 1347, 1283, 1166 cm ^-1 .

Example 45 1- (6-Bromonaphthalene-2-sulfonyl) -4- [4- (2-diisopropylaminoethyl) benzoyl] piperazine In the same manner as in Example 39, 1- (tert-butoxycarbonyl) ) -4- [4- (2-Diisopropylaminoethyl) benzoyl]
After treating piperazine (161 mg) with hydrochloric acid, 6-bromonaphthalene
Reaction with 2-sulfonyl chloride (128 mg) gave the title compound (68 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.50-2.
77 (4H, m), 2.92-3.20 (6H, m), 3.73 (4H, brs), 7.16
(2H, d, J = 8.4Hz), 7.21 (2H, d, J = 8.4Hz), 7.69-7.8
0 (2H, m), 7.85 (1H, d, J = 8.8Hz), 7.91 (1H, d, J =
8.8Hz), 8.13 (1H, s), 8.29 (1H, s). IR (KBr): 163
5, 1455, 1428, 1347, 1284, 1166 cm ^-1 .Example 46 1- (6-chloronaphthalene-2-sulfonyl) -4- (4-diisopropylaminomethyl-2-methoxybenzoyl) piperazine 1- (6 -Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), 4-diisopropylaminomethyl-2-methoxybenzoic acid (77 mg), triethylamine (35 mg) and HOBt
(43 mg) in DMF (10 ml) was added with WSC hydrochloride (61 mg) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, ethyl acetate and aqueous sodium bicarbonate were added to the residue, the organic layer was separated, washed with water, and extracted with 1N hydrochloric acid. The aqueous extract was made alkaline with aqueous sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue obtained by concentration was crystallized from ether to give the title compound (99 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6 Hz), 2.98 (2
H, quint, J = 6.6Hz), 3.00 (2H, m), 3.18 (2H, m), 3.
36 (2H, m), 3.61 (5H, s), 3.89 (2H, m), 6.91 (1H,
d, J = 7.6Hz), 6.98 (1H, s), 7.02 (1H, d, J = 7.6Hz),
7.60 (1H, dd, J = 2.2, 8.8Hz), 7.76 (1H, dd, J = 2.0,
(8.8Hz), 7.88-7.96 (3H, m), 8.30 (1H, s) .IR (KBr): 1635, 1463, 1436, 1347, 1166 cm ^-1 .

Example 47 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (90 mg) ), 4- (4-pyridyl) benzoic acid (52 mg), triethylamine (35 mg) and HOBt (39 mg) in DMF (10 ml)
C hydrochloride (55 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, ethyl acetate and aqueous sodium bicarbonate were added to the residue, the organic layer was separated, washed with water, and extracted with 1N hydrochloric acid. The aqueous extract was made alkaline with aqueous sodium hydroxide, extracted with dichloromethane, dried and concentrated.
The residue obtained by concentration was crystallized from ether to give the title compound (122 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, brs), 3.76 (4H, brs),
7.38-7.49 (4H, m), 7.56-7.68 (3H, m), 7.75 (1H,
d, J = 8.4Hz), 7.89-7.98 (3H, m), 8.31 (1H, s), 8.68
(2H, d, J = 5.8Hz). IR (KBr): 1635, 1596, 1432, 1347, 1330, 1284, 1166
cm ^-1 . Example 48 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (3-pyridyl) benzoyl] piperazine As in Example 46, 1- (6-chloronaphthalene-2- (Sulfonyl) piperazine hydrochloride (100 mg), 4- (3-pyridyl) benzoic acid (57 mg), triethylamine (40 mg) and HOBt (43 m
A solution of g) in DMF (10 ml) was reacted with WSC hydrochloride (61 mg) to give the title compound (106 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.76 (4H, brs),
7.34-7.46 (3H, m), 7.54-7.64 (3H, m), 7.77 (1H, d
d, J = 2.0, 8.8Hz), 7.85 (1H, dt, J = 1.4, 8.0Hz), 7.8
9-7.97 (3H, m), 8.32 (1H, s), 8.63 (1H, dd, J = 1.4,
4.8Hz), 8.82 (1H, d, J = 1.4Hz). IR (KBr): 1635, 1428, 1347, 1284, 1166 cm ^-1 .

Example 49 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (1H-imidazol-1-yl) benzoyl] piperazine In the same manner as in Example 46, 1- (6- Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), 4- (1H-imidazole
1-yl) benzoic acid (55 mg), triethylamine (40 mg)
By reacting WSC hydrochloride (61 mg) with a solution of HOBt (43 mg) in DMF (10 ml), the title compound as colorless crystals (124 mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 3.12 (4H, brs), 3.74 (4H, brs),
7.22 (1H, s), 7.27 (1H, s), 7.40 (2H, d, J = 9.2H
z), 7.45 (2H, d, J = 9.2Hz), 7.60 (1H, dd, J = 2.0, 8.
8Hz), 7.76 (1H, dd, J = 2.0, 8.8Hz), 7.86 (1H, s),
7.88-7.97 (3H, m), 8.31 (1H, s). IR (KBr): 1635, 1455, 1436, 1345, 1286, 1166 cm ^-1 . Example 50 1- (6-chloronaphthalene-2-sulfonyl) ) -4- [4- (1,2,4-Triazol-1-yl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg ), 4- (1,2,4-triazol-1-yl) benzoic acid (55 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (107
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, brs), 3.72 (4H, brs),
7.47 (2H, d, J = 8.8Hz), 7.60 (1H, dd, J = 1.8, 8.8H
z), 7.67-7.80 (3H, m), 7.89-7.98 (3H, m), 8.12 (1
H, s), 8.31 (1H, d, J = 1.8Hz), 8.58 (1H, s) .IR (KBr): 1637, 1610, 1459, 1438, 1345, 1330, 1280
cm ^-1 .

Example 51 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (1,2,4-triazol-4-yl) benzoyl] piperazine In the same manner as in Example 46, 1 -(6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), 4- (1,2,4-triazol-4yl) benzoic acid (55 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (54
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, brs), 3.74 (4H, brs),
7.42 (2H, d, J = 8.8Hz), 7.52 (2H, d, J = 8.8Hz), 7.6
1 (1H, dd, J = 1.8, 8.8Hz), 7.76 (1H, dd, J = 1.8, 8.8
Hz), 7.90-7.98 (3H, m), 8.12 (1H, s), 8.32 (1H, d,
J = 1.8Hz), 8.48 (2H, s) .IR (KBr): 1633, 1610, 1527, 1459, 1436, 1345, 133
0, 1164 cm ^-1 . Example 52 1- [4- (N-tert-butoxycarbonylpiperidin-4-yl)
Benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), 4- (N-tert- Butoxycarbonyl-piperidin-4-yl) benzoic acid (88 mg), a solution of triethylamine (40 mg) and HOBt (43 mg) in DMF (10 ml) was reacted with WSC hydrochloride (61 mg) to give colorless crystals. The title compound (153 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.50-1.85 (4H,
m), 2.58-2.90 (3H, m), 3.11 (4H, brs), 3.71 (4H, b
rs), 4.23 (2H, brd, J = 11.0Hz), 7.18 (2H, d, J = 8.4H
z), 7.25 (2H, d, J = 8.4Hz), 7.60 (1H, dd, J = 2.2, 8.
8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.96 (3H,
m), 8.30 (1H, s) .IR (KBr): 1683, 1635, 1428, 1347, 1284, 1166 cm ^-1 .

Example 53 1- [4- (1-tert-butoxycarbonyl-4-piperazinyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine In the same manner as in Example 46, 1- (6 -Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), 4- (1-tert-butoxycarbonyl-4-piperazinyl) benzoic acid (88 mg), DMF of triethylamine (40 mg) and HOBt (43 mg) (10 ml) solution
The title compound (128 mg) as colorless crystals was obtained by reacting with WSC hydrochloride (61 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 3.09 (4H, m), 3.1
8 (4H, m), 3.56 (4H, m), 3.74 (4H, m), 6.82 (2H,
d, J = 8.8Hz), 7.25 (2H, d, J = 8.8Hz), 7.59 (1H, dd, J
= 2.2, 8.8Hz), 7.75 (1H, dd, J = 1.4, 8.8Hz), 7.87-7.
96 (3H, m), 8.29 (1H, s). IR (KBr): 1695, 1627, 1608, 1427, 1232, 1166 cm ^-1 . Example 54 1- (6-chloronaphthalene-2-sulfonyl)- 4- [2- (4-pyridyl) -4-thiazolecarbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), 2- (4-pyridyl) in the same manner as in Example 46. )-Four-
Thiazolecarboxylic acid (60 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (133) as colorless crystals.
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.22 (4H, brs), 3.92 (2H, brs),
4.18 (2H, brs), 7.58 (1H, dd, J = 2.0, 8.8Hz), 7.73
(2H, d, J = 6.2Hz), 7.78 (1H, dd, J = 1.8, 8.8Hz), 7.8
7-7.96 (3H, m), 8.05 (1H, s), 8.33 (1H, s), 8.74
(2H, d, J = 6.2Hz). IR (KBr): 1629, 1596, 1461, 1345, 1330, 1241, 1164
cm ^-1 .

Example 55 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (4-pyridyl) -2-thiazolecarbonyl] piperazine 1- (6-Chloronaphthalene) (-2-sulfonyl) piperazine hydrochloride (100 mg), 4- (4-pyridyl) -2-
Thiazolecarboxylic acid (60 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (113) as colorless crystals.
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.26 (4H, t, J = 5.0Hz), 3.95 (2
H, brs), 4.70 (2H, brs), 7.58 (1H, dd, J = 2.0, 8.8H
z), 7.68 (2H, d, J = 6.2Hz), 7.78 (1H, dd, J = 1.8, 8.
8Hz), 7.85-7.96 (4H, m), 8.34 (1H, s), 8.70 (2H,
d, J = 6.2Hz). IR (KBr): 1625, 1600, 1492, 1459, 1345, 1330, 128
0, 1164 cm ^-1. In the same manner as in Example 56 1- (6-chloronaphthalene-2-sulfonyl) -4- [2- (4-pyridyl) -5- thiazolecarbonyl] piperazine Example 46, 1- ( 6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), 2- (4-pyridyl) -5-
Thiazolecarboxylic acid (60 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (118) as colorless crystals.
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.18 (4H, t, J = 5.0Hz), 3.88 (4
H, t, J = 5.0Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.73-
7.80 (3H, m), 7.90-7.98 (4H, m), 8.32 (1H, m), 8.7
4 (2H, d, J = 6.2Hz). IR (KBr): 1623, 1594, 1436, 1345, 1164 cm ^-1 .

Example 57 1- (6-Bromonaphthalene-2-sulfonyl) -4- [2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (6-Bromonaphthalene) (-2-sulfonyl) piperazine hydrochloride (112 mg), 2- (4-pyridyl) -5-
Thiazolecarboxylic acid (60 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (47) as colorless crystals.
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.18 (4H, t, J = 5.0Hz), 3.88 (4
H, t, J = 5.0Hz), 7.69-7.80 (4H, m), 7.86 (1H, d, J =
8.8Hz), 7.92 (1H, d, J = 8.8Hz), 7.96 (1H, s), 8.12
(1H, s), 8.31 (1H, s), 8.73 (2H, d, J = 6.0 Hz) .IR (KBr): 1622, 1435, 1346, 1163 cm ^-1 .Example 58 1- (6-chloro Naphthalene-2-sulfonyl) -4- [5- (4-pyridyl) -2-thenoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), as in Example 46. 5- (4-pyridyl) -2-
Thiophenecarboxylic acid (60 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (82
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.16 (4H, t, J = 5.0Hz), 3.89 (4
H, t, J = 5.0Hz), 7.23 (1H, d, J = 4.0Hz), 7.38 (1H,
d, J = 4.0Hz), 7.43 (2H, d, J = 6.2Hz), 7.59 (1H, dd, J
= 1.8, 8.8Hz), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.
96 (3H, m), 8.31 (1H, d, J = 1.8Hz), 8.62 (2H, d, J =
6.0Hz) .IR (KBr): 1622, 1597, 1460, 1418, 1346, 1331, 128
3, 1264, 1165 cm ^-1 .

Example 59 1- (6-bromonaphthalene-2-sulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine In the same manner as in Example 46, 1- (6-bromonaphthalene-2-sulfonyl) ) Piperazine hydrochloride (112 mg), 4- (4-pyridyl) benzoic acid (57 mg), triethylamine (40 mg) and HOBt (43 m
A solution of g) in DMF (10 ml) was reacted with WSC hydrochloride (61 mg) to give the title compound (84 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.73 (4H, brs),
7.42 (2H, d, J = 8.2Hz), 7.46 (2H, d, J = 6.2Hz), 7.6
3 (2H, d, J = 8.2Hz), 7.70-7.80 (2H, m), 7.86 (1H, d,
J = 8.8Hz), 7.92 (1H, d, J = 8.8Hz), 8.13 (1H, s), 8.
30 (1H, m), 8.68 (2H, d, J = 6.2Hz) .IR (KBr): 1636, 1456, 1431, 1346, 1329, 1285, 1165
cm ^-1 . Example 60 1- (6-Bromonaphthalene-2-sulfonyl) -4- [4- (3-pyridyl) benzoyl] piperazine 1- (6-Bromonaphthalene-2- (Sulfonyl) piperazine hydrochloride (112 mg), 4- (3-pyridyl) benzoic acid (57 mg), triethylamine (40 mg) and HOBt (43 m
A solution of g) in DMF (10 ml) was reacted with WSC hydrochloride (61 mg) to give the title compound (101 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.74 (4H, brs),
7.34-7.47 (3H, m), 7.58 (2H, d, J = 8.4Hz), 7.68-7.
96 (5H, m), 8.13 (1H, s), 8.30 (1H, s), 8.62 (1H, d
d, J = 1.4, 4.8Hz), 8.81 (1H, d, J = 2.2Hz) .IR (KBr): 1634, 1456, 1427, 1346, 1329, 1285, 1163
cm ^-1 .

Example 61 1- (6-Bromonaphthalene-2-sulfonyl) -4- [4- (1H-imidazol-1-yl) benzoyl] piperazine 1- (6-bromonaphthalene-2-sulfonyl) piperazine (Bromonaphthalene-2-sulfonyl) piperazine hydrochloride (112 mg), 4- (1H-imidazole
1-yl) benzoic acid (55 mg), triethylamine (40 mg)
By reacting WSC hydrochloride (61 mg) with a solution of HOBt (43 mg) in DMF (10 ml), the title compound as colorless crystals (122 mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.74 (4H, brs),
7.22 (1H, s), 7.28 (1H, s), 7.40 (2H, d, J = 8.8H
z), 7.45 (2H, d, J = 8.8Hz), 7.73 (1H, dd, J = 2.0, 8.
8Hz), 7.76 (1H, dd, J = 2.0, 8.8Hz), 7.82-7.88 (2H,
m), 7.92 (1H, d, J = 8.8Hz), 8.13 (1H, d, J = 2.0Hz),
8.30 (1H, s). IR (KBr): 1636, 1611, 1456, 1433, 1344, 1329, 128
5, 1262, 1163 cm ^-1. Example 62 1- (6-chloronaphthalene-2-sulfonyl) -4- [5- (4-pyridyl) -2-furoyl] Similar piperazine Example 46, 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (80 mg), 5- (4-pyridyl) -2-furancarboxylic acid (44 mg), triethylamine (30 mg) and HO
The title compound (90 mg) was obtained as pale green crystals by reacting a solution of Bt (33 mg) in DMF (10 ml) with WSC hydrochloride (49 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.21 (4H, t, J = 5.0Hz), 3.98 (4
H, brs), 6.90 (1H, d, J = 3.6Hz), 7.07 (1H, d, J = 3.6
Hz), 7.47 (2H, d, J = 6.2Hz), 7.58 (1H, dd, J = 1.8,
8.8Hz), 7.57 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.96 (3
H, m), 8.33 (1H, s), 8.65 (2H, d, J = 6.2Hz) .IR (KBr): 1626, 1607, 1427, 1346, 1165 cm ^-1 .

Example 63 1- (6-Chloronaphthalene-2-sulfonyl) -4- [6- (4-pyridyl) nicotinoyl] piperazine In the same manner as in Example 46, 1- (6-chloronaphthalene-2-sulfonyl) ) Piperazine hydrochloride (80 mg), 6- (4-pyridyl) nicotinic acid (47 mg), triethylamine (30 mg) and HOBt (33 m
A solution of g) in DMF (10 ml) was reacted with WSC hydrochloride (49 mg) to give the title compound (103 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (4H, brs), 3.77 (4H, brs),
7.60 (1H, dd, J = 2.0,8.8Hz), 7.76 (1H, dd, J = 1.8,
8.8Hz), 7.80-7.97 (7H, m), 8.31 (1H, s), 8.66 (1H,
d, J = 1.6Hz), 8.74 (2H, d, J = 5.8Hz) .IR (KBr): 1634, 1593, 1456, 1435, 1346, 1331, 128
5, 1165 cm ^-1. Example 64 1- (6-chloronaphthalene-2-sulfonyl) -4- [2- (4-pyridyl) -4-methyl-5-thiazolecarboxylic carbonyl] Similar piperazine Example 46 , 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (80 mg), 2- (4-pyridyl) -4-methyl-5-thiazolecarboxylic acid (51 mg), triethylamine (30 mg) and HOBt A title compound (100 mg) as colorless crystals was obtained by reacting a solution of (33 mg) in DMF (10 ml) with WSC hydrochloride (49 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.15 (4H, t, J = 5.
0Hz), 3.77 (4H, m), 7.60 (1H, dd, J = 1.8, 8.8Hz),
7.69-7.80 (3H, m), 7.90-7.98 (3H, m), 8.32 (1H,
s), 8.71 (2H, d, J = 6.2Hz) .IR (KBr): 1634, 1597, 1456, 1435, 1346, 1329, 128
1, 1258, 1165 cm ^-1 .

Example 65 1- (6-Bromonaphthalene-2-sulfonyl) -4- [5- (4-pyridyl) -2-thenoyl] piperazine 1- (6-Bromonaphthalene-2-sulfonyl) piperazine 2-sulfonyl) piperazine hydrochloride (112 mg), 5- (4-pyridyl) -2-
Thiophenecarboxylic acid (60 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (131) as colorless crystals.
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.16 (4H, t, J = 4.9Hz), 3.88 (4
H, t, J = 4.9Hz), 7.22 (1H, d, J = 4.2Hz), 7.37 (1H,
d, J = 4.2Hz), 7.42 (2H, d, J = 5.8Hz), 7.68-7.80 (2H,
m), 7.85 (1H, d, J = 8.8Hz), 7.92 (1H, d, J = 8.8Hz),
8.12 (1H, s), 8.30 (1H, s), 8.62 (2H, d, J = 5.8Hz) .IR (KBr): 1620, 1597, 1456, 1418, 1344, 1331, 128
. 3, 1264, 1163 cm ^-1 Example 66 1- (6-bromo-2-sulfonyl) -4- [4- (1,2,4-triazole --4-yl) benzoyl] piperazine Example As in 46, 1- (6-bromonaphthalene-2-sulfonyl) piperazine hydrochloride (112 mg), 4- (1,2,4-triazol-4-yl) benzoic acid (55 mg), triethylamine (40 m
g) and HOBt (43 mg) in DMF (10 ml) were added to WSC hydrochloride (61 m2).
g) to give the title compound (139) as colorless crystals.
mg). ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.72 (4H, brs),
7.42 (2H, d, J = 8.2Hz), 7.50 (2H, d, J = 8.2Hz), 7.7
3 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8
Hz), 7.86 (1H, d, J = 8.8Hz), 7.92 (1H, d, J = 8.8Hz),
8.12 (1H, s), 8.29 (1H, s), 8.48 (2H, s) .IR (KBr): 1634, 1526, 1456, 1435, 1345, 1329, 128
5, 1163 cm ^-1 .

Example 67 1- (6-Bromonaphthalene-2-sulfonyl) -4- [2- (4-pyridyl) -4-methyl-5-thiazolecarbonyl] piperazine In the same manner as in Example 46, 1- ( 6-bromonaphthalene-2-sulfonyl) piperazine hydrochloride (112 mg), 2- (4-pyridyl) -4-
By reacting WSC hydrochloride (61 mg) with a solution of methyl-5-thiazolecarboxylic acid (64 mg), triethylamine (40 mg) and HOBt (43 mg) in DMF (10 ml), the title compound as colorless crystals ( 124 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.15 (4H, t, J = 4.
8Hz), 3.76 (4H, m), 7.68-7.80 (4H, m), 7.86 (1H,
d, J = 8.8Hz), 7.93 (1H, d, J = 8.8Hz), 8.13 (1H, s),
8.31 (1H, s), 8.70 (2H, d, J = 6.2Hz) .IR (KBr): 1634, 1433, 1346, 1329, 1281, 1256, 1165
cm ^-1. Example 68 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (4-piperidyl) benzoyl] piperazine hydrochloride 1- [4- (N-tert-butoxycarbonyl-piperidine -4 -Il)
To a solution of [benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (125 mg) in ethyl acetate (0.5 ml) was added a 4N solution of hydrochloric acid in ethyl acetate (4 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ether, the precipitate was collected by filtration, washed with ether, and dried to give the title compound (105 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.35 (4H, m), 2.77 (1H,
m), 2.90-3.20 (6H, m), 3.40-3.90 (6H, m), 7.26 (4
H, s), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.76 (1H, d, J
= 8.8Hz), 7.90-7.96 (3H, m), 8.31 (1H, s), 9.50-9.9
0 (2H, br). IR (KBr): 1627, 1457, 1436, 1345, 1330, 1284, 1164
cm ^-1 .

Example 69 1- (6-Chloronaphthalene-2-sulfonyl) -4- (4-piperazinylbenzoyl) piperazine hydrochloride In the same manner as in Example 68, 1- [4- (N-tert -Butoxycarbonylpiperidin-4-yl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine
(N-tert-butoxycarbonylpiperazinyl) benzoyl]
It was synthesized using -4- (6-chloronaphthalene-2-sulfonyl) piperazine. ¹ H-NMR (DMSO-d ₆ ) δ: 3.05 (4H, br)
s), 3.21 (4H, brs), 3.46
(4H, brs), 3.60 (4H, br)
s), 6.94 (2H, d, J = 8.6H)
z), 7.24 (2H, d, J = 8.6H)
z), 7.68 (1H, dd, J = 1.8,
8.8 Hz), 7.80 (1H, d, J = 8.
8Hz), 8.10-8.25 (3H, m),
8.46 (1H, s), 9.10 (2H, br)
s). IR (KBr): 1625, 1448, 134
7, 1332, 1289, 1156 cm ^-1 . Example 70 1- (4-Diethylaminobenzoyl) -4- (2-naphthalenesulfonyl) piperazine 1- (2-Naphthalenesulfonyl) piperazine hydrochloride (625 mg)
To a solution of and 4-diethylaminobenzoic acid (386 mg) in DMF (12 ml) was added diethyl cyanophosphate (489 mg), followed by triethylamine (606 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol containing 10% ammonia = 20: 1) to give the title compound (250 mg) as a colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (6H, t, J = 7.0Hz), 3.09 (4
H, t, J = 5.0Hz), 3.34 (4H, t, J = 7.0Hz), 3.76 (4H,
t, J = 5.0Hz), 6.55 (2H, d, J = 8.8Hz), 7.21 (2H, d, J =
8.8Hz), 7.58-7.76 (3H, m), 7.90-8.03 (3H, m), 8.32
(1H, s). IR (KBr): 1606, 1525, 1409, 1347, 1263, 1195, 1166
cm ^-1 .

Example 71 1- (4-Diethylaminobenzoyl) -4- (2-naphthalenesulfonyl) piperazine hydrochloride The compound obtained in Example 70 was dissolved in ethyl acetate.
A 4N solution of hydrochloric acid in ethyl acetate was added, and the resulting precipitate was collected by filtration and dried to give the title compound (230 mg) as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, t, J = 7.0Hz), 3.14 (4
H, brs), 3.35-4.00 (8H, m), 7.48 (2H, d, J = 8.4Hz),
7.60-7.85 (5H, m), 7.90-8.05 (3H, m), 8.34 (1H,
IR (KBr): 1635, 1438, 1347, 1166 cm ^-1 . Example 72 1- (4-Amidinobenzoyl) -4- (2-naphthalenesulfonyl) piperazine 1- (2-naphthalenesulfonyl) piperazine hydrochloride Salt (313 mg)
Baking soda solution (20 ml) -dioxane (20 ml) solution
Amidinobenzoyl chloride hydrochloride (219 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, dichloromethane and water were added, and the organic layer was separated, and extracted with 1N hydrochloric acid.
The extract was made alkaline with an aqueous sodium hydroxide solution, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (223 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.08 (4H, brs), 3.00-3.60 (4
H, br), 3.70 (1H, brs), 7.39 (2H, d, J = 8.0Hz), 7.60
-7.80 (5H, m), 8.00-8.28 (3H, m), 8.45 (1H, s) .IR (KBr): 3229, 1638, 1586, 1387, 1348, 1169 cm ^-1 .

Example 73 1- (4-tert-butoxycarbonylamidinobenzoyl) -4-
(6-Chloronaphthalene-2-sulfonyl) piperazine 4-Amidinobenzoyl chloride hydrochloride (85 mg )
Was added, and the mixture was stirred at room temperature for 1 hour. Then, DMF (10 ml) and di-t-butyl dicarbonate (200 mg) were added, and the mixture was stirred at 50 ° C for 30 minutes. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1: 1) to give the title compound (171 m) as colorless crystals.
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 3.08 (4H, brs),
3.49 (2H, brs), 3.85 (2H, brs), 7.32 (2H, d, J = 8.4
Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, dd, J =
1.8, 8.8Hz), 7.83 (2H, d, J = 8.4Hz), 7.90-7.98 (3H,
m), 8.30 (1H, d, J = 1.8Hz). IR (KBr): 1615, 1281, 1165, 1138 cm ^-1 .

Example 74 1- (4-Amidinobenzoyl) -4- (6-chloronaphthalene-2-
Sulfonyl) piperazine hydrochloride 1- (4-tert-butoxycarbonylamidinobenzoyl) -4-
(6-chloronaphthalene-2-sulfonyl) piperazine (150 m
g) was added with 4N hydrochloric acid ethyl acetate solution (15 ml) and left at room temperature for 5 hours. The precipitate formed by adding ether was collected by filtration, washed with ether and dried to give the title compound (1
02 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.08 (4H, brs), 3.60 (2H, br
s), 3.73 (2H, brs), 7.56 (2H, d, J = 8.4Hz), 7.73 (1
H, d, J = 8.8Hz), 7.82 (2H, d, J = 8.4Hz), 8.18 (1H,
d, J = 8.8Hz), 8.22-8.32 (2H, m), 8.50 (1H, s), 9.11
(2H, brs), 9.39 (2H, brs) .IR (KBr): 3061, 1686, 1626, 1462, 1445, 1346, 133
4, 1289, 1157 cm ^-1. Example 75 1- [4- (2,3-di -tert- butoxycarbonyl guanidino) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6 -Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg), 4-guanidinobenzoate hydrochloride (125 mg), HO
Bt (86 mg) and triethylamine (250 mg) in DMF (15 m
g) WSC (122 mg) was added to the solution, and the mixture was stirred at room temperature for 2 hours.
Then, di-t-butyl dicarbonate (350 mg) was added and the mixture was added at 50 ° C for 30 minutes.
Stirred for minutes. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 1) to give the title compound (325) as colorless crystals.
mg). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (18H, s), 3.11 (4H, brs),
3.73 (4H, brs), 7.13 (2H, d, J = 8.4Hz), 7.32 (2H,
d, J = 8.4Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.76 (1H,
dd, J = 1.8, 8.8Hz), 7.90-7.98 (3H, m), 8.32 (1H,
s), 9.38 (2H, brs) .IR (KBr): 3380, 1723, 1613, 1346, 1273, 1250, 1146
cm ^-1 .

Example 76 1- (4-guanidinobenzoyl) -4- (6-chloronaphthalene-2
-Sulfonyl) piperazine hydrochloride 1- [4- (2,3-di-tert-butoxycarbonylguanidino) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (295 mg) in 4N ethyl acetate hydrochloride The solution (20 ml) was added and left at room temperature for 3 hours. The precipitate formed by adding ether was collected by filtration, washed with ether, and dried to give the title compound (191 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.06 (4H, brs), 3.57 (4H, br
s), 7.30-7.60 (5H, m), 7.72 (1H, d, J = 8.8Hz), 7.82
(1H, d, J = 8.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.22-8.32
(2H, m), 8.50 (1H, s) .IR (KBr): 3102, 1676, 1626, 1603, 1570, 1458, 143
9, 1345, 1283, 1264, 1165 cm ^-1 . Example 77 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (N-methoxycarbonylamidino) benzoyl] piperazine 1- (6-chloro To a solution of (naphthalene-2-sulfonyl) piperazine hydrochloride (143 mg) and triethylamine (208 mg) in dichloromethane (134 mg) was added 4-amidinobenzoyl chloride hydrochloride (108 mg), the mixture was stirred at room temperature for 1 hour, and DMF
(10 ml) and methyl chlorocarbonate (200 mg).
For 30 minutes. The reaction solution was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated. Purification by silica gel column chromatography (ethyl acetate / methanol = 40: 1) gave the title compound (41 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.01 (4H, brs), 3.35-4.00 (4H,
br), 3.79 (3H, s), 6.50 (1H, br), 7.36 (2H, d, J =
8.4Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, dd,
J = 1.8, 8.8Hz), 7.86 (2H, d, J = 8.4Hz), 7.90-7.98
(3H, m), 8.31 (1H, s), 9.60 (1H, br) .IR (KBr): 3303, 1618, 1522, 1437, 1346, 1269, 116
5, 1138 cm ^-1 .

Example 78 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (2,3-bis
(Methoxycarbonyl) guanidino) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (2,3-bis (methoxycarbonyl) guanidino) benzoic acid (170 mg) The title compound (62 mg) was obtained as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (4H, brs), 3.56 (3H, s),
3.67 (3H, s), 3.74 (4H, brs), 7.15 (2H, d, J = 8.4H
z), 7.34 (2H, d, J = 8.4Hz), 7.60 (1H, dd, J = 1.8, 8.
8Hz), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.98 (3H,
m), 8.31 (1H, s), 9.29 (1H, brs), 9.52 (1H, brs) .IR (KBr): 3389, 1732, 1615, 1437, 1252, 1165 cm ^-1 . Example 79 1- ( 6-chloronaphthalene-2-sulfonyl) -4- [4- (3-methoxycarbonylguanidino) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (3- Using methoxycarbonylguanidino) benzoic acid (170 mg) in the same manner as in Example 46, the title compound (90 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.11 (4H, brs), 3.71 (3H, s),
3.75 (4H, brs), 7.12 (2H, d, J = 8.4Hz), 7.33 (2H,
d, J = 8.4Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H,
dd, J = 1.8, 8.8Hz), 7.89-7.97 (3H, m), 8.31 (1H,
s) .IR (KBr): 3302, 3059, 1613, 1528, 1439, 1346, 128
5, 1242, 1165 cm ^-1 .

Example 80 1- [1- (tert-butoxycarbonylamidino) piperidine-4
-Ylcarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 1- (tert-butoxycarbonylamidino) piperidine-4 Using -ylcarboxylic acid (214 mg) and in the same manner as in Example 46, the title compound (295 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.55-1.90 (4H,
m), 2.60 (1H, m), 2.88-3.14 (6H, m), 3.50-3.77 (4
H, m), 4.10 (2H, m), 7.59 (1H, dd, J = 1.8, 8.8Hz),
7.75 (1H, dd, J = 2.0, 8.8Hz), 7.87-7.98 (3H, m), 8.
31 (1H, s). IR (KBr): 1747, 1651, 1611, 1302, 1154 cm ^-1 . Example 81 1- (1-Amidinopiperidin-4-ylcarbonyl) -4- (6-chloronaphthalene- 2-sulfonyl) piperazine hydrochloride 1- [1- (N ¹ , N ² -bis-tert-butoxycarbonylamidino) piperidin-4-ylcarbonyl] -4- (6-chloronaphthalene (-2-sulfonyl) piperazine
(270 mg) was treated with hydrochloric acid to give the title compound as a colorless solid (164 m
g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.70 (4H, m), 2.77-3.12
(6H, m), 3.20 (1H, m), 3.58 (4H, m), 3.79 (2H, m),
7.41 (4H, s), 7.73 (1H, dd, J = 2.2, 8.8Hz), 7.82 (1
H, dd, J = 1.8, 8.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.23-
8.34 (2H, m), 8.51 (1H, s) .IR (KBr): 3324, 3144, 1659, 1617, 1456, 1345, 1159
cm ^-1 .

Example 82 1- [1- (tert-butoxycarbonyl) piperidin-4-ylacetyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine Hydrochloride (300 mg) and 1- (tert-butoxycarbonyl) piperidine-
A colorless amorphous title compound (420 mg) was obtained in the same manner as in Example 46 using 4-ylacetic acid (211 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, m), 1.43 (9H, s), 1.6
0 (2H, m), 1.90 (1H, m), 2.13 (2H, d, J = 7.0Hz), 2.
66 (2H, m), 3.07 (4H, m), 3.56 (2H, m), 3.71 (2H, m
m), 4.02 (2H, m), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.7
5 (1H, dd, J = 2.0, 8.8Hz), 7.88-7.96 (3H, m), 8.30
(1H, s). IR (KBr): 1686, 1649, 1426, 1346, 1285, 1165 cm ^-1 . Example 83 1- (6-Chloronaphthalene-2-sulfonyl) -4- (piperidine-
4-ylacetyl) piperazine hydrochloride In the same manner as in Example 76, 1- [1- (tert-butoxycarbonyl) piperidin-4-ylacetyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (390 mg) ) Was treated with hydrochloric acid to give the title compound (344 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.28 (2H, m),
1.72 (2H, m), 1.89 (1H,
m), 2.21 (2H, d, J = 6.6 Hz),
2.78 (2H, m), 2.96 (4H,
m), 3.14 (2H, m), 3.54 (4
H, brs), 7.73 (1H, dd, J =
1.8, 8.8 Hz), 7.82 (1H, d
d, J = 1.8, 8.8 Hz0, 8.18 (1
H, d, J = 8.8 HGz), 8.22-8.3.
2 (2H, m), 8.50 (1H, s),
8.60-9.00 (2H, m). IR (KBr): 3532, 3368, 161
5, 1456, 1343, 1331, 127
7, 1155 cm ^-1 .

Example 84 1- (4-tert-butoxycarbonylaminomethylbenzoyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100% mg) and 4-tert-butoxycarbonylaminomethylbenzoic acid (73 mg) to give the title compound (163 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.09 (4H, brs),
3.73 (4H, brs), 4.31 (2H, d, J = 6.2Hz), 4.88 (1H, b
rs), 7.28 (4H, s), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.
75 (1H, dd, J = 2.0, 8.8Hz0, 7.88-7.98 (3H, m), 8.30
(1H, s). IR (KBr): 3328, 1705, 1628, 1514, 1456, 1431, 134
6, 853, 1264, 1165 cm ^-1 . Example 85 1- (4-Aminomethylbenzoyl) -4- (6-chloronaphthalene
2-Sulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- (4-tert-butoxycarbonylaminomethylbenzoyl) -4- (6-chloronaphthalene-
2- (Sulfonyl) piperazine (133 mg) was treated with hydrochloric acid to give the title compound (94 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.06 (4H, m), 3.20-3.80 (4H,
br), 4.04 (2H, m), 7.37 (2H, d, J = 8.2Hz), 7.49 (2
H, d, J = 8.2Hz), 7.73 (1H, dd, J = 1.8, 8.8Hz), 7.82
(1H, dd, J = 1.6, 8.8Hz), 8.14-8.44 (6H, m), 8.50 (1
H, s) .IR (KBr): 1624, 1466, 1442, 1346, 1335, 1292, 1157
cm ^-1. Example 86 1- (4-tert- butoxycarbonylamino cyclohexane -1
-Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (300 mg) and 4-tert-butoxycarbonylaminocyclohexane-1-ylcarboxylic acid The title compound (440 mg) was obtained as colorless crystals in the same manner as in Example 46 using the acid (211 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.40-1.80 (8H,
m), 2.43 (1H, m), 3.07 (4H, m), 3.59 (1H, m), 3.71
(4H, brs), 4.68 (1H, brs), 7.59 (1H, dd, J = 2.0,
8.8Hz), 7.75 (1H, dd, J = 2.0, 8.8Hz), 7.88-7.97 (3
H, m), 8.31 (1H, s). IR (KBr): 3326, 1701, 1638, 1456, 1346, 1165 cm ^-1 . Example 87 1- (4-aminocyclohexane-1-ylcarbonyl) -4 -(6-
Chloronaphthalene-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- (4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine (410 mg) was treated with hydrochloric acid to give the title compound (370 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-2.00 (8H, m), 2.65 (1H,
m), 2.97 (4H, brs), 3.17 (1H, m), 3.55 (4H, brs),
7.73 (1H, dd, J = 1.8, 8.8Hz), 7.81 (1H, dd, J = 1.8,
8.8Hz), 7.88 (3H, brs), 8.17 (1H, d, J = 8.8Hz), 8.2
3-8.31 (2H, m), 8.50 (1H, s) .IR (KBr): 3374, 1624, 1452, 1345, 1331, 1163 cm ^-1 .

Example 88 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (2,3-di-t
ert-butoxycarbonylguanidino) cyclohexane-1-
Ylcarbonyl] piperazine 1- (4-aminocyclohexane-1-ylcarbonyl) -4- (6-
(Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (220
mg), triethylamine (232 mg) in methanol (10 ml)
To a solution of -tetrahydrofuran (10 ml) was added N, N'-di-tert-butoxycarbonyl-S-methylisothiourea (135 mg), and the mixture was stirred at 40 ° C for 24 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (170 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.90 (8H, m), 1.46 (9H,
s), 1.48 (9H, s), 2.44 (1H, m), 3.07 (4H, m), 3.58
(2H, m), 3.70 (2H, m), 4.27 (1H, m), 7.59 (1H, d
d, J = 1.8, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz), 7.8
8-7.96 (3H, s), 8.30 (1H, s), 8.62 (1H, d, J = 7.8H
z), 11.42 (1H, brs) .IR (KBr): 3322, 1717, 1643, 1614, 1344, 1165, 113
In 6, 1119 cm ^-1. Example 89 1- (6-chloronaphthalene-2-sulfonyl) -4- (4-guanidino cyclohexane-1-ylcarbonyl) same method as piperazine hydrochloride Example 76, 1- (6-chloronaphthalene-2-
Sulfonyl) -4- [4- (2,3-di-tert-butoxycarbonylguanidino) cyclohexane-1-ylcarbonyl] piperazine (150 mg) was treated with hydrochloric acid to give the title compound (84
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.70 (8H, m), 2.60 (1H,
m), 2.96 (4H, m), 3.50-3.70 (5H, m), 7.05 (4H, b
r), 7.48 (1H, m), 7.72 (1H, d, J = 8.4Hz), 7.81 (1H,
d, J = 8.8Hz), 8.17 (1H, d, J = 8.4Hz), 8.22-8.33 (2H,
m), 8.50 (1H, s) .IR (KBr): 3162, 1624, 1454, 1345, 1331, 1163 cm ^-1 .

Example 90 1- [1- (2,3-Di-tert-butoxycarbonylamidino) piperidin-4-ylacetyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine Same as in Example 88. By the method, 1- (piperidin-4-ylacetyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (190 mg) was added to N, N'-di-tert-butoxycarbonyl.
Reaction with -S-methylisothiourea (117 mg) gave the title compound (120 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (18H, s), 1.20-1.80 (4H,
m), 2.04 (1H, m), 2.15 (2H, d, J = 6.4Hz), 2.89 (2H,
m), 3.07 (4H, m), 3.55 (2H, m), 3.72 (2H, m), 4.08
(2H, m), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, d
d, J = 1.8, 8.8Hz), 7.88-7.96 (3H, m), 8.30 (1H, s),
IR (KBr): 1746, 1634, 1607, 1366, 1300, 1165 cm ^-1 . Example 91 1- (1-amidinopiperidin-4-ylacetyl) -4- (6-chloro Naphthalene-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- [1- (2,3-di-tert-butoxycarbonylamidino) piperidin-4-ylacetyl] -4-
(6-chloronaphthalene-2-sulfonyl) piperazine (105 m
g) was treated with hydrochloric acid to give the title compound (69 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (2H, m), 1.63 (2H, m),
1.91 (1H, m), 2.20 (2H, d, J = 6.6Hz), 2.80-3.03 (6H,
m), 3.54 (4H, brs), 3.75 (2H, brd, J = 13.6Hz), 7.3
5 (4H, brs), 7.73 (1H, dd, J = 2.0, 8.8Hz), 7.82 (1
H, dd, J = 1.8, 8.8Hz), 8.17 (1H, d, J = 8.8Hz), 8.22-
8.32 (2H, m), 8.50 (1H, s) .IR (KBr): 3304, 3144, 1643, 1613, 1452, 1345, 1163
cm ^-1 .

Example 92 1- (5-tert-butoxycarbonylaminopentanoyl) -4-
Example using (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (300 mg) and 5-tert-butoxycarbonylaminopentanoic acid (188 mg) A colorless amorphous title compound (377 mg) was obtained in the same manner as in 46. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H, s), 1.40-1.62 (4H,
m), 2.25 (2H, t, J = 7.0Hz), 3.00-3.15 (6H, m), 3.56
(2H, m), 3.71 (2H, m), 4.55 (1H, brs), 7.59 (1H,
dd, J = 2.0, 8.8Hz), 7.75 (1H, dd, J = 2.0, 8.8Hz), 7.
88-8.00 (3H, m), 8.30 (1H, s) .IR (KBr): 3339, 1701, 1647, 1456, 1346, 1248, 1165
cm ^-1 . Example 93 1- (5-aminopentanoyl) -4- (6-chloronaphthalene-2-
Sulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- (5-tert-butoxycarbonylaminopentanoyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine (343 mg) was treated with hydrochloric acid. Thus, the title compound (295 mg) was obtained as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (4H, m), 2.26 (2H, m),
2.70 (2H, m), 2.96 (4H, m), 3.54 (4H, m), 7.73 (1H,
dd, J = 2.2, 8.8Hz), 7.82 (1H, dd, J = 1.8, 8.8Hz),
7.93 (3H, brs), 8.18 (1H, d, J = 8.8Hz), 8.22-8.32
(2H, m), 8.50 (1H, s) .IR (KBr): 1655, 1435, 1345, 1330, 1157 cm ^-1 .

Example 94 1- (6-chloronaphthalene-2-sulfonyl) -4- [5- (N, N'-di-
tert-butoxycarbonylguanidino) pentanoyl] piperazine In the same manner as in Example 88, 1- (5-aminopentanoyl)
4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (145 mg) was reacted with N, N'-di-tert-butoxycarbonyl-S-methylisothiourea (95 mg) to give a colorless solid. The title compound (175 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.70 (4H, m), 1.48 (9H,
s), 1.49 (9H, s), 2.56 (2H, m), 3.06 (4H, m), 3.37
(2H, m), 3.56 (2H, m), 3.71 (2H, m), 7.58 (1H, d
d, J = 1.8, 8.8Hz), 7.75 (1H, dd, J = 2.0, 8.8Hz), 7.8
8-7.96 (3H, m), 8.27 (1H, brs), 8.30 (1H, s), 11.4
6 (1H, brs) .IR (KBr): 3324, 1721, 1644, 1368, 1331, 1165, 1134
cm ^-1 . Example 95 1- (6-chloronaphthalene-2-sulfonyl) -4- (5-guanidinopentanoyl) piperazine hydrochloride In the same manner as in Example 76, 1- (6-chloronaphthalene-2) -
Sulfonyl) -4- [5- (N, N'-di-tert-butoxycarbonyl-
(Guanidino) pentanoyl] piperazine (145 mg) was treated with hydrochloric acid to give the title compound (81 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.40 (4H, m), 2.25 (2H, m),
2.90-3.10 (6H, m), 3.54 (4H, m), 7.09 (4H, br), 7.6
0 (1H, m), 7.73 (1H, dd, J = 2.2, 8.8Hz), 7.81 (1H, d
d, J = 1.8, 8.8Hz), 8.17 (1H, d, J = 8.8Hz), 8.22-8.33
(2H, m), 8.50 (1H, s) .IR (KBr): 3160, 1647, 1628, 1454, 1345, 1331, 1163
cm ^-1 .

Example 96 1- (6-chloronaphthalene-2-sulfonyl) -4- (1-tert-butoxycarbonylpiperidin-4-ylcarbonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride Using a salt (200 mg) and N-tert-butoxycarbonylisonipecotic acid (132 mg), the title compound (296 mg) was obtained as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.45-1.70 (4H,
m), 2.50 (1H, m), 2.69 (2H, m), 3.08 (4H, m), 3.61
(2H, brs), 3.69 (2H, brs), 4.08 (2H, m), 7.59 (1H,
dd, J = 1.8, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz),
7.88-7.95 (3H, m), 8.30 (1H, s). IR (KBr): 1684, 1645, 1429, 1165 cm ^-1 . Example 97 1- (6-Chloronaphthalene-2-sulfonyl) -4- (4-Piperidinecarbonyl) piperazine hydrochloride In the same manner as in Example 76, 1- (6-chloronaphthalene-2-
Sulfonyl) -4- (1-tert-butoxycarbonylpiperidine
(-4-ylcarbonyl) piperazine (276 mg) was treated with hydrochloric acid to give the title compound (217 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.63 (4H, m), 2.84 (4H, m),
2.97 (4H, brs), 3.16 (1H, m), 3.58 (4H, m), 7.72
(1H, dd, J = 2.2, 8.8Hz), 7.81 (1H, dd, J = 1.8, 8.8H
z), 8.16 (1H, d, J = 8.8Hz), 8.22-8.30 (2H, m), 8.51
(1H, s), 8.53 (2H, br) .IR (KBr): 3576, 1636, 1458, 1342, 1333, 1234, 1163
cm ^-1 .

Example 98 4- [4- (4- (6-chloronaphthalene-2-sulfonyl) piperazine-1-carbonyl) phenyl] pyridine 1-oxide 1- (6-chloronaphthalene-2-sulfonyl) -4 -[4- (4-Pyridyl) benzoyl] piperazine (200 mg) in dichloromethane (2
To the solution (5 ml) was added m-chloroperbenzoic acid (140 mg), and the mixture was stirred at room temperature for 2 hours. Dilute the reaction with dichloromethane,
The extract was washed with a 1N aqueous solution of sodium hydroxide and brine, dried and concentrated, and crystallized from dichloromethane / hexane to give the title compound (188 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, brs), 3.76 (4H, br),
7.43 (2H, d, J = 8.4Hz), 7.48 (2H, d, J = 7.2Hz), 7.55-
7.64 (3H, m), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.90-7.9
8 (3H, m), 8.26 (2H, d, J = 7.2Hz), 8.32 (1H, s). IR (KBr): 1630, 1460, 1346, 1262, 1165, 729 cm ^-1 . Example 99 1 -[4- (1-acetimidoylpiperidin-4-yl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- [4- (piperidin-4-yl) benzoyl] -4- ( To a solution of 6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (40 mg) and triethylamine (156 mg) in methanol (15 ml) was added ethylacetimidate hydrochloride (46 mg).
Stir for 5 hours. The reaction solution was concentrated, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with dichloromethane. After drying, the concentrated residue was dissolved in ethyl acetate, an ethyl acetate solution was added, and the resulting precipitate was collected by filtration, washed with ether and dried to give the title compound as a colorless solid (42 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.95 (4H, m), 2.30 (3H,
s), 2.80-3.33 (7H, m), 3.57 (4H, brs), 4.01 (1H,
m), 4.21 (1H, m), 7.28 (4H, s), 7.72 (1H, dd, J = 2.
2, 8.8Hz), 7.81 (1H, dd, J = 2.0, 8.8Hz), 8.17 (1H,
d, J = 8.8Hz), 8.22-8.34 (2H, m), 8.49 (1H, s), 8.63
(1H, brs), 9.20 (1H, brs) .IR (KBr): 3067, 1684, 1632, 1433, 1342, 1281, 1165
cm ^-1 .

Example 100 1- (1-acetimidoylpiperidin-4-ylcarbonyl)-
4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- (piperidin-4-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (180 mg) and ethylacetimidate Example 99 was prepared using the hydrochloride (485 mg).
The title compound (133 mg) was obtained as colorless crystals in the same manner as in the above. ¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.70 (4H, m), 2.22 (3H,
s), 2.80-3.20 (7H, m), 3.55 (2H, m), 3.63 (2H, m),
3.81 (1H, m), 3.99 (1H, m), 7.72 (1H, d, J = 8.8Hz),
7.81 (1H, d, J = 8.8Hz), 8.17 (1H, d, J = 8.8Hz), 8.2
2-8.31 (2H, m), 8.51 (1H, s), 8.56 (1H, m), 9.03 (1
H, m) .IR (KBr): 3069, 1674, 1624, 1454, 1345, 1163 cm ^-1 . Example 101 1- (6-chloronaphthalene-2-sulfonyl) -4- (2-guanidino-4- Methyl-5-thiazolecarbonyl) piperazine hydrochloride Using 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 2-guanidino-4-methyl-5-thiazolecarboxylic acid (115 mg) In the same manner as in Example 46, 1-
(6-chloronaphthalene-2-sulfonyl) -4- (2-guanidino-
4-Methyl-5-thiazolecarbonyl) piperazine was synthesized and treated with an ethyl acetate hydrochloride solution to give the title compound (240 mg) as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 2.18 (3H, s), 3.06 (4H, brs),
3.61 (4H, brs), 7.72 (1H, dd, J = 2.2, 8.8Hz), 7.82
(1H, dd, J = 2.0, 8.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.2
2-8.32 (6H, m), 8.50 (1H, s), 12.51 (1H, br) .IR (KBr): 3314, 3061, 1694, 1613, 1491, 1462, 143
1, 1346, 1333, 1314, 1169 cm ^-1 .

Example 102 1- (6-chloronaphthalene-2-sulfonyl) -4- (trans-4-cyanocyclohexane-1-ylcarbonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (400 mg) and trans-4-cyanocyclohexane-1-ylcarboxylic acid (177 mg) were used to obtain the title compound (468 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.80 (6H, m), 2.10-2.22 (2
H, m), 2.30-2.50 (2H, m), 3.08 (4H, m), 3.58 (2H,
m), 3.70 (2H, m), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.7
5 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.96 (3H, m), 8.30
(1H, s). IR (KBr): 2240, 1645, 1454, 1346, 1165, 729 cm ^-1 . Example 103 1- (trans-4-amidinocyclohexane-1-ylcarbonyl) -4- (6- Chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) -4- (trans-4-cyanocyclohexane-1-ylcarbonyl) piperazine (446 mg)
8% dioxane hydrochloride / ethanol (9/1) solution (15 ml)
Was added and left at room temperature for 5 hours. After concentrating the solvent, a 15% ammonia ethanol solution (20 ml) was added and the mixture was stirred for 15 hours. The reaction solution was concentrated, 1N aqueous sodium hydroxide solution was added to the residue, extracted with dichloromethane, dried and concentrated, the residue was dissolved in ethyl acetate, ethyl acetate solution was added, and the resulting precipitate was collected by filtration. Colorless solid title compound (514
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.83 (8H, m), 2.26-2.55
(2H, m), 2.98 (4H, m), 3.55 (4H, m), 7.72 (1H, dd,
J = 2.2, 8.8Hz), 7.82 (1H, dd, J = 1.8, 8.8Hz), 8.17 (1
H, d, J = 8.8Hz), 8.22-8.31 (2H, m), 8.50 (1H, s),
8.56 (2H, brs), 8.75 (2H, brs) .IR (KBr): 3077, 1686, 1624, 1454, 1345, 1163, 729
cm ^-1 .

Example 104 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) Using piperazine hydrochloride (400 mg) and trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarboxylic acid (281 mg),
In the same manner as in Example 46, the title compound (547 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.96-1.18 (2H, m), 1.42 (9H,
s), 1.50-1.70 (2H, m), 1.95-2.10 (2H, m), 2.28 (1
H, m), 3.07 (4H, m), 3.39 (1H, m), 3.58 (2H, brs),
3.69 (2H, brs), 4.33 (1H, brs), 7.58 (1H, dd, J =
1.8, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz), 7.87-7.9
6 (3H, m), 8.30 (1H, s) .IR (KBr): 3333, 1699, 1634, 1454, 1346, 1165, 731
cm ^-1 . Example 105 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4
-(6-Chloronaphthalene-2-sulfonyl) piperazine (527 m
g) was treated with hydrochloric acid to give the title compound as a colorless solid (444 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.43 (4H, m), 1.59 (2H,
m), 1.89 (2H, m), 2.45 (1H, m), 2.90 (1H, m), 2.96
(4H, brs), 3.56 (4H, brs), 7.72 (1H, d, J = 8.8Hz),
7.81 (1H, d, J = 8.8Hz), 7.98 (3H, brs), 8.10-8.30
(3H, m), 8.50 (1H, s) .IR (KBr): 2911, 1651, 1638, 1341, 1325, 1148, 731
cm ^-1 .

Example 106 1- (trans-4-acetimidoylaminocyclohexane-1-
Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
Using 4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (160 mg) and ethylacetimidate hydrochloride (418 mg), the title compound as colorless crystals (136 mg) in the same manner as in Example 99. ). ¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.40 (4H, m), 1.57 (2H,
m), 1.80 (2H, m), 2.11 (3H, s), 2.45 (1H, m), 2.90-
3.05 (5H, m), 3.56 (4H, m), 7.72 (1H, dd, J = 2.2,
8.8Hz), 7.80 (1H, dd, J = 1.8, 8.8Hz), 8.10-8.32 (3
H, m), 8.50 (1H, s), 9.01 (1H, m), 9.31 (1H, m), 9.
73 (1H, brs) .IR (KBr): 3055, 1682, 1635, 1474, 1445, 1345, 116
3, 729 cm ^-1. EXAMPLE 107 1- [trans-4- (2,3- di -tert- butoxycarbonyl) guanidino cyclohexane-1-ylcarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) Piperazine In the same manner as in Example 88, 1- (trans-4-aminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2
-Sulfonyl) piperazine hydrochloride (220 mg) with N, N'-di-ter
t-butoxycarbonyl-S-methylisothiourea (162 m
g) to give the title compound (112 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.30 (2H, m), 1.48 (18H,
s), 1.50-1.70 (4H, m), 2.00-2.20 (2H, m), 2.29 (1H,
m), 3.07 (4H, m), 3.58 (2H, m), 3.69 (2H, m), 3.9
7 (1H, m), 7.59 (1H, dd, J = 2.2, 8.8Hz), 7.75 (1H,
dd, J = 1.8, 8.8Hz), 7.88-7.96 (3H, m), 8.18 (1H, d,
J = 8.8Hz), 8.30 (1H, s), 11.50 (1H, brs) .IR (KBr): 3324, 1720, 1644, 1615, 1345, 1165, 1128
cm ^-1 .

Example 108 1- (6-Chloronaphthalene-2-sulfonyl) -4- (trans-4-guanidinocyclohexane-1-ylcarbonyl) piperazine hydrochloride In the same manner as in Example 76, 1- [trans -4- (2,3-di-tert-
Butoxycarbonyl) guanidinocyclohexane-1-ylcarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (135 mg) was treated with hydrochloric acid to give the title compound (112 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.70 (6H, m), 1.73-1.90
(2H, m), 2.95 (4H, brs), 3.56 (4H, brs), 7.71 (1H,
d, J = 8.6Hz), 7.80 (1H, d, J = 8.4Hz), 8.10-8.30 (3
H, m), 8.49 (1H, s). IR (KBr): 1678, 1636, 1454, 1346, 1254, 1159 cm ^-1 . Example 109 1- (trans-4-formimidoylaminocyclohexane-1-)
Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
Using 4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (180 mg) and ethylformimidate hydrochloride (418 mg), the title compound as colorless crystals (164 mg) in the same manner as in Example 99. ). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.45 (4H, m), 1.60 (2H,
m), 1.80 (2H, m), 2.42 (1H, m), 2.96 (4H, brs), 3.3
5 (1H, m), 3.55 (4H, m), 7.72 (1H, dd, J = 2.2, 8.8H
z), 7.81 (1H, dd, J = 1.4, 8.8Hz), 7.95 (1H, m), 8.1
6 (1H, d, J = 8.8Hz), 8.20-8.30 (2H, m), 8.50 (1H,
s), 8.70-9.20 (2H, m), 9.70 (1H, m) .IR (KBr): 3017, 1705, 1624, 1454, 1345, 1163 cm ^-1 .

Example 110 1- [2- (1-tert-butoxycarbonylpiperidin-4-yl) -4
-Methyl-5-thiazolecarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (400 mg) and 2- (1-tert-butoxy) Carbonyl piperidine
Using 4-yl) -4-methyl-5-thiazolecarboxylic acid (375 mg), the title compound was obtained as colorless crystals in the same manner as in Example 46.
(700 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.50-1.78 (2H,
m), 1.95-2.10 (2H, m), 2.32 (3H, s), 2.82 (2H, m),
3.02 (1H, m), 3.12 (4H, m), 3.72 (4H, m), 4.18 (2
H, m), 7.60 (1H, dd, J = 2.0, 8.8Hz), 7.75 (1H, dd,
J = 1.8, 8.8Hz), 7.89-7.96 (3H, m), 8.31 (1H, d, J =
1.0Hz). IR (KBr): 1686, 1634, 1427, 1165, 731 cm ^-1 . Example 111 1- (6-chloronaphthalene-2-sulfonyl) -4- [2- (piperidin-4-yl) -4-Methyl-5-thiazolecarbonyl] piperazine hydrochloride In the same manner as in Example 76, 1- [2- (1-tert-butoxycarbonylpiperidin-4-yl) -4-methyl-5-thiazolecarbonyl]- 4- (6-Chloronaphthalene-2-sulfonyl) piperazine (673 mg) was treated with hydrochloric acid to give the title compound as a colorless solid
(589 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.70-2.00 (2H, m), 2.03-2.20
(2H, m), 2.21 (3H, s), 2.96 (1H, m), 3.04 (4H, m),
3.20-3.65 (8H, m), 7.72 (1H, d, J = 8.8Hz), 7.80 (1
H, d, J = 8.4Hz), 8.10-8.31 (3H, m), 8.49 (1H, s),
8.90 (2H, br). IR (KBr): 2957, 2802, 2718, 1618, 1431, 1345, 133
3, 1165 cm ^-1 .

Example 112 1- [2- (1-acetimidoylpiperidin-4-yl) -4-methyl-5-thiazolecarbonyl] -4- (6-chloronaphthalene-2
-Sulfonyl) piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) -4- [4-methyl-2-
(Piperidin-4-yl) -5-thiazolecarbonyl] piperazine hydrochloride (190 mg) and ethylacetimidate hydrochloride (4
18 mg) to give the title compound (178 mg) as colorless crystals in the same manner as in Example 99. ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.90 (2H, m), 2.00-2.20
(2H, m), 2.21 (3H, s), 2.28 (3H, s), 3.04 (4H, br
s), 3.05-3.40 (3H, m), 3.59 (4H, brs), 3.90-4.00
(2H, m), 7.72 (1H, dd, J = 1.8, 8.8Hz), 7.81 (1H, d
d, J = 1.8, 8.8Hz), 8.17 (1H, d, J = 8.8Hz), 8.24-8.32
(2H, m), 8.49 (1H, s), 8.68 (1H, m), 9.20 (1H,
m) .IR (KBr): 3074, 1671, 1624, 1439, 1345, 1163, 727
cm- ¹ . Example 113 Ethyl 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylate 4- (6 Using -chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylic acid ethyl hydrochloride (1258 mg) and trans-4-cyanocyclohexane-1-ylcarboxylic acid (735 mg), colorless in the same manner as in Example 46. The title compound (940 mg) was obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.98-1.25 (2H, m), 1.27 (3H, t,
J = 7.2Hz), 1.43 (9H, s), 1.50-2.55 (11H, m), 3.25-
3.90 (4H, m), 4.19 (2H, q, J = 7.2Hz), 4.38 (1H, m),
4.43 (1H, brs), 7.58 (1H, dd, J = 1.8, 8.8Hz), 7.75
(1H, dd, J = 1.8,8.8Hz), 7.87-7.96 (3H, m), 8.32 (1
H, s) .IR (KBr): 3316, 1738, 1699, 1651, 1366, 1167 cm ^-1 .

Example 114 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylic acid 1- (trans-4 1N hydroxylation in a solution of ethyl -tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylate (740 mg) in ethanol (15 ml) Sodium aqueous solution
(10 ml) was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, the residue was dissolved in water, adjusted to pH = 2 with 1N hydrochloric acid, extracted with dichloromethane and dried to obtain the title compound (614 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.30 (2H, m), 1.35 (9H,
s), 1.37-2.85 (9H, m), 3.00-3.20 (2H, m), 3.63 (1H,
m), 3.93 (1H, m), 4.17 (1H, m), 5.07 (1H, m), 6.73
(1H, m), 7.67-7.83 (2H, m), 8.10-8.30 (3H, m), 8.
51 (1H, s) .IR (KBr): 3326, 1742, 1686, 1628, 1541, 1520, 135
. 4, 1292, 1165 cm ^-1 Example 115 1- (trans-4- aminocyclohexane-1-ylcarbonyl) -
Ethyl 4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylate In the same manner as in Example 76, 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl)- Four
Ethyl-(6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylate (190 mg) was treated with hydrochloric acid to give the title compound (132 mg) as a colorless solid. ¹ H-NMR (CDCl3) δ: 1.20-1.35 (3H, m), 1.40-2.65 (1
1H, m), 3.14 (1H, m), 3.45-3.90 (3H, m), 4.10-4.30
(2H, m), 4.40 (1H, m), 5.27 (1H, m), 7.59 (1H, d,
J = 8.8Hz), 7.77 (1H, m), 7.80-8.00 (3H, m), 8.32 (3
H, brs), 8.33 (1H, s) .IR (KBr): 3353, 1732, 1622, 1456, 1348, 1213, 1165
cm ^-1 .

Example 116 1- (trans-4-acetimidoylaminocyclohexane-1-)
Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylic acid ethyl hydrochloride 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
Using ethyl 4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylate hydrochloride (125 mg) and ethylacetimidate hydrochloride (386 mg), colorless crystals were obtained in the same manner as in Example 99. The title compound (110 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (3H, t, J = 7.0Hz), 1.20-
2.70 (11H, m), 2.11 (3H, s), 3.37 (1H, m), 3.67 (1
H, m), 3.95-4.40 (5H, m), 5.16 (1H, m), 5.27 (1H,
m), 7.74 (1H, d, J = 8.8Hz), 7.81 (1H, d, J = 8.4Hz),
8.15-8.32 (3H, m), 8.54 (1H, s), 8.55 (1H, brs),
8.99 (1H, brs), 9.29 (1H, brs). IR (KBr): 3056, 1738, 1640, 1435, 1344, 1161 cm ^-1 . Example 117 1- (trans-4-tert-butoxycarbonylaminocyclohexane) -1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) -2-thiomorpholinocarbonylpiperazine 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6 -Chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylic acid (300 mg), HOBt (95
mg) and thiomorpholine (60 mg) in DMF (20 ml).
19 mg) and stirred at room temperature for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (216 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.20 (2H, m), 1.43 (9H,
s), 1.50-1.92 (3H, m), 1.98-2.12 (2H, m), 2.28-2.7
0 (6H, m), 2.79 (1H, dd, J = 4.6, 12.0Hz), 3.40 (1H,
m), 3.60-3.95 (7H, m), 4.13 (1H, m), 4.34 (1H, m),
5.36 (1H, brs), 7.59 (1H, dd, J = 2.0, 8.8Hz), 7.75
(1H, dd, J = 2.0, 8.8Hz), 7.86-7.98 (3H, m), 8.33 (1
H, s) .IR (KBr): 3318, 1699, 1645, 1422, 1366, 1341, 1165
cm ^-1 .

Example 118 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (6-chloronaphthalene-2-sulfonyl) -2-thiomorpholinocarbonylpiperazine hydrochloride In the same manner as in Example 76, 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl)- Four
-(6-Chloronaphthalene-2-sulfonyl) -2-thiomorpholinocarbonylpiperazine (188 mg) was treated with hydrochloric acid to give the title compound (145 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.40-2.60 (11H, m), 2.98 (4H,
m), 3.14 (1H, m), 3.40-3.90 (7H, m), 4.35 (1H, m),
5.28 (1H, m), 7.59 (1H, d, J = 8.2Hz), 7.75 (1H, d,
J = 8.4Hz), 7.88-8.00 (3H, m), 8.32 (1H, s), 8.33
(3H, brs). IR (KBr): 3385, 1740, 1626, 1454, 1346, 1163 cm ^-1 . Example 119 1- (trans-4-acetimidoylaminocyclohexane-1-
Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) -2-thiomorpholinocarbonylpiperazine hydrochloride 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
Using 4- (6-chloronaphthalene-2-sulfonyl) -2-thiomorpholinocarbonylpiperazine hydrochloride (135 mg) and ethylacetimidate hydrochloride (386 mg), colorless crystals were obtained in the same manner as in Example 99. The title compound (149 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-2.60 (11H, m), 2.11 (3H,
s), 2.76 (4H, m), 3.60-4.40 (9H, m), 5.19 (1H,
m), 7.73 (1H, d, J = 8.8Hz), 7.80 (1H, d, J = 8.8Hz),
8.14-8.33 (3H, m), 8.54 (1H, s), 8.74 (1H, brs),
9.02 (1H, brs), 9.33 (1H, brs) .IR (KBr): 3021, 1740, 1682, 1626, 1453, 1346, 1161
cm ^-1 .

Example 120 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylic acid hydrochloride In the same manner as in Example 76, 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4
-(6-Chloronaphthalene-2-sulfonyl) -2-piperazinecarboxylic acid (200 mg) was treated with hydrochloric acid to give the title compound (130 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-2.60 (10H, m), 2.92 (2H,
m), 3.65 (2H, m), 3.90-4.40 (2H, m), 5.08 (1H,
m), 7.73 (1H, d, J = 8.8Hz), 7.80 (1H, d, J = 8.8Hz),
7.99 (3H, brs), 8.17 (1H, d, J = 8.8Hz), 8.20-8.33
(2H, m), 8.52 (1H, s). IR (KBr): 1734, 1624, 1453, 1342, 1213, 1163 cm ^-1 . Example 121 1- (6-Chloronaphthalene-2-sulfonyl) -4 -[4- (4-Imidazolyl) benzoyl] piperazine Performed using 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (4-imidazolyl) benzoic acid (109 mg) The title compound as colorless crystals in the same manner as in Example 46.
(210 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.11 (4H, brs), 3.73 (4H, brs),
7.26 (1H, s), 7.29 (2H, d, J = 8.0Hz), 7.58 (1H, d
d, J = 1.8, 8.8Hz), 7.61 (1H, s), 7.71 (2H, d, J = 8.0H
z), 7.75 (1H, dd, J = 1.4, 8.8Hz), 7.88-7.96 (3H,
m), 8.29 (1H, s) .IR (KBr): 3065, 1613, 1458, 1435, 1346, 1331, 128
5, 1165 cm ^-1 .

Example 122 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (1-tetrazolyl) benzoyl] piperazine 1- (6-Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) ) And 4- (1-tetrazolyl) benzoic acid (110 mg) using the same method as in Example 46 to give the title compound as colorless crystals.
(244 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, brs), 3.75 (4H, brs),
7.54 (2H, d, J = 8.8Hz), 7.60 (1H, dd, J = 1.8, 8.8H
z), 7.72-7.80 (3H, m), 7.90-7.98 (3H, m), 8.31 (1
H, s), 9.01 (1H, s). IR (KBr): 1634, 1470, 1437, 1346, 1165 cm ^-1 . Example 123 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4 -(2-Tetrazolyl) benzoyl] piperazine Using 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (2-tetrazolyl) benzoic acid (110 mg), In the same manner, the title compound as colorless crystals
(256 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.72 (4H, brs),
7.52 (2H, d, J = 8.6Hz), 7.60 (1H, dd, J = 1.8, 8.8H
z), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.90-7.97 (3H,
m), 8.18 (2H, d, J = 8.6Hz), 8.31 (1H, s), 8.67 (1H,
s) .IR (KBr): 1636, 1456, 1435, 1346, 1285, 1165 cm ^-1 .

Example 124 1- (6-Bromonaphthalene-2-sulfonyl) -4- [5- (4-pyridyl) -1,3,4-thiadiazol-2-carbonyl] piperazine 1- (6- (Bromonaphthalene-2-sulfonyl) piperazine hydrochloride (112 mg) and 5- (4-pyridyl) -1,3,4-thiadiazol-2
Using -carboxylic acid (60 mg) and in the same manner as in Example 46, the title compound (89 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.25 (4H, m), 3.94 (2H, t, J = 5.
0Hz), 4.53 (2H, t, J = 5.0Hz), 7.67-7.95 (6H, m), 8.
10 (1H, d, J = 1.6Hz), 8.31 (1H, s), 8.79 (2H, brs) .IR (KBr): 1620, 1346, 1331, 1279, 1163 cm ^-1 . Example 125 1- ( 6-bromonaphthalene-2-sulfonyl) -4- [6- (1H-imidazol-1-yl) nicotinoyl] piperazine 1- (6-bromonaphthalene-2-sulfonyl) piperazine hydrochloride (112 mg) and 6 -(1H-Imidazol-1-yl) nicotinic acid
(55 mg) and the title compound (130 mg) as colorless crystals was obtained in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (4H, brs), 3.76 (4H, brs),
7.22 (1H, s), 7.38 (1H, dd, J = 0.8, 8.4Hz), 7.63
(1H, s), 7.70-7.97 (5H, m), 8.13 (1H, s), 8.30 (1
H, s), 8.36 (1H, s), 8.43 (1H, d, J = 1.4Hz) .IR (KBr): 1634, 1595, 1495, 1480, 1456, 1435, 134
6, 1163 cm ^-1 .

Example 126 1- (6-Bromonaphthalene-2-sulfonyl) -4- [4- (1H-imidazol-1-ylmethyl) benzoyl] piperazine 1- (6-bromonaphthalene-2-sulfonyl) Using piperazine hydrochloride (112 mg) and 4- (1H-imidazole-1-ylmethyl) benzoic acid (58 mg), the title compound (142 mg) was obtained as colorless crystals in the same manner as in Example 46. Was. ¹ H-NMR (CDCl ₃ ) δ: 3.09 (4H, br)
s), 3.70 (4H, brs), 5.13
(2H, s), 6.88 (1H, s), 7.
10 (1H, s), 7.14 (2H, d,
J = 8.2 Hz), 7.29 (2H, d, J =
8.2 Hz), 7.54 (1H, s), 7.73
(1H, dd, J = 1.8, 8.8 Hz),
7.75 (1H, dd, J = 1.8, 8.8H
z), 7.85 (1H, d, J = 8.8 Hz),
7.92 (1H, d, J = 8.8 Hz),
8.12 (1H, d, J = 1.8 Hz);
29 (1H, s). IR (KBr): 1634, 1456, 134
5, 1329, 1283, 1163 cm ^-1 . Example 127 1- (6-bromonaphthalene-2-sulfonyl) -4- [6- (4-
Pyridyl) nicotinoyl] piperazine 1- (6-bromonaphthalene-2-sulfonyl) piperazine hydrochloride (112 mg) and 6- (4-pyridyl) nicotinic acid (58 mg) in the same manner as in Example 46. Colorless crystals of the title compound (1
52 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.15 (4H, brs), 3.75 (4H, brs),
7.69-7.96 (8H, m), 8.13 (1H, s), 8.30 (1H, s), 8.
66 (1H, s), 8.75 (2H, d, J = 6.0Hz) .IR (KBr): 1636, 1539, 1456, 1435, 1346, 1285, 1165
cm ^-1 .

Example 128 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (1,2,3-triazol-1-yl) benzoyl] piperazine 1- (6-chloronaphthalene- 2-sulfonyl) piperazine hydrochloride (100 mg) and 4- (1,2,3-triazol-1-yl) benzoic acid
(55 mg) and the title compound (78 mg) as colorless crystals was obtained in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, brs), 3.73 (4H, brs),
7.49 (2H, d, J = 8.6Hz), 7.61 (1H, dd, J = 1.8, 8.8H
z), 7.72-7.84 (3H, m), 7.87 (1H, s), 7.90-7.98 (3
H, m), 8.00 (1H, s), 8.32 (1H, s) .IR (KBr): 1636, 1495, 1435, 1346, 1331, 1265, 1165
cm ^-1 . Example 129 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (1,2,3-triazol-2-yl) benzoyl] piperazine 1- (6-chloronaphthalene 2-sulfonyl) piperazine hydrochloride (100 mg) and 4- (1,2,3-triazol-2-yl) benzoic acid
(55 mg) and colorless crystals of the title compound (98 mg) were obtained in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.74 (4H, brs),
7.44 (2H, d, J = 8.6Hz), 7.60 (1H, dd, J = 1.8, 8.8H
z), 7.76 (1H, dd, J = 1.4, 8.8Hz), 7.83 (2H, s), 7.9
0-7.97 (3H, m), 8.10 (2H, d, J = 8.6Hz), 8.31 (1H,
s) .IR (KBr): 1636, 1433, 1410, 1346, 1285, 1261, 1165
cm ^-1 .

Example 130 4- (6-Chloronaphthalene-2-sulfonyl) -1- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine-2-
Ethyl carboxylate 4- (6-chloronaphthalene-2-sulfonyl) -piperazine-2-
Using ethyl carboxylate hydrochloride (150 mg) and 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (101 mg), the title compound (200 mg) was obtained in the same manner as in Example 46. mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.2Hz), 2.60-3.0
0 (6H, m), 3.50-3.90 (3H, m), 4.25 (2H, q, J = 7.2H
z), 4.49 (1H, d, J = 12.0Hz), 7.61 (1H, dd, J = 1.8,
8.8Hz), 7.70-7.82 (3H,), 7.88-7.98 (3H, m), 8.34
(1H, s), 8.72 (2H, d, J = 6.2 Hz). IR (KBr): 1740, 1645, 1348, 1217, 1165 cm ^-1 . Example 131 1- (6-Chloronaphthalene-2-sulfonyl) ) -4- [2-Chloro-4-
(4-Pyridyl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (220 mg) and 2-chloro-4- (4-pyridyl) benzoic acid (148 m
Using g) and in the same manner as in Example 46, the title compound (304 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (2H, m), 3.24 (2H, m), 3.4
0 (2H, m), 3.94 (2H, m), 7.31 (1H, d, J = 7.8Hz), 7.
44 (2H, d, J = 6.0Hz), 7.50-7.65 (3H, m), 7.76 (1H,
d, J = 8.4Hz), 7.90-7.98 (3H, m), 8.32 (1H, s), 8.70
(2H, d, J = 6.0Hz). IR (KBr): 1645, 1595, 1456, 1437, 1346, 1285, 1165
cm ^-1 .

Example 132 1- [2-Chloro-4- (4-pyridyl) benzoyl] -4- (4-vinylbenzenesulfonyl) piperazine 1- (4-vinylbenzenesulfonyl) piperazine hydrochloride (200
mg) and 2-chloro-4- (4-pyridyl) benzoic acid (162 mg) in the same manner as in Example 46 to give the title compound as colorless crystals.
(266 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.03 (2H, m), 3.16 (2H, m), 3.3
9 (2H, m), 3.92 (2H, m), 5.48 (1H, d, J = 11.0Hz),
5.91 (1H, d, J = 17.6Hz), 6.78 (1H, dd, J = 11.0,17.6H
z), 7.34 (1H, d, J = 8.0Hz), 7.45 (2H, d, J = 6.0Hz)
7.52-7.60 (3H, m), 7.64 (1H, d, J = 2.0Hz), 7.71 (2
H, d, J = 8.4Hz), 8.70 (2H, d, J = 6.0Hz). IR (KBr): 1645, 1595, 1435, 1350, 1285, 1167 cm ^-1 . Example 133 1- (6- Chloronaphthalene-2-sulfonyl) -4- [6- (pyrrol
1-yl) nicotinoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 6- (pyrrol-1-yl) nicotinic acid (109 mg)
And the title compound (178 mg) was obtained as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, m), 3.76 (4H, m), 6.3
7 (2H, t, J = 2.2Hz), 7.30 (1H, d, J = 8.4Hz), 7.48 (2
H, t, J = 2.2Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.70-
7.80 (2H, m), 7.90-7.98 (3H, m), 8.31 (1H, s), 8.3
6 (1H, d, J = 2.2Hz). IR (KBr): 1636, 1597, 1495, 1345, 1165 cm ^-1 .

Example 134 1- (6-Chloronaphthalene-2-sulfonyl) -4- [5- (1-methyl
-3-trifluoromethyl-5-pyrazolyl) -2-thenoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 5- (1-methyl-3-trifluoromethyl- Using (5-pyrazolyl) -2-thiophenecarboxylic acid (160 mg),
In the same manner as in Example 46, the title compound as colorless crystals (314 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (4H, m),
3.87 (4H, m), 3.99 (3H,
s), 6.78 (1H, s), 7.19 (2
H, s), 7.59 (1H, dd, J = 2.
2, 8.8 Hz), 7.76 (1H, dd,
J = 2.0, 8.8 Hz), 7.90-7.95
(3H, m), 8.31 (1H, s). IR (KBr): 1622, 1424, 134
6, 1271, 1165, 1136 cm ^-1 . Example 135 1- (3-cyanostyrene-β (E) -sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 4-methyl-2- (4-pyridyl ) -5-thiazolecarboxylic acid (220
mg) and 1- (3-cyanostyrene-β (E) -sulfonyl) piperazine hydrochloride (314 mg) to give the title compound (318 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.30 (4H, m), 3.8
0 (4H, m), 6.75 (1H, d, J = 15.4Hz), 7.49 (1H, d, J =
15.4Hz), 7.58 (1H, t, J = 8.0Hz), 7.69-7.82 (5H, m),
8.72 (2H, d, J = 6.0Hz) .IR (KBr): 2232, 1634, 1597, 1435, 1346, 1327, 127
9, 1256, 1155 cm ^-1 .

Example 136 1- (4-methoxystyrene-β (E) -sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 4-methyl-2- ( 4-pyridyl) -5-thiazolecarboxylic acid (220
mg) and 1- (4-methoxystyrene-β (E) -sulfonyl) piperazine (282 mg) to give the title compound (403 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 3.25 (4H, m), 3.7
8 (4H, m), 3.86 (3H, s), 6.50 (1H, d, J = 15.8Hz),
6.94 (2H, d, J = 8.4Hz), 7.45 (1H, d, J = 15.8Hz), 7.4
6 (2H, d, J = 8.4Hz), 7.75 (2H, d, J = 6.0Hz), 8.72 (2
H, d, J = 6.0Hz) .IR (KBr): 1634, 1603, 1512, 1424, 1344, 1325, 125
8, 1152 cm ^-1. Example 137 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (5-pyrimidyl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride Using the salt (100 mg) and 4- (5-pyrimidyl) benzoic acid (58 mg) in the same manner as in Example 46, the title compound (1
20 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.14 (4H, brs), 3.74 (4H, br),
7.47 (2H, d, J = 8.4Hz), 7.55-7.65 (3H, m), 7.76 (1H,
dd, J = 1.4, 8.8Hz), 7.90-7.98 (3H, m), 8.31 (1H,
s), 8.93 (2H, s), 9.24 (1H, s) .IR (KBr): 1638, 1414, 1346, 1165 cm ^-1 .

Example 138 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4-methyl-2-
(2-pyrazinyl) -5-thiazolecarbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (2-pyrazinyl) -5-thiazolecarboxylic acid ( (64 mg) to give the title compound (134 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 3.15 (4H, m), 3.7
6 (4H, m), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H,
dd, J = 1.8, 8.8Hz), 7.90-7.98 (3H, m), 8.31 (1h,
s), 8.53 (1H, dd, J = 1.4, 2.6Hz), 8.63 (1H, d, J = 2.
6Hz), 9.37 (1H, d, J = 1.4Hz) .IR (KBr): 1634, 1456, 1427, 1346, 1329, 1279, 125
2, 1165 cm ^-1. Example 139 1- (6-chloronaphthalene-2-sulfonyl) -4- [4-methyl-2-
(4-pyridyl) pyrimidine-5-carbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (4-pyridyl) pyrimidine-5-
The title compound (140 mg) as colorless crystals was obtained in the same manner as in Example 46 using carboxylic acid (62 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 3.07 (2H, m), 3.2
3 (2H, m), 3.43 (2H, m), 3.95 (2H, m), 7.62 (1H, d
d, J = 1.8, 8.8Hz), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.9
0-7.98 (3H, m), 8.27 (2H, d, J = 6.2Hz), 8.32 (1H,
d, J = 1.2Hz), 8.50 (1H, s), 8.78 (2H, d, J = 6.2Hz). IR (KBr): 1644, 1422, 1331, 1165 cm ^-1 .

Example 140 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4-methyl-5-
(4-Pyridyl) -2-thiazolecarbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4-methyl-5- (4-pyridyl) -2-thiazolecarboxylic acid ( 127 mg) to give the title compound (229 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H, s), 3.22 (4H, t, J = 4.
9Hz), 3.90 (2H, brs), 4.60 (2H, brs), 7.33 (2H, d,
J = 6.0Hz), 7.58 (1H, dd, J = 1.8, 8.8Hz), 7.78 (1H, d
d, J = 1.8, 8.8Hz), 7.88-7.96 (3H, m), 8.32 (1H, s),
8.68 (2H, d, J = 6.0 Hz). IR (KBr): 1622, 1470, 1454, 1346, 1165 cm ^-1 . Example 141 1- [4- (2-aminothiazol-4-yl) benzoyl] -4- (6-
Chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (2-aminothiazol-4-yl) benzoic acid
(127 mg) and the title compound (235 mg) as colorless crystals was obtained in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (4H, brs), 3.72 (4H, brs),
5.04 (2H, brs), 6.76 (1H, s), 7.31 (2H, d, J = 8.2H
z), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.73-7.80 (3H,
m), 7.88-7.96 (3H, m), 8.30 (1H, s) .IR (KBr): 3314, 1609,1537, 1522, 1435, 1344, 1331,
1285, 1165 cm ^-1 .

Example 142 1- (6-chloronaphthalene-2-sulfonyl) -4- [3- (4-aminophenyl) propionyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 3- (4-aminophenyl) propionic acid (96 m
Using g) and in the same manner as in Example 46, the title compound (205 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (2H, t, J = 7.5Hz), 2.77 (2
(H, t, J = 7.5Hz), 2.93 (2H, m), 3.04 (2H, m), 3.44
(2H, m), 3.71 (2H, m), 6.52 (2H, d, J = 8.2Hz), 6.90
(2H, d, J = 8.2Hz), 7.59 (1H, dd, J = 2.2, 8.8Hz), 7.7
3 (1H, dd, J = 1.8,8.8Hz), 7.88-7.96 (3H, m), 8.29
(1H, s). IR (KBr): 1636, 1518, 1447, 1344, 1329, 1165 cm ^-1 .

Example 143 1- (6-Bromonaphthalene-2-sulfonyl) -4- [4-methyl-2-
(3-Pyridyl) -5-thiazolecarbonyl] piperazine 1- (6-bromonaphthalene-2-sulfonyl) piperazine hydrochloride (112 mg) and 4-methyl-2- (3-pyridyl) -5-thiazolecarboxylic acid ( The title compound (156 mg) as colorless crystals was obtained in the same manner as in Example 46 using the compound (64 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.15 (4H, m), 3.7
7 (4H, m), 7.38 (1H, m), 7.73 (1H, dd, J = 1.8, 8.8H
z), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.86 (1H, d, J = 8.
8Hz), 7.93 (1H, d, J = 8.8Hz), 8.10-8.20 (2H, m), 8.
30 (1H, s), 8.67 (1H, m), 9.07 (1H, m). IR (KBr): 1628, 1460, 1435, 1346, 1335, 1159 cm ^-1 . Example 144 1- (4-diisopropyl Aminomethylbenzoyl) -4- (1-octanesulfonyl) piperazine 1- (4-diisopropylaminomethylbenzoyl) piperazine (200 mg) and 1-octanesulfonyl chloride (154 m
Using g), a syrupy title compound (200 mg) was obtained in the same manner as in Example 23. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, m), 1.02 (12H, d, J =
6.6Hz), 1.20-1.50 (10H, m), 2.80-3.10 (6H, m), 3.30
(2H, m), 3.65 (2H, s), 3.20-3.90 (4H, br), 7.29 (2
H, d, J = 8.2Hz), 7.41 (2H, d, J = 8.2Hz) .IR (Neat): 1634, 1460, 1431, 1364, 1285, 1155 c
m ^-1 .

Example 145 1- (4-Chlorostyrene-β-sulfonyl) -4- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Piperazine dihydrochloride (200 mg) in ethyl acetate (10 ml) /
To a solution of aqueous sodium hydrogen carbonate (10 ml) was added 4-chlorostyrene-β-sulfonyl chloride (275 mg), and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, washed with brine, dried and concentrated. Purification by silica gel column chromatography (ethyl acetate) gave the title compound (169 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 3.28 (4H, m), 3.7
9 (4H, m), 6.64 (1H, d, J = 15.4Hz), 7.43 (4H, s),
7.46 (1H, d, J = 15.4Hz), 7.76 (2H, d, J = 6.2Hz), 8.7
2 (2H, d, J = 6.2Hz). IR (KBr): 1628, 1597, 1441, 1344, 1325, 1283, 1155
cm ^-1 .

Example 146 1- (4'-chlorobiphenyl-4-sulfonyl) -4- [4-methyl-2
-(4-Pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Piperazine dihydrochloride (200 mg) and 4'-chlorobiphenyl
Example 1 using -4-sulfonyl chloride (177 mg)
The title compound (237 mg) was obtained as colorless crystals in the same manner as in 45. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H, s), 3.13 (4H, m), 3.7
8 (4H, m), 7.47 (2H, d, J = 8.4Hz), 7.56 (2H, d, J =
8.4Hz), 7.70-7.77 (4H, m), 7.82 (2H, d, J = 8.4Hz),
8.71 (2H, d, J = 6.2Hz). IR (KBr): 1632, 1597, 1435, 1350, 1167 cm ^-1 .

Example 147 1- (2-Naphthalenesulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
The title compound (143 mg) was obtained as colorless crystals in the same manner as in Example 145 using piperazine dihydrochloride (200 mg) and 2-naphthalenesulfonyl chloride (140 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s),
3.15 (4H, m), 3.76 (4H,
m), 7.60-7.78 (5H, m), 7.
90-8.05 (3H, m), 8.35 (1
H, s), 8.70 (2H, d, J = 6.2)
Hz). IR (KBr): 1626, 1437, 134
8, 1165 cm ^-1 .

Example 148 1- (4-Bromobenzenesulfonyl) -4- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
The title compound (177 mg) as colorless crystals was obtained in the same manner as in Example 145 using piperazine dihydrochloride (200 mg) and 4-bromobenzenesulfonyl chloride (158 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.09 (4H, m), 3.7
6 (4H, m), 7.61 (2H, d, J = 8.4Hz), 7.68-7.80 (4H,
m), 8.72 (2H, d, J = 6.2Hz). IR (KBr): 1632, 1431, 1352, 1169 cm ^-1 .

Example 149 1- (6-Chloronaphthalene-2-sulfonyl) -4- [5- (4-pyridyl) -1,3,4-dithiadiazol-2-carbonyl] piperazine 1- (6- (Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 5- (4-pyridyl) -1,3,4-dithiadiazo-
The title compound (157 mg) was obtained as colorless crystals in the same manner as in Example 46, using l-2-carboxylic acid (120 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.26 (4H, m), 3.94 (2H, m), 4.5
3 (2H, m), 7.59 (1H, dd, J = 2.0, 8.8Hz), 7.74-7.85
(3H, m), 7.88-7.98 (3H, m), 8.33 (1H, s), 8.80 (2
(H, d, J = 6.2Hz). IR (KBr): 1622, 1346, 1281, 1165 cm ^-1 .

Example 150 1- (6-chloronaphthalene-2-sulfonyl) -4- [4-methyl-2-
(3-Pyridyl) -5-thiazolecarbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4-methyl-2- (3-pyridyl) -5-thiazolecarboxylic acid ( 128 mg) to give the title compound (255 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.15 (4H, m), 3.7
7 (4H, m), 7.38 (1H, dd, J = 4.8, 7.6Hz), 7.60 (1H,
d, J = 8.8Hz), 7.76 (1H, d, J = 8.8Hz), 7.89-7.98 (3H,
m), 8.16 (1H, d, J = 7.6Hz), 8.32 (1H, s), 8.67 (1
H, d, J = 4.8Hz), 9.07 (1H, s) .IR (KBr): 1634, 1433, 1346, 1331, 1165 cm ^-1 .

Example 151 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4-ethyl-2-
(4-Pyridyl) -5-thiazolecarbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (150 mg) and 4-ethyl-2- (4-pyridyl) -5-thiazolecarboxylic acid ( In the same manner as in Example 46, the title compound (209 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.0Hz), 2.71 (2
(H, q, J = 7.0Hz), 3.14 (4H, m), 3.76 (4H, m), 7.60
(1H, dd, J = 2.2, 8.8Hz), 7.70-7.80 (3H, m), 7.90-7.
98 (3H, m), 8.32 (1H, s), 8.70 (2H, d, J = 6.2Hz) .IR (KBr): 1628, 1439, 1346, 1287, 1163 cm ^-1 .

Example 152 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4-ethyl-2-
(3-Pyridyl) -5-thiazolecarbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (150 mg) and 4-ethyl-2- (3-pyridyl) -5-thiazolecarboxylic acid ( In the same manner as in Example 46, the title compound (200 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.0Hz), 2.70 (2
(H, q, J = 7.0Hz), 3.15 (4H, m), 3.76 (4H, m), 7.37
(1H, m), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.76 (1H, d
d, J = 1.8, 8.8Hz), 7.90-7.98 (3H, m), 8.17 (1H, m),
8.31 (1H, s), 8.66 (1H, dd, J = 1.6, 5.0Hz), 9.08 (1
H, d, J = 1.6Hz). IR (KBr): 1628, 1458, 1431, 1346, 1333, 1157 cm ^-1 .

Example 153 1- (6-Chloronaphthalene-2-sulfonyl) -4- [6- (1H-imidazol-1-yl) nicotinyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) Using colorless crystals of piperazine hydrochloride (100 mg) and 6- (1H-imidazol-1-yl) nicotinic acid (55 mg), the title compound (101 mg) was obtained in the same manner as in Example 46. Was. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (4H, m), 3.76 (4H, m), 7.2
1 (1H, s), 7.37 (1H, d, J = 8.4Hz), 7.60 (1H, dd, J =
1.8, 8.8Hz), 7.63 (1H, s), 7.76 (1H, dd, J = 1.8, 8.
8Hz), 7.84 (1H, dd, J = 2.2, 8.4Hz), 7.90-7.98 (3H,
m), 8.31 (1H, s), 8.35 (1H, s), 8.42 (1H, d, J = 2.2
Hz). IR (KBr): 1645, 1595, 1497, 1346, 1333, 1291, 1167
cm ^-1 .

Example 154 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (1H-imidazol-1-ylmethyl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) Using piperazine hydrochloride (100 mg) and 4- (1H-imidazol-1-ylmethyl) benzoic acid (58 mg), the title compound (108 mg) was obtained as colorless crystals in the same manner as in Example 46. Was. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (4H, brs), 3.67 (4H, br),
5.13 (2H, s), 6.88 (1H, s), 7.10 (1H, s), 7.13 (2
H, d, J = 8.4Hz), 7.29 (2H, d, J = 8.4Hz), 7.54 (1H,
s), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, dd, J =
1.8, 8.8Hz), 7.88-7.96 (3H, m), 8.29 (1H, s) .IR (KBr): 1634, 1456, 1433, 1345, 1283, 1165 cm ^-1 .

Example 155 4- (6-Chloronaphthalene-2-sulfonyl) -1- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine-2-
Carboxylic acid 4- (6-chloronaphthalene-2-sulfonyl) -1- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine-2-
To a solution of ethyl carboxylate (100 mg) in methanol (20 ml) was added a 1 N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction mixture and add 1N aqueous hydrochloric acid
(5 ml) was added, and the resulting precipitate was collected by filtration and dried to give the title compound (17 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 2.20-5.30 (10H, m), 7.72 (1
H, d, J = 8.4Hz), 7.77-7.86 (3H, m), 8.17 (1H, d, J =
8.8Hz), 8.22-8.32 (2H, m), 8.51 (1H, s), 8.69 (2H,
d, J = 4.8Hz) .IR (KBr): 1732, 1634, 1346, 1163 cm ^-1 .

Example 156 1- (3-Chlorostyrene-β (E) -sulfonyl) -4- [4-methyl-
2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Piperazine dihydrochloride (150 mg) and 3-chlorostyrene-β
Example 1 was prepared using (E) -sulfonyl chloride (108 mg).
The title compound (73 mg) was obtained as colorless crystals in the same manner as in Step 45. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.28 (4H, m), 3.3
7 (4H, m), 6.68 (1H, d, J = 15.4Hz), 7.35-7.53 (5H,
m), 7.76 (2H, d, J = 6.0Hz), 8.72 (2H, d, J = 6.0Hz) .IR (KBr): 1634, 1595, 1429, 1346, 1327, 1279, 125
6, 1155 cm ^-1 .

Example 157 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (4-nitrobenzenesulfonyl) piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
The title compound (186 mg) as colorless crystals was obtained in the same manner as in Example 145 using piperazine dihydrochloride (200 mg) and 4-nitrobenzenesulfonyl chloride (125 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s),
3.15 (4H, m), 3.78 (4H,
m), 7.74 (2H, d, J = 6.0H)
z), 7.96 (2H, d, J = 8.8H)
z), 8.42 (2H, d, J = 8.8H
z), 8.72 (2H, d, J = 6.0H)
z). IR (KBr): 1634, 1530, 142
9, 1352, 1171 cm ^-1 .

Example 158 1- (4-Fluorobenzenesulfonyl) -4- [4-methyl-
2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Example 145 was performed using piperazine dihydrochloride (150 mg) and 4-fluorobenzenesulfonyl chloride (85 mg).
In the same manner as in the above, the title compound (122 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.08 (4H, m), 3.7
6 (4H, m), 7.26 (2H, t, J = 8.6Hz), 7.74 (2H, d, J =
6.0Hz), 7.79 (2H, dd, J = 4.8, 8.6Hz), 8.72 (2H, d,
J = 6.0Hz) .IR (KBr): 1634, 1593, 1493, 1435, 1350, 1171 cm ^-1 .

Example 159 1- (4-Chlorobenzenesulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
The title compound (68 mg) as colorless crystals was obtained in the same manner as in Example 145 using piperazine dihydrochloride (150 mg) and 4-chlorobenzenesulfonyl chloride (96 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.09 (4H, m), 3.7
6 (4H, m), 7.55 (2H, d, J = 8.4Hz), 7.70 (2H, d, J =
8.4Hz), 7.74 (2H, d, J = 6.2Hz), 8.72 (2H, d, J = 6.2H
z) .IR (KBr): 1634, 1427, 1352, 1279, 1256, 1169 cm ^-1 .

Example 160 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (p-styrenesulfonyl) piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
The title compound (122 mg) as colorless crystals was obtained in the same manner as in Example 145 using piperazine dihydrochloride (200 mg) and p-styrenesulfonyl chloride (123 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.09 (4H, m), 3.7
5 (4H, m), 5.48 (1H, d, J = 10.8Hz), 5.92 (1H, d, J =
17.6Hz), 6.78 (1H, dd, J = 10.8, 17.6Hz), 7.57 (2H,
d, J = 8.4Hz), 7.71 (2H, d, J = 8.4Hz), 7.74 (2H, d, J
= 6.0Hz), 8.71 (2H, d, J = 6.0Hz) .IR (KBr): 1634, 1595, 1427, 1350, 1167 cm ^-1 .

Example 161 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (4-Toluenesulfonyl) piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
The title compound (129 mg) as colorless crystals was obtained in the same manner as in Example 145 using piperazine dihydrochloride (150 mg) and 4-toluenesulfonyl chloride (79 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 2.47 (3H, s), 3.0
6 (4H, m), 3.75 (4H, m), 7.36 (2H, d, J = 8.4Hz), 7.
64 (2H, d, J = 8.4Hz), 7.74 (2H, d, J = 6.0Hz), 8.71 (2
H, d, J = 6.0Hz) .IR (KBr): 1628, 1435, 1346, 1281, 1256, 1165 cm ^-1 .

Example 162 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- [5- (2-pyridyl) thiophen-2-sulfonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Using piperazine dihydrochloride (150 mg) and 5- (2-pyridyl) thiophene-2-sulfonyl chloride (119 mg) in the same manner as in Example 145, the title compound (46 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s), 3.20 (4H, m), 3.7
9 (4H, m), 7.29 (1H, m), 7.54 (1H, d, J = 4.0Hz), 7.
57 (1H, d, J = 4.0Hz), 7.67-7.84 (4H, m), 8.61 (1H,
d, J = 4.8Hz), 8.71 (2H, d, J = 6.2Hz). IR (KBr): 1634, 1426, 1354, 1163 cm ^-1 .

Example 163 1- [5- (3-Isoxazolyl) thiophen-2-sulfonyl] -4-
[4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Using piperazine dihydrochloride (150 mg) and 5- (3-isoxazolyl) thiophen-2-sulfonyl chloride (114 mg) in the same manner as in Example 145, the title compound was obtained as colorless crystals.
(84 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 3.19 (4H, m), 3.8
1 (4H, m), 6.56 (1H, d, J = 1.8Hz), 7.54 (2H, s), 7.
75 (2H, d, J = 6.0Hz), 8.33 (1H, d, J = 1.8Hz), 8.72 (2
H, d, J = 6.0Hz) .IR (KBr): 1634, 1597, 1418, 1358, 1163 cm ^-1 .

Example 164 1- [5- (benzenesulfonyl) thiophen-2-sulfonyl]-
4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Using colorless crystals of piperazine dihydrochloride (150 mg) and 5- (benzenesulfonyl) thiophen-2-sulfonyl chloride (134 mg) in the same manner as in Example 145, the title compound was obtained as colorless crystals.
(167 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H, s), 3.17 (4H, m), 3.8
0 (4H, m), 7.54-7.70 (3H, m), 7.72 (1H, d, J = 1.8H
z), 7.78 (2H, d, J = 6.0Hz), 7.94-8.02 (2H, m), 8.34
(1H, d, J = 1.8Hz), 8.74 (2H, d, J = 6.0Hz). IR (KBr): 1634, 1447, 1362, 1323, 1155 cm ^-1 .

Example 165 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- [5- (5-trifluoromethyl-2-pyridinesulfonyl)
Thiophene-2-sulfonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Using piperazine dihydrochloride (150 mg) and 5- (5-trifluoromethyl-2-pyridinesulfonyl) thiophen-2-sulfonyl chloride (163 mg) in the same manner as in Example 145, the title compound was obtained as colorless crystals. (234 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H, s), 3.17 (4H, m), 3.5
3 (4H, m), 7.78 (2H, d, J = 6.2Hz), 7.97 (1H, d, J =
1.6Hz), 8.20-8.40 (3H, m), 8.73 (2H, d, J = 6.2Hz),
8.98 (1H, s) .IR (KBr): 1634, 1595, 1327, 1165, 1142 cm ^-1 .

Example 166 1- (4-Carboxybenzenesulfonyl) -4- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Piperazine dihydrochloride (180 mg) and triethylamine (25
To a solution of 3 mg) in dichloromethane (20 ml) was added 4-chlorosulfonylbenzoic acid (108 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the obtained residue was dissolved in water.
The precipitate formed by neutralization with 1 N hydrochloric acid was collected by filtration, washed with water, and dried to give the title compound (174 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 2.36 (3H, s), 3.04 (4H, m),
3.63 (4H, m), 7.80-7.90 (4H, m), 8.17 (2H, d, J = 8.8
Hz), 8.71 (2H, d, J = 5.8Hz) .IR (KBr): 1715, 1638, 1431, 1358, 1283, 1254, 1169
cm ^-1 .

Example 167 1- (4-Methoxycarbonylbenzenesulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4- Pyridyl) -5-thiazolecarbonyl
Piperazine dihydrochloride (180 mg) and triethylamine (25
To a solution of 3 mg) in dichloromethane (20 ml) was added 4-chlorosulfonylbenzoic acid (108 mg), and the mixture was stirred at room temperature for 1 hour. Subsequently, an ether solution of diazomethane was added to the reaction solution until a yellow color was formed, concentrated, and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (158 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H, s), 3.11 (4H, m), 3.7
7 (4H, m), 3.99 (3H, s), 7.74 (2H, d, J = 6.2Hz), 7.
84 (2H, d, J = 8.6Hz), 8.24 (2H, d, J = 8.6Hz), 8.72 (2
H, d, J = 6.2Hz) .IR (KBr): 1728, 1634, 1435, 1354, 1281, 1171, 1107
cm ^-1 .

Example 168 1- (4-cyanostyrene-β (E) -sulfonyl) -4- [4-methyl-
2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (15
Using 2 mg) and 1- (4-cyanostyrene-β (E) -sulfonyl) piperazine (190 mg), the title compound as colorless crystals (225 mg) was obtained in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.31 (4H, m), 3.8
0 (4H, m), 6.78 (1H, d, J = 15.2Hz), 7.51 (1H, d, J =
15.2Hz), 7.61 (2H, d, J = 8.4Hz), 7.70-7.80 (4H, m),
8.73 (2H, d, J = 6.2Hz). IR (KBr): 2228, 1634, 1597, 1429, 1348, 1325, 127
9, 1256, 1155 cm ^-1 .

Example 169 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (4-trifluoromethylstyrene-β (E) -sulfonyl)
Piperazine 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (82
mg) and 1- (4-trifluoromethylstyrene-β (E) -sulfonyl) piperazine hydrochloride (130 mg) to give the title compound (170 mg) as colorless crystals in the same manner as in Example 46. Was. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 3.30 (4H, m), 3.8
0 (4H, m), 6.76 (1H, d, J = 15.6Hz), 7.53 (1H, d, J =
15.6Hz), 7.62 (2H, d, J = 8.4Hz), 7.71 (2H, d, J = 8.4H
z), 7.75 (2H, d, J = 6.0Hz), 8.72 (2H, d, J = 6.0Hz) .IR (KBr): 1634, 1429, 1348, 1325, 1155, 1127, 1067
cm ^-1 .

Example 170 1- (2H-benzopyran-3-ylsulfonyl) -4- [4-methyl-2
-(4-Pyridyl) -5-thiazolecarbonyl] piperazine 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (70
mg) and 1- (2H-benzopyran-3-ylsulfonyl) piperazine hydrochloride (100 mg) to give the title compound (120 mg) as a colorless solid in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.33 (4H, m), 3.7
8 (4H, m), 4.88 (2H, s), 6.92 (1H, d, J = 8.0Hz), 7.
01 (1H, m), 7.20 (1H, dd, J = 1.4, 8.0Hz), 7.29 (1H,
s), 7.32 (1H, m), 7.76 (2H, d, J = 6.2Hz), 8.72 (2
H, d, J = 6.2Hz) .IR (KBr): 1634, 1607, 1429, 1346, 1329, 1279, 1159
cm ^-1 .

Example 171 1- (2H-3,4-dihydrobenzopyran-3-ylsulfonyl) -4
-[4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Piperazine 1- (2H-benzopyran-3-ylsulfonyl) -4- [4-methyl-2
-(4-pyridyl) -5-thiazolecarbonyl] piperazine (5
0 mg) in methanol was subjected to catalytic reduction using palladium on carbon as a catalyst to give the title compound (50 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 3.10-3.40 (6H,
m), 3.45-3.82 (5H, m), 4.34-4.52 (2H, m), 6.82-7.2
0 (4H, m), 7.76 (2H, d, J = 6.2Hz), 8.73 (2H, d, J = 6.
2Hz). IR (KBr): 1628, 1491, 1439, 1424, 1327, 1315, 1150
cm ^-1 .

Example 172 1- [4- (4-Pyridyl) benzoyl] -4- (p-styrenesulfonyl) piperazine 1- (p-styrenesulfonyl) piperazine hydrochloride (288 mg)
Using 4- (4-pyridyl) benzoic acid (240 mg) and the title compound as colorless crystals (315 mg) in the same manner as in Example 46.
I got ¹ H-NMR (CDCl ₃ ) δ: 3.07 (4H, br)
s), 3.78 (4H, brs), 5.48
(1H, d, J = 10.6 Hz), 5.92
(1H, d, J = 17.6 Hz), 6.78
(1H, dd, J = 10.6, 17.6 Hz),
7.42-7.50 (4H, m), 7.57
(2H, d, J = 8.4 Hz), 7.65 (2
H, d, J = 8.0 Hz), 7.71 (2H,
d, J = 8.4 Hz), 8.69 (2H,
d, J = 6.0 Hz). IR (KBr): 1628, 1593, 143
1, 1346, 1283, 1171 cm ^-1 .

Example 173 1- [4- (3-Pyridyl) benzoyl] -4- (p-styrenesulfonyl) piperazine 1- (p-styrenesulfonyl) piperazine hydrochloride (288 mg)
Using 4- (3-pyridyl) benzoic acid (200 mg) and the title compound (355 mg) as colorless crystals in the same manner as in Example 46.
I got ¹ H-NMR (CDCl ₃ ) δ: 3.07 (4H, brs), 3.71 (4H, brs),
5.48 (1H, d, J = 11.0Hz), 5.92 (1H, d, J = 17.6Hz),
6.78 (1H, dd, J = 11.0, 17.6Hz), 7.36-7.76 (9H, m),
7.89 (1H, m), 8.62 (1H, dd, J = 1.6, 4.8Hz), 8.82 (1
H, d, J = 1.6Hz) .IR (KBr): 1624, 1458, 1431, 1346, 1285, 1171 cm ^-1 .

Example 174 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (2-pyrazinyl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg ) And 4- (2-pyrazinyl) benzoic acid (58 mg) to give the title compound (136 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, brs), 3.78 (4H, br),
7.45 (2H, d, J = 8.0Hz), 7.60 (1H, dd, J = 2.2, 8.8Hz),
7.76 (1H, dd, J = 1.6, 8.8Hz), 7.90-7.97 (3H, m), 8.
03 (2H, d, J = 8.0Hz), 8.31 (1H, s), 8.55 (1H, d, J =
2.6Hz), 8.65 (1H, dd, J = 1.4, 2.6Hz), 9.02 (1H, d,
J = 1.4Hz) .IR (KBr): 1628, 1464, 1433, 1350, 1289, 1167 cm ^-1 .

Example 175 1- (4-Cyanobenzenesulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [4-methyl-2- (4-pyridyl) ) -5-Thiazolecarbonyl]
The title compound (314 mg) as colorless crystals was obtained in the same manner as in Example 145 using piperazine dihydrochloride (300 mg) and 4-cyanobenzenesulfonyl chloride (167 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H, s), 3.30 (4H, m), 3.8
0 (4H, m), 6.77 (1H, d, J = 15.4Hz), 7.50 (1H, d, J =
15.4Hz), 7.60 (2H, d, J = 8.4Hz), 7.70-7.80 (4H, m),
8.72 (2H, d, J = 6.2Hz). IR (KBr): 2234, 1630, 1595, 1456, 1441, 1348, 128
5, 1260, 1165 cm ^-1 .

Example 176 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (4-trifluoromethoxybenzenesulfonyl) piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Using piperazine dihydrochloride (150 mg) and 4-trifluoromethoxybenzenesulfonyl chloride (108 mg)
In the same manner as in Example 145, the title compound (15
2 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.11 (4H, m), 3.7
7 (4H, m), 7.40 (2H, d, J = 8.8Hz), 7.74 (2H, d, J =
6.0Hz), 7.82 (2H, d, J = 8.8Hz), 8.71 (2H, d, J = 6.0H
z) .IR (KBr): 1630, 1595, 1439, 1356, 1273, 1256, 122
1, 1163 cm ^-1 .

Example 177 1- (5-Chloro-3-methylbenzo [b] thiophen-2-sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- [ 4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Using colorless crystals of the title compound (158 mg) in the same manner as in Example 145, using piperazine dihydrochloride (150 mg) and 5-chloro-3-methylbenzo [b] thiophen-2-sulfonyl chloride (117 mg). ). ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 2.69 (3H, s), 3.2
8 (4H, m), 3.79 (4H, m), 7.50 (1H, dd, J = 1.8, 8.4H
z), 7.74 (2H, d, J = 6.0hz), 7.78 (1H, d, J = 8.4Hz),
7.83 (1H, d, J = 1.8Hz), 8.72 (2H, d, J = 6.0Hz). IR (KBr): 1634, 1431, 1352, 1281, 1165 cm ^-1 .

Example 178 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (3-pyrazolyl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) ) And 4- (3-pyrazolyl) benzoic acid (109 mg) to give the title compound (253 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.12 (4H, brs), 3.75 (4H, brs),
6.63 (1H, d, J = 2.2Hz), 7.35 (2H, d, J = 8.4Hz), 7.5
5-7.65 (2H, m), 7.72-7.82 (3H, m), 7.88-7.98 (3H, m
m), 8.31 (1H, s) .IR (KBr): 3196, 1628, 1615, 1435, 1346, 1283, 126
4, 1165 cm ^-1 .

Example 179 1- [4- (2-Amino-4-pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride Salt (200 mg) and 4- (2-amino-4-pyrimidyl) benzoic acid (1
(24 mg) to give the title compound (273 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 3.11 (4H, brs), 3.74 (4H, brs),
5.11 (2H, s), 7.01 (1H, d, J = 5.0Hz), 7.39 (2H, d,
J = 8.4Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, d
d, J = 1.8, 8.8Hz), 7.88-8.02 (5H, m), 8.30 (1H, s),
8.37 (1H, d, J = 5.0Hz). IR (KBr): 3468, 3289, 3160, 1622, 1574, 1462, 134
6, 1335, 1289, 1157 cm ^-1 .

Example 180 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (tert-butoxycarbonylcarbazoyl) benzoyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (tert-butoxycarbonylcarbazoyl) benzoic acid (162 mg) were obtained in the same manner as in Example 46 to obtain the title compound (339 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 3.10 (4H, brs),
3.49 (2H, br), 3.84 (2H, br), 6.70 (1H, brs), 7.32
(2H, d, J = 8.2Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.
70-7.82 (3H, m), 7.88-7.96 (3H, m), 8.20 (1H, br
s), 8.30 (1H, s) .IR (KBr): 3266, 1682, 1628, 1456, 1437, 1346, 128
5, 1265, 1252, 1165 cm ^-1 .

Example 181 1- (6-chloronaphthalene-2-sulfonyl) -4- (4-carbazoylbenzoyl) piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) hydrochloride
Sulfonyl) -4- [4- (tert-butoxycarbonylcarbazoyl) benzoyl] piperazine (319 mg) was treated with hydrochloric acid to give the title compound (241 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.07 (4H, brs), 3.65 (4H, br
s), 7.47 (2H, d, J = 8.4Hz), 7.72 (1H, d, J = 8.8Hz),
7.81 (1H, d, J = 8.8Hz), 7.89 (2H, d, J = 8.4Hz), 8.18
(1H, d, J = 8.0Hz), 8.22-8.32 (2H, m), 8.49 (1H, s),
11.47 (1H, br). IR (KBr): 3075, 2853, 2610, 1620, 1346, 1335, 128
9, 1155 cm ^-1 .

Example 182 1- [4- (5-Aminoisoxazol-3-yl) benzoyl] -4-
(6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (5-aminoisoxazol-3-yl) benzoic acid (118 mg) And the title compound (243 mg) was obtained as colorless crystals in the same manner as in Example 46. ¹ H-NMR (DMSO-d ₆ ) δ: 3.06 (4H, br
s), 3.61 (4H, brs), 5.40.
(1H, s), 6.81 (2H, brs),
7.38 (2H, d, J = 8.2 Hz);
68-7.86 (4H, m), 8.18 (1
H, d, J = 8.6 Hz), 8.26 (1H,
s), 8.28 (1H, d, J = 8.6H)
z), 8.50 (1H, s). IR (KBr): 3420, 1636, 160
9, 1474, 1441, 1344, 133
1, 1289, 1159 cm ^-1 .

Example 183 1- [4- (3-Aminopyrazol-5-yl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) Using colorless amorphous title compound (264 mg) in the same manner as in Example 46, using piperazine hydrochloride (200 mg) and 4- (3-aminopyrazol-5-yl) benzoic acid (117 mg). Obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.10 (4H, brs), 3.72 (4H, brs),
5.89 (1H, s), 7.29 (2H, d, J = 8.4Hz), 7.52 (2H, d,
J = 8.4Hz), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, d
d, J = 1.8, 8.8Hz), 7.88-7.96 (3H, m), 8.30 (1H, s) .IR (KBr): 3214, 1626, 1433, 1346, 1331, 1285, 1165
cm ^-1 .

Example 184 1- [4- (5-Amino-1,3,4-oxadiazol-2-yl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6 -Chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (5-amino-1,3,4-oxadiazol-2
Using (-yl) benzoic acid (118 mg), the title compound (226 mg) was obtained as colorless crystals in the same manner as in Example 46. ¹ H-NMR (DMSO-d ₆ ) δ: 3.08 (4H, brs), 3.60 (4H, b
r), 7.32 (2H, brs), 7.47 (2H, d, J = 8.2Hz), 7.68-7.8
6 (4H, m), 8.18 (1H, d, J = 8.8Hz), 8.24-8.32 (2H,
m), 8.50 (1H, s) .IR (KBr): 3303, 3108, 1665, 1630, 1595, 1426, 133
3, 1155 cm ^-1 .

Example 185 1- (4-tert-Butoxycarbonylamidinobenzenesulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (4-cyanobenzenesulfonyl) -4- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine (233 mg)
And ethanol (0.3 ml) in dichloromethane (20 m
l) The solution was saturated with hydrochloric acid gas under ice cooling and allowed to stand for 1 day. After concentrating the reaction solution, use a saturated ammonia ethanol solution.
(20 ml), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, the residue was dissolved in DMF (20 ml), triethylamine (1 ml) and di-t-butyl dicarbonate (1 ml) were added, and the mixture was stirred at 40 ° C for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (139 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.56 (9H, s), 2.47 (3H, s), 3.0
6 (4H, m), 3.75 (4H, m), 7.76 (2H, d, J = 6.2Hz), 7.
82 (2H, d, J = 8.6Hz), 8.03 (2H, d, J = 8.6Hz), 8.72 (2
(H, d, J = 6.2Hz). IR (KBr): 1622, 1522, 1435, 1354, 1281, 1256, 116
9, 1140 cm ^-1 .

Example 186 1- (4-Amidinobenzenesulfonyl) -4- [4-methyl-2- (4-
Pyridyl) -5-thiazolecarbonyl] piperazine dihydrochloride In the same manner as in Example 76, 1- (4-tert-butoxycarbonylamidinobenzenesulfonyl) -4- [4-methyl-2- (4-
Pyridyl) -5-thiazolecarbonyl] piperazine (139 m
g) was treated with hydrochloric acid to give the title compound as a colorless solid (120 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.41 (3H, s), 3.09 (4H, brs),
3.66 (4H, brs), 7.98 (2H, d, J = 8.4Hz), 8.11 (2H,
d, J = 8.4Hz), 8.22 (2H, m), 8.89 (2H, d, J = 5.2Hz),
9.47 (2H, s), 9.67 (2H, s) .IR (KBr): 2980 (br), 1682, 1634, 1522, 1464, 1441,
1424, 1350, 1279, 1169cm ^-1 .

Example 187 1- (3-tert-butoxycarbonylamidinostyrene-β-sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine Same as in Example 185 By the method, 1- (3-cyanostyrene-β
-Sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine (272 mg) gave the title compound (211 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.56 (9H, s), 2.53 (3H, s), 3.2
9 (4H, m), 3.79 (4H, m), 6.80 (1H, d, J = 15.4Hz),
7.46-7.67 (3H, m), 7.74-7.85 (3H, m), 8.14 (1H,
s), 8.71 (2H, d, J = 6.0Hz). IR (KBr): 1622, 1520, 1435, 1348, 1318, 1281, 125
6, 1155 cm ^-1 .

Example 188 1- (3-Amidinostyrene-β-sulfonyl) -4- [4-methyl-2
-(4-Pyridyl) -5-thiazolecarbonyl] piperazine dihydrochloride 1- (3-tert-butoxycarbonylamidinostyrene-β-sulfonyl) -4- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine (19
0 mg) was treated with hydrochloric acid to give the title compound (186 mg) as a colorless solid
I got ¹ H-NMR (DMSO-d ₆ ) δ: 2.46 (3H, s), 3.24 (4H, brs),
3.70 (4H, brs), 7.54 (2H, s), 7.70 (1H, t, J = 8.0H
z), 7.91 (1H, d, J = 8.0Hz), 8.09 (1H, d, J = 8.0Hz),
8.19 (2H, m), 8.36 (1H, s), 8.88 (2H, m), 9.29 (2
H, s), 9.53 (2H, s) .IR (KBr): 3005 (br), 1678, 1632, 1522, 1464, 1441,
1426, 1345, 1279, 1154cm ^-1 .

Example 189 1- (4-Amidinostyrene-β-sulfonyl) -4- [4-methyl-2
-(4-Pyridyl) -5-thiazolecarbonyl] piperazine 1- (4-cyanostyrene-β-sulfonyl) -4- [4-methyl-2-
(4-pyridyl) -5-thiazolecarbonyl] piperazine (12
2 mg) and methanol (15 ml) in dichloromethane (1
5 ml) The solution was saturated with hydrochloric acid gas under ice cooling and allowed to stand for 1 day. After concentrating the reaction solution, use a saturated ammonia ethanol solution.
(20 ml), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol = 20/1) to give the title compound (19 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.30 (4H, m), 3.8
0 (4H, m), 6.75 (1H, d, J = 15.4Hz), 7.53 (1H, d, J =
15.4Hz), 7.59 (2H, d, J = 8.6Hz), 7.75 (2H, d, J = 6.0H
z), 7.88 (2H, d, J = 8.6Hz), 8.72 (2H, d, J = 6.0Hz) .IR (KBr): 3196, 1680, 1615, 1431, 1346, 1325, 127
9, 1258, 1155 cm ^-1 .

Example 190 1- [4- (6-tert-butoxycarbonylamino-3-pyridyl)
Benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (6-tert-butoxycarbonylamino-3
Using -pyridyl) benzoic acid (181 mg), the title compound (265 mg) was obtained as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 3.13 (4H, brs),
3.75 (4H, brs), 7.39 (2H, d, J = 8.4Hz), 7.41 (1H, b
rs), 7.54 (2H, d, J = 8.4Hz), 7.60 (1H, dd, J = 1.8,
8.8Hz), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.84 (1H, dd,
J = 2.4, 8.8Hz), 7.90-7.97 (3H, m), 8.02 (1H, d, J =
8.8Hz), 8.31 (1H, s), 8.43 (1H, d, J = 2.4Hz) .IR (KBr): 3407, 1725, 1634, 1530, 1348, 1285, 125
2, 1165 cm ^-1 .

Example 191 1- [4- (6-Amino-3-pyridyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- [4 -(6-tert-Butoxycarbonylamino-3-pyridyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (245 mg) was treated with hydrochloric acid to give the title compound (204 mg) as a colorless solid. Was. ¹ H-NMR (DMSO-d ₆ ) δ: 3.07 (4H, brs), 3.50 (4H, b
r), 7.07 (1H, m), 7.43 (2H, d, J = 8.4Hz), 7.68 (2H,
d, J = 8.4Hz), 7.72 (1H, dd, J = 1.8, 8.8Hz), 7.82 (1
H, dd, J = 1.8, 8.8Hz), 8.08 (2H, br), 8.18 (1H, d,
J = 8.4Hz), 8.23-8.33 (4H, m), 8.50 (1H, s) .IR (KBr): 3079, 1672, 1626, 1345, 1283, 1163 cm ^-1 .

Example 192 1- [4- (2-tert-butoxycarbonylamino-3,4,5,6-tetrahydro-4-pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (2-tert-butoxycarbonylamino-
3,4,5,6-tetrahydro-4-pyrimidyl) benzoic acid (155 m
g) was used to give the title compound (287 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.90 (1H, m), 2.1
7 (1H, m), 2.90-3.90 (11H, m), 4.64 (1H, m), 7.30
(4H, s), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.76 (1H, d
d, J = 1.4, 8.8Hz), 7.90-7.97 (3H, m), 8.31 (1H, s) .IR (KBr): 3280, 1640, 1346, 1157 cm ^-1 .

Example 193 1- [4- (2-Amino-3,4,5,6-tetrahydro-4-pyrimidyl)
Benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- [4- (2-tert-butoxycarbonylamino-3,4,5,6-tetrahydro- 4-Pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (257 mg) was treated with hydrochloric acid to give the title compound as a colorless solid
(189 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.85 (1H, m), 2.10 (1H, m),
2.90-3.80 (10H, m), 4.68 (1H, m), 6.88-7.04 (2H,
m), 7.31 (2H, d, J = 8.0Hz), 7.37 (2H, d, J = 8.0Hz),
7.73 (1H, d, J = 8.8Hz), 7.81 (1H, d, J = 8.8Hz), 8.12
-8.32 (4H, m), 8.49 (1H, s) .IR (KBr): 3216, 3073, 1674, 1632, 1437, 1346, 133
3, 1159 cm ^-1 .

Example 194 1- [4- (2-tert-butoxycarbonylamino-5-pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl)
Piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (2-tert-butoxycarbonylamino-5
Example 46 using (-pyrimidyl) benzoic acid (182 mg).
In the same manner as in the above, the title compound (315 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.56 (9H, s), 3.13 (4H, brs),
3.74 (4H, brs), 7.42 (2H, d, J = 8.4Hz), 7.52 (2H,
d, J = 8.4Hz), 7.60 (1H, dd, J = 2.0, 8.8Hz), 7.69 (1H,
brs), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.89-7.97 (3H,
m), 8.31 (1H, s), 8.76 (2H, s) .IR (KBr): 3403, 1717, 1624, 1481, 1350, 1327, 1165
cm ^-1 .

Example 195 1- [4- (2-Amino-5-pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine In the same manner as in Example 76, 1- [4- ( 2-tert-Butoxycarbonylamino-5-pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (280 mg) is treated with hydrochloric acid, returned to a free form with aqueous sodium hydrogen carbonate, and re-produced from ethyl acetate. Crystallization gave the title compound (112 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 3.12 (4H, brs), 3.75 (4H, brs),
5.16 (2H, brs), 7.39 (2H, d, J = 8.4Hz), 7.49 (2H, brs)
d, J = 8.4Hz), 7.60 (1H, dd, J = 1.8, 8.8Hz), 7.76 (1
H, dd, J = 1.8, 8.8Hz), 7.89-7.97 (3H, m), 8.31 (1H,
s), 8.51 (2H, s) .IR (KBr): 3333, 3200, 1649, 1626, 1607, 1429, 133
1, 1155 cm ^-1 .

Example 196 1- (6-chloronaphthalene-2-sulfonyl) -4- [3- (4-pyridyl) propioyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (150 mg) ) And 3- (4-pyridyl) propionic acid (66 mg)
And colorless crystals of the title compound (162 mg) were obtained in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (2H, t, J = 7.6Hz), 2.89 (2
(H, t, J = 7.6Hz), 3.04 (4H, m), 3.52 (2H, m), 3.72
(2H, m), 7.07 (2H, d, J = 6.2Hz), 7.60 (1H, dd, J = 2.
0, 8.8Hz), 7.74 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.98
(3H, m), 8.30 (1H, s), 8.43 (2H, d, J = 6.2Hz). IR (KBr): 1640, 1346, 1331, 1244, 1167 cm ^-1 .

Example 197 1- [4- (2-tert-butoxycarbonylamino-3,4,5,6-tetrahydro-5-pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4- (2-tert-butoxycarbonylamino-
3,4,5,6-tetrahydro-5-pyrimidyl) benzoic acid (184 m
g) to give the title compound (262 mg) as colorless crystals in the same manner as in Example 46. ¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (9H, s), 2.90-3.20 (5H,
m), 3.20-3.80 (8H, m), 7.28 (2H, d, J = 8.0Hz), 7.34
(2H, d, J = 8.0Hz), 7.72 (1H, dd, J = 2.0, 8.8Hz), 7.8
0 (1H, dd, J = 1.8, 8.8Hz), 8.17 (1H, d, J = 8.8Hz),
8.23-8.35 (4H, m), 8.48 (1H, s) .IR (KBr): 3281, 2847, 1644, 1450, 1431, 1362, 128
1, 1157 cm ^-1 .

Example 198 1- [4- (2-Amino-3,4,5,6-tetrahydro-5-pyrimidyl)
Benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- [4- (2-tert-butoxycarbonylamino-3,4,5,6-tetrahydro- 5-Pyrimidyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (235 mg) was treated with hydrochloric acid to give the title compound as a colorless solid
(188 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 3.05 (4H, br)
s), 3.15 (1H, m), 3.20-3.
75 (8H, m), 7.15 (2H, br
s), 7.30 (2H, d, J = 8.4H)
z), 7.36 (2H, d, J = 8.4H
z), 7.73 (1H, dd, J = 2.0,
8.8 Hz), 7.82 (1H, dd, J =
1.8, 8.8 Hz), 8.15-8.32 (5
H, m), 8.50 (1H, d, J = 1.4)
Hz). IR (KBr): 3200, 3061, 167
1, 1638, 1427, 1348, 128
9, 1159 cm ^-1 .

Example 199 1- (6-chloronaphthalene-2-sulfonyl) -4- (4-pyridylmethoxyacetyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and 4 -Pyridylmethoxyacetic acid (117 mg) and the title compound as colorless crystals in the same manner as in Example 46.
(165 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.08 (4H, brs), 3.61 (2H, m),
3.72 (2H, m), 4.14 (2H, s), 4.51 (2H, s), 7.15 (2H,
d, J = 5.8Hz), 7.60 (1H, dd, J = 2.0, 8.8Hz), 7.72 (1
H, dd, J = 1.8, 8.8Hz), 7.86-7.96 (3H, m), 8.28 (1H,
s), 8.52 (2H, d, J = 5.8Hz) .IR (KBr): 1665, 1445, 1345, 1333, 1283, 1242, 116
9, 1134 cm ^-1 .

Example 200 1- [4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl) piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
Using piperazine dihydrochloride (353 mg) and 2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (327 mg), the title of colorless crystals was obtained in the same manner as in Example 145. The compound (435 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.00-3.15 (6H,
m), 3.77 (4H, m), 3.85-4.00 (2H, m), 4.82 (1 / 3x2H,
s), 4.88 (2 / 3x2H, s), 7.33-7.44 (1H, m), 7.52-7.6
6 (2H, m), 7.74 (2H, d, J = 6.2Hz), 8.72 (2H, d, J = 6.
IR (KBr): 1696, 1634, 1433, 1348, 1167 cm ^-1 .

Example 201 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (1,2,3,4-tetrahydroisoquinoline-7-sulfonyl)
Piperazine 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
To a solution of -4- (2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl) piperazine (400 mg) in methanol (10 ml), add 15% ammonia methanol solution
(15 ml) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated, ethyl acetate-1N hydrochloric acid was added to the residue, the aqueous layer was separated, adjusted to pH = 10 with 1N aqueous sodium hydroxide solution, extracted with dichloromethane, dried and concentrated to obtain an amorphous phase. The title compound (337 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 2.90 (2H, t, J = 5.
8Hz), 3.06 (4H, m), 3.19 (2H, t, J = 5.8Hz), 3.75 (4
H, m), 4.08 (2H, s), 7.27 (1H, d, J = 8.0Hz), 7.41 (1
H, d, J = 1.8Hz), 7.49 (1H, dd, J = 1.8, 8.0Hz), 7.75
(2H, d, J = 6.2Hz), 8.72 (2H, d, J = 6.2Hz). IR (KBr): 1638, 1429, 1348, 1161, 727 cm ^-1 .

Example 202 1- (2-acetimidoyl-1,2,3,4-tetrahydroisoquinolin-7-sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl ] Piperazine dihydrochloride 1- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl]
-4- (1,2,3,4-tetrahydroisoquinoline-7-sulfonyl)
Piperazine (150 mg) and ethylacetimidate hydrochloride
(383 mg) to give the title compound (186 mg) as a colorless solid in the same manner as in Example 99. ¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (6H, s), 3.01 (4H, brs),
3.11 (2H, m), 3.68 (4H, m), 3.80 (2H, m), 4.81 (1
/ 2x2H, s), 4.87 (1 / 2x2H, s), 7.50-7.75 (3H, m), 7.9
2 (2H, d, J = 6.2Hz), 8.69 (1H, brs), 8.76 (2H, d, J
= 6.2Hz), 9.25-9.38 (1H, m) .IR (KBr): 3065, 1672, 1632, 1426, 1345, 1279, 1161
cm ^-1 .

Example 203 1- [4- (1-Imidazolyl) benzoyl] -4- [6- (2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl] piperazine 1- [4- (1 -Imidazolyl) benzoyl] piperazine dihydrochloride
(329 mg) and 6- (2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl chloride (417 mg) in the same manner as in Example 145 to give the title compound as colorless crystals (435 mg) I got ¹ H-NMR (CDCl ₃ ) δ: 3.12 (4H, brs), 3.74 (4H, brs),
4.89 (2H, s), 7.23 (1H, s), 7.28 (1H, t, J = 1.2H
z), 7.40 (2H, d, J = 9.0Hz), 7.46 (2H, d, J = 9.0Hz),
7.57 (1H, dd, J = 2.2, 8.8Hz), 7.72 (1H, dd, J = 1.8,
8.8Hz), 7.87 (1H, s), 7.92-7.99 (2H, m), 8.21 (1H,
s), 8.27 (1H, s) .IR (KBr): 1744, 1634, 1609, 1211, 1163 cm ^-1 .

Example 204 1- (6-Aminonaphthalene-2-sulfonyl) -4- [4- (1-imidazolyl) benzoyl] piperazine 1- [4- (1-Imidazolyl) benzoyl] -4- [6- To a solution of (2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl] piperazine (400 mg) in acetic acid (5 ml) was added zinc dust (1 g), and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was dissolved in 0.5N hydrochloric acid, washed with ethyl acetate, made alkaline with a 1N aqueous sodium hydroxide solution, and the resulting precipitate was collected by filtration. Washed with water and dried to give the title compound as a colorless solid (187
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.98 (4H, m), 3.57 (4H, br),
5.95 (2H, s), 6.89 (1H, s), 7.06 (1H, d, J = 8.8Hz),
7.13 (1H, s), 7.47 (2H, d, J = 8.2Hz), 7.48 (1H, d,
J = 8.8Hz), 7.66 (1H, d, J = 8.8Hz), 7.69 (2H, d, J =
8.2Hz), 7.81 (1H, s), 7.83 (1H, d, J = 8.8Hz), 8.08
(1H, s), 8.34 (1H, s) .IR (KBr): 3353, 1628, 1524, 1507, 1437, 1345, 131
0, 1285, 1159 cm ^-1 .

Example 205 1- [4- (1-Imidazolyl) benzoyl] -4- [7- (2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl] piperazine 1- [4- (1 -Imidazolyl) benzoyl] piperazine dihydrochloride
(329 mg) and 7- (2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl chloride (417 mg) in the same manner as in Example 145 to give the title compound as colorless crystals (520 mg) I got ¹ H-NMR (CDCl ₃ ) δ: 3.12 (4H, brs), 3.70 (4H, brs),
4.89 (2H, s), 7.24 (1H, s), 7.25-7.32 (2H, m), 7.
40 (2H, d, J = 9.0Hz), 7.46 (2H, d, J = 9.0Hz), 7.61 (1
H, dd, J = 2.2, 8.8Hz), 7.67 (1H, dd, J = 1.8, 8.8Hz),
7.89 (1H, s), 7.93 (1H, d, J = 8.8Hz), 7.96 (1H, d,
J = 8.8Hz), 8.24 (1H, s), 8.27 (1H, s) .IR (KBr): 3223, 1748, 1611, 1507, 1283, 1206, 116
7, 1103 cm ^-1 .

Example 206 1- (7-Aminonaphthalene-2-sulfonyl) -4- [4- (1-imidazolyl) benzoyl] piperazine 1- [4- (1-imidazolyl) benzoyl] -4- [7- To a solution of (2,2,2-trichloroethoxycarbonylamino) naphthalene-2-sulfonyl] piperazine (475 mg) in acetic acid (5 ml) was added zinc dust (1 g), and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was dissolved in 0.5N hydrochloric acid, washed with ethyl acetate, made alkaline with a 1N aqueous sodium hydroxide solution, and the resulting precipitate was collected by filtration. After washing with water and drying, the title compound (32
5 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.02 (4H, m), 3.59 (4H, br),
5.73 (2H, s), 6.99 (1H, s), 7.12 (1H, s), 7.14 (1
H, d, J = 8.2Hz), 7.29 (1H, d, J = 8.2Hz), 7.47 (2H,
d, J = 8.0Hz), 7.64-7.80 (4H, m), 7.85 (1H, d, J = 8.6
Hz), 7.93 (1H, s), 8.30 (1H, s) .IR (KBr): 3351, 1632, 1510, 1460, 1437, 1342, 1163
cm ^-1 .

Example 207 1- [4- (1-Imidazolyl) benzoyl] -4- (p-styrenesulfonyl) piperazine 1- [4- (1-Imidazolyl) benzoyl] piperazine dihydrochloride
(200 mg) and p-styrenesulfonyl chloride (123 mg)
Was used to obtain the title compound (234 mg) as a colorless solid in the same manner as in Example 145. ¹ H-NMR (CDCl ₃ ) δ: 3.06 (4H, brs), 3.74 (4H, brs),
5.48 (1H, d, J = 10.6Hz), 5.92 (1H, d, J = 17.6Hz),
6.78 (1H, dd, J = 10.6, 17.6Hz), 7.23 (1H, s), 7.29
(1H, t, J = 1.2Hz), 7.42 (2H, d, J = 8.8Hz), 7.48 (2H,
d, J = 8.8Hz), 7.57 (2H, d, J = 8.6Hz), 7.71 (2H, d,
J = 8.6Hz), 7.87 (1H, s) .IR (KBr): 1632, 1611, 1433, 1348, 1285, 1262, 1165
cm ^-1 .

Example 208 1- (6-Chloronaphthalene-2-sulfonyl) -4- [4- (guanidinomethyl) benzoyl] piperazine hydrochloride 1- [4- (tert-butoxy) hydrochloride was prepared in the same manner as in Example 76. Carbonylguanidinomethyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine (300 mg) was treated with hydrochloric acid to give the title compound (250 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.06 (4H, brs), 3.57 (4H, br
s), 4.40 (2H, d, J = 6.2Hz), 7.33 (4H, s), 7.72 (1H,
dd, J = 1.8, 8.8Hz), 7.82 (1H, dd, J = 1.4, 8.8Hz),
8.18 (1H, d, J = 8.8Hz), 8.23-8.31 (2H, m), 8.49 (1
H, s) .IR (KBr): 3150, 1689, 1613, 1441, 1344, 1283, 126
5, 1163 cm ^-1 .

Example 209 1- (6-Fluoronaphthalene-2-sulfonyl) -4- [4- (1-imidazolyl) benzoyl] piperazine 1- [4- (1-Imidazolyl) benzoyl] piperazine dihydrochloride
(200 mg) and 6-fluoronaphthalene-2-sulfonyl chloride (150 mg) were obtained in the same manner as in Example 145 to give the title compound (176 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.13 (4H, br)
s), 3.74 (4H, brs), 7.23
(1H, t, J = 1.2 Hz), 7.28 (1
H, t, J = 1.2 Hz), 7.40 (2H,
d, J = 8.8 Hz), 7.45 (2H,
d, J = 8.8 Hz), 7.57 (1H, d
d, J = 2.2, 8.8 Hz), 7.76 (1
H, dd, J = 1.4, 8.8 Hz), 7.8
6 (1H, s), 7.92-8.05 (3H,
m), 8.33 (1H, s). IR (KBr): 1634, 1611, 146
8, 1435, 1346, 1252, 1163
cm ^-1 .

Example 210 1- (trans-4-propioimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene
2-Sulfonyl) piperazine hydrochloride In the same manner as in Example 99, 1- (trans-4-aminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2
-Sulfonyl) piperazine hydrochloride (130 mg) and ethyl propioimidate hydrochloride (379 mg) were used to give the title compound (114 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t, J = 7.6Hz), 1.20-
1.50 (4H, m), 1.55-1.70 (2H, m), 1.73-1.87 (2H, m),
2.37 (2H, q, J = 7.6Hz), 2.50 (1H, m), 2.96 (4H, br
s), 3.41 (1H, m), 3.57 (4H, m), 7.72 (1H, dd, J = 1.
8, 8.8Hz), 7.82 (1H, dd, J = 1.8, 8.8Hz), 8.17 (1H,
d, J = 8.8Hz), 8.22-8.32 (2H, m), 8.50 (1H, s), 8.62
(1H, brs), 9.02 (1H, brs), 9.38 (1H, brd, J = 7.8H
z) .IR (KBr): 3067, 1676, 1640, 1456, 1346, 1331, 1165
cm ^-1 .

Example 211 4- (trans-4-acetimidoylaminocyclohexane-1-)
Ylcarbonyl) -1- (6-chloronaphthalene-2-sulfonyl) piperazine-2-acetic acid methyl hydrochloride In the same manner as in Example 76, 4- (trans-4-tert-butoxycarbonylaminocyclohexane-1-yl Carbonyl) -1
-(6-Chloronaphthalene-2-sulfonyl) piperazine-2-acetic acid methyl hydrochloride (240 mg) was treated with hydrochloric acid to give 4- (trans-4-
Aminocyclohexane-1-ylcarbonyl) -1- (6-chloronaphthalene-2-sulfonyl) piperazine-2-acetic acid methyl chloride hydrochloride, and subsequently, in the same manner as in Example 99, ethylacetimidate hydrochloride (488 mg) to give the title compound (175 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.00-4.60 (25
H, m), 7.56 (1H, m), 7.70
−8.00 (4H, m), 8.40 (1H,
s), 8.73 (1H, br), 9.06
(1H, br), 9.65 (1H, br). IR (KBr): 3063, 1732, 168
2, 1634, 1454, 1435, 132
9, 1159 cm ^-1 .

Example 212 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2
-Sulfonyl) piperazine-2-carboxylic acid hydrochloride In the same manner as in Example 99, 1- (trans-4-aminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2
-Sulfonyl) piperazine-2-carboxylic acid hydrochloride (140 mg)
And ethylacetimidate hydrochloride (335 mg) to give the title compound (71 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-4.40 (16H, m), 2.11 (3H,
s), 4.98-5.10 (1H, m), 7.65-7.82 (2H, m), 7.95 (1
H, brs), 8.10-8.33 (3H, m), 8.52 (1H, s), 9.03 (1
H, brs), 9.34 (1H, brs) .IR (KBr): 3065 (br), 1732, 1680, 1630, 1439, 1346,
1163 cm ^-1 .

Example 213 1- (trans-4-acetylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (trans-4-aminocyclohexane-1-ylcarbonyl )-
Acetic anhydride (50 mg) was added to a solution of 4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (50 mg) and triethylamine (30 mg) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (41 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.20 (2H, m), 1.45-1.75 (4
H, m), 1.94 (3H, s), 1.95-2.10 (2H, m), 2.29 (1H,
m), 3.08 (4H, m), 3.50-3.80 (5H, m), 5.20 (1H, d,
J = 7.2Hz), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, d
d, J = 1.8, 8.8Hz), 7.86-7.97 (3H, m), 8.31 (1H, s) .IR (KBr): 3264, 1634, 1454, 1346, 1163, 729 cm ^-1 .

Example 214 1- (trans-4-methoxycarbonylacetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (trans-4-acetimidoyl) Aminocyclohexane-1-
Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine (300 mg) and triethylamine (199 m
g) in dichloromethane (30 ml)
(192 mg) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (171 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (2H, m), 1.45-1.75 (4H,
m), 1.95-2.10 (2H, m), 2.11 (3H, s), 2.36 (1H, m),
3.09 (4H, m), 3.38 (1H, m), 3.65 (4H, m), 3.67 (3
H, s), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.76 (1H, dd,
J = 1.8, 8.8Hz), 7.86-7.97 (3H, m), 8.31 (1H, s), 9.
90 (1H, br) .IR (KBr): 1652, 1630, 1599, 1447, 1346, 1260, 116
5, 1080, 731 cm ^-1 .

Example 215 1- (cis-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) Using piperazine hydrochloride (200 mg) and cis-4-tert-butoxycarbonylaminocyclohexane-1-ylcarboxylic acid (141 mg) in the same manner as in Example 46, to give the title compound as colorless crystals.
(313 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.38 (2H, m), 1.41 (9H,
s), 1.42-1.87 (6H, m), 2.43 (1H, m), 3.07 (4H, t,
J = 5.4Hz), 3.50-3.80 (5H, m), 4.70 (1H, m), 7.59 (1
H, dd, J = 2.0, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz),
7.87-7.97 (3H, m), 8.30 (1H, s) .IR (KBr): 3324, 1703, 1644, 1456, 1364, 1346, 133
1, 1165 cm ^-1 .

Example 216 1- (cis-4-aminocyclohexane-1-ylcarbonyl) -4-
(6-Chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- (cis-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4-in the same manner as in Example 76
(6-chloronaphthalene-2-sulfonyl) piperazine (293 m
g) was treated with hydrochloric acid to give the title compound as a colorless solid (270 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.75 (8H, m), 2.66 (1H,
m), 2.96 (4H, m), 3.17 (1H, m), 3.55 (4H, m), 7.72
(1H, dd, J = 2.0, 8.8Hz), 7.81 (1H, d, J = 8.8Hz), 7.8
3 (3H, brs), 8.12-8.30 (3H, m), 8.50 (1H, s) .IR (KBr): 2944, 1622, 1454, 1345, 1331, 1163 cm ^-1 .

Example 217 1- (cis-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl)
Piperazine hydrochloride In the same manner as in Example 99, 1- (cis-4-aminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-
The title compound (95 mg) was obtained as a colorless solid by using (sulfonyl) piperazine hydrochloride (120 mg) and ethylacetimidate hydrochloride (314 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.75 (8H, m), 2.13 (3H,
s), 2.64 (1H, m), 2.96 (4H, m), 3.56 (4H, m), 3.66
(1H, m), 7.72 (1H, d, J = 8.8Hz), 7.81 (1H, d, J = 8.8
Hz), 8.12-8.30 (3H, m), 8.50 (1H, s), 8.57 (1H, br
s), 9.05-9.20 (2H, m) .IR (KBr): 3056, 1684, 1624, 1453, 1346, 1331, 1163
cm ^-1 .

Example 218 1- [trans-4- (1-acetoxyethoxycarbonylacetimidoylamino) cyclohexane-1-ylcarbonyl] -4-
(6-chloronaphthalene-2-sulfonyl) piperazine 1- (trans-4-acetimidoylaminocyclohexane-1-
Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), O- (1-acetoxyethoxycarbonyl) -4-nitrophenol (63 mg) and diisopropylethylamine (72 mg) DMF (4 ml)
The solution was stirred at 50 ° C. for 15 hours. Concentrate the reaction,
The residue obtained by dissolving in ethyl acetate, washing with water, an aqueous solution of sodium hydrogen carbonate and brine, drying and concentrating is purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless solid (89 mg) ). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (2H, m), 1.49 (3H, d, J = 5.
6Hz), 1.45-1.80 (4H, m), 1.99 (2H, m), 2.05 (3H,
s), 2.12 (3H, s), 2.35 (1H, m), 3.09 (4H, m), 3.39
(1H, m), 3.59 (2H, m), 3.72 (2H, m), 6.84 (1H, q,
J = 5.6Hz), 7.60 (1H, dd, J = 2.0, 8.8Hz), 7.76 (1H, d
d, J = 1.8, 8.8Hz), 7.87-7.97 (3H, m), 8.31 (1H, s),
9.88 (1H, br) .IR (KBr): 3300, 1748, 1686, 1647, 1597, 1559, 145
2, 1346, 1258, 1165, 1115, 1080 cm ^-1 .

Example 219 1- [trans-4- (2-acetoxy-1,1-dimethylethoxycarbonylacetimidoylamino) cyclohexane-1-ylcarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) Piperazine 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100%) in the same manner as in Example 218
mg) and O- (2-acetoxy-1,1-dimethylethoxycarbonyl) -4-nitrophenol (70 mg) were reacted to give the title compound (60 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.80 (6H, m), 1.48 (6H,
s), 2.00 (2H, m), 2.07 (3H, s), 2.10 (3H, s), 2.36
(1H, m), 3.09 (4H, m), 3.37 (1H, m), 3.59 (2H,
m), 3.71 (2H, m), 4.29 (2H, s), 7.60 (1H, dd, J = 1.
8, 8.8Hz), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.87-7.96
(3H, m), 8.31 (1H, s), 9.78 (1H, br) .IR (KBr): 3300, 1736, 1638, 1599, 1555, 1453, 134
6, 1258, 1163 cm ^-1 .

Example 220 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (6-chloronaphthalene-2-sulfonyl) piperazine-2-acetic acid methyl hydrochloride 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4 in the same manner as in Example 76
Methyl-(6-chloronaphthalene-2-sulfonyl) piperazine-2-acetate (140 mg) was treated with hydrochloric acid to give the title compound (87 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.14-1.40 (4H, m), 1.59 (2H,
m), 1.89 (2H, m), 2.15-5.00 (14H, m), 7.65-7.93 (5
H, m), 8.16 (1H, d, J = 8.8Hz), 8.20-8.30 (2H, m), 8.
49 (1H, s) .IR (KBr): 2946, 1730, 1624, 1439, 1339, 1165 cm ^-1 .

Example 221 1- (trans-4-acetimidoylaminocyclohexane-1-
Ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine-2-acetic acid methyl hydrochloride In the same manner as in Example 99, 1- (trans-4-aminocyclohexane-1-ylcarbonyl) -4 -(6-chloronaphthalene-2
-Sulfonyl) piperazine-2-acetic acid methyl hydrochloride (75 mg)
And ethyl acetate imidate hydrochloride (335 mg) to give the title compound (57 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.90 (8H, m), 2.11 (3H,
s), 2.20-2.50 (3H, m), 2.70-2.90 (2H, m), 3.20-5.00
(6H, m), 3.55 (2 / 3x3H, s), 3.61 (1 / 3x3H, s), 7.72
(1H, dd, J = 1.8, 8.8Hz), 7.80 (1H, d, J = 8.8Hz), 8.1
6 (1H, d, J = 8.8Hz), 8.20-8.33 (2H, m), 8.50 (1H,
s), 8.57 (1H, s), 9.05 (1H, s), 9.38 (1H, brd, J =
IR (KBr): 3059, 1732, 1686, 1640, 1439, 1389, 126
7, 1165 cm ^-1 .

Example 222 1- (6-Chloronaphthalene-2-sulfonyl) -4- (cis-4-guanidinocyclohexane-1-ylcarbonyl) piperazine hydrochloride 1- (cis-4-aminocyclohexane-1-yl Carbonyl) -4-
(6-Chloronaphthalene-2-sulfonyl) piperazine hydrochloride
(100 mg), a solution of 1-amidinopyrazole hydrochloride (47 mg) and triethylamine (100 mg) in methanol (10 ml) were stirred at room temperature for 1 day. The reaction solution was concentrated, dichloromethane was added, and the mixture was washed with a 1N aqueous sodium hydroxide solution.
After drying and concentration, the residue was dissolved in ethyl acetate, and the title compound (88 mg) was obtained as a colorless solid as a hydrochloride using hydrochloric acid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.70 (8H, m), 2.60 (1H,
m), 2.96 (4H, m), 3.40-3.70 (5H, m), 7.00 (4H, b
r), 7.49 (1H, m), 7.72 (1H, dd, J = 1.4, 8.8Hz), 7.80
(1H, d, J = 8.6Hz), 8.16 (1H, d, J = 8.8Hz), 8.20-8.3
2 (2H, m), 8.50 (1H, s) .IR (KBr): 3160, 1644, 1624, 1454, 1345, 1331, 1163
cm ^-1 .

Example 223 1- (trans-4-tert-butoxycarbonylmethylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene
N, N-dimethylformamide of 2- (sulfonyl) piperazine 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine (500 mg) (20 ml) 60% sodium hydride (55 mg) in solution
After stirring for 10 minutes, methyl iodide (1 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (560 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.80 (8H, m), 1.43 (9H,
s), 2.27 (1H, m), 2.70 (3H, s), 3.07 (4H, m), 3.59
(2H, m), 3.70 (2H, m), 3.78 (1H, m), 7.59 (1H, d
d, J = 1.8, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz), 7.8
7-7.97 (3H, m), 8.30 (1H, s) .IR (KBr): 1682, 1651, 1454, 1366, 1346, 1325, 1165
cm ^-1 .

Example 224 1- (6-chloronaphthalene-2-sulfonyl) -4- (trans-4-methylaminocyclohexane-1-ylcarbonyl) -piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) -piperazine hydrochloride Trans-4-tert-butoxycarbonylmethylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine (535 mg) was treated with hydrochloric acid to give the title compound (41
1 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (4H, m), 1.65 (2H, m),
1.99 (2H, m), 2.40-2.50 (4H, m), 2.85 (1H, m), 2.96
(4H, m), 3.56 (4H, m), 7.73 (1H, dd, J = 2.0,8.8H
z), 7.78 (1H, dd, J = 1.8, 8.8Hz), 8.17 (1H, d, J = 8.
8Hz), 8.22-8.30 (2H, m), 8.51 (1H, s), 8.79 (2H, b
rs) .IR (KBr): 2948, 2728, 1624, 1458, 1346, 1155 cm ^-1 .

Example 225 1- (trans-4-acetimidoylmethylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 99, 1- (6-chloronaphthalene-2-
Sulfonyl) -4- (trans-4-methylaminocyclohexane-
The title compound (89 mg) was obtained as a colorless solid using 1-ylcarbonyl) piperazine hydrochloride (100 mg) and ethylacetimidate hydrochloride (254 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.75 (8H, m), 2.23 (2 / 3x
3H, s), 2.30 (1 / 3x3H, s), 2.50 (1H, m), 2.84 (2 / 3x3
H, s), 2.92 (1 / 3x3H, s), 2.96 (4H, m), 3.56 (4H,
m), 3.70 (1H, m), 7.72 (1H, dd, J = 1.8, 8.8Hz), 7.8
1 (1H, d, J = 8.8Hz), 8.12-8.30 (3H, m), 8.50 (1H,
s) .IR (KBr): 3079, 1620, 1454, 1344, 1331, 1163 cm ^-1 .

Example 226 1- (4-aminobenzoyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (250 mg) and 4- Using aminobenzoic acid (105 mg), the title compound was obtained as colorless crystals in the same manner as in Example 46.
(285 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.08 (4H, m), 3.73 (4H, m), 3.8
8 (2H, s), 6.59 (2H, d, J = 8.6Hz), 7.15 (2H, d, J =
8.6Hz), 7.59 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, dd,
J = 1.8, 8.8Hz), 7.88-7.96 (3H, m), 8.30 (1H, s) .IR (KBr): 3351, 3223, 1624, 1605, 1345, 1329, 128
5, 1262, 1165 cm ^-1 .

Example 227 1- (6-Chloronaphthalene-2-sulfonyl) -4- (trans-4-thioureidocyclohexane-1-ylcarbonyl) piperazine 1- (trans-4-aminocyclohexane-1-ylcarbonyl )-
4- (6-chloronaphthalene-2-sulfonyl) piperazine (200
mg)) in dichloromethane (10 ml), triethylamine (107 mg) was added, followed by benzoyl isothiocyanate (83 mg), and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate) to give a colorless solid 1- (trans-4-benzoylthioureidocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2- Sulfonyl) piperazine
(268 mg) was obtained. The obtained compound was dissolved in tetrahydrofuran (10 ml) and methanol (4 ml), 1N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, acidified with dilute hydrochloric acid, extracted with ethyl acetate, concentrated and purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless solid (15
5 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.95 (8H, m), 2.40 (1H,
m), 2.96 (4H, m), 3.55 (4H, m), 3.75 (1H, m), 6.77
(1H, brs), 7.48 (2H, brs), 7.72 (1H, dd, J = 2.2, 8.
8Hz), 7.80 (1H, dd, J = 1.8, 8.8Hz), 8.16 (1H, d, J =
8.8Hz), 8.20-8.33 (2H, m), 8.49 (1H, s) .IR (KBr): 3291, 3169, 1636, 1605, 1439, 1346, 1165
cm ^-1 .

Example 228 1- (6-Chloronaphthalene-2-sulfonyl) -4- [trans-4- (2-
Imidazolylamino) cyclohexane-1-ylcarbonyl] piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) -4- (trans-4-thioureidocyclohexane-1-ylcarbonyl) piperazine (145 mg) in methanol ( To the solution (20 ml) was added methyl iodide (1.5 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was dissolved in ethanol (20 ml), 2,2-dimethoxyethylamine (89 mg) was added, and the mixture was refluxed for 15 hours. The reaction mixture was concentrated, and concentrated hydrochloric acid was added to the obtained residue (20 ml).
Was added and stirred at 45 ° C. for 30 minutes. The residue obtained by concentrating the reaction solution was dissolved in dichloromethane (20 ml), and triethylamine (2 ml) and di-tert-butyl dicarbonate were dissolved.
(2 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give a colorless solid of 1- (6-chloronaphthalene-2-sulfonyl) -4- [trans-4- (1- (tert-butoxycarbonyl-2-imidazolylamino) cyclohexane-1
[-Ylcarbonyl] piperazine (78 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.30 (2H, m), 1.57 (9H,
s), 1.60-1.75 (4H, m), 2.17-2.40 (3H, m), 3.08 (4
H, m), 3.50-3.80 (5H, m), 6.38 (1H, brd, J = 7.6Hz),
6.52 (1H, d, J = 2.0Hz), 6.76 (1H, d, J = 2.0Hz), 7.5
9 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz)
Hz), 7.87-7.96 (3H, m), 8.30 (1H, s). In the same manner as in Example 76, 1- (6-chloronaphthalene-2-
Sulfonyl) -4- [trans-4- (1-tert-butoxycarbonyl-
2-Imidazolylamino) cyclohexane-1-ylcarbonyl] piperazine (78 mg) was treated with hydrochloric acid to give the title compound (42 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.50 (4H, m), 1.57 (2H,
m), 1.85 (2H, m), 2.49 (1H, m), 2.96 (4H, m), 3.34
(1H, m), 3.56 (4H, m), 6.91 (2H, s), 7.71 (1H, dd,
J = 1.8, 8.8Hz), 7.80 (1H, d, J = 8.8Hz), 7.95 (1H,
d, J = 8.0Hz), 8.16 (1H, d, J = 8.8Hz), 8.20-8.32 (2H,
m), 8.49 (1H, s), 11.88 (2H, brs) .IR (KBr): 3121, 2938, 1671, 1628, 1346, 1169 cm ^-1 .

Example 229 1- (6-chloronaphthalene-2-sulfonyl) -4- [trans-4- (2-
[Imidazolinylamino) cyclohexane-1-ylcarbonyl] piperazine hydrochloride 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (100 mg), triethylamine (120 mg)
2-methylthioimidazoline (116 m
g) was added and refluxed for 48 hours. The reaction mixture is concentrated and silica gel column chromatography (dichloromethane / 1
Purification was performed using 0% ammonia-containing methanol (10/1), and the title compound (30 mg) was obtained as a colorless solid as a hydrochloride salt with a 4N hydrochloric acid-ethyl acetate solution. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.40 (4H, m), 1.55 (2H,
m), 1.82 (2H, m), 2.48 (1H, m), 2.95 (4H, m), 3.23
(1H, m), 3.55 (8H, m), 7.72 (1H, d, J = 8.8Hz), 7.80
(1H, d, J = 8.8Hz), 8.16 (1H, d, J = 8.8Hz), 8.20-8.3
2 (2H, m), 8.50 (1H, s) .IR (KBr): 3121, 3032, 2944, 1672, 1628, 1346, 1167
cm ^-1 .

Example 230 1- (6-chloronaphthalene-2-sulfonyl) -4- [trans-4- (1,1
2,4-Triazol-4-yl) cyclohexane-1-ylcarbonyl] piperazine 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
A solution of 4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (200 mg) and N, N-dimethylformamide azine dihydrochloride (120 mg) in pyridine (10 ml) was refluxed for 48 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / 10% ammonia-containing methanol = 10/1) to give the title compound (120 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.95 (6H, m), 2.24 (2H,
m), 2.49 (1H, m), 3.10 (4H, m), 3.63 (2H, m), 3.73
(2H, m), 4.07 (1H, m), 7.60 (1H, dd, J = 1.8, 8.8H
z), 7.75 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.97 (3H,
m), 8.18 (2H, s), 8.31 (1H, s) .IR (KBr): 1634, 1454, 1345, 1331, 1163 cm ^-1 .

Example 231 1- (7-Chloro-2H-benzopyran-3-sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (7-chloro- Using 2H-benzopyran-3-sulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (63 mg), colorless in the same manner as in Example 46. The title compound (110 mg) was obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s),
3.32 (4H, m), 3.78 (4H,
m), 4.88 (2H, d, J = 0.6H
z), 6.94 (1H, d, J = 1.8H
z), 7.00 (1H, dd, J = 1.8,
8.0 Hz), 7.13 (1H, d, J = 8.
0 Hz), 7.25 (1H, s), 7.76
(2H, d, J = 6.0 Hz), 8.73 (2
H, d, J = 6.0 Hz). IR (KBr): 1634, 1599, 142
4, 1348, 1327, 1256, 1157
cm ^-1 .

Example 232 1- (6-Chloro-2H-benzopyran-3-sulfonyl) -4-
[4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (6-chloro-2H-benzopyran-3-sulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (4 Using -pyridyl) -5-thiazolecarboxylic acid (63 mg), the title compound (121 mg) was obtained as colorless crystals in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.33 (4H, m), 3.7
8 (4H, m), 4.88 (2H, d, J = 1.0Hz), 6.86 (1H, d, J =
8.8Hz), 7.16-7.30 (3H, m), 7.76 (2H, d, J = 6.2Hz),
8.73 (2H, d, J = 6.2Hz). IR (KBr): 1626, 1480, 1429, 1346, 1157 cm ^-1 .

Example 233 1- (5-Chloro-2H-benzopyran-3-sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (5-chloro- Using 2H-benzopyran-3-sulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (63 mg), colorless in the same manner as in Example 46. The title compound (118 mg) was obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.34 (4H, m), 3.7
9 (4H, m), 4.86 (2H, d, J = 1.0Hz), 6.84 (1H, dt, J =
1.0, 8.2Hz), 7.06 (1H, dd, J = 1.0, 8.2Hz), 7.24 (1
H, t, J = 8.2Hz), 7.60 (1H, d, J = 1.0Hz), 7.76 (2H, d,
J = 6.0Hz), 8.73 (2H, d, J = 6.0Hz) .IR (KBr): 1636, 1597, 1449, 1429, 1348, 1325, 1159
cm ^-1 .

Example 234 1- (4-chlorobenzoylmethanesulfonyl) -4- [4-methyl
-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (4-chlorobenzoylmethanesulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (65 mg) and colorless crystals of the title compound (126 mg) were obtained in the same manner as in Example 46. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 3.43 (4H, m), 3.7
3 (4H, m), 4.58 (2H, s), 7.51 (2H, d, J = 8.6Hz), 7.
78 (2H, d, J = 6.0Hz), 7.97 (2H, d, J = 8.6Hz), 8.73 (2
H, d, J = 6.0Hz) .IR (KBr): 1684, 1632, 1591, 1429, 1348, 1279, 1163
cm ^-1 .

Example 235 1- [4- (2-Aminoimidazol-1-yl) benzoyl] -4- (6
-Chloronaphthalene-2-sulfonyl) piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (347 mg) and 4- (2-aminoimidazole-1-yl)
Using a mixture of benzoic acid and 4- (1-tert-butoxycarbonyl-2-imidazolylamino) benzoic acid in a ratio of 1: 3 (228 mg) in the same manner as in Example 46, the mixture was subjected to column separation. Then, the title compound (138 mg) was obtained as colorless crystals as a hydrochloride salt in an ethyl acetate solution of hydrochloric acid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.08 (4H, brs), 3.81 (4H, m),
7.12 (1H, d, J = 2.0Hz), 7.20 (1H, d, J = 2.0Hz), 7.5
4 (4H, s), 7.70-7.87 (4H, m), 8.18 (1H, d, J = 8.6H
z), 8.24-8.34 (2H, m), 8.51 (1H, s), 12.42 (1H,
s) .IR (KBr): 3077, 1655, 1630, 1611, 1439, 1346, 133
1, 1283, 1165 cm ^-1 .

Example 236 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (2-imidazolylamino) benzoyl] piperazine hydrochloride 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (347 mg) and 4- (2-aminoimidazole-1-yl)
Using a mixture of benzoic acid and 4- (1-tert-butoxycarbonyl-2-imidazolylamino) benzoic acid in a ratio of 1: 3 (228 mg) in the same manner as in Example 46, the mixture was subjected to column separation. Then, the title compound (49 mg) was obtained as colorless crystals as a hydrochloride salt in an ethyl acetate solution of hydrochloric acid. ¹ H-NMR (DMSO-d ₆ ) δ: 3.06 (4H, brs), 3.59 (4H, br
s), 7.18 (2H, s), 7.20 (2H, d, J = 8.8Hz), 7.35 (2H,
d, J = 8.8Hz), 7.73 (1H, dd, J = 2.0, 8.8Hz), 7.82 (1
H, dd, J = 1.8, 8.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.23-
8.33 (2H, m), 8.50 (1H, s), 10.60 (1H, s) .IR (KBr): 2909, 1642, 1609, 1346, 1159 cm ^-1 .

Example 237 1- [2- (4-Chlorophenyl) ethinsulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 4-methyl-2- (4- Pyridyl) -5-thiazolecarboxylic acid (72
mg) was refluxed in thionyl chloride (3 ml) for 1 hour. The residue obtained by concentrating the reaction solution was dissolved in dichloromethane (10 ml), 1- [2- (4-chlorophenyl) ethinsulfonyl) piperazine hydrochloride (100 mg) was added, and triethylamine was added.
(90 mg) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (130 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H, s), 3.33 (4H, m), 3.8
6 (4H, m), 7.43 (2H, d, J = 8.8Hz), 7.54 (2H, d, J =
8.8Hz), 7.77 (2H, d, J = 6.0Hz), 8.73 (2H, d, J = 6.0H
z) .IR (KBr): 2182, 1632, 1435, 1360, 1169 cm ^-1 .

Example 238 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (7-chloro-2H-benzopyran
3-Sulfonyl) piperazine hydrochloride 1- (7-chloro-2H-benzopyran-3-sulfonyl) piperazine hydrochloride (200 mg) and trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarboxylic acid (140 mg) In the same manner as in Example 46, the title compound (285 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (2H, m), 1.44 (9H, s), 1.5
5-1.80 (4H, m), 2.09 (2H, m), 2.37 (1H, m), 3.24
(4H, m), 3.42 (1H, m), 3.60 (2H, m), 3.71 (2H, m),
4.38 (1H, brs), 4.87 (2H, s), 6.92 (1H, d, J = 1.8H
z), 6.98 (1H, dd, J = 1.8, 8.0Hz), 7.12 (1H, d, J = 8.0
Hz), 7.22 (1H, s) .IR (KBr): 1694, 1634, 1454, 1157 cm ^-1 .

Example 239 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (7-chloro-2H-benzopyran-3-sulfonyl) piperazine hydrochloride 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4 in the same manner as in Example 76
-(7-Chloro-2H-benzopyran-3-sulfonyl) piperazine
(260 mg) was treated with hydrochloric acid to give the title compound (231
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.50 (4H, m), 1.69 (2H,
m), 1.94 (2H, m), 2.52 (1H, m), 2.95 (1H, m), 3.12
(4H, m), 3.56 (4H, m), 4.95 (2H, s), 7.05 (1H, s),
7.09 (1H, d, J = 8.4Hz), 7.40 (1H, s), 7.46 (1H, d,
J = 8.4Hz), 7.87 (3H, brs) .IR (KBr): 3412, 2920, 1647, 1599, 1337, 1146 cm ^-1 .

Example 240 1- (trans-4-acetimidoylaminocyclohexane-1-
Ylcarbonyl) -4- (7-chloro-2H-benzopyran-3-sulfonyl) piperazine hydrochloride In the same manner as in Example 99, 1- (trans-4-aminocyclohexane-1-ylcarbonyl) -4- ( Using 7-chloro-2H-benzopyran-3-sulfonyl) piperazine hydrochloride (150 mg) and ethylacetimidate hydrochloride (389 mg), the title compound (158 mg) was obtained as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.95 (8H, m), 2.13 (3H,
s), 2.60 (1H, m), 3.13 (4H, brs), 3.57 (4H, brs),
4.10 (1H, m), 4.96 (2H, s), 7.05 (1H, d, J = 1.8Hz),
7.11 (1H, dd, J = 1.8, 8.2Hz), 7.41 (1H, s), 7.47
(1H, d, J = 8.2Hz), 8.59 (1H, brs), 9.07 (1H, brs),
9.41 (1H, m) .IR (KBr): 3231, 3077, 1636, 1601, 1439, 1344, 132
7, 1150 cm ^-1 .

Example 241 1- [trans-4- (N ² -methoxycarbonylacetimidoylamino) cyclohexan-1-ylcarbonyl] -4- (7-chloro-2H-benzopyran-3-sulfonyl) piperazine In the same manner as 214, 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (7-
Using chloro-2H-benzopyran-3-sulfonyl) piperazine hydrochloride (100 mg) and methyl chlorocarbonate (60 mg), the title compound (64 mg) was obtained as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.50 (2H, m), 1.55-1.90 (4
H, m), 2.09 (2H, m), 2.18 (3H, s), 2.43 (1H, m),
3.26 (4H, m), 3.46 (1H, m), 3.61 (2H, m), 3.69 (3
H, s), 3.72 (2H, m), 4.87 (2H, s), 6.92 (1H, d, J =
1.8Hz), 6.98 (1H, dd, J = 1.8, 8.2Hz), 7.12 (1H, d, J
= 8.2Hz), 7.23 (1H, s) .IR (KBr): 3312, 1640, 1601, 1561, 1445, 1260, 1150
cm ^-1 .

Example 242 1- [trans-4- (N ² -ethoxycarbonylacetimidoylamino) cyclohexane-1-ylcarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine As in Example 214 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-
Chloronaphthalene-2-sulfonyl) piperazine (200 mg)
And ethyl chloride (68 mg) to give the title compound (128 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.40 (5H, m), 1.45-1.80 (4
H, m), 2.02 (2H, m), 2.13 (3H, s), 2.36 (1H, m),
3.08 (4H, m), 3.38 (1H, m), 3.59 (2H, m), 3.71 (2
H, m), 4.09 (2H, q, J = 7.0Hz), 7.59 (1H, d, J = 8.4H
z), 7.75 (1H.d.J = 8.4Hz), 7.90-8.00 (3H, m), 8.31
(1H, s), 9.85 (1H, br) .IR (KBr): 3300 (br), 1638, 1601, 1560, 1453, 1346,
1258, 1202, 1165, 1080cm ^-1 .

Example 243 1- [trans-4- (N ² -isopropoxycarbonylacetimidoylamino) cyclohexan-1-ylcarbonyl] -4- (6
-Chloronaphthalene-2-sulfonyl) piperazine In the same manner as in Example 214, 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-
Chloronaphthalene-2-sulfonyl) piperazine (200 mg)
And isopropyl chlorocarbonate (77 mg) to give the title compound (126 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.40 (8H, m), 1.45-1.85 (4
H, m), 2.02 (2H, m), 2.11 (3H, s), 2.35 (1H, m),
3.09 (4H, m), 3.37 (1H, m), 3.59 (2H, m), 3.71 (2
H, m), 4.84 (1H, m), 7.59 (1H, d, J = 8.8Hz), 7.75
(1H, d, J = 8.8Hz), 7.86-8.00 (3H, m), 8.31 (1H, s),
9.89 (1H, br). IR (KBr): 3274 (br), 1649, 1601, 1557, 1441, 1346,
1258, 1165, 1113 cm ^-1 .

Example 244 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (4-styrenesulfonyl) piperazine 1- (4-styrenesulfonyl) piperazine hydrochloride (300 mg)
And trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarboxylic acid (251 mg) using Example 4
In the same manner as in 6, the title compound (462 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (2H, m), 1.43 (9H, s), 1.5
0-1.75 (4H, m), 2.07 (2H, m), 2.30 (1H, m), 3.01
(4H, m), 3.40 (1H, m), 3.57 (2H, m), 3.68 (2H, m),
4.33 (1H, brs), 5.46 (1H, d, J = 11.0Hz), 5.90 (1H,
d, J = 17.6Hz), 6.76 (1H, dd, J = 11.0, 17.6Hz), 7.55
(2H, d, J = 8.4Hz), 7.70 (2H, d, J = 8.4Hz). IR (KBr): 1701, 1640, 1350, 1167 cm ^-1 .

Example 245 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (4-styrenesulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4
-(4-Styrenesulfonyl) piperazine (435 mg) was treated with hydrochloric acid to give the title compound (357 mg) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.50 (4H, m), 1.62 (2H,
m), 1.91 (2H, m), 2.48 (1H, m), 2.88 (5H, m), 3.55
(4H, m), 5.49 (2H, d, J = 11.0Hz), 6.04 (1H, d, J = 18.
0Hz), 6.85 (1H, dd, J = 11.0, 18.0Hz), 7.69 (2H, d,
J = 8.6Hz), 7.75 (2H, d, J = 8.6Hz), 7.90 (3H, brs) .IR (KBr): 3117, 3036, 1617, 1518, 1431, 1346, 127
7, 1165 cm ^-1 .

Example 246 1- (trans-4-acetimidoylaminocyclohexane-1-)
Ylcarbonyl) -4- (4-styrenesulfonyl) piperazine In the same manner as in Example 99, 1- (trans-4-aminocyclohexane-1-ylcarbonyl) -4- (4-styrenesulfonyl) piperazine hydrochloride ( (300 mg) and ethylacetoimidate hydrochloride (896 mg) to give the title compound as colorless crystals.
(166 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, m), 1.50-1.80 (4H,
m), 1.95 (3H, s), 2.07 (2H, m), 2.35 (1H, m), 3.01
(4H, m), 3.46 (1H, m), 3.57 (2H, m), 3.69 (2H,
m), 5.47 (1H, d, J = 11.0Hz) l, 5.90 (1H, d, J = 17.6H)
z), 6.76 (1H, dd, J = 11.0, 17.6Hz), 7.55 (2H, d, J =
8.4Hz), 7.70 (2H, d, J = 8.4Hz) .IR (KBr): 3300, 2940, 1632, 1449, 1433, 1348, 1165
cm ^-1 .

Example 247 1- (trans-4-bisethoxycarbonylguanidinocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2
-Sulfonyl) piperazine 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
To a solution of 4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride (1.0 g) and triethylamine (1.07 g) in ethanol (30 ml) was added N, N'-bis (tert-butoxycarbonyl) -S- Methyl isothiourea (922 mg) was added, and the mixture was refluxed for 48 hours. The reaction solution was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (612 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (2H, m), 1.29 (3H, t, J = 6.
8Hz), 1.30 (3H, t, J = 6.8Hz), 1.50-1.75 (4H, m), 2.
10 (2H, m), 2.32 (1H, m), 3.07 (4H, m), 3.58 (2H, m
m), 3.70 (2H, m), 3.98 (1H, m), 4.12 (2H, q, J = 6.8
Hz), 4.20 (2H, q, J = 6.8Hz), 7.59 (1H, dd, J = 2.2,
8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz), 7.86-8.00 (3
H, m), 8.18 (1H, d, J = 7.6Hz), 8.30 (1H, s), 11.74
(1H, s) .IR (KBr): 3328, 1726, 1640, 1431, 1264, 1165 cm ^-1 .

Example 248 1- (trans-4-ethoxycarbonylguanidinocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (trans-4-bisethoxycarbonylguanidinocyclohexane- 1-ylcarbonyl) -4- (6-chloronaphthalene-2
(Sulfonyl) piperazine hydrochloride (180 mg) in ethanol
(4 ml) and a 1N aqueous solution of sodium hydroxide (4 ml) were added to a solution of tetrahydrofuran (4 ml), followed by stirring at room temperature for 15 hours. The reaction was concentrated and extracted with dichloromethane,
After washing with water and drying, the solvent was concentrated to give the title compound (161 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, m), 1.26 (3H, t, J = 7.
0Hz), 1.50-1.80 (4H, m), 2.08 (2H, m), 2.35 (1H,
m), 3.08 (4H, m), 3.24 (1H, m), 3.58 (2H, m), 3.69
(2H, m), 4.06 (2H, q, J = 7.0Hz), 6.10 (2H, br), 7.5
9 (1H, dd, J = 1.8, 8.8Hz), 7.75 (1H, dd, J = 1.8, 8.8Hz)
Hz), 7.88-7.98 (3H, m), 8.30 (1H, s) .IR (KBr): 3380, 1626, 1588, 1346, 1306, 1277, 1165
cm ^-1 .

Example 249 1- (5-Chlorobenzofuran-2-sulfonyl) -4- [4-methyl-
2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (5-chlorobenzofuran-2-sulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid Using the acid (65 mg) and in the same manner as in Example 46, the title compound (108 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s),
3.38 (4H, m), 3.78 (4H,
m), 7.35 (1H, d, J = 0.8H
z), 7.47 (1H, dd, J = 1.8,
8.8 Hz), 7.53 (1H, d, J = 8.
8Hz), 7.70 (1H, m), 7.77
(2H, m), 8.75 (2H, brs). IR (KBr): 1636, 1597, 144
1, 1368, 1279, 1256, 1165
cm ^-1 .

Example 250 1- (6-Chlorobenzofuran-2-sulfonyl) -4- [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (6-chlorobenzofuran-2- Using colorless crystals of the title compound (110 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 3.37 (4H, m), 3.7
8 (4H, m), 7.35-7.42 (2H, m), 7.61 (1H, d, J = 2.0H
z), 7.64 (1H, d, J = 8.8Hz), 7.75 (2H, d, J = 6.2Hz),
8.72 (2H, d, J = 6.2Hz). IR (KBr): 1634, 1462, 1445, 1368, 1167 cm ^-1 .

Example 251 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4- (5-chlorobenzofuran-2-
Using sulfonyl) piperazine 1- (5-chlorobenzofuran-2-sulfonyl) piperazine hydrochloride (200 mg) and trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarboxylic acid (148 mg), Example 46 was used. In the same manner, the title compound as colorless crystals
(214 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (2H, m), 1.43 (9H, s), 1.5
0-1.80 (4H, m), 2.07 (2H, m), 2.30 (1H, m), 3.30
(4H, m), 3.42 (1H, m), 3.60 (2H, m), 3.71 (2H, m),
4.35 (1H, brs), 7.33 (1H, s), 7.44 (1H, dd, J = 1.
8, 8.8Hz), 7.50 (1H, d, J = 8.8Hz), 7.68 (1H, d, J =
1.8Hz). IR (KBr): 3330, 1699, 1645, 1441, 1366, 1165 cm ^-1 .

Example 252 1- (trans-4-aminocyclohexane-1-ylcarbonyl)-
4- (5-chlorobenzofuran-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 76, 1- (trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl) -4
-(5-chlorobenzofuran-2-sulfonyl) piperazine (20
0 mg) was treated with hydrochloric acid to give the title compound (176 mg) as a colorless solid
I got ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.50 (4H, m), 1.64 (2H,
m), 1.91 (2H, m), 2.92 (1H, m), 3.19 (5H, m), 3.57
(4H, m), 7.58 (1H, dd, J = 2.2, 9.0Hz), 7.66 (1H, s),
7.80 (1H, d, J = 9.0Hz), 7.91 (1H, d, J = 2.2Hz), 7.9
8 (3H, brs) .IR (KBr): 2920, 1647, 1443, 1364, 1155, 1127 cm ^-1 .

Example 253 1- (trans-4-acetimidoylaminocyclohexane-1-)
Ylcarbonyl) -4- (5-chlorobenzofuran-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 99, 1- (trans-4-aminocyclohexane-1-ylcarbonyl) -4- (5-chloro Benzofuran
The title compound (104 mg) was obtained as a colorless solid using (-2-sulfonyl) piperazine hydrochloride (160 mg) and ethylacetimidate hydrochloride (428 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.50 (4H, m), 1.63 (2H,
m), 1.84 (2H, m), 2.12 (3H, s), 2.50 (1H, m), 3.19
(4H, m), 3.35 (1H, m), 3.57 (4H, m), 7.59 (1H, dd,
J = 2.2, 9.0Hz), 7.67 (1H, d, J = 0.8Hz), 7.80 (1H,
d, J = 9.0Hz), 7.92 (1H, d, J = 2.2Hz), 8.56 (1H, br
s), 9.04 (1H, brs), 9.36 (1H, m).

Example 254 1- (5-Chloro-1-methylindole-2-sulfonyl) -4- [4-
Methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (5-chloro-1-methylindole-2-sulfonyl) piperazine hydrochloride (228 mg) and 4-methyl-2- (4-pyridyl The title compound (50 mg) was obtained as a colorless solid in the same manner as in Example 46, using) -5-thiazolecarboxylic acid (220 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s),
3.29 (4H, m), 3.78 (4H,
m), 3.96 (3H, s), 7.09 (1
H, s), 7.32 (1H, d, J = 8.8)
Hz), 7.39 (1H, dd, J = 1.8,
8.8 Hz), 7.67 (1H, d, J =
(1.8 Hz), 7.74 (2H, d, J = 6.
0 Hz), 8.71 (2H, d, J = 6.0H)
z). IR (KBr): 1632, 1597, 146
2, 1354, 1154 cm ^-1 .

Example 255 1- (6-Chloronaphthalene-2-sulfonyl) -4-
(4-diisopropylaminomethylbenzoyl) piperidine 4- (4-diisopropylaminomethylbenzoyl)-
A mixture of 1-tritylpiperidine (1.3 g) and 80% aqueous acetic acid (20 ml) was stirred at 80 ° C. for 1 hour. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off to obtain 4- (4-diisopropylaminomethylbenzoyl) piperidine as an oil (1.0 g). This oil (302 mg) in THF (1
0 ml) to the solution was added 6-chloronaphthalene-2-sulfonyl chloride (261 mg), and the mixture was stirred at room temperature for 1 hour.
An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residue was subjected to silica gel chromatography,
Elution with hexane-ethyl acetate (4: 1) gave the title compound (0.15 g). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (12H, d, J = 6.6 Hz), 1.92
(4H, m), 2.62 (2H, m), 2.97 (2H, m), 3.20 (1H, m), 3.6
5 (2H, s), 3.83 (2H, m), 7.43 (2H, d, J = 8.2Hz), 7.58
(1H, m), 7.76 (2H, d, J = 8.2Hz), 7.82 (1H, m), 7.91 (3
H, m), 8,34 (1H, s).

Example 256 1- (3,4-Methylenedioxybenzenesulfonyl)
-4- [4-Methyl-2- (4-pyridyl) thiazole-5-carbonyl] piperazine 1-tert-butoxycarbonyl-4- (3,4-methylenedioxybenzenesulfonyl) piperazine (0.5
To a solution of g) in ethyl acetate (2 ml) was added 4N HCl ethyl acetate (10 ml), and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration to obtain 3,4-methylenedioxybenzenesulfonylpiperazine hydrochloride (0.39 g). Triethylamine (0.05 ml), 4-methyl-2- (4-pyridyl) thiazole-5-carboxylic acid (74 mg) and WS were added to a dichloromethane (3 ml) solution of the crystals (100 mg).
C (70 mg) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract is washed with water,
After drying (MgSO ₄ ), the solvent was distilled off to obtain the title compound as crystals. The crystals were collected by filtration and washed with ether (90
mg). ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s), 3.07 (4H, m),
3.75 (4H, m), 6.12 (2H, s), 6.93 (1H, d, J = 8.2Hz), 7.
17 (2H, s), 7.31 (1H, d, J = 8.2Hz), 7.74 (2H, d, J = 6.2H
z), 8.71 (2H, d, J = 6.2Hz) .IR (KBr): 1626, 1479, 1427, 1342, 1250 cm ^-1 .

Example 257 1- (6-Chloronaphthalene-2-sulfonyl) -4-
[4- (4-pyridyl) benzoyl] -2-piperazinecarboxylate ethyl hydrochloride 2-piperazinecarboxylate ethyl dihydrochloride (231 m
g), 4- (4-pyridyl) benzoic acid (199 mg), H
To a mixture of OBT (191 mg), triethylamine (0.34 ml) and dichloromethane (8 ml) was added WSC (230 m
g) was added and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residue was washed with THF (5
ml), triethylamine (0.17 ml) and 6-chloronaphthalene-2-sulfonyl chloride were added, and the mixture was stirred at room temperature for 2 hours. Evaporate the solvent, add water,
Extracted with ethyl acetate. The extract is washed with water and dried (MgSO
₄ ) After that, the solvent was distilled off. The residue was subjected to silica gel chromatography, eluted with hexane-acetone (1: 1), concentrated, and dissolved in ethyl acetate (5 ml). 4N
HCl-ethyl acetate (1 ml) was added, and the precipitated crystals were collected by filtration (180 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (3H, br), 3.38 (2H,
m), 3.79 (4H, m), 3.84 (2H, q, J = 7.0Hz), 4.78 (1H, b
r), 7.49 (2H, d, J = 7.8Hz), 7.70 (1H, dd, J = 1.8, 8.8H
z), 7.86 (1H, d, J = 8.8Hz), 8.06 (2H, d, J = 7.8Hz), 8.
14 (1H, d, J = 6.6Hz), 8.22 (3H, m), 8.33 (2H, d, J = 6.4H
z), 8.53 (1H, s), 8.96 (2H, d, J = 6.4Hz).

Example 258 1- (6-chloronaphthalene-2-sulfonyl) -4-
[4- (4-Pyridyl) benzoyl] -2-piperazinecarboxylic acid 1- (6-chloronaphthalene-2-sulfonyl) -4-
Ethyl (4-pyridyl) benzoyl-2-piperazinecarboxylate hydrochloride (100 mg), THF-EtOH
(1: 1, 2 ml) and 1N NaOH (1.3 ml) was stirred at room temperature for 20 minutes and 1N HCl (1.3 ml) was added.
l) was added, and water was further added to obtain the title compound (38 m).
g). ¹ H-NMR (DMSO-d ₆ ) δ: 3.35 (5H, m), 3.80 (1H, m),
4.66 (1H, brs), 7.41 (2H, d, J = 8.2Hz), 7.65-7.80 (6
H, m), 8.11-8.25 (3H, m), 8.51 (1H, s), 8.66 (2H, d,
J = 6Hz).

Example 259 1- (6-chloronaphthalene-2-sulfonyl) -4-
[2- (2-tert-butoxycarbonylamino-5)
-Pyridyl) -4-methylthiazole-5-carbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride and 2- (2-tert-butoxycarbonylamino-5-pyridyl) -4-methyl- The title compound was obtained from 5-thiazolecarboxylic acid in the same manner as in Example 46. ¹ H-NMR (DMSO-d ₆ ) δ: 1.49 (9H, s), 2.30 (3H, s),
3.08 (4H, brs), 3.65 (4H, brs), 7.71 (1H, d, J = 9.2H
z), 7.81 (1H, d, J = 8.6Hz), 7.91 (1H, d, J = 8.8Hz), 8.
15-8.29 (4H, m), 8.50 (1H, s), 8.72 (1H, d, J = 2.2Hz),
10.13 (1H, s).

Example 260 1- (6-Chloronaphthalene-2-sulfonyl) -4-
[2- (2-Amino-5-pyridyl) -4-methylthiazole-5-carbonyl] piperazine 1- (6-chloronaphthalene-2-sulfonyl) -4-
(2- (2-tert-butoxycarbonylamino-5
-Pyridyl) -4-methylthiazole-5-carbonyl) piperazine (180 mg) and trifluoroacetic acid (1.0 m
The mixture of 1) was stirred at room temperature for 1 hour and concentrated. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off.
The residue was crystallized from ethyl acetate to give the title compound, ethyl acetate sorbate (134 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.18 (3H, t, J = 7.0 Hz), 1.9
9 (3H, s), 2.25 (3H, s), 3.06 (4H, br), 3.64 (4H, br),
4.02 (2H, q, J = 7.0Hz), 6.48 (1H, d, J = 8.6Hz), 6.56 (2
H, s), 7.71 (1H, d, J = 8.8Hz), 7.80 (2H, m), 8.17 (1H,
s), 8.50 (1H, s).

Example 261 1- (trans-4-tert-butoxycarbonylaminomethylcyclohexane-1-carbonyl) -4-
(6-Chloronaphthalene-2-sulfonyl) piperazine Same as in Example 46 from 1- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride and trans-4-tert-butoxycarbonylaminomethylcyclohexane-1-carboxylic acid The title compound was obtained by the method. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (2H, m), 1.42 (9H, s),
1.30-1.81 (6H, m), 2.29 (1H, m), 2.91-3.09 (6H, m),
3.59 (2H, brs), 3.69 (2H, brs), 4.52 (1H, s), 7.58 (1
H, dd, J = 1.8, 8.8Hz), 7.90 (3H, m), 8.30 (1H, s).

Example 262 1- (trans-4-aminomethylcyclohexane-
1-carbonyl) -4- (6-chloronaphthalene-2-
Sulfonyl) piperazine hydrochloride 1- (trans-4-tert-butoxycarbonylaminomethylcyclohexane-1-carbonyl) -4-
(6-Chloronaphthalene-2-sulfonyl) piperazine (0.7 g) and 4N HCl-ethyl acetate (10 ml)
Was stirred at room temperature for 1 hour, and the precipitated title compound was collected by filtration (0.48 g). ¹ H-NMR (DMSO-d ₆ ) δ: 0.89-1.76 (8
H, m), 2.45 (1H, m), 2.59
(2H, m), 2.96 (4H, b), 3.5
5 (4H, br), 3.76 (1H, brs),
7.71 (1H, dd, J = 1.8, 8.8H
z), 7.79 (1H, dd, J = 1.8,
8.8 Hz), 7.89 (2H, br), 8.1
6 (1H, d, J = 8.8 Hz), 8.26 (1
H, d, J = 8.8 Hz), 8.50 (1H,
s).

Example 263 1- (trans-4-guanidinomethylcyclohexane-1-carbonyl) -4- (6-chloronaphthalene-
2-sulfonyl) piperazine hydrochloride 1- (trans-4-aminomethylcyclohexane-
1-carbonyl) -4- (6-chloronaphthalene-2-
Sulfonyl) piperazine hydrochloride (200 mg), N ¹ , N ²
A mixture of -bis-tert-butoxycarbonyl-S-methylisothiourea (131 mg) and ethanol (2 ml) was refluxed for 1 hour. The solvent was distilled off, and the precipitated crystals were collected by filtration. This crystal was treated with 4N HCl-ethyl acetate (4m
1) and stirred at room temperature for 15 hours. The solvent was distilled off, and the precipitated crystals were collected by filtration to give the title compound (120 m
g). ¹ H-NMR (DMSO-d ₆ ) δ: 0.93-1.75 (8H, m), 2.41 (3
H, m), 2.95 (4H, br), 3.55 (4H, br), 4.43 (1H, br),
7.70 (1H, d, J = 8.8Hz), 7.79 (1H, d, J = 8.8Hz), 8.16 (1
H, d, J = 8.8Hz), 8.42 (1H, d, J = 9.6Hz), 8.49 (1H, s).

Example 264 1- [4- (2-Amidino-1-ethenyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 103, 6-chloronaphthalene
The title compound was obtained as colorless crystals using (-2-sulfonyl) -1- [4- (2-cyano-1-ethenyl) benzoyl] piperazine. ¹ H-NMR (DMSO-d ₆ ) δ: 3.07 (4H, brs), 3.30-3.90 (4
H, m), 6.80 (1H, d, J = 16.4Hz), 7.44 (2H, d, J = 8.0H
z), 7.60 (2H, d, J = 8.0Hz), 7.73 (1H, dd, J = 8.8, 2.
2Hz), 7.79-7.92 (2H, m), 8.19 (1H, d, J = 8.8Hz), 8.
24-8.32 (2H, m), 8.50 (1H, s), 8.76 (2H, brs), 9.19
(2H, brs). IR (KBr): 3056, 1684, 1609, 1343, 1287, 1161, 725,
579 cm ^-1 .

Example 265 1- [4- (2-Amidinoethyl) benzoyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine hydrochloride In the same manner as in Example 103, 4- (6-chloro) Naphthalene
The title compound was obtained as colorless crystals using (-2-sulfonyl) -1- [4- (2-cyanoethyl) benzoyl] piperazine. ¹ H-NMR (DMSO-d ₆ ) δ: 2.61-2.73 (2H, m), 2.89-3.01
(2H, m), 3.05 (4H, brs), 3.55 (4H, br), 7.27 (4H,
s), 7.72 (1H, dd, J = 8.6, 2.2Hz), 7.82 (1H, dd, J =
8.6, 1.8Hz), 8.18 (1H, d, J = 8.8Hz), 8.24-8.30 (2H,
m), 8.49 (1H, s), 8.59 (2H, brs), 9.04 (2H, brs) .IR (KBr): 3059, 1686, 1620, 1348, 1167, 727, 581 c
m ^-1 .

Example 266 1- (7-Chloro-2H-benzothiopyran-3-sulfonyl) -4- [4
-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (7-chloro-2H-benzothiopyran-3-sulfonyl) piperazine hydrochloride (100 mg) and 4-methyl-2- (4-pyridyl )-Five-
Example 46 was prepared using thiazolecarboxylic acid (60 mg).
In the same manner as in the above, the title compound (108 mg) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.31 (4H, m), 3.6
2 (2H, d, J = 0.6Hz), 3.78 (4H, m), 7.13-7.36 (4H,
m), 7.79 (2H, m), 8.72 (2H, m) .IR (KBr): 1630, 1435, 1345, 1327, 1285, 1258, 1155
cm ^-1 .

Example 267 1- (7-Chlorochromone-3-sulfonyl) -4- [4-methyl-2- (4
-Pyridyl) -5-thiazolecarbonyl] piperazine 1- (7-chlorochromone-3-sulfonyl) piperazine hydrochloride
(100 mg) and 4-methyl-2- (4-pyridyl) -5-thiazolecarboxylic acid (60 mg) to give the title compound (123 mg) as colorless crystals in the same manner as in Example 46. . ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 3.52 (4H, m), 3.7
6 (4H, m), 7.50 (1H, dd, J = 1.8, 8.4Hz), 7.59 (1H,
d, J = 1.8Hz), 7.76 (2H, d, J = 6.2Hz), 8.18 (1H, d, J
= 8.4Hz), 8.66 (1H, s), 8.72 (2H, d, J = 6.2Hz) .IR (KBr): 1655, 1628, 1615, 1425, 1360, 1348, 133
7, 1283, 1171, 1159 cm ^-1 .

Example 268 1- [trans-4- (N ² -pivaloyloxymethoxycarbonylacetimidoylamino) cyclohexane-1-ylcarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine In the same manner as in Example 218, 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2-sulfonyl) piperazine (500 mg) and O
-(Pivaloyloxymethoxycarbonyl) -4-nitrophenol (343 mg) to give the title compound as colorless crystals
(271 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (9H, s), 1.32 (2H, m), 1.5
0-1.80 (4H, m), 2.04 (2H, m), 2.14 (3H, s), 2.34
(1H, m), 3.09 (4H, m), 3.40 (1H, m), 3.60 (2H, m),
3.71 (2H, m), 5.76 (2H, s), 7.60 (1H, dd, J = 1.6,
8.8Hz), 7.76 (1H, dd, J = 1.8, 8.8Hz), 7.88-7.97 (3H,
m), 8.31 (1H, s) .IR (KBr): 1746, 1694, 1645, 1632, 1557, 1454, 134
8, 1258, 1165 cm ^-1 .

[0259] Example 269 1- [trans-4- [N 2 - (5- methyl-2-oxo-1,3-Jiokisorenin-4-yl-methoxycarbonyl) acetimidoyl amino] cyclohexane-1-ylcarbonyl] -4- (6-chloronaphthalene-2-sulfonyl) piperazine 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4- (6-chloronaphthalene-2) in the same manner as in Example 218 -Sulfonyl) piperazine (500 mg) and O
Reaction of-(5-methyl-2-oxo-1,3-dioxorenin-4-ylmethoxycarbonyl) -4-nitrophenol (341 mg) gave the title compound (363 mg) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (2H, m), 1.50-1.80 (4H,
m), 2.08 (2H, m), 2.13 (3H, s), 2.14 (2H, s), 2.38
(1H, m), 3.09 (4H, m), 3.40 (1H, m), 3.60 (2H,
m), 3.70 (2H, m), 4.81 (2H, s), 7.60 (1H, dd, J = 2.
0, 8.8Hz), 7.76 (1H, dd, J = 2.0, 8.8Hz), 7.87-7.96
(3H, m), 8.31 (1H, s), 9.80 (1H, br) .IR (KBr): 1819, 1645, 1634, 1597, 1559, 1435, 134
6, 1258, 1198, 1163 cm ^-1 .

Example 270 1- (7-Chloro-4-hydroxyquinoline-3-sulfonyl) -4-
[4-Methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (7-chloro-4-hydroxyquinoline-3-sulfonyl) piperazine hydrochloride (500 mg) and 4-methyl-2- ( 4-pyridyl) -5-
Example 46 was prepared using thiazolecarboxylic acid (302 mg).
In the same manner as in the above, the title compound (589 mg) was obtained as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 2.39 (3H, s), 3.35 (4H, m),
3.60 (4H, m), 7.48 (1H, dd, J = 1.8, 8.8Hz), 7.73 (1
H, d, J = 1.8Hz), 7.84 (2H, d, J = 6.0Hz), 8.15 (1H,
d, J = 8.8Hz), 8.55 (1H, s), 8.70 (2H, d, J = 6.0Hz). IR (KBr): 1620, 1601, 1460, 1321, 1281, 1159 cm ^-1 .

Example 271 1- (4,7-Dichloroquinoline-3-sulfonyl) -4- [4-methyl-
2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 1- (7-chloro-4-hydroxyquinoline-3-sulfonyl) -4-
A suspension of [4-methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine (200 mg) in phosphoryl chloride (6 ml) was refluxed for 2 hours. The reaction solution is concentrated, ice water is added to the residue, and an aqueous solution of sodium hydrogen carbonate is added.The mixture is extracted with dichloromethane, dried and concentrated to give the title compound as brown crystals
(223 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H, s), 3.47 (4H, m), 3.7
8 (4H, m), 7.74 (1H, dd, J = 2.0, 9.0Hz), 7.77 (2H,
d, J = 6.0Hz), 8.21 (1H, d, J = 2.0Hz), 8.38 (1H, d, J
= 9.0Hz), 8.72 (2H, d, J = 6.0Hz) .IR (KBr): 1634, 1601, 1470, 1435, 1362, 1339, 116
7, 1152 cm ^-1 .

Example 272 1- (7-Chloroquinoline-3-sulfonyl) -4- [4-methyl-2- (4
-Pyridyl) -5-thiazolecarbonyl] piperazine 1- (4,7-dichloroquinoline-3-sulfonyl) -4- [4-methyl-
2- (4-pyridyl) -5-thiazolecarbonyl] piperazine
(200 mg) and a suspension of zinc dust (250 mg) in acetic acid (6 ml) were stirred at 80 ° C. for 2 hours. The reaction solution was concentrated, the residue was dissolved in dichloromethane-methanol, and insolubles were removed by filtration. The filtrate was concentrated, washed with 1 N hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water, and dried to obtain the title compound (43 mg) as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ: 2.39 (3H, s), 3.10-3.70 (4H,
m), 7.45 (1H, d, J = 8.4Hz), 7.71 (1H, s), 7.85 (2H,
d, J = 6.0Hz), 8.14 (1H, d, J = 8.4Hz), 8.53 (2H, s),
8.70 (2H, d, J = 6.0Hz). IR (KBr): 1620, 1593, 1524, 1460, 1348, 1157, 1136
cm ^-1 .

Example 273 1- (5-Chlorobenzo [b] thiophen-2-sulfonyl) -4- [4-
Methyl-2- (4-pyridyl) -5-thiazolecarbonyl] piperazine 5-chlorobenzo [b] thiophene (245 mg) in THF (5 ml)
1.6M n-butyllithium hexane solution (1.0 m
l) was added under ice-cooling, and the mixture was stirred for 10 minutes. This solution was added to a solution of sulfuryl chloride (0.241 ml) in hexane (5 ml) under ice-cooling, and the mixture was stirred for 1 hour. Water was added to the reaction solution, which was extracted with ether. The extract was added to a mixture of 1-Boc-piperazine (298 mg), an aqueous solution of sodium hydrogen carbonate (5 ml) and ethyl acetate (5 ml), and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed with brine, dried and concentrated. The residue obtained is purified by silica gel column chromatography (hexane:
The product was purified by ethyl acetate = 3: 1). The resulting 1- (tert
To a solution of (butoxycarbonyl) -4- (5-chlorobenzo [b] thiophen-2-sulfonyl) piperazine (68 mg) was added 4N hydrochloric acid in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 1 hour.
After concentrating the reaction solution, it was dissolved in DMF (5 ml), and 4-methyl-2-
(4-Pyridyl) -5-thiazolecarboxylic acid (44 mg), triethylamine (0.028 ml), HOBt (31 mg) and WSC hydrochloride (38 mg) were added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction solution, the organic layer was separated, and washed with water and saturated saline. The crystals obtained after drying and concentration were washed with ethyl acetate and ether to give the title compound as colorless crystals (33 mg)
I got ¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.24 (4H, t, J = 4.
9Hz), 3.75-3.85 (4H, m), 7.51 (1H, dd, J = 8.8, 2.2H
z), 7.72-7.77 (3H, m), 7.83 (1H, d, J = 8.8Hz), 7.91
(1H, d, J = 1.8Hz), 8.72 (2H, d, J = 6.2Hz). IR (KBr): 1632, 1435, 1283, 1159, 945, 725 cm ^-1 .

Experimental Example 1 Inhibition of human activated blood coagulation factor X (FXa) Experimental method: 0.05M Tris buffer (pH 8.3) containing 0.145M salt and 2mM calcium chloride in cuvette
225 μl, 5 μl of sample (dissolve test compound in dimethyl sulfoxide) and human FXa (0.3 unit / m
l) After adding 10 μl and reacting at 37 ° C. for 10 minutes,
Add 10 μl of substrate (3 mM, S-2765) and add
The reaction was performed at 10 ° C. for 10 minutes. Then, 50% acetic acid aqueous solution 25μ
The reaction was stopped by adding 1
The change in absorbance at 5 nm was measured, and the concentration (IC ₅₀ ) that inhibited the FXa action by 50% was determined. Experimental results: [Table 1] shows the IC ₅₀ . From this, it is clear that the compound of the present invention exhibits an FXa inhibitory action.

[Table 1]

Experimental Example 2 (1) In Vitro Coagulation Time Measuring Method (a) 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). 3 μl of the drug was added to 97 μl of human normal plasma (fresh human plasma FFP, Sekisui Chemical Co., Ltd.) 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). The clotting time doubled concentration was calculated based on the clotting time when DMSO was added instead of the drug.

(B) Method of measuring intrinsic coagulation time (APTT) Measurement was performed using an automatic blood coagulation time measuring apparatus (STAcompact, DIAGNOSTICA STAGO) using STA-APTT-LT (DIAGNOSTICA STAGO). 3 μl of the drug was added to 97 μl of human normal plasma (fresh human plasma FFP, Sekisui Chemical). 50 μl of the active partial thromboplastin solution was added to 50 μl of plasma, and 37
Pre-warmed at 4 ° C. for 4 minutes. 50 μl of a 20 mmol / l CaCl ₂ solution was added and the time to coagulation was measured. The drug was used after dissolving in DMSO. Coagulation time 2-fold extended concentration is D instead of drug
It was calculated based on the coagulation time when MSO was added.

(C) Thrombin time (TT) measuring method Automatic blood coagulation time measuring apparatus (Biomatic B10, Sarstedt)
It measured using. Thrombin from human plasma (Sigma)
Was dissolved in distilled water to give 2.3 NIH units / ml.
97μl of normal human plasma (fresh human plasma FFP, Sekisui Chemical)
Was added thereto, and the mixture was pre-warmed at 37 ° C. for 3 minutes. To 100 μl of the above plasma, 200 μl of a thrombin solution was added, and the time until 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.

(2) Ex vivo clotting time measurement method (mouse) (a) Intravenous administration Male ICR mice (25-35 g, Slc) were used. Under anesthesia with pentobarbital (50 mg / kg, ip), the drug was administered once via the tail vein at a volume of 5 ml / kg. 5 minutes after administration, 3.8% sodium citrate (titral,
(Yamanouchi Pharmaceutical) 0.8 ml of blood was collected at 1/10 volume 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. Coagulation time was measured using PT-Test Wako (Wako Pure Chemical Industries) and an automatic blood coagulation time measurement 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.

(B) Oral administration Male ICR mice (25-35 g, Slc) were used. The drug was orally administered to mice fasted for 12 hours or more at a volume of 5 ml / kg. One hour after administration, pentobarbital (50 mg / k
g, ip) Blood was collected from the abdominal aorta under anesthesia. Drugs
The suspension was used 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.

(3) Ex vivo clotting time measurement method (rat) (a) Oral administration Male Sprague-Dawley rat (250-350 g, CLEA Japan)
It was used. 5ml / kg drug in rats fasted for more than 12 hours
Was administered by gavage at a volume of. 2 hours after administration, under anesthesia with pentobarbital (50 mg / kg, ip), 2 ml of blood was collected from the abdominal aorta with 1/10 volume of 3.8% sodium citrate (Citral, Yamanouchi Pharmaceutical), and centrifuged at 3000 rpm for 15 minutes to obtain plasma. Was. 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. Coagulation time was measured using PT-Test Wako (Wako Pure Chemical Industries) and an automatic blood coagulation time measurement device (STA compac
t, DIAGNOSTICA STAGO). 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. The drug was used by suspending it in 0.5% methylcellulose, and the control group received 0.5% methylcellulose instead of the drug.

(B) Intravenous administration Male Sprague-Dawley rats (250-350 g, CLEA Japan)
It was used. Under anesthesia with pentobarbital (50 mg / kg, ip), the drug was administered once via the tail vein at a volume of 5 ml / kg. Five minutes after the administration, 2 ml of blood was collected from the abdominal aorta with 1/10 volume of 3.8% sodium citrate (Citral, Yamanouchi Pharmaceutical), and centrifuged at 3000 rpm for 15 minutes to obtain plasma. 50 μl of the above plasma
Of the rabbit brain-derived tissue thromboplastin solution
After adding 0 μl, the time until coagulation was measured. The clotting time was measured using an automatic blood clotting time measuring device (STA compact, DIAGNOSTICA STAGO) using PT-Test Wako (Wako Pure Chemical Industries, Ltd.). 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.

(4) Arteriovenous shunt method (rat) (a) Oral administration The method of Umetsu et al. (Thromb. Haemostas., 39 : 74-83, 197)
According to 8). Male Sprague-Dawley rats (250-350
g, Clea Japan). The drug was orally administered to rats fasted for 12 hours or more at a volume of 5 ml / kg. Administration 2
After an hour, an extracorporeal circuit of a polyethylene tube with a silk thread was formed between the left jugular vein and the right jugular vein under anesthesia with pentobarbital (50 mg / kg, ip). To prevent blood coagulation, the tube was previously filled with physiological saline containing heparin (50 U / ml). The blood is circulated for 15 minutes, during which the wet weight of the thrombus adhering to the silk thread is measured using an analytical balance with a windshield (BP110S,
Satorius). The activity of the drug was shown as a ratio (%) of the wet weight of the drug-administered group to the wet weight of the thrombus of the control group. Use the drug suspended in 0.5% methylcellulose,
The control group received 0.5% methylcellulose instead of the drug.

(B) Intravenous administration The method of Umetsu et al. (Thromb. Haemostas., 39 : 74-83, 197)
According to 8). Male Sprague-Dawley rats (250-350
g, Clea Japan). Pentobarbital (50m
g / kg, ip) Under anesthesia, an extracorporeal circuit of a polyethylene tube with a silk thread was created between the left jugular vein and the right jugular vein.
To prevent blood clotting, pre-load heparin (50U /
ml) of saline. Drug 5m from tail vein
A single dose was administered in a volume of 1 / kg, and blood circulation was started 5 minutes after the administration. The blood is circulated for 15 minutes, during which the wet weight of the thrombus adhering to the silk thread is measured using an analytical balance with a windshield (BP110S, Satoriu
s). The activity of the drug was shown as a ratio (%) of the wet weight of the drug-administered group to the wet weight of the thrombus of the control group. The drug was used after being dissolved in physiological saline, and the control group was administered with physiological saline instead of the drug.

[0274]

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 various diseases (thrombosis of arteries and veins, etc.) based on thrombus and infarction
Used advantageously for the prevention and treatment of

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/54 A61K 31/54 C07D 211/62 C07D 211/62 213/56 213/56 213/82 213/82 233/60 233 / 60 233/61 103 233/61 103 239/04 239/04 249/08 513 249/08 513 295/22 295/22 A 401/04 207 401/04 207 233 233 239 239 405 405/04 213 405/04 213 409/04 213 409/04 213 231 231 417/04 211 417/04 211 213 213 241 241 241 417/14 209 417/14 209 213 213

Claims (26)

[Claims] (1) Formula (1) [Wherein, R ¹ represents a hydrocarbon group or a heterocyclic group which may be substituted, and ring A represents a compound of the formula: And a group represented by the formula: X represents a divalent nitrogen-containing heterocyclic group which may be further substituted in addition to the group represented by Is a bond or an optionally substituted alkylene chain; Z is (1) an amino group substituted with an optionally substituted hydrocarbon group; (2) an imidoyl group optionally substituted; or (3) It represents a nitrogen-containing heterocyclic group which may be substituted.
Provided that X is a bond and Z may be substituted 6
When it is a membered aromatic nitrogen-containing heterocyclic group, Y is an optionally substituted divalent hydrocarbon group or divalent unsaturated heterocyclic group. Or a salt thereof. 2. The compound according to claim 1, wherein R ¹ is an optionally substituted hydrocarbon group. 3. The compound according to claim 1, wherein R ¹ is an aryl group optionally substituted with a halogen atom. (4) ring A is a compound of the formula [In the formula, B represents a CH or nitrogen atom, and m and n each represent 2 or 3. The compound according to claim 1, which is a group represented by the formula: 5. The compound according to claim 4, wherein B is a nitrogen atom. 6. The compound according to claim 4, wherein m and n are 2. 7. The compound according to claim 1, wherein Y is an optionally substituted divalent aromatic heterocyclic group. 8. The compound according to claim 1, wherein Y is a phenylene group which may be substituted. 9. The compound according to claim 1, wherein Y is an optionally substituted cyclohexylene group. 10. The compound according to claim 1, wherein Z is an optionally substituted nitrogen-containing heterocyclic group. 11. The compound according to claim 1, wherein Z is an amidino group which may be substituted. 12. The compound according to claim 1, wherein Z is a guanidino group which may be substituted. 13. Z is (1) a mono- or di-C _1-6 alkylamino in which the alkyl moiety may be substituted by phenyl, (2) guanidino, (3) formimidoylamino, (4) aceto The compound according to claim 1, which is imidoylamino or (5) piperidino. 14. Z is a compound of the formula -N (R ")-C (R ') = NR or -C (R') = NR wherein R" is hydrogen or _C1-6.
R is hydrogen, C _1-6 alkyl group, C _1-6 alkanoyl group or benzoyl group, R ′ is hydrogen, C
_1-6 alkyl group, C _1-6 alkanoyl group, benzoyl group, C _1-6 alkoxy group or C _1-6 alkyl group, C
_1-6 represents an amino group which may have 1 or 2 substituents selected from an alkanoyl group and a benzoyl group]]. 15. Z is a compound of the formula -NH-C (R ') = NH or-
C (R ′) ＝ NH wherein R ′ is a C _1-6 alkyl group or C
_{A 1-6} alkyl group, a C _1-6 alkanoyl group and an amino group which may have 1 or 2 substituents selected from a benzoyl group]. . 16. R ¹ is (1) a C _1-10 alkyl group, (2)
C _2-6 alkenyl group, (3) C _2-6 alkynyl group, (4)
A C _6-14 aryl group or (5) a heteroatom selected from oxygen, sulfur and nitrogen other than carbon atom 1
(I) a 5- to 6-membered aromatic monocyclic heterocyclic group, (ii) an 8- to 12-membered fused aromatic heterocyclic group, and (iii) a 3- to 8-membered saturated or A heterocyclic group selected from unsaturated non-aromatic heterocyclic groups;
Groups represented by-(5) are (a) C _1-6 alkoxy, halogen, C _1-6 alkyl, amino, hydroxy,
Cyano or amidino optionally substituted by a C _1-6 alkyl group, (b) C _1-6 alkoxy, halogen, C _1-6 alkyl, amino, hydroxy, optionally substituted by cyano or amidino C _{6 -14} aryl group, (c) each containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom, and each represented by C _1-6 alkyl, C _1-6 alkanoyl or benzoyl Optionally substituted (i) a 5- to 6-membered aromatic monocyclic heterocyclic group, (ii) an 8- to 12-membered fused aromatic heterocyclic group and (iii) a 3- to 8-membered saturated or unsaturated group A heterocyclic group selected from the non-aromatic heterocyclic groups of (d) C _1-6 alkyl, C
_1-6 alkanoyl, benzoyl, optionally halogenated C _1-6 alkoxy-carbonyl, C _1-6 alkylimidoyl, formimidoyl or amino group optionally substituted with amidino, (e) C _{1 -6} alkyl, C _1-6 alkanoyl, benzoyl or optionally halogenated C _1-6 alkoxy optionally - substituted by a carbonyl imidoyl group, (f) C _1-6 alkyl, C _1-6 alkanoyl An amidino group optionally substituted with benzoyl or a C _1-6 alkoxy-carbonyl which may be halogenated, (g) a C _1-6 alkyl, C _1-6 alkanoyl, benzoyl or halogenated Good C
Hydroxy group optionally substituted with _1-6 alkoxy-carbonyl, (h) carboxyl group, (i) C _1-6 alkoxy-carbonyl group, (j) C _1-6 alkyl as substituent, C _1-6 Amino, hydroxy, halogen, nitro, cyano optionally having 1 to 2 substituents selected from alkanoyl and benzoyl, C _1-6 alkyl optionally substituted with 1 to 5 halogen atoms or A C _7-12 aryloxycarbonyl group which may have a C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms, (k) C _1-6 alkyl as a substituent, C _{1 -6} optionally substituted with one or two substituents selected from alkanoyl and benzoyl, amino, hydroxy, halogen, nitro, cyano, C _1-6 optionally substituted with 1 to 5 halogen atoms Alkyl or A C _6-10 aryl-C _1-4 alkoxy-carbonyl group which may have a C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms, (l) a halogen atom, (m ) Cyano, (n) nitro or (o) C
_1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl,
C _7-11 aralkyl and a heterocyclic group (the heterocyclic group contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms, and (i) 5 to 6
Selected from a membered aromatic monocyclic heterocyclic group, (ii) an 8- to 12-membered fused aromatic heterocyclic group and (iii) a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group. Ring A may be substituted with a carbonyl group having one selected substituent, and ring A has the formula Wherein B represents a CH or nitrogen atom, m and n each represent 2 or 3, and ring A is a group represented by the formula: And a group represented by the formula: (A) carboxyl group, (b) C
_1-6 alkoxy-carbonyl group, (c) amino optionally having one or two substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl as substituents,
Hydroxy, halogen, nitro, cyano, 1
To five may have a C _1-6 alkoxy which may be substituted at C _1-6 alkyl or 1-5 halogen atoms substituted with a halogen atom, C _7-12
Amino, hydroxy, halogen, nitro, cyano which may have 1 to 2 substituents selected from aryloxycarbonyl group or (d) substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl ,
C optionally substituted with 1 to 5 halogen atoms
_1-6 alkyl or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms,
Y may be further substituted with a C _6-10 aryl-C _1-4 alkoxy-carbonyl group, and Y is (1) a linear C _1-10
An alkylene group, (2) a C _3-9 cycloalkylene group,
(3) a C _6-10 arylene group, (4) a C _7-10 aralkylene group, (5) a compound containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms.
A 6- or 6-membered divalent aromatic heterocyclic group or (6) a 5- or 6-membered divalent saturated or heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom; And represents an unsaturated non-aromatic heterocyclic group;
Each represents (a) a halogen atom, (b) a cyano group, (c) a C _1-6 alkyl group optionally substituted with halogen, amino, carboxyl or hydroxy, or (d) 1 to 5 X may be substituted with a C _1-6 alkoxy group which may be substituted with a halogen atom, X represents a bond or linear C _1-6 alkylene, and Z represents (1) C _1-10 alkyl. An amino group optionally substituted with one or two substituents selected from a group and a C _6-14 aryl group, (2) a formula —N (R ″) — C (R ′) = NR or — C
(R ′) ＝ NR (wherein, R ″ represents hydrogen or a C _1-6 alkyl group, R represents hydrogen, a C _1-6 alkyl group, a C _1-6 alkanoyl group or a benzoyl group, R ′ Is hydrogen, C _1-6 alkyl group, C _1-6 alkanoyl group, benzoyl group, C
A substituent 1 to 1 selected from a _1-6 alkoxy group or a C _1-6 alkyl group, a C _1-6 alkanoyl group and a benzoyl group;
Represents an amino group which may have 2) or (3) 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to (3) carbon atoms And (a) a halogen atom, (b) an amino group,
(C) halogen, amino, carboxyl or hydroxy substituted optionally C _1-6 alkyl group, (d) carboxyl group, (e) C _1-6 alkoxy - carbonyl group, C ₁ as (f) substituent _-6 alkyl, C _1-6 alkanoyl and benzoyl, optionally having one or two substituents selected from amino, hydroxy, halogen,
Nitro, cyano, C _1-6 alkyl optionally substituted with 1 to 5 halogen atoms or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms , A C _7-12 aryloxycarbonyl group or (g) amino, hydroxy optionally having 1-2 substituents selected from C _1-6 alkyl, C _1-6 alkanoyl and benzoyl as substituents; Having halogen, nitro, cyano, C _1-6 alkyl optionally substituted with 1 to 5 halogen atoms or C _1-6 alkoxy optionally substituted with 1 to 5 halogen atoms. And a 5- to 6-membered aromatic or non-aromatic monocyclic nitrogen-containing heterocyclic group which may be substituted with a C _6-10 aryl-C _1-4 alkoxy-carbonyl group. Compound. (17) 1- (6-chloronaphthalene-2-sulfonyl)-
4- [4- (4-pyridyl) -benzoyl] piperazine, 1- (6-chloronaphthalene-2-sulfonyl) -4- [4- (1H-imidazole-1
-Yl) benzoyl] piperazine, 1- (6-chloronaphthalene
2-sulfonyl) -4- [2- (4-pyridyl) -4-methyl-5-thiazolylcarbonyl] piperazine, 1- (trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl) -4 -(6-chloronaphthalene-2-sulfonyl) piperazine, 1- (6-chloronaphthalene-2-sulfonyl) -4- (trans-4-guanidinocyclohexane-1-ylcarbonyl) piperazine, or a salt thereof Item 7. The compound according to Item 1. (18) A pharmaceutical composition comprising the compound according to (1). 19. The composition according to claim 18, which is an anticoagulant. 20. The composition according to claim 18, which is an activated blood coagulation factor X inhibitor. 21. The composition according to claim 18, which is an agent for preventing or treating myocardial infarction, cerebral thrombosis or deep vein thrombosis. 22. A compound represented by the formula: R ¹ SO ₂ Q wherein Q is a halogen atom, and other symbols are as defined in claim 1. And a salt thereof, and a compound represented by the formula: [Wherein the ring A is a compound of the formula: Represents a nitrogen-containing heterocyclic group which may be further substituted in addition to the group represented by, and the other symbols have the same meanings as in claim 1. Or a salt thereof, or a compound represented by the formula: Wherein the ring A is of the formula In addition to the group represented by, a nitrogen-containing heterocyclic group which may be further substituted, and other symbols have the same significance as described in claim 1. And a salt thereof and a compound represented by the formula: [The symbols in the formula are as defined in claim 1. The method for producing a compound according to claim 1, wherein the compound is reacted with a compound represented by the formula: or a salt thereof or a reactive derivative thereof. 23. A compound of the formula [The symbols in the formula are as defined in claim 1. And a salt thereof and a compound represented by the formula: R ¹⁰ OH wherein R ¹⁰ represents a lower alkyl group. A compound represented by the formula: or a salt thereof. [The symbols in the formula are as defined above. ] Or a salt thereof. 24. The formula: [The symbols in the formula are as defined in claim 23. And a salt thereof and a compound represented by the formula: [Wherein, R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group. ]
Wherein the compound is reacted with a compound represented by the formula: or a salt thereof. [The symbols in the formula are as defined above. ] Or a salt thereof. 25. The formula [In the formula, ring B represents an optionally substituted divalent non-aromatic heterocyclic group, and the other symbols have the same meanings as in claim 1. And a salt thereof, and a compound represented by the formula: [In the formula, R ¹⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ¹⁵ represents a lower alkyl group, U represents an oxygen atom or a sulfur atom, V represents a hydrogen atom, Represents an optionally substituted hydrocarbon group or an amino group which may be substituted with an optionally substituted hydrocarbon group. Wherein the compound or a salt thereof is reacted with a compound represented by the formula: [The symbols in the formula are as defined above. ] Or a salt thereof. 26. A compound of the formula [In the formula, R ¹³ represents a hydrogen atom or a hydrocarbon group which may be substituted, and the other symbols have the same meanings as in claim 1. And a salt thereof and a compound represented by the formula: [In the formula, R ¹⁴ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ¹⁵ represents a lower alkyl group, U represents an oxygen atom or a sulfur atom, V represents a hydrogen atom, Represents an optionally substituted hydrocarbon group or an amino group which may be substituted with an optionally substituted hydrocarbon group. A compound represented by the formula: or a salt thereof. [The symbols in the formula are as defined above. ] Or a salt thereof.