JPH11171865A - Fused heterocyclic compound - Google Patents

Abstract

(57) Abstract: has strong 5-HT ₂ receptor antagonism, combines the peripheral circulation improving action in addition to inhibiting platelet aggregation, thromboembolism, chronic arterial occlusion, ischemic heart disease And other useful compounds as therapeutic agents. SOLUTION: 4-amino-N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N-
It has been found that a fused heterocyclic compound such as (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide, an optical isomer thereof or a pharmaceutically acceptable salt thereof is a compound meeting the above-mentioned object. Was done.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention has a potent 5-HT ₂ receptor antagonism, and has thromboembolism, chronic arterial occlusion, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disorder, migraine, diabetes The present invention relates to a novel fused heterocyclic compound useful as a therapeutic agent for diseases such as congenital peripheral neuropathy and postherpetic neuralgia.

[0002]

2. Description of the Related Art Serotonin (5-hydroxytryptamine; hereinafter referred to as 5-HT) remarkably enhances platelet aggregation by collagen, epinephrine and adenosine diphosphate. Serotonin 2 (hereinafter referred to as 5-HT ₂₎ receptors other platelet aggregation, erythrocyte deformability, vasoconstriction, involved in increased vascular permeability. For chronic arterial occlusion, 5-H
Since high collateral of T sensitive develops, 5-HT ₂ Suppressing receptor, than an extension of the whole body of the vessel causing the extension of the fault local vascular improving peripheral circulation. Therefore, a search for a 5-HT ₂ receptor antagonist has been conducted. For example, Japanese Patent Publication No. 13427/1988 discloses a (3-aminopropoxy) bibenzyl derivative which has a platelet aggregation inhibitory effect and is used for the prophylactic treatment of thrombosis. It has been disclosed. Also, 5-
Sarpogrelate hydrochloride selective for the HT ₂ receptor has been reported to be effective in migraine, diabetic peripheral neuropathy, and postherpetic neuralgia. However, their platelet aggregation inhibitory action and vasoconstriction inhibitory action are not always satisfactory, and compounds having even better activity are desired. Japanese Patent Publication No. 7-45496 discloses an aryl (or heteroaryl) piperazinylalkylazole derivative effective for anxiety, depression, withdrawal syndrome, cognitive impairment, and hypertension, which has an amide bond. No compounds are shown. JP-A-7-2426
Substituted cyclic amine compounds having a 5-HT ₂ receptor antagonism is disclosed in JP 29.

[0003]

SUMMARY OF THE INVENTION The present invention relates to 5-HT ₂
An object of the present invention is to provide a novel compound having a receptor antagonism, a platelet aggregation inhibitory effect, and a peripheral circulation improving effect.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a novel fused heterocyclic compound represented by the following general formula (I), an optically active form thereof or a pharmaceutically acceptable salt thereof can be obtained. Has potent 5-HT ₂ receptor antagonism,
It has been found that, in addition to the platelet aggregation inhibitory effect, it also has a peripheral circulation improving effect. Therefore, the compound of the present invention may be useful for diseases such as thromboembolism, chronic arterial occlusion, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disorder, migraine, diabetic peripheral neuropathy, and postherpetic neuralgia. That is, the present invention is as follows. 1. General formula (I)

[0005]

Embedded image [Wherein, R represents the following formula (1), (2), (3),
It represents a group selected from (4), (5), (6), (7) and (8).

[0006]

Embedded imageR¹Is hydrogen, alkyl, hydroxy, amino, aryl
Alkyl, or phenyl which may have a substituent or
Represents a heteroaryl. R^TwoIs hydrogen, alkyl, reed
, Arylalkyl, or an optionally substituted
Represents nyl or heteroaryl. A can be placed anywhere
Substituent R^Three(R^ThreeIs hydrogen, alkyl, hydroxy, alcohol
Represents xy, amino or dialkylamino. Have)
Straight or branched having 1 to 4 carbon atoms
Shows a chain alkylene. Y is absent or oxygen
Atom, sulfur atom, SO, SO_TwoOr NR ^Four(R^Four
Is hydrogen, alkyl, aryl, heteroaryl, aryl
Represents alkyl or acyl. ). B is arbitrary
A substituent R at the position^Threea (R^Threea is hydrogen, alkyl, hydroxy
Represents alkoxy, alkoxy, amino or dialkylamino
You. ) Having 1 to 4 carbon atoms
Shows a chain or branched alkylene. Z is 1-8 carbon atoms
Alkyl, cycloalkyl having 3 to 8 carbon atoms
Alkyl, phenyl or heteroaryl optionally having substituent (s)
Indicates a reel. D is a straight chain having 1 to 8 carbon atoms or
Shows a branched alkylene chain. QT is CH, CH_Two−
N, (CH_Two)_Two-N, CH_TwoRepresents -CH or CH = C
You. G is absent or a straight chain having 1 to 8 carbon atoms.
Or branched alkylene chain, carbonyl or CH (O
H). However, QT is CH_Two-N, (CH_Two) _Two−
When indicating N, G does not exist or has 1 to 8 carbon atoms.
Linear or branched alkylene chain or carbonyl
Is shown. R is the formula (7) or (8), and
R^TwoRepresents hydrogen, and QT represents CH_TwoIndicates -N
G is a straight or branched chain having 1 to 8 carbon atoms
Shows an alkylene chain or carbonyl. Ar represents a substituent
Aryl, heteroaryl or fused hetero
Represents a loaryl. A heterocyclic compound represented by the formula
Or an optical isomer or a pharmaceutically acceptable salt thereof.

[0007] 2. In the general formula (I), R is a group represented by the formula
From the group of (1), (5), (6), (7) and (8)
Represents a selected group;¹Is hydrogen, alkyl, hydroxy
With amino, aryl, or alkyl substituents
Phenyl or heteroaryl;^TwoIs water
Element, alkyl, acyl, arylalkyl or substituent
A phenyl or heteroaryl which may have
A represents a substituent R at any position^Three(R^ThreeIs hydrogen, alkyl,
Hydroxy, alkoxy, amino or dialkylamido
No. ) Having 1 to 4 carbon atoms.
A linear or branched alkylene, wherein Y is present
Or no oxygen atom, sulfur atom, SO, SO_Twoif
Or N-R ^Four(R^FourIs hydrogen, alkyl, aryl, hete
Represents loaryl, arylalkyl or acyl. )
And B represents a substituent R at any position^Threea (R^Threea is hydrogen,
Alkyl, hydroxy, alkoxy, amino or dial
Indicates killamino. ) Having 1 to 1 carbon atoms
A straight or branched alkylene having 4 carbon atoms;
Is an alkyl having 1 to 8 carbons, 3 to 8 carbons
Having cycloalkyl, optionally substituted phenyl
Or D represents heteroaryl, and D has 1 to 8 carbon atoms.
A straight or branched alkylene chain;
CH, CH_Two-N, (CH_Two)_Two-N, CH_Two-CH or
Represents CH = C, G is absent, or has 1 to 8 carbon atoms
A linear or branched alkylene chain having
Or CH (OH), provided that QT is CH_Two-N
Or (CH_Two)_TwoIf -N, G is absent,
Linear or branched alkylene having 1 to 8 carbon atoms
Represents a chain or a carbonyl, and R is a group represented by the formula (7) or
(8) and R^TwoRepresents hydrogen, and Q-
T is CH_TwoWhen indicating -N, G has 1 to 8 carbon atoms
Linear or branched alkylene chain or carbonyl
And Ar represents an aryl or heteroaryl which may have a substituent.
1 represents a reel or a fused heteroaryl;
The fused heterocyclic compound according to the above, its optical isomer or its
Pharmaceutically acceptable salts.

[0008] 3. In the general formula (I), R is a group represented by the formula
From the group of (1), (5), (6), (7) and (8)
Represents a selected group;¹Represents hydrogen or alkyl,
R^TwoIs hydrogen, alkyl, acyl, arylalkyl or
Is phenyl or heteroaryl which may have a substituent
A represents a substituent R at any position^Three(R^ThreeIs hydrogen or
Represents alkyl. ) Having 1 to 1 carbon atoms
A straight-chain or branched alkylene having 4 alkyl groups;
Is not present and B is a substituent R at any position^Threea (R^Threea is hydrogen
Or alkyl. ) Which can have
Represents a linear or branched alkylene having 1 to 4
And Z is an alkyl having 1 to 8 carbons,
Cycloalkyl having 8 substituents which may have a substituent
Enyl or heteroaryl, wherein D is 1-8 carbon atoms
A straight or branched alkylene chain having
-T is CH, CH_Two-N, (CH_Two)_Two-N, CH_Two-C
H or CH = C, G is absent or methyl
, Carbonyl or CH (OH), provided that Q-
T is CH_Two-N or (CH_Two)_TwoWhen indicating -N, G is
Absent, represents methylene or carbonyl, and
R is formula (7) or (8), and R ^TwoProduces hydrogen
And QT is CH_TwoWhen -N is indicated, G is
Represents tylene or carbonyl, and Ar has a substituent
Aryl, heteroaryl or fused heteroaryl
A fused heterocyclic compound according to the above 1, which is
An optical isomer or a pharmaceutically acceptable salt thereof.

4. In the general formula (I), R represents a group selected from the group of the formulas (1), (7) and (8), R ¹ represents hydrogen or alkyl, and R ² represents hydrogen, alkyl, arylalkyl or substituted. Represents phenyl or heteroaryl which may have a group, and A represents a straight chain having 1 to 4 carbon atoms which can have a substituent R ³ (R ³ represents hydrogen or alkyl) at any position. or shows a branched alkylene, Y is absent, B is from 1 to 4 carbon atoms which may have a substituent R ³ a (R ³ a is hydrogen or alkyl.) at an arbitrary position A linear or branched alkylene having 1 to 8 carbon atoms.
An alkyl having 3 to 8 carbon atoms, a cycloalkyl having 3 to 8 carbon atoms, an optionally substituted phenyl or heteroaryl, D represents ethylene, and QT represents CH, C
_{H 2 -N, (CH 2)} 2 -N, CH 2 -CH or CH =
Represents C, G is absent, represents methylene or carbonyl, provided that R is of formula (7) or (8),
And when R ² represents hydrogen and QT represents CH ₂ —N, G represents methylene or carbonyl;
Represents an optionally substituted aryl, heteroaryl or fused heteroaryl; the fused heterocyclic compound, optical isomer or pharmaceutically acceptable salt thereof according to the above 1.

[0010] 5. In the general formula (I), R represents the formula (1), (7) or (8), R ¹ represents hydrogen, R ² represents methyl, A represents ethylene, Y does not exist, B represents ethylene, Z represents phenyl or heteroaryl which may have a substituent, D represents ethylene, QT represents CH ₂ —N or CH ₂ —CH, and G does not exist , Methylene or carbonyl, and Ar represents an optionally substituted aryl, heteroaryl or fused heteroaryl; the fused heterocyclic compound according to the above 1, which is an optical isomer or a pharmaceutically acceptable salt thereof salt.

6. (2) 4-amino-N- (2- (4-
(4-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide, (51) 4-amino-N
-(2- (4- (4-chlorophenyl) piperazine-1
-Yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide, (65) 4-amino-N- (2- (4-benzoyl) Piperidin-1-yl) ethyl) -N- (4
5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide, (79) N- (2
-(4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide, (80) N -(2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide, and (116) N − (2- (4-
2. The fused heterocyclic compound according to the above 1, which is selected from (4-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide, or a pharmaceutically acceptable salt thereof. Possible salt.

7. The fused heterocyclic compound according to 1 above,
A pharmaceutical composition comprising the optical isomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive. 8. 2. A medicament comprising the fused heterocyclic compound according to 1 above, an optical isomer thereof or a pharmaceutically acceptable salt thereof. 9. Condensed heterocyclic compound of the above 1, wherein, 5-HT ₂ receptor antagonist consisting of an optical isomer thereof or a pharmaceutically acceptable salt thereof. 10. A platelet aggregation inhibitor comprising the condensed heterocyclic compound according to the above item 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Specific examples of each group in the above general formula (I) are as follows. ^{R 1, R 2, R 3} , R 3 a, R
Alkyl in ⁴ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary
Grade butyl, pentyl, hexyl, heptyl, octyl,
1 to 1 carbon atoms such as decyl, hexadecyl and octadecyl
It represents 18 alkyl, and preferably has 1 to 4 carbon atoms. R ¹ , R ² , and Z optionally having a substituent in phenyl or heteroaryl include (1) halogen selected from fluorine, chlorine, bromine, and iodine, and (2) methyl, ethyl, propyl, isopropyl, and butyl. Alkyl having 1 to 4 carbon atoms selected from butyl, isobutyl, tertiary butyl, etc., and (3) alkyl and oxygen having 1 to 4 carbon atoms selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, etc. (4) haloalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, (5) hydroxy, (6) amino, (7) dimethylamino, diethylamino, N-methyl-N-ethylamino Dialkylamino, each independently having an alkyl having 1 to 4 carbon atoms selected from the group consisting of It refers to phenyl substituents capable of having one or more, thienyl, furyl, pyridyl and the like. Acyl in R ² and R ⁴ means alkyl having 1 to 4 carbon atoms, 3 to 8 carbon atoms selected from formyl, acetyl, propionyl, cyclopentanoyl, cyclohexanoyl, benzoyl, benzylcarbonyl and the like.
Consisting of an aryl or heteroaryl such as phenyl, thienyl, pyridyl and the like which may have one or more substituents as mentioned in cycloalkyl, phenyl or heteroaryl optionally having substituent (s) in R ¹ and carbonyl Shows the group to be formed.

The arylalkyl represented by R ¹ , R ² and R ⁴ is composed of alkyl having 1 to 4 carbon atoms and phenyl, and is benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl And so on. A straight or branched chain having 1 to 4 carbon atoms which can have a substituent R ³ (R ³ represents hydrogen, alkyl, hydroxy, alkoxy, amino or alkylamino) at any position in A Alkylene is
Formulas CH (R ³ ), CH ₂ CH (R ³ ), CH (R ³ ) CH ₂ , CH (R ³ ) CH ₂ CH ₂ , CH ₂ CH (R ³ ) CH ₂ , CH ₂ CH ₂ CH (R ³ ), CH (R ³ ) CH ₂ CH ₂ CH ₂ , CH ₂ CH (R ³ ) CH ₂ CH ₂ , CH ₂ CH ₂ CH (R ³ ) CH ₂ , CH ₂ CH ₂ CH ₂ CH (R ³ ) And alkylenes represented by and the like. Alkoxy at R ^3, R ³ a, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like composed alkoxy and a tertiary alkyl and oxygen atoms of 1 to 4 carbon atoms selected from butoxy it can. Examples of the dialkylamino include dialkylaminos each independently having an alkyl having 1 to 4 carbon atoms selected from dimethylamino, diethylamino, N-methyl-N-ethylamino and the like. Aryl in R ⁴ includes phenyl and naphthyl, and heteroaryl includes thienyl, furyl, pyridyl and the like. Substituents R ³ a (R ³ a is hydrogen, alkyl, hydroxy, alkoxy,. Showing an amino or dialkylamino) at any position in the B linear or branched having from 1 to 4 carbon atoms which may have a As the chain alkylene, the same alkylene as A can be mentioned. Alkyl in R ³ a, alkoxy, amino include the same R ^3.

The alkyl having 1 to 8 carbon atoms in Z includes methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, secondary butyl, tertiary butyl, pentyl,
Represents alkyl such as hexyl, heptyl, and octyl.
C3-8 cycloalkyl means cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. The linear or branched alkylene chain having 1 to 8 carbon atoms in D and G includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, octamethylene, methylmethylene, dimethylmethylene, 1- Methyl ethylene, 2-methyl ethylene, 1,1-dimethyl ethylene, 2,2-dimethyl ethylene, ethyl methylene, diethyl methylene, 1-ethyl ethylene, 2-ethyl ethylene, 1-methyl trimethylene, 1,1-dimethyl tri Methylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 3-ethyltrimethylene and the like . A
Aryl in r represents phenyl, naphthyl, 2-indanyl or the like. Heteroaryl refers to a 5- or 6-membered aromatic ring having one or two nitrogens, oxygens, and sulfurs as hetero atoms in the ring, and includes pyridyl, furyl, thienyl, and pyrimidinyl. Fused heteroaryl refers to a structure in which heteroaryl and aryl or heteroaryls share a part of each other's ring and are fused, and 1,2-benzisoxazol-3-yl, 1,2-benzisothiazole- 3-yl, indol-3-yl, 1-benzofuran-3-yl, 1-benzothiophen-3-yl and the like. In addition, these substituents are (1) halogens selected from fluorine, chlorine, bromine and iodine, and (2) carbon numbers 1 to 1 selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like. Alkyl (4), (3) alkoxy composed of an alkyl having 1 to 4 carbon atoms selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy and the like, and an oxygen atom, (4)
Haloalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, etc., (5) hydroxy, (6) amino, (7) dimethylamino, diethylamino, N-methyl-N-ethylamino, etc., alkyl having 1 to 4 carbon atoms. Dialkylamino, each independently having the formula (8):
Represents nitro or the like, and may be substituted one or more times on aryl, heteroaryl, or fused heteroaryl.

As R, formulas (1) and (5) to (8) are preferable, and (7) is particularly preferable. R ¹ is preferably hydrogen or alkyl, and particularly preferably hydrogen. R ² is preferably hydrogen, alkyl or phenyl, particularly preferably alkyl. R ³ is preferably hydrogen or alkyl,
Particularly, hydrogen is preferable. A is preferably a linear alkylene having 1 to 4 carbon atoms, particularly methylene, ethylene and trimethylene. Y does not exist or is preferably an oxygen atom,
In particular, it should not be present. B is preferably ethylene. Z is alkyl having 1 to 4 carbons, 5 to 5 carbons
Preference is given to cycloalkyl having 6 substituents, optionally substituted phenyl or heteroaryl, and particularly preferred is optionally substituted phenyl. D is preferably ethylene. The Q-T CH ₂ -C or CH ₂ -N is preferred. G is absent or carbonyl is preferred, especially carbonyl. As a combination of QT and G, a combination in which QT represents CH ₂ —C and G is carbonyl is preferable. Ar is preferably aryl or heteroaryl which may have a substituent, and particularly preferably phenyl, naphthyl, thienyl and pyridyl which can have one or more substituents such as alkyl, alkoxy and halogen.

The compounds of general formula (I) and their pharmaceutically acceptable salts include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid,
Phosphoric acid, nitric acid, etc. or organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid , Camphorsulfonic acid, ascorbic acid, etc.). In addition, oxalate may be used for the purpose of crystallization of the compound. Since the compound of the formula (I) and the hydrate or a pharmaceutically acceptable salt thereof may be present in the form of a hydrate or a solvate, these hydrates (1/2 hydrate, 1/3 hydrate, monohydrate, 3
/ 2 hydrate, 2 hydrate, 3 hydrate, etc.) and solvates are also included in the present invention. When the compound of the formula (I) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention. The compound of the present invention contained in the general formula (I) can be synthesized by the following method. In the reaction formulas, the definition of each symbol is as defined above unless otherwise specified. 1. A method for synthesizing a compound wherein R is a group of the formula (1). (1)

[0018]

Embedded image Journal of Heterocyclic Chem. 28
Vol., P. 513 (1991), and tetrahedron (T
etrahedron) Vol. 23, p. 2081 (196
According to the method described in 7), a compound of the general formula (11) can be obtained. The compound of the general formula (11) is dissolved in a solvent (eg, methylene chloride, chloroform, benzene, toluene, etc.) which does not hinder the progress of the reaction and an appropriate base (eg, sodium hydrogen carbonate, potassium carbonate, sodium carbonate) in a 1% to supersaturated aqueous solution. A compound of the general formula (12) (wherein L represents a linear or branched alkylene chain having 1 to 7 carbon atoms; V is chlorine, bromine, iodine, methanesulfonyloxy, p -Represents a leaving group such as toluenesulfonyloxy, etc. W represents a leaving group forming an active ester such as chlorine, bromine, iodine or imidazole.
By reacting for 5 to 24 hours, the compound represented by the general formula (13) can be obtained. The compound of general formula (13) and the compound of general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them) A mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine and the like, and reacted at room temperature to 100 ° C. for 1 to 24 hours to obtain a compound represented by the general formula (15). The indicated compound can be obtained. The compound of the general formula (15) is refluxed from -78 ° C in a solvent that does not hinder the progress of the reaction (eg, tetrahydrofuran, diethyl ether, diisopropyl ether) using a suitable reducing agent (eg, borane, lithium aluminum hydride). The compound of the general formula (16) can be obtained by reacting at a temperature for 1 to 24 hours. The general formula (1
In a solvent which does not hinder the progress of the reaction (e.g., chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile), a suitable base (triethylamine, pyridine, sodium hydride,
The compound of the general formula (18) can be obtained by reacting the compound of the general formula (17) with potassium hydride or the like. (2)

[0019]

Embedded image The reaction of the compound of the general formula (11) with the compound of the general formula (19) (wherein J represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy) is hindered. In a non-solvent (such as dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any mixed solvent thereof), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, Room temperature to 100 ° C using a base such as pyridine or dimethylaminopyridine
To give a compound represented by the general formula (20). In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (21) can be obtained by reacting with a compound of the general formula (17) using potassium or the like. (3)

[0020]

Embedded image Journal of Heterocyclic Chem. 28
Vol., P. 513 (1991), the compound represented by the general formula (22) is obtained from the compound represented by the general formula (11), and the compound represented by the general formula (23) is represented by the compound represented by the general formula (22). A compound is obtained. The general formula (23) and the general formula (2)
Potassium carbonate in a solvent that does not interfere with the reaction with the compound of 4) (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or a mixed solvent thereof); The compound represented by the general formula (20) can be obtained by reacting at room temperature to 100 ° C. for 1 to 24 hours using a base such as sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine and dimethylaminopyridine. .
In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (2) is reacted with the compound of the general formula (17) using
The compound of 1) can be obtained. (4)

[0021]

Embedded image The compound of general formula (23) and the compound of general formula (25) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide,
1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide,
The compound represented by the general formula (21) can be obtained by reacting at room temperature to 100 ° C. for 1 to 24 hours using a base such as triethylamine, pyridine, dimethylaminopyridine, sodium hydride and potassium hydride. (5)

[0022]

Embedded image In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (2) is reacted with the compound of the general formula (17) using
The compound of 6) can be obtained. The compound of the general formula (26) and the compound of the general formula (19) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2).
-Imidazolidinone, acetonitrile or any mixture thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride,
Use a base such as potassium hydride at room temperature to 100 ° C for 1 hour.
The compound represented by the general formula (21) can be obtained by reacting for up to 24 hours. (6)

[0023]

Embedded image Potassium carbonate, sodium hydroxide in a solvent which does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) Using a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride or potassium hydride (where E is a primary alcohol such as tetrahydropyranyl) The compound of the general formula (28) can be obtained by reacting the compound with a general protecting group. The compound of the general formula (29) can be obtained by deprotecting the compound of the general formula (28) using a suitable acid (hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.). General formula (29)
Suitable halogenating agents (phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, etc.)
Or a sulfonic acid halide (methanesulfonyl chloride,
The reaction is carried out at 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours in a solvent (eg, chloroform, methylene dichloride, ethylene dichloride) which does not hinder the progress of the reaction using p-toluenesulfonyl chloride). ) Can be obtained. The compound of general formula (30) and the compound of general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them) Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, etc.
To give a compound represented by the general formula (21). 2. A method for synthesizing a compound wherein R is a group of the formula (2). (1)

[0024]

Embedded image Pharmaceutical Bulletin (Pharma
Ceutical Bull. ) Vol. 2, p. 72 (19
According to the method described in 54), a compound of the general formula (31) can be obtained. The compound of the general formula (31) and the compound of the general formula (24) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) ), Potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine and the like.
The reaction is carried out at a temperature of 1 to 24 hours at a temperature of the general formula (32).
Can be obtained. The compound of the general formula (32) is dissolved in a solvent (chloroform,
Methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.) and a suitable base (triethylamine, pyridine, sodium hydride, potassium hydride, etc.), by reacting with the compound of the general formula (17), The compound of the general formula (33) can be obtained. 3. A method for synthesizing a compound wherein R is a group of the formula (3). (1)

[0025]

Embedded image The compound of the general formula (34) is reacted with acetic acid in the presence of a suitable catalyst (nickel, Raney nickel, palladium-carbon, iron).
The compound of the general formula (35) can be obtained by hydrogenation in a solvent such as methanol, ethanol and butanol which does not hinder the progress of the reaction. General formula (35)
A compound that does not hinder the progress of the reaction (methylene chloride,
Formula (1) in a 1% to supersaturated aqueous solution of 1% to a supersaturated aqueous solution of a suitable base (sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc.) at 0 ° C. to room temperature.
2) wherein L represents a linear or branched alkylene chain having 1 to 7 carbon atoms; V represents chlorine, bromine,
It represents a leaving group such as iodine, methanesulfonyloxy, p-toluenesulfonyloxy and the like. W represents a leaving group that forms an active ester such as chlorine, bromine, iodine, and imidazole. ) For 0.5 to 24 hours to give the compound represented by the general formula (36). The compound of general formula (36) and the compound of general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-
Dimethyl-2-imidazolidinone, acetonitrile,
Water, toluene, or any mixture thereof),
1 to 24 at room temperature to 100 ° C. using a base such as potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine and dimethylaminopyridine.
The compound represented by the general formula (37) can be obtained by reacting for a time. The compound of the general formula (37) is refluxed from -78 ° C. in a solvent that does not hinder the progress of the reaction (eg, tetrahydrofuran, diethyl ether, diisopropyl ether) using a suitable reducing agent (eg, borane, lithium aluminum hydride). The compound of the general formula (38) can be obtained by reacting at a temperature for 1 to 24 hours. In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), an appropriate base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (3) is reacted with the compound of the general formula (17) using potassium or the like.
Compound 9) can be obtained. (2)

[0026]

Embedded image In a solvent which does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) The compound of the general formula (4) is reacted with the compound of the general formula (17) using potassium or the like.
0) can be obtained. The compound of the general formula (40) and the compound of the general formula (19) are mixed in a solvent which does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2).
-Imidazolidinone, acetonitrile or any mixture thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride,
Use a base such as potassium hydride at room temperature to 100 ° C for 1 hour.
The compound represented by the general formula (41) can be obtained by reacting for up to 24 hours. (3)

[0027]

Embedded image Potassium carbonate, sodium hydroxide, in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) Using a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride or potassium hydride (where E is a primary alcohol such as tetrahydropyranyl) The compound of general formula (42) can be obtained by reacting the compound with a general protecting group. The compound of the general formula (43) can be obtained by deprotecting the compound of the general formula (42) using an appropriate acid (hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.). General formula (43)
Suitable halogenating agents (phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, etc.)
Or a sulfonic acid halide (methanesulfonyl chloride,
The reaction is carried out in a solvent (eg, chloroform, methylene dichloride, ethylene dichloride) at 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours using a solvent (eg, p-toluenesulfonyl chloride) which does not hinder the progress of the reaction. ) Can be obtained. The compound of general formula (44) and the compound of general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them). Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, etc.
To give a compound represented by the general formula (41). 4. A method for synthesizing a compound wherein R is a group of the formula (4). (1)

[0028]

Embedded image Pharmaceutical Bulletin (Pharma
Ceutical Bull. ) Vol. 2, p. 72 (19
According to the method described in 54), a compound of the general formula (45) can be obtained. The compound of the general formula (45) is dissolved in a solvent (methylene chloride, chloroform, benzene, toluene, etc.) that does not hinder the progress of the reaction and a suitable base (baking soda, potassium carbonate, sodium carbonate, etc.) from 1% to 0 ° C.
At room temperature to a compound of the general formula (12) wherein L is
Shows a linear or branched alkylene chain with up to 7 V represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy and p-toluenesulfonyloxy. W represents a leaving group that forms an active ester such as chlorine, bromine, iodine, and imidazole. ) For 0.5 to 24 hours to give the compound represented by the general formula (46). The compound of the general formula (46) and the compound of the general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them) Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine or the like, and reacted at room temperature to 100 ° C. for 1 to 24 hours to obtain the compound represented by the general formula (47). The indicated compound can be obtained. The compound of the formula (47) is refluxed from -78 ° C. in a solvent which does not hinder the progress of the reaction (eg, tetrahydrofuran, diethyl ether, diisopropyl ether) using a suitable reducing agent (eg, borane, lithium aluminum hydride). By reacting at a temperature for 1 hour to 24 hours, the general formula (4)
The compound of 8) can be obtained. In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), an appropriate base (triethylamine, pyridine, sodium hydride, hydrogenation) The compound of the general formula (49) can be obtained by reacting the compound with the compound of the general formula (17) using potassium or the like. (2)

[0029]

Embedded image In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (4) is reacted with the compound of the general formula (17) using potassium or the like.
The compound of 6) can be obtained. The compound of the general formula (46) and the compound of the general formula (19) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2).
-Imidazolidinone, acetonitrile or any mixture thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride,
Use a base such as potassium hydride at room temperature to 100 ° C for 1 hour.
The compound represented by the general formula (47) can be obtained by reacting for up to 24 hours. (3)

[0030]

Embedded image Potassium carbonate, sodium hydroxide, in a solvent which does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) Using a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride or potassium hydride (where E is a primary alcohol such as tetrahydropyranyl) The compound of the formula (48) can be obtained by reacting the compound with a general protecting group. The compound of the general formula (49) can be obtained by deprotecting the compound of the general formula (48) using a suitable acid (hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.). General formula (49)
Suitable halogenating agents (phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, etc.)
Or a sulfonic acid halide (methanesulfonyl chloride,
The reaction is carried out in a solvent (eg, chloroform, methylene dichloride, ethylene dichloride) at 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours using a solvent that does not hinder the progress of the reaction using p-toluenesulfonyl chloride or the like. ) Can be obtained. The compound of general formula (50) and the compound of general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them) Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, etc.
To give a compound represented by the general formula (47). 5. A method for synthesizing a compound wherein R is a group of the formula (5). (1)

[0031]

Embedded image In a suitable solvent (benzene, toluene, xylene, or any mixed solvent thereof), the compound of the general formula (51) is
By reacting dimethyl sulfate with the reflux temperature of the solvent, a compound of the general formula (52) is obtained. General formula (5
The compound of 2) is converted to a suitable solvent (methanol, ethanol,
In the presence of semicarbazide in a solvent such as butanol, isopropanol or any mixed solvent thereof) at room temperature to the reflux temperature of the solvent for 1 to 24 hours, the compound of the general formula (53) is obtained. Solvents (methylene chloride, chloroform, benzene, toluene, etc.) which do not hinder the progress of the reaction of the compound of general formula (53) and a suitable base (sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc.)
In a 1% to supersaturated aqueous solution at 0 ° C. to room temperature, wherein L represents a linear or branched alkylene chain having 1 to 7 carbon atoms. V represents chlorine or bromine , Iodine, methanesulfonyloxy, p-toluenesulfonyloxy, etc. W represents chlorine, bromine, iodine,
Indicates a leaving group that forms an active ester such as imidazole. ) For 0.5 to 24 hours to give the compound represented by the general formula (54). The compound of the general formula (54) and the compound of the general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them). Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine and the like, and reacted at room temperature to 100 ° C. for 1 to 24 hours to obtain a compound of the general formula (55). The indicated compound can be obtained. The compound of the formula (55) is refluxed from -78 ° C. in a solvent that does not hinder the progress of the reaction (eg, tetrahydrofuran, diethyl ether, diisopropyl ether) using a suitable reducing agent (eg, borane, lithium aluminum hydride). The compound of the formula (56) can be obtained by reacting at a temperature for 1 to 24 hours. In a solvent which does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) The compound of the general formula (5) is reacted with the compound of the general formula (17) using potassium or the like.
Compound 7) can be obtained. (2)

[0032]

Embedded image In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (5) is reacted with the compound of the general formula (17) using
The compound of 8) can be obtained. The compound of the general formula (58) and the compound of the general formula (19) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2).
-Imidazolidinone, acetonitrile or any mixture thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride,
Use a base such as potassium hydride at room temperature to 100 ° C for 1 hour.
The compound represented by the general formula (59) can be obtained by reacting for up to 24 hours. (3)

[0033]

Embedded image Potassium carbonate, sodium hydroxide in a solvent which does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) Using a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride or potassium hydride (where E is a primary alcohol such as tetrahydropyranyl) The compound of general formula (60) can be obtained by reacting the compound with a general protecting group. The compound of the general formula (61) can be obtained by deprotecting the compound of the general formula (60) using a suitable acid (hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.). General formula (61)
Suitable halogenating agents (phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, etc.)
Or a sulfonic acid halide (methanesulfonyl chloride,
Using a reaction (eg, chloroform, methylene dichloride, ethylene dichloride) in a solvent that does not hinder the progress of the reaction using p-toluenesulfonyl chloride) at a temperature of 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours, the general formula (62) ) Can be obtained. The compound of the general formula (62) and the compound of the general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them) Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, etc.
To give a compound represented by the general formula (59). 6. A method for synthesizing a compound wherein R is a group of the formula (6). (1)

[0034]

Embedded image A compound of the general formula (63) is dissolved in an aqueous sodium hydroxide solution,
By reacting with hydroxylamine hydrochloride at room temperature for 1 to 24 hours, the compound represented by the general formula (64) can be obtained. The compound of the formula (64) is dissolved in a solvent (methylene chloride, chloroform, benzene, toluene, etc.) that does not hinder the progress of the reaction and a suitable base (sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc.) in a 1% to supersaturated aqueous solution. A compound of the general formula (12) (wherein L represents a linear or branched alkylene chain having 1 to 7 carbon atoms; V is chlorine, bromine, iodine, methanesulfonyloxy, p -Represents a leaving group such as toluenesulfonyloxy, etc., and W represents a leaving group which forms an active ester such as chlorine, bromine, iodine, imidazole, etc.) for 0.5 to 24 hours. ) Can be obtained. The compound of the general formula (65) and the compound of the general formula (14) are mixed in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them). Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine and the like at a temperature of from room temperature to 100 ° C. for 1 to 24 hours to give the compound of the general formula (66) The indicated compound can be obtained. The compound of the formula (66) is refluxed from -78 ° C. in a solvent that does not hinder the progress of the reaction (eg, tetrahydrofuran, diethyl ether, diisopropyl ether) using a suitable reducing agent (eg, borane, lithium aluminum hydride). By reacting at a temperature for 1 to 24 hours, the general formula (67) is obtained.
Can be obtained. In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a compound of the general formula (67) is mixed with a suitable base (triethylamine, pyridine, sodium hydride, hydrogen). The compound of the general formula (68) can be obtained by reacting with a compound of the general formula (17) using potassium chloride or the like. (2)

[0035]

Embedded image In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (6) is reacted with the compound of the general formula (17) using potassium or the like.
Compound 9) can be obtained. The compound of the general formula (69) and the compound of the general formula (19) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2).
-Imidazolidinone, acetonitrile or any mixture thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride,
Use a base such as potassium hydride at room temperature to 100 ° C for 1 hour.
The compound represented by the general formula (70) can be obtained by reacting for up to 24 hours. (3)

[0036]

Embedded image Potassium carbonate, sodium hydroxide in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) Using a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride, or potassium hydride (where E is a primary alcohol such as tetrahydropyranyl) The compound of general formula (71) can be obtained by reacting the compound with a general protecting group. The compound of the general formula (72) can be obtained by deprotecting the compound of the general formula (71) using a suitable acid (hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.). General formula (72)
Suitable halogenating agents (phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, etc.)
Or a sulfonic acid halide (methanesulfonyl chloride,
Using a reaction (eg, chloroform, methylene dichloride, ethylene dichloride) in a solvent that does not hinder the progress of the reaction using p-toluenesulfonyl chloride or the like at 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours, the general formula (73) ) Can be obtained. The compound of the general formula (73) and the compound of the general formula (14) are mixed in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them). Mixed solvent, etc.), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, etc.
To give a compound represented by the general formula (70). 7. A method for synthesizing a compound wherein R is a group of the formula (7). (1)

[0037]

Embedded image In a solvent that does not hinder the progress of the reaction (methanol, ethanol, propanol, isopropanol, butanol, tertiary butyl alcohol, etc.),
A compound of the general formula (74) at room temperature to a reflux temperature of a solvent of 1 to 1
By reacting for 24 hours, the compound represented by the general formula (75) can be obtained. Solvents (methylene chloride, chloroform, benzene, toluene, etc.) and an appropriate base (sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc.)
% To a supersaturated aqueous solution at 0 ° C. to room temperature, wherein L represents a linear or branched alkylene chain having 1 to 7 carbon atoms. V represents chlorine, bromine, iodine , Methanesulfonyloxy, p-toluenesulfonyloxy, etc. W represents a leaving group that forms an active ester such as chlorine, bromine, iodine, imidazole, etc.)
And for 0.5 to 24 hours.
The compound shown in 6) can be obtained. General formula (7
The compound of 6) and the compound of the general formula (14) in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any mixed solvent thereof) ), Potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine and the like, and reacted at room temperature to 100 ° C. for 1 to 24 hours to obtain a compound represented by the general formula (77). Can be obtained. The compound of the general formula (77) is treated with a suitable reducing agent (borane, lithium aluminum hydride, etc.) in a solvent that does not hinder the progress of the reaction (eg, tetrahydrofuran, diethyl ether, diisopropyl ether, etc.).
The compound of the general formula (78) can be obtained by reacting at 8 ° C. to the reflux temperature of the solvent for 1 to 24 hours. In a solvent which does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) The compound of the general formula (7) is reacted with the compound of the general formula (17) using potassium or the like.
Compound 9) can be obtained. (2)

[0038]

Embedded image In a solvent that does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), a suitable base (triethylamine, pyridine, sodium hydride, hydrogenation) is used. The compound of the general formula (8) is reacted with the compound of the general formula (17) using potassium or the like.
0) can be obtained. The compound of the general formula (80) and the compound of the general formula (19) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2).
-Imidazolidinone, acetonitrile or any mixture thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride,
Use a base such as potassium hydride at room temperature to 100 ° C for 1 hour.
The compound represented by the general formula (81) can be obtained by reacting for up to 24 hours. (3)

[0039]

Embedded image Potassium carbonate, sodium hydroxide in a solvent which does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) Using a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride or potassium hydride (where E is a primary alcohol such as tetrahydropyranyl) The compound of general formula (82) can be obtained by reacting the compound with a general protecting group. The compound of the general formula (83) can be obtained by deprotecting the compound of the general formula (82) using a suitable acid (hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.). General formula (83)
Suitable halogenating agents (phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, etc.)
Or a sulfonic acid halide (methanesulfonyl chloride,
The reaction is carried out at 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours in a solvent (chloroform, methylene dichloride, ethylene dichloride, etc.) that does not hinder the progress of the reaction using p-toluenesulfonyl chloride, etc. ) Can be obtained. The compound of the general formula (84) and the compound of the general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them) Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, etc.
To give a compound represented by the general formula (81). 8. A method for synthesizing a compound wherein R is a group of the formula (8). (1)

[0040]

Embedded image Journal of Heterocyclic Chem. No. 19
Vol., P. 1355 (1982), using a compound of the formula (85) which does not hinder the progress of the reaction (e.g., methanol, ethanol, propanol, butanol, ethylene glycol, diethylene glycol, or any mixed solvent thereof). The compound of the general formula (86) can be obtained by heating for 1 to 24 hours in the presence of hydrazine and a base (such as sodium hydroxide and potassium hydroxide). The compound of the general formula (87) can be obtained by reacting the compound of the general formula (86) with a mixed acid (arbitrary mixture of sulfuric acid and nitric acid) under ice cooling to room temperature. The compound of the general formula (88) can be obtained by adding the iron powder to the compound of the general formula (87) in the presence of hydrochloric acid or acetic acid and reacting at room temperature to the reflux temperature of the solvent for 1 to 24 hours. A compound of the general formula (88) is dissolved in a solvent (methylene chloride, chloroform, benzene, toluene, etc.) which does not hinder the progress of the reaction and a suitable base (sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc.) in a 1% to supersaturated aqueous solution. A compound of the general formula (12) (wherein L represents a linear or branched alkylene chain having 1 to 7 carbon atoms; V is chlorine, bromine, iodine, methanesulfonyloxy, p -Represents a leaving group such as toluenesulfonyloxy, etc. W represents a leaving group forming an active ester such as chlorine, bromine, iodine or imidazole.
By reacting for 5 to 24 hours, the compound represented by the general formula (89) can be obtained. The compound of the general formula (89) and the compound of the general formula (14) are mixed in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them). Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine and the like, and reacted at room temperature to 100 ° C. for 1 to 24 hours to obtain a compound represented by the general formula (90). The indicated compound can be obtained. The compound of the formula (90) is refluxed from -78 ° C. in a solvent that does not hinder the progress of the reaction (eg, tetrahydrofuran, diethyl ether, diisopropyl ether) using a suitable reducing agent (eg, borane, lithium aluminum hydride). The compound of the general formula (91) can be obtained by reacting at a temperature for 1 to 24 hours. The general formula (9
In a solvent (chloroform, methylene dichloride, ethylene dichloride, ethylene, dimethylformamide, toluene, acetonitrile, etc.) which does not hinder the progress of the reaction, a suitable base (triethylamine, pyridine, sodium hydride,
The compound of the general formula (92) can be obtained by reacting with a compound of the general formula (17) using potassium hydride or the like. (2)

[0041]

Embedded image In a solvent which does not hinder the progress of the reaction (chloroform, methylene dichloride, ethylene dichloride, dimethylformamide, toluene, acetonitrile, etc.), an appropriate base (triethylamine, pyridine, sodium hydride, hydrogenation) The compound of the general formula (9) is reacted with the compound of the general formula (17) using potassium or the like.
The compound of 3) can be obtained. The compound of the general formula (93) and the compound of the general formula (19) are mixed in a solvent that does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2).
-Imidazolidinone, acetonitrile or any mixture thereof), potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride,
Use a base such as potassium hydride at room temperature to 100 ° C for 1 hour.
The compound represented by the general formula (94) can be obtained by reacting for up to 24 hours. (3)

[0042]

Embedded image Potassium carbonate, sodium hydroxide in a solvent which does not hinder the progress of the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, or any mixed solvent thereof) Using a base such as potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, sodium hydride or potassium hydride (where E is a primary alcohol such as tetrahydropyranyl) The compound of general formula (95) can be obtained by reacting the compound with a general protecting group. The compound of the general formula (96) can be obtained by deprotecting the compound of the general formula (95) using an appropriate acid (hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.). General formula (96)
Suitable halogenating agents (phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, etc.)
Or a sulfonic acid halide (methanesulfonyl chloride,
Using a reaction (eg, chloroform, methylene dichloride, ethylene dichloride) in a solvent that does not hinder the progress of the reaction using p-toluenesulfonyl chloride) at a temperature of 0 ° C. to the reflux temperature of the solvent for 1 to 24 hours, the general formula (97) ) Can be obtained. The compound of the general formula (97) and the compound of the general formula (14) are reacted in a solvent that does not hinder the reaction (dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, water, toluene, or any of them) Mixed solvent), potassium carbonate, sodium hydroxide, potassium tertiary butoxide, triethylamine, pyridine, dimethylaminopyridine, etc.
To give a compound represented by the general formula (94).

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method. When the resulting product is racemic, for example, by fractional recrystallization of a salt with an optically active acid,
Alternatively, it can be divided into a desired optically active substance by passing through a column filled with an optically active carrier. Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using an optically active raw material compound or the like. Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

When the fused heterocyclic compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof is used as a medicament, the compound of the present invention is pharmaceutically acceptable carrier (excipient,
Pharmaceutical compositions or preparations (tablets, pills, capsules, granules, powders, syrups) obtained by mixing with binders, disintegrants, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, etc. It can be administered orally or parenterally in the form of emulsions, elixirs, suspensions, solutions, injections, drops or suppositories. The pharmaceutical composition can be formulated according to a usual method. As used herein, parenteral refers to subcutaneous injection, intravenous injection,
This includes intramuscular injection, intraperitoneal injection, infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono- or di- or triglycerides. Suppositories for rectal administration are solid at room temperature, such as the drug and a suitable nonirritating excipient, for example, cocoa butter or polyethylene glycols, but liquid at intestinal temperatures and melt in the rectum, It can be manufactured by mixing with a substance that releases a drug. Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills, and capsules. In such dosage forms, the active ingredient compound may include at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans, pectins, Gum tragacanth, gum arabic, gelatin, collagen,
It can be mixed with casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also comprise, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbins, ascorbic acid And antioxidants such as α-tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavorants, perfumes and the like. Tablets and pills can also be prepared with enteric coating. Liquid preparation for oral administration is a pharmaceutically acceptable emulsion,
Examples include syrups, elixirs, suspensions, solutions and the like, which may contain an inert diluent commonly used in the art, for example, water.

The compound of formula (I), an optical isomer or a pharmaceutically acceptable salt thereof has a potent 5-HT ₂ receptor antagonistic action, and has an inhibitory action on platelet aggregation as well as an action on improving peripheral circulation. Therefore, the compound of the present invention is effective as a therapeutic agent for diseases such as thromboembolism, chronic arterial occlusion, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disorder, migraine, diabetic peripheral neuropathy, and postherpetic neuralgia. is there. The dosage is age,
Determined according to body weight, general health, gender, diet, administration time, administration method, excretion rate, drug combination, the degree of the condition of the patient being treated at the time, and other factors. . The compound of the present invention, its optical isomer or pharmaceutically acceptable salt thereof can be safely used with low toxicity, and its daily dose depends on the condition and weight of the patient, the type of compound, the administration route, etc. Depends on
For example, parenterally, subcutaneously, intravenously, intramuscularly, or rectally, about 0.01 to 50 mg / person / day, preferably 0.1 mg / person / day.
01-20 mg / person / day, orally about 0.01-150 mg / person / day, preferably 0.1-1
It is desirable to administer 00 mg / person / day.

[0046]

EXAMPLES The present invention will be described in more detail with reference to raw material synthesis examples, working examples, formulation examples and experimental examples, but the present invention is not limited thereto. Raw Material Synthesis Example 1 8.0 g of 2-cyanocyclohexanone was added to formamide 1
Dissolved in 00 ml and heated at 160 ° C. After completion of the reaction, the reaction solution was cooled to room temperature and poured into a saturated aqueous solution of potassium carbonate. The mixture was extracted three times with chloroform, and the organic layer was dried over magnesium sulfate. The organic layer was filtered and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration and washed with isopropyl alcohol to obtain 5.1 g of 4-amino-5,6,7,8-tetrahydroquinazoline. Melting point 216
220 ° C

Raw Material Synthesis Example 2 10 g of 4-amino-5,6,7,8-tetrahydroquinazoline was dissolved in 200 ml of 35% hydrochloric acid and heated under reflux for 24 hours. After completion of the reaction, the reaction solution was made alkaline by adding potassium carbonate, extracted with chloroform, and the organic layer was dried over magnesium sulfate. The organic layer was filtered and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration, washed with isopropyl ether, and treated with 4-hydroxy-5,6,7,8-
8.5 g of tetrahydroquinazoline were obtained. Melting point 164
-165 ° C Raw material synthesis example 3 8.0 g of 4-hydroxy-5,6,7,8-tetrahydroquinazoline is dissolved in 50 ml of phosphorus oxychloride,
The mixture was heated under reflux for 3 hours. After completion of the reaction, the reaction solution was poured into ice water, and potassium carbonate was added to make the solution alkaline. The mixture was extracted with chloroform, and the organic layer was dried over magnesium sulfate. The organic layer was filtered and the solvent was distilled off under reduced pressure. The precipitated crystals are collected by filtration, washed with isopropyl ether, and then washed with 4-chloro-5,6,7,8-tetrahydroquinazoline 6.6.
g was obtained. Melting point 78-80 ° C Raw material synthesis example 4 4-Amino-5,6,7,8-tetrahydroquinazoline (7.0 g) was dissolved in chloroform (100 ml) and potassium carbonate aqueous solution (100 ml), and chloroacetyl chloride 3 was dissolved under vigorous stirring under ice-cooling. .2 ml was added dropwise. Then, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration to obtain 8.2 g of N- (5,6,7,8-tetrahydroquinazolin-4-yl) -2-chloroacetamide. 220 ° C

Material Synthesis Example 5 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (3.4 g) and N- (4
3.5 g of (-chlorophenyl) piperazine hydrochloride was added to 4 g of potassium carbonate and 1 g of potassium iodide in 30 ml of dimethylformamide, and the mixture was stirred at room temperature for 24 hours. After evaporating the solvent under reduced pressure, water was added to the residue and extracted with chloroform. Magnesium sulfate was added to the extract, the solvent was dried, filtered, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to give N- (5,6,7,
8-tetrahydroquinazolin-4-yl) -2- (4
2.6 g of-(4-chlorophenyl) piperazin-1-yl) acetamide were obtained. 1.3 g of lithium aluminum hydride was suspended in 50 ml of tetrahydrofuran,
At ℃ 2.6 g of this compound were added. The mixture was further stirred at room temperature for 30 minutes and cooled to 0 ° C. Ethyl acetate was slowly added dropwise to the reaction solution, and water was further added dropwise. The resulting aluminum hydroxide was filtered through celite and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is recrystallized from isopropyl alcohol to give 4-((2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8. -Tetrahydroquinazoline
7 g were obtained. Melting point 121-123 ° C Raw Material Synthesis Example 6 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (2.0 g) and N- (4
-Fluorophenyl) piperazine was reacted with 1.9 g of N- (5,6,7,8-
Tetrahydroquinazolin-4-yl) -2- (4-
2.0 g of (4-fluorophenyl) piperazin-1-yl) acetamide were obtained. Further, 1.7 g of this compound was reacted in the same manner as in Synthesis Example 5 of the starting material to give 4-((2-
1.5 g of (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline were obtained. 114-115 ° C

Raw Material Synthesis Example 7 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide and N- (4-bromophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give N- (5,6,7,8-tetrahydroquinazolin-4-yl ) To give 2- (4- (4-bromophenyl) piperazin-l-yl) acetamide. Further, this compound was reacted by the same operation as in Raw Material Synthesis Example 5,
4-((2- (4- (4-bromophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline is obtained. Raw Material Synthesis Example 8 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (1.0 g) and N- (4
-Methylphenyl) piperazine was reacted with 0.8 g of N- (5,6,7,8-tetrahydroquinazolin-4-yl) -2- (4- (4
1.3 g of -methylphenyl) piperazin-1-yl) acetamide were obtained. Further, this compound was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) amino)
-5,6,7,8-tetrahydroquinazoline 0.4g
I got ¹ H-NMR (CF ₃ COOH) δ: 1.94-2.1
2 (4H, m), 2.47 (3H, s), 2.50-
2.59 (2H, m), 2.85-2.96 (2H,
m), 3.88-3.98 (2H, m), 4.06-
4.91 (10H, m), 7.45-7.52 (4H,
m), 8.66 (1H, s)

Raw Material Synthesis Example 9 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (1.0 g) and N- (4
-Methoxyphenyl) piperazine (0.9 g) was reacted in the same manner as in Raw Material Synthesis Example 5 to give N- (5,6,7,8-
Tetrahydroquinazolin-4-yl) -2- (4-
0.9 g of (4-methoxyphenyl) piperazin-1-yl) acetamide was obtained. Further, 0.9 g of this compound was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2-
0.4 g of (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was obtained. Melting point 112-113 ° C Raw material synthesis example 10 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (1.0 g) and N- (3
-Chlorophenyl) piperazine was reacted with 1.0 g of N- (5,6,7,8-tetrahydroquinazolin-4-yl) -2- (4- (3
1.0 g of -chlorophenyl) piperazin-1-yl) acetamide were obtained. This compound was reacted in the same manner as in Synthesis Example 5 of the starting material to give 4-((2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) amino)
-5,6,7,8-tetrahydroquinazoline 0.3g
I got Melting point 97-99 ° C Raw material synthesis example 11 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (1.5 g) and 1- (3
-Trifluoromethylphenyl) piperazine was reacted with 1.2 g of N- (5,
6,7,8-tetrahydroquinazolin-4-yl)-
1.3 g of 2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) acetamide was obtained. Further, 1.3 g of this compound was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) amino)-
0.6 g of 5,6,7,8-tetrahydroquinazoline was obtained. Melting point 109-111 ° C

Raw Material Synthesis Example 12 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide and 1- (4-dimethylaminophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give N- (5,6,7,8-tetrahydroquinazoline-4- Yl) -2- (4- (4-Dimethylaminophenyl) piperazin-1-yl) acetamide is obtained. Further, this compound was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2- (4- (4-dimethylaminophenyl) piperazin-1-yl) ethyl) amino)
-5,6,7,8-Tetrahydroquinazoline is obtained. Raw Material Synthesis Example 13 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide and 1- (3,4-difluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give N- (5,6,7,8-tetrahydroquinazoline-4 -Yl) -2- (4- (3,4-difluorophenyl) piperazin-l-yl) acetamide is obtained. Further, this compound was reacted by the same operation as in Raw Material Synthesis Example 5 to give 4-((2- (4- (3,4-difluoroenyl) piperazin-1-yl) ethyl) amino)-
5,6,7,8-Tetrahydroquinazoline is obtained. Raw material synthesis example 14 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide and 1- (2,4-difluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give N- (5,6,7,8-tetrahydroquinazoline-4 -Yl) -2- (4- (2,4-difluorophenyl) piperazin-l-yl) acetamide is obtained. This compound was reacted in the same manner as in Synthesis Example 5 of the starting material to give 4-((2- (4- (2,4-difluoroenyl) piperazin-1-yl) ethyl) amino)-
5,6,7,8-Tetrahydroquinazoline is obtained.

Starting Material Synthesis Example 15 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (3.0 g) and 4- (6
-Fluoro-1,2-benzisoxazol-3-yl) piperidine and 3.2 g of N- (5,6,7,8-tetrahydroquinazoline-4) -Yl) -2- (4- (6-fluoro-
2.0 g of 1,2-benzisoxazol-3-yl) piperidin-1-yl) acetamide was obtained. Further, 2.0 g of this compound was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl). Ill)
1.0 g of ethyl) amino) -5,6,7,8-tetrahydroquinazoline was obtained. Melting point 106-107 ° C Raw material synthesis example 16 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide (1.5 g) and 4- (5
-Methyl-1-benzofuran-3-yl) piperidine and 1.5 g of N,
-(5,6,7,8-Tetrahydroquinazoline-4-
Yl) -2- (4- (5-methyl-1-benzofuran-
3-yl) piperidin-1-yl) acetamide 1.2
g was obtained. Further, 1.2 g of this compound was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2- (4- (5-methyl-1-benzofuran-3-yl) piperidin-1-yl) ethyl) amino ) 0.6 g of -5,6,7,8-tetrahydroquinazoline was obtained. ¹ H-NMR (CF ₃ COOH) δ: 1.95-2.3
4 (6H, m), 2.46 (3H, s), 2.39-
2.64 (4H, m), 2.82-2.96 (2H,
m), 3.10-3.27 (1H, m), 3.28-
3.44 (2H, m), 3.64-3.77 (2H,
m), 4.03-4.18 (2H, m), 4.22-
4.38 (2H, m), 7.18 (1H, d, J = 9H
z), 7.34 (1H, s), 7.36 (1H, d, J
= 9 Hz), 7.43 (1H, s), 8.66 (1H,
s)

Material Synthesis Example 17 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide and 4-phenylpipe
Lysine was reacted with lysine in the same manner as in Raw Material Synthesis Example 5 to give N-
(5,6,7,8-tetrahydroquinazoline-4-i
) -2- (4- (4-phenylpiperidin-1-i)
L) Acetamide is obtained. Further synthesis of this compound as raw material
The reaction was carried out in the same manner as in Example 5 to give 4-((2- (4-Fe
Nilpiperidin-1-yl) ethyl) amino) -5
6,7,8-Tetrahydroquinazoline is obtained. Raw Material Synthesis Example 18 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide and 1,2,3,6-
Example of raw material synthesis using tetrahydro-4-phenylpyridine
The reaction was carried out in the same manner as in Step 5, and N- (5, 6, 7, 8-
Trahydroquinazolin-4-yl) -2- (4-
(1,2,3,6-tetrahydro-4-phenylpyri
(Gin-1-yl) acetamide is obtained. Furthermore, this compound
The product was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2
-(1,2,3,6-tetrahydro-4-phenylpi
Lysin-1-yl) ethyl) amino) -5,6,7,8
Obtaining tetrahydroquinazoline; Raw material synthesis example 19 4-amino-5,6,7,8-tetrahydroquinazolyl
1.0 g of triethylamine and 1.4 ml of triethylamine
4-nitrobenzoyl chloride under ice-cooling
1.3 g were added. Stir at room temperature for 3 hours and add 4-d
Add 1.3 g of trobenzoyl chloride and reflux for 1 hour.
Was. The reaction solution was poured into an aqueous potassium carbonate solution under ice-cooling, and chloro
Extracted with Holm. After drying over magnesium sulfate, remove the solvent
The residue is purified by silica gel column chromatography.
Purified, N- (5,6,7,8-tetrahydroquinazo
0.5 g of (phosphin-4-yl) -4-nitrobenzamide
Obtained. ¹H-NMR (CDCl_Three) Δ: 1.66-2.
05 (4H, m), 2.52-3.04 (4H, m),
7.93-8.92 (6H, m)

Starting Material Synthesis Example 20 4-amino-5,6,7,8-tetrahydroquinazoline (1.0 g) and benzoyl chloride (0.95 g) were reacted in the same manner as in Starting Material Synthesis Example 19 to give N- (5,6 , 7,8
-Tetrahydroquinazolin-4-yl) benzamide (1.1 g) was obtained. ¹ H-NMR (CDCl 3) δ: 1.71-2.00
(4H, m), 2.67 (2H, t, J = 7 Hz),
2.93 (2H, t, J = 7 Hz), 7.43-7.6
5 (3H, m), 7.92 (2H, d, J = 8 Hz),
8.59 (1H, s), 8.69 (1H, s) Raw material synthesis example 21 4-amino-5,6,7,8-tetrahydroquinazoline and 4-chlorobenzoyl chloride were synthesized in the same manner as in raw material synthesis example 19. The reaction is performed by the operation to obtain N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-chlorobenzamide. Raw Material Synthesis Example 22 30 g of sodium methoxide was dissolved in 500 ml of methanol, and 51 g of acetamidine hydrochloride was added. The precipitated crystals were removed by filtration, and the filtrate was distilled off under reduced pressure. 50 g of 2-cyanocyclohexanone and 500 m of n-butanol were added to the residue.
and heated to reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 12 g of 4-amino-2-methyl-5,6,7,8-tetrahydroquinazoline. ¹ H-NMR (CDCl ₃ ) δ: 1.76-1.92
(4H, m), 2.30-2.40 (2H, m), 2.
45 (3H, m), 2.64-2.74 (2H, m),
4.9-5.1 (2H, brs)

Raw Material Synthesis Example 23 4-amino-2-methyl-5,6,7,8-tetrahydroquinazoline (4 g) and chloroacetyl chloride (3.9 m)
1 and N- (2-methyl-5,6,7,8-tetrahydroquinazoline-4-
4.2 g of yl) -2-chloroacetamide were obtained. ¹ H-NMR (CDCl 3) δ: 1.77-1.96
(4H, m), 2.56 (2H, t, J = 6 Hz),
2.60 (3H, s), 2.85 (2H, t, J = 6H)
z), 4.49 (2H, s), 8.14-8.26 (1
H, brs) Raw material synthesis example 24 N- (2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl) -2-chloroacetamide and 1-
(4-Fluorophenyl) piperazine was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -2-methyl- 5,6,7,8-Tetrahydroquinazoline is obtained. Starting Material Synthesis Example 25 4-Amino-2-methyl-5,6,7,8-tetrahydroquinazoline and 4-nitrobenzoyl chloride were reacted in the same manner as in Starting Material Synthesis Example 19 to give N- (2-methyl-5 , 6,7,8-Tetrahydroquinazolin-4-yl) -4-nitrobenzamide. Raw Material Synthesis Example 26 85 g of benzamidine hydrochloride and 50 g of 2-cyanocyclohexanone were reacted by the same operation as in Raw Material Synthesis Example 22,
14 g of 4-amino-2-phenyl-5,6,7,8-tetrahydroquinazoline was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.94
(4H, m), 2.32-2.44 (2H, m), 2.
74-2.86 (2H, m), 4.78-5.0 (2
H, brs), 7.35-7.48 (3H, m), 8.
23-8.35 (2H, m)

Raw Material Synthesis Example 27 4-amino-2-phenyl-5,6,7,8-tetrahydroquinazoline (4 g) and chloroacetyl chloride (2.8)
The reaction was carried out in the same manner as in Raw Material Synthesis Example 4 using
4.3 g of-(2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl) -2-chloroacetamide
I got Melting point 277-279 ° C / decomposition Raw material synthesis example 28 N- (2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl) -2-chloroacetamide 1.0
g and 1- (4-fluorophenyl) piperazine 0.8 g
Was reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2-
(4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -2-phenyl-5,6,7,8
-0.84 g of tetrahydroquinazoline was obtained. Melting point 1
51-152 ° C Raw Material Synthesis Example 29 4-Amino-2-phenyl-5,6,7,8-tetrahydroquinazoline and 4-nitrobenzoyl chloride were reacted in the same manner as in Raw Material Synthesis Example 19 to give N- (2 -Phenyl-5,6,7,8-tetrahydroquinazoline-4
-Yl) -4-nitrobenzamide is obtained. Raw Material Synthesis Example 30 1-Chloro-5,6,7,8-tetrahydroisoquinoline and 1- (2-aminoethyl) -4- (4-fluorophenyl) piperazine are dissolved in dimethylformamide, and potassium carbonate is added. Heat and stir at 70 ° C. After completion of the reaction, the solvent is distilled off under reduced pressure, an aqueous potassium carbonate solution is added, and the mixture is extracted with chloroform. Dry over magnesium sulfate and evaporate the solvent under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 1-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroisoquinoline.

Starting Material Synthesis Example 31 1-Chloro-5,6,7,8-tetrahydroisoquinoline and 1- (2-aminoethyl) -4-benzoylpiperidine were reacted in the same manner as in Starting Material Synthesis Example 19 to give 1 −
((2- (4-benzoylpiperidin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroisoquinoline is obtained. Starting Material Synthesis Example 32 4-Amino-5,6,7,8-tetrahydroquinoline was reacted with chloroacetyl chloride in the same manner as in Starting Material Synthesis Example 4 to give N- (5,6,7,8-tetrahydroquinoline. -4-yl) -2-chloroacetamide is obtained. Raw Material Synthesis Example 33 N- (5,6,7,8-tetrahydroquinoline-4-
Yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 4-((2- (4- (4-fluorophenyl) piperazin-1-yl). Ethyl) amino) -5,6,7,
8-tetrahydroquinoline is obtained. Starting Material Synthesis Example 34 4-Amino-5,6,7,8-tetrahydroquinoline and 4-nitrobenzoyl chloride are reacted in the same manner as in Starting Material Synthesis Example 19 to give N- (5,6,7,8-tetrahydroquinoline). (Hydroquinolin-4-yl) -4-nitrobenzamide is obtained. Starting Material Synthesis Example 35 4-amino-5,6,7,8-tetrahydroisoquinoline was reacted with chloroacetyl chloride in the same manner as in Starting Material Synthesis Example 4 to give N- (5,6,7,8-tetrahydroisoquinoline. -4-yl) -2-chloroacetamide is obtained. Material Synthesis Example 36 N- (5,6,7,8-tetrahydroisoquinoline-
4-yl) -2-chloroacetamide was reacted with 1- (4-fluorophenyl) piperazine by the same operation as in Raw Material Synthesis Example 5 to give 4-((2- (4- (4-fluorophenyl) piperazine-1- Yl) ethyl) amino) -5
6,7,8-Tetrahydroisoquinoline is obtained. Starting Material Synthesis Example 37 Starting material synthesis example 19 using 4-amino-5,6,7,8-tetrahydroisoquinoline and 4-nitrobenzoyl chloride.
To obtain N- (5,6,7,8-tetrahydroquinolin-4-yl) -4-nitrobenzamide.

Starting Material Synthesis Example 38 2-Methoxy-3,4,5,6-tetrahydropyridine and semicarbazide are refluxed in ethanol. The reaction is cooled to room temperature and the solvent is distilled off under reduced pressure. The residue was purified using silica gel column chromatography to give 3-amino-5,6,7,8-tetrahydro-1,2,4-
Triazolo [4,3-a] pyridine is obtained. Raw material synthesis example 39 3-amino-5,6,7,8-tetrahydro-1,
2,4-Triazolo [4,3-a] pyridine and chloroacetyl chloride were reacted by the same operation as in Raw Material Synthesis Example 4 to give N- (5,6,7,8-tetrahydro-1,2,2
4-triazolo [4,3-a] pyridin-3-yl)-
This gives 2-chloroacetamide. Raw Material Synthesis Example 40 N- (5,6,7,8-tetrahydro-1,2,4-
Triazolo [4,3-a] pyridin-3-yl) -2-
Chloroacetamide and 1- (4-fluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-chloroacetamide.
((2- (4- (4-fluorophenyl) piperazine-
1-yl) ethyl) amino) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridine is obtained. Raw material synthesis example 41 3-amino-5,6,7,8-tetrahydro-1,
2,4-Triazolo [4,3-a] pyridine and 4-nitrobenzoyl chloride were reacted in the same manner as in Raw Material Synthesis Example 19 to give N- (5,6,7,8-tetrahydro-
1,2,4-triazolo [4,3-a] pyridine-3-
Yl) -4-nitrobenzamide.

Raw Material Synthesis Example 42 10 g of 2-cyanocyclohexanone and 9.8 g of sodium hydroxide were dissolved in 200 ml of water, and 11.3 g of hydroxylamine hydrochloride was added at room temperature and stirred. After completion of the reaction, the reaction solution was extracted with chloroform, and the organic layer was dried over magnesium sulfate. The organic layer was filtered and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration and washed with isopropyl ether to obtain 9.0 g of 3-amino-4,5,6,7-tetrahydro-2,1-benzisoxazole. Melting point 112-114 ° C Raw material synthesis example 43 3-amino-4,5,6,7-tetrahydro-2,1
-Benzisoxazole (4.0 g) and chloroacetyl chloride (4.8 ml) were reacted in the same manner as in Raw Material Synthesis Example 4 to give N- (4,5,6,7-tetrahydro-2,1-
5.1 g of benzisoxazol-3-yl) -2-chloroacetamide were obtained. Melting point 121-122 ° C Raw material synthesis example 44 N- (4,5,6,7-tetrahydro-2,1-benzisoxazol-3-yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine Was reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2- (4- (4
-Fluorophenyl) piperazin-1-yl) ethyl)
Amino) -4,5,6,7-tetrahydro-2,1-
Obtain benzisoxazole. Raw Material Synthesis Example 45 3-Amino-4,5,6,7-tetrahydro-2,1
-Benzisoxazole and 4-nitrobenzoyl chloride were reacted in the same manner as in Raw Material Synthesis Example 19 to give N-
(4,5,6,7-Tetrahydro-2,1-benzisoxazol-3-yl) -4-nitrobenzamide is obtained.

Material Synthesis Example 46 3-Amino-4,5,6,7-tetrahydro-2,1
-Benzisoxazole and benzoyl chloride as raw materials
The reaction was carried out in the same manner as in Example 19, and N- (4, 5, 6,
7-tetrahydro-2,1-benzisoxazole-
3-yl) benzamide is obtained. Raw material synthesis example 47 1-methyl-4,5,6,7-tetrahydro-1H-
Dissolve 1 g of indazol-4-one in ethylene glycol
1.66 g of hydrazine monohydrate and hydroxylated at room temperature
2.2 g of potassium was added and heated at 180 ° C. for 2 hours.
After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate.
Was. Dry over magnesium sulfate and evaporate the solvent under reduced pressure.
Was. Purify the residue by silica gel column chromatography
And 1-methyl-4,5,6,7-tetrahydro-1
H-indazole was obtained quantitatively. ¹ H-NMR (CDCl_Three) Δ: 1.63-1.75
(2H, m), 1.75-1.86 (2H, m), 2.
45-2.57 (4H, m), 3.71 (3H, s),
7.21 (1H, s) Raw material synthesis example 48 1-methyl-4,5,6,7-tetrahydro-1H-
Indazole is dissolved in water-methanol and sulfurized under ice cooling.
The acid is added dropwise, followed by nitric acid. After completion of the reaction, the reaction solution is
Add potassium carbonate and extract with chloroform.
Dry over magnesium sulfate and evaporate the solvent under reduced pressure. Residue
Was purified by silica gel column chromatography.
Methyl-3-nitro-4,5,6,7-tetrahydro
Obtain indazole. Raw material synthesis example 49 1-methyl-3-nitro-4,5,6,7-tetrahi
Dronedazole is dissolved in 35% hydrochloric acid-methanol,
Add iron powder under ice cooling. After the reaction is complete, pour the reaction solution into ice water.
Add potassium carbonate and extract with chloroform. Sulfuric acid
Dry over magnesium and evaporate the solvent under reduced pressure. Residue
Purified by Ricagel column chromatography,
No-1-methyl-4,5,6,7-tetrahydro-1
H-indazole is obtained.

Starting Material Synthesis Example 50 3-Amino-1-methyl-4,5,6,7-tetrahydro-1H-indazole was reacted with chloroacetyl chloride in the same manner as in Starting Material Synthesis Example 4 to give N- (1 -Methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) -2-chloroacetamide is obtained. Raw material synthesis example 51 N- (1-methyl-4,5,6,7-tetrahydro-
1H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (4-fluorophenyl) piperazine in the same manner as in Synthesis Example 5 of the starting material, to give 3-((2- (4- (4
-Fluorophenyl) piperazin-1-yl) ethyl)
Amino) -1-methyl-4,5,6,7-tetrahydro-1H-indazole is obtained. Starting Material Synthesis Example 52 3-Amino-1-methyl-4,5,6,7-tetrahydro-1H-indazole and 4-nitrobenzoyl chloride were reacted in the same manner as in Starting Material Synthesis Example 19 to give N-
(1-Methyl-4,5,6,7-tetrahydro-1H
-Indazol-3-yl) -4-nitrobenzamide. Raw material synthesis example 53 1-phenyl-4,5,6,7-tetrahydro-1H
-Indazol-4-one is reacted in the same manner as in Synthesis Example 47 of the starting material to obtain 1-phenyl-4,5,6,7-tetrahydro-1H-indazole.

Material Synthesis Example 54 1-Phenyl-4,5,6,7-tetrahydro-1H
-Indazole is reacted in the same manner as in Raw Material Synthesis Example 48 to obtain 1-phenyl-3-nitro-4,5,6,7-tetrahydroindazole. Starting Material Synthesis Example 55 1-Phenyl-3-nitro-4,5,6,7-tetrahydroindazole was reacted in the same manner as in Starting Material Synthesis Example 49 to give 3-amino-1-phenyl-4,5,6,6. 7-
This gives tetrahydro-1H-indazole. Starting Material Synthesis Example 56 3-Amino-1-phenyl-4,5,6,7-tetrahydro-1H-indazole was reacted with chloroacetyl chloride in the same manner as in Starting Material Synthesis Example 4 to give N- (1-phenyl- (4,5,6,7-Tetrahydro-1H-indazol-3-yl) -2-chloroacetamide is obtained. Starting Material Synthesis Example 57 N- (1-phenyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine were used in the same manner as in Starting Material Synthesis Example 5. And the reaction was performed using 3-((2- (4-
(4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -1-phenyl-4,5,6,7-tetrahydro-1H-indazole is obtained. Starting Material Synthesis Example 58 3-Amino-1-phenyl-4,5,6,7-tetrahydro-1H-indazole was reacted with 4-nitrobenzoyl chloride in the same manner as in Starting Material Synthesis Example 19 to give N-
(1-phenyl-4,5,6,7-tetrahydro-1
(H-indazol-3-yl) -4-nitrobenzamide is obtained.

Starting Material Synthesis Example 59 3-Amino-1-methyl-4,5,6,7-tetrahydro-1H-indazole was reacted with benzoyl chloride in the same manner as in Starting Material Synthesis Example 19 to give N- (1- Methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) benzamide is obtained. Raw material synthesis example 60 N- (1-methyl-4,5,6,7-tetrahydro-
1H-indazol-3-yl) -2-chloroacetamide was reacted with 1-phenylpiperazine in the same manner as in Synthesis Example 5 of the starting material to give 3-((2- (4-phenylpiperazin-1-yl) ethyl) amino) -1-methyl-4,5,
6,7-Tetrahydro-1H-indazole is obtained. Raw Material Synthesis Example 61 N- (1-methyl-4,5,6,7-tetrahydro-
1H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (4-chlorophenyl) piperazine in the same manner as in Synthesis Example 5 of the starting material, to give 3-((2- (4- (4
-Chlorophenyl) piperazin-1-yl) ethyl) amino) -1-methyl-4,5,6,7-tetrahydro-1H-indazole is obtained.

Raw Material Synthesis Example 62 N- (1-Methyl-4,5,6,7-tetrahydro-
1H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (4-methylphenyl) piperazine by the same operation as in Raw Material Synthesis Example 5 to give 3-((2- (4- (4
-Methylphenyl) piperazin-1-yl) ethyl) amino) -1-methyl-4,5,6,7-tetrahydro-1H-indazole is obtained. Raw material synthesis example 63 N- (1-methyl-4,5,6,7-tetrahydro-
1H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (4-methoxyphenyl) piperazine in the same manner as in Synthesis Example 5 of the starting material to give 3-((2- (4-
(4-Methoxyphenyl) piperazin-1-yl) ethyl) amino) -1-methyl-4,5,6,7-tetrahydro-1H-indazole is obtained. Raw Material Synthesis Example 64 40 g of 2-cyanocyclohexanone was dissolved in ethanol, 15 ml of methylhydrazine was added at room temperature, and the mixture was heated under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give 3-amino-2-methyl-4,5,6,7-tetrahydro-2H.
-25 g of indazole were obtained. Melting point 53-56 ° C Raw material synthesis example 65 The same operation as raw material synthesis example 4 was performed using 3-amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole 5.5 g and chloroacetyl chloride 3.2 ml. To obtain 4.5 g of N- (2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -2-chloroacetamide. 152-153 ° C

Material Synthesis Example 66 N- (2-methyl-4,5,6,7-tetrahydro-
4.5 g of 2H-indazol-3-yl) -2-chloroacetamide and 4.6 g of 1- (4-chlorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-g.
((2- (4- (4-chlorophenyl) piperazine-1
-Yl) ethyl) amino) -2-methyl-4,5,6
5.7 g of 7-tetrahydro-2H-indazole was obtained. Melting point 88-90 ° C Raw material synthesis example 67 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2- (4-
(4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole is obtained. Raw material synthesis example 68 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 1- (4-bromophenyl) piperazine were reacted by the same operation as in Raw Material Synthesis Example 5 to give 3-((2- (4- (4
-Bromophenyl) piperazin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole is obtained. Raw Material Synthesis Example 69 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (4-methylphenyl) piperazine in the same manner as in Synthesis Example 5 of the starting material, to give 3-((2- (4- (4
This gives -methylphenyl) piperazin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole.

Material Synthesis Example 70 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (4-methoxyphenyl) piperazine in the same manner as in Synthesis Example 5 of the starting material to give 3-((2- (4-
(4-Methoxyphenyl) piperazin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole is obtained. Raw Material Synthesis Example 71 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (3-chlorophenyl) piperazine in the same manner as in Synthesis Example 5 of the starting material, to give 3-((2- (4- (3
-Chlorophenyl) piperazin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole is obtained. Raw Material Synthesis Example 72 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 1- (2-chlorophenyl) piperazine were reacted by the same operation as in Synthesis Example 5 of the starting material, and 3-((2- (4- (2
-Chlorophenyl) piperazin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole is obtained. Raw Material Synthesis Example 73 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide was reacted with 1-phenylpiperazine in the same manner as in Synthesis Example 5 of the starting material, to give 3-((2- (4-phenylpiperazin-1-yl) ethyl) amino) -2-methyl-4,5,
6,7-Tetrahydro-2H-indazole is obtained.

Raw Material Synthesis Example 74 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 1- (3-trifluoromethylphenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2
-(4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) amino) -2-methyl-4,
5,6,7-Tetrahydro-2H-indazole is obtained. Material Synthesis Example 75 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide was reacted with 1- (4-dimethylaminophenyl) piperazine in the same manner as in Synthesis Example 5 of the starting material to give 3-((2-
(4- (4-dimethylaminophenyl) piperazine-1
-Yl) ethyl) amino) -2-methyl-4,5,6
7-Tetrahydro-2H-indazole is obtained. Material Synthesis Example 76 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 1- (3,4-difluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2-
(4- (3,4-difluorophenyl) piperazine-1
-Yl) ethyl) amino) -2-methyl-4,5,6
7-Tetrahydro-2H-indazole is obtained. Material Synthesis Example 77 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 1- (2,4-difluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2-
(4- (2,4-difluorophenyl) piperazine-1
-Yl) ethyl) amino) -2-methyl-4,5,6
7-Tetrahydro-2H-indazole is obtained. Raw Material Synthesis Example 78 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidine were reacted by the same operation as in Raw Material Synthesis Example 5 to give 3- ( (2- (4- (6-fluoro-1,
2-benzisoxazol-3-yl) piperidine-1
-Yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole is obtained.

Raw Material Synthesis Example 79 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 4- (5-methyl-1-benzofuran-3-yl)
Piperidine was reacted in the same manner as in Raw Material Synthesis Example 5 to give 3
-((2- (4- (5-methyl-1-benzofuran-3)
-Yl) piperidin-1-yl) ethyl) amino)-
4,5,6,7-tetrahydro-2-methyl-2H-
Obtain indazole. Starting Material Synthesis Example 80 3-amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole (4.5 g) and 4-nitrobenzoyl chloride (5.6 g) were reacted in the same manner as in Starting Material Synthesis Example 19. 5.8 g of N- (2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -4-nitrobenzamide were obtained. Melting point 250-251 ° C Raw material synthesis example 81 2.3 g of 3-amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole and 2.1 g of benzoyl chloride were obtained in the same manner as in Raw material synthesis example 19. React
N- (2-methyl-4,5,6,7-tetrahydro-
1.9 g of 2H-indazol-3-yl) benzamide
I got Melting point 184-185 ° C. Raw material synthesis example 82 3-Amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole and 2-pyridinecarbonyl chloride are reacted in the same operation as in raw material synthesis example 19, N-
(2-methyl-4,5,6,7-tetrahydro-2H
-Indazol-3-yl) -2-pyridinecarboxamide is obtained. Starting Material Synthesis Example 83 3-Amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole and 4-chlorobenzoyl chloride were reacted in the same manner as in Starting Material Synthesis Example 19 to give N-
(2-methyl-4,5,6,7-tetrahydro-2H
-Indazol-3-yl) -4-chlorobenzamide.

Starting Material Synthesis Example 84 3-Amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole and 4-methoxybenzoyl chloride were reacted in the same manner as in Starting Material Synthesis Example 19 to give N-
(2-methyl-4,5,6,7-tetrahydro-2H
-Indazol-3-yl) -4-methoxybenzamide. Starting Material Synthesis Example 85 3-Amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole was reacted with 3-pyridinecarbonyl chloride in the same manner as in Starting Material Synthesis Example 19 to give N-
(2-methyl-4,5,6,7-tetrahydro-2H
-Indazol-3-yl) -3-pyridinecarboxamide is obtained. Starting Material Synthesis Example 86 3-Amino-2-methyl-4,5,6,7-tetrahydro-2H-indazole and 4-fluorobenzoyl chloride were reacted in the same manner as in Starting Material Synthesis Example 19 to give N-
(2-methyl-4,5,6,7-tetrahydro-2H
-Indazol-3-yl) -4-fluorobenzamide. Raw Material Synthesis Example 87 40 g of 2-cyanocyclohexanone and 15 ml of phenylhydrazine were reacted by the same operation as in Raw Material Synthesis Example 64,
25 g of 3-amino-2-phenyl-4,5,6,7-tetrahydro-2H-indazole were obtained. Melting point 143
-144 ° C Raw Material Synthesis Example 88 Reaction of 5.5 g of 3-amino-2-phenyl-4,5,6,7-tetrahydro-2H-indazole with 3.2 ml of chloroacetyl chloride in the same manner as in Raw Material Synthesis Example 4. Then, 4.5 g of N- (2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -2-chloroacetamide was obtained. Melting point 161-162 ° C

Raw Material Synthesis Example 89 4.5 g of N- (2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine 4.6 g was reacted in the same manner as in Raw Material Synthesis Example 5 to give 3 g
-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -2-phenyl-4,
5,6,7-tetrahydro-2H-indazole5.
7 g were obtained. Melting point 124-125 ° C Raw material synthesis example 90 3-Amino-2-phenyl-4,5,6,7-tetrahydro-2H-indazole and 4-nitrobenzoyl chloride were reacted in the same manner as in Raw material synthesis example 19, N-
(2-phenyl-4,5,6,7-tetrahydro-2
(H-indazol-3-yl) -4-nitrobenzamide is obtained. Raw Material Synthesis Example 91 2-cyanocyclohexanone (11 g) and hydrazine monohydrate (3.2 g) were dissolved in ethanol (100 ml) and heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
7.6 g of amino-4,5,6,7-tetrahydro-2H-indazole were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.67-1.82
(4H, m), 2.24-2.38 (4H, m), 2.
48-2.58 (2H, m), 2.62 (3H, s),
5.00-5.30 (3H, brs) Raw material synthesis example 92 3-amino-4,5,6,7-tetrahydro-1H-
Indazole (70 g) was dissolved in ethylene dichloride (700 ml), and tertiary butoxycarbonyl anhydride (65.4) was added at room temperature.
g was added. After completion of the reaction, isopropyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration to give 3-amino-2-tert-butoxycarbonyl-.
40 g of 4,5,6,7-tetrahydro-2H-indazole was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.80
(4H, m), 1.64 (9H, s), 2.22-2.
30 (2H, m), 2.56-2.63 (2H, m),
4.98-5.10 (2H, brs)

Starting Material Synthesis Example 93 3-amino-2-tertiary-butoxycarbonyl-4,5
6,7-Tetrahydro-2H-indazole and 4-nitrobenzoyl chloride were reacted in the same manner as in Raw Material Synthesis Example 19 to give N- (2-tert-butoxycarbonyl-4,
5,6,7-tetrahydro-2H-indazole-3
-Yl) -4-nitrobenzamide is obtained. Starting Material Synthesis Example 94 3-cyanopyran-4-one and methylhydrazine were reacted in the same manner as in Starting Material Synthesis Example 64 to give 3-amino-2-
Methyl-2,4,6,7-tetrahydropyrano [4,
3-c] pyrazole is obtained. Starting Material Synthesis Example 95 3-Amino-2-methyl-2,4,6,7-tetrahydropyrano [4,3-c] pyrazole and chloroacetyl chloride were reacted in the same manner as in Starting Material Synthesis Example 4 to give N. −
(2-Methyl-2,4,6,7-tetrahydropyrano [4,3-c] pyrazol-3-yl) -2-chloroacetamide is obtained. Starting Material Synthesis Example 96 N- (2-Methyl-2,4,6,7-tetrahydropyrano [4,3-c] pyrazol-3-yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine Was reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2
-(4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -2-methyl-2,4,6,7-
Tetrahydropyrano [4,3-c] pyrazole is obtained.

Starting Material Synthesis Example 97 3-Amino-2-methyl-2,4,6,7-tetrahydropyrano [4,3-c] pyrazole and 4-nitrobenzoyl chloride were prepared in the same manner as in Starting Material Synthesis Example 19. And N- (2-methyl-2,4,6,7-tetrahydropyrano [4,3-c] pyrazol-3-yl) -4-
Obtain nitrobenzamide. Starting Material Synthesis Example 98 3-cyanothiopyran-4-one and methylhydrazine were reacted in the same manner as in Starting Material Synthesis Example 64 to give 3-amino-
This gives 2-methyl-2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazole. Starting Material Synthesis Example 99 3-Amino-2-methyl-2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazole and chloroacetyl chloride are reacted in the same manner as in Starting Material Synthesis Example 4,
N- (2-methyl-2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) -2-
Obtain chloroacetamide. Raw material synthesis example 100 N- (2-methyl-2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) -2-
Chloroacetamide and 1- (4-fluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-chloroacetamide.
((2- (4- (4-fluorophenyl) piperazine-
1-yl) ethyl) amino) -2-methyl-2,4,
6,7-Tetrahydrothiopyrano [4,3-c] pyrazole is obtained.

Starting Material Synthesis Example 101 3-Amino-2-methyl-2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazole and 4-nitrobenzoyl chloride were prepared in the same manner as in Starting Material Synthesis Example 19. The reaction is performed by the operation to obtain N- (2-methyl-2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) -4-nitrobenzamide. Starting Material Synthesis Example 102 3-Cyano-1-methyl-4-piperidone and methylhydrazine were reacted in the same manner as in Starting Material Synthesis Example 64 to give 3-
Amino-4,5,6,7-tetrahydro-2H-2,
This gives 5-dimethylpyrido [4,3-c] pyrazole. Raw Material Synthesis Example 103 3-Amino-4,5,6,7-tetrahydro-2H-
2,5-Dimethylpyrido [4,3-c] pyrazole and chloroacetyl chloride were reacted in the same manner as in Raw Material Synthesis Example 4 to give N- (4,5,6,7-tetrahydro-2H
-2,5-dimethylpyrido [4,3-c] pyrazole-
3-yl) -2-chloroacetamide is obtained. Raw Material Synthesis Example 104 N- (4,5,6,7-tetrahydro-2H-2,5
-Dimethylpyrido [4,3-c] pyrazol-3-yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2- (4 -(4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7
-To obtain tetrahydro-2H-2,5-dimethylpyrido [4,3-c] pyrazole. Raw Material Synthesis Example 105 3-Amino-4,5,6,7-tetrahydro-2H-
2,5-dimethylpyrido [4,3-c] pyrazole and 4
-Nitrobenzoyl chloride was reacted in the same manner as in Starting Material Synthesis Example 19 to give N- (4,5,6,7-tetrahydro-2H-2,5-dimethylpyrido [4,3-c] pyrazol-3-yl ) -4-Nitrobenzamide is obtained.

Starting Material Synthesis Example 106 2-cyano-4-methylcyclohexanone and methylhydrazine were reacted in the same manner as in Starting Material Synthesis Example 64 to give 3-
Amino-2,5-dimethyl-4,5,6,7-tetrahydro-2H-indazole is obtained. Starting Material Synthesis Example 107 3-Amino-2,5-dimethyl-4,5,6,7-tetrahydro-2H-indazole was reacted with chloroacetyl chloride in the same manner as in Starting Material Synthesis Example 4 to give N-
(2,5-Dimethyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -2-chloroacetamide is obtained. Raw Material Synthesis Example 108 N- (2,5-dimethyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -2-chloroacetamide and 1- (4-fluorophenyl) piperazine are used as raw material synthesis examples. The reaction was carried out in the same manner as in 5, and 3-((2-
(4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -2,5-dimethyl-4,5
6,7-Tetrahydro-2H-indazole is obtained. Starting Material Synthesis Example 109 3-Amino-2,5-dimethyl-4,5,6,7-tetrahydro-2H-indazole was reacted with 4-nitrobenzoyl chloride in the same manner as in Starting Material Synthesis Example 19,
N- (2,5-dimethyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) -4-nitrobenzamide is obtained.

Raw Material Synthesis Example 110 N- (5,6,7,8-tetrahydroquinazoline-4
1- (5,6,7,8-tetrahydroquinazolin-4-yl) -2- (4- (2-Chlorophenyl) piperazin-1-yl) acetamide is obtained. Further, this compound was reacted by the same operation as in Raw Material Synthesis Example 5,
4-((2- (4- (2-Chlorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline is obtained. Raw material synthesis example 111 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -2-chloroacetamide and 1-phenylpiperazine were reacted in the same manner as in Raw Material Synthesis Example 5 to give 1-
(5,6,7,8-Tetrahydroquinazolin-4-yl) -2- (4-phenylpiperazin-1-yl) acetamide is obtained. This compound was reacted in the same manner as in Synthesis Example 5 of the starting material to give 4-((2- (4-phenylpiperazin-1-yl) ethyl) amino) -5,6,7,8.
Obtaining tetrahydroquinazoline; Raw Material Synthesis Example 112 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide was reacted with 4-phenylpiperidine by the same operation as in Raw Material Synthesis Example 5 to give 3-((2- (4-phenylpiperidin-1-yl) ethyl) amino) -2-methyl-4,5,
6,7-Tetrahydro-2H-indazole is obtained. Raw Material Synthesis Example 113 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide was reacted with 4- (4-fluorophenyl) piperidine in the same manner as in Synthesis Example 5 of the starting material, to give 3-((2- (4-
(4-Fluorophenyl) piperidin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole is obtained.

Raw Material Synthesis Example 114 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 4-phenyl-1,2,3,6-tetrahydropyridine were reacted in the same manner as in Synthesis Example 5 of the starting material to give 3-
((2- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) ethyl) amino) -2-methyl-4,5,6,7-tetrahydro-2H-indazole is obtained. . Raw Material Synthesis Example 115 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) -2-chloroacetamide and 4- (4-fluorophenyl) -1,2,3,6-
Tetrahydropyridine was reacted in the same manner as in Raw Material Synthesis Example 5 to give 3-((2- (4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine-1-
Yl) ethyl) amino) -2-methyl-4,5,6,7
-To obtain tetrahydro-2H-indazole. Raw material synthesis example 116 N- (2-methyl-4,5,6,7-tetrahydro-
2H-indazol-3-yl) benzamide 0.9 g
Was dissolved in 10 ml of dimethylformamide, and 155 mg of sodium hydride was added at room temperature. The mixture was stirred at room temperature for 30 minutes, and 2-((3,4,5,6-tetrahydropyran-
0.74 g of 2-yl) oxy) ethyl bromide was added. The reaction was carried out at room temperature for 1 hour and at 70 ° C. for 5 hours, and the solvent was distilled off under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 5 ml of methanol and 100 mg of p-toluenesulfonic acid were added to the residue.
Was added and the mixture was heated and stirred at 60 ° C. for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give N- (2-hydroxyethyl) -N- (2-methyl-4,5,6,7-tetrahydrohydrogen. 1.08 g of (-2H-indazol-3-yl) benzamide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.50-1.85
(4H, m), 2.05-2.18 (1H, m), 2.
30-2.45 (1H, m), 2.45-2.59 (2
H, m), 3.56 (3H, s), 3.70-4.00.
(4H, m), 7.16-7.39 (5H, m)

Raw Material Synthesis Example 117 N- (2-hydroxyethyl) -N- (2-methyl-
1.08 g of 4,5,6,7-tetrahydro-2H-indazol-3-yl) benzamide was added to chloroform 1
The solution was dissolved in 0 ml, and 0.4 ml of thionyl chloride was added dropwise under ice cooling. After stirring at room temperature overnight, the reaction solution was poured into ice-potassium carbonate aqueous solution. After extraction with chloroform and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue is purified by silica gel chromatography, and N- (2-chloroethyl)
-N- (2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) benzamide 0.8
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.48-1.79
(4H, m), 1.99-2.13 (1H, m), 2.
27-2.40 (1H, m), 2.48-2.57 (2
H, m), 3.55 (3H, s), 3.56-3.70.
(1H, m), 3.72-3.84 (1H, m), 3.
89-4.00 (1H, m), 4.12-4.24 (1
H, m), 7.19-7.37 (5H, m) Formulas 30 to 41 show the structural formulas of the compounds obtained in the above synthesis examples of the raw materials.

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Example 1 4-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline and triethylamine were dissolved in chloroform. Under ice cooling, 4-nitrobenzoyl chloride is added. After completion of the reaction, the reaction solution was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain N- (2
-(4- (4-Fluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-nitrobenzamide is obtained. This compound is dissolved in a 35% hydrochloric acid-methanol mixed solvent, and tin powder is added under ice cooling. After completion of the reaction, the reaction solution is made basic with an aqueous potassium carbonate solution and extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl). -N-
(5,6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained. Example 2 4-((2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was reacted in the same manner as in Example 1. , N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,
(6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained.

Example 3 4-((2- (4- (4-bromophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was prepared in the same manner as in Example 1. The reaction was carried out by operation and N- (2- (4- (4-bromophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4- Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-bromophenyl) piperazin-1-yl) ethyl) -N- (5,
(6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained. Example 4 4-((2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was reacted in the same manner as in Example 1. To give N- (2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-nitrobenzamide. obtain. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) -N- (5,
(6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained. Example 5 4-((2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was reacted in the same manner as in Example 1. To give N- (2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-
This gives tetrahydroquinazolin-4-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained.

Example 6 4-((2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was treated in the same manner as in Example 1. And N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-nitrobenzamide Get. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,
(6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained. Example 7 4-((2- (4- (2-chlorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was reacted in the same manner as in Example 1. , N- (2- (4- (2-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (2-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,
(6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained. Example 8 4-((2- (4-phenylpiperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was reacted in the same manner as in Example 1, and N- ( 2-
(4-phenylpiperazin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydroquinazolin-4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2
-(4-phenylpiperazin-1-yl) ethyl) -N
-(5,6,7,8-Tetrahydroquinazoline-4-
Il) to obtain benzamide. Example 9 4-((2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) amino) -5
6,7,8-Tetrahydroquinazoline was reacted in the same manner as in Example 1, and N- (2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) was reacted.
-N- (5,6,7,8-tetrahydroquinazoline-
4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N
-(2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8
-Tetrahydroquinazolin-4-yl) benzamide.

Example 10 4-((2- (4- (4-dimethylaminophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,
8-Tetrahydroquinazoline was reacted in the same manner as in Example 1 to give N- (2- (4- (4-dimethylaminophenyl) piperazin-1-yl) ethyl) -N- (5,
6,7,8-tetrahydroquinazolin-4-yl)-
4-nitrobenzamide is obtained. This compound was prepared in Example 1
The reaction was carried out in the same manner as described above, and 4-amino-N- (2- (4
-(4-Dimethylaminophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide is obtained. Example 11 4-((2- (4- (3,4-difluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,
8-Tetrahydroquinazoline was reacted in the same manner as in Example 1 to give N- (2- (4- (3,4-difluorophenyl) piperazin-1-yl) ethyl) -N- (5,
6,7,8-tetrahydroquinazolin-4-yl)-
4-nitrobenzamide is obtained. This compound was prepared in Example 1
The reaction was carried out in the same manner as described above, and 4-amino-N- (2- (4
-(3,4-Difluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide is obtained. Example 12 4-((2- (4- (2,4-difluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,
8-Tetrahydroquinazoline was reacted in the same manner as in Example 1 to give N- (2- (4- (2,4-difluorophenyl) piperazin-1-yl) ethyl) -N- (5,
6,7,8-tetrahydroquinazolin-4-yl)-
4-nitrobenzamide is obtained. This compound was prepared in Example 1
The reaction was carried out in the same manner as described above, and 4-amino-N- (2- (4
-(2,4-Difluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide is obtained. Example 13 4-((2- (4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl) ethyl) amino) -5,6,7,8-tetra Hydroquinazoline was reacted in the same manner as in Example 1, and N- (2-
(4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydroquinazolin-4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2
-(4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained.

Example 14 4-((2- (4- (5-methyl-1-benzofuran-
3-yl) piperidin-1-yl) ethyl) amino)-
Example 1, using 5,6,7,8-tetrahydroquinazoline
And N- (2- (4- (5-methyl-1-benzofuran-3-yl) piperidin-1-yl) ethyl) -N- (5,6,7,8-tetra Hydroquinazolin-4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4
-Amino-N- (2- (4- (5-methyl-1-benzofuran-3-yl) piperidin-1-yl) ethyl)-
N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) benzamide is obtained. Example 15 4-((2- (4-phenylpiperidin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline was reacted in the same manner as in Example 1 to give N- ( 2-
(4-phenylpiperidin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydroquinazolin-4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2
-(4-phenylpiperidin-1-yl) ethyl) -N
-(5,6,7,8-Tetrahydroquinazoline-4-
Il) to obtain benzamide. Example 16 4-((2- (1,2,3,6-tetrahydro-4-
Phenylpyridin-1-yl) ethyl) amino) -5
6,7,8-Tetrahydroquinazoline was reacted in the same manner as in Example 1 to give N- (2- (1,2,3,6-tetrahydro-4-phenylpyridin-1-yl) ethyl)- This gives N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (1,2,3,6-tetrahydro-4-
Phenylpyridin-1-yl) ethyl) -N- (5,
(6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained. Example 17 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -4-nitrobenzamide is dissolved in dimethylformamide and at room temperature one equivalent of sodium hydride and a catalytic amount of sodium iodide are added. After stirring at room temperature for 30 minutes, a solution of 4-benzoyl-1- (2-chloroethyl) piperidine in dimethylformamide is added dropwise at 70 ° C. After completion of the reaction, the solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,7 , 8-Tetrahydroquinazolin-4-yl) -4-nitrobenzamide. This compound is dissolved in a 35% hydrochloric acid-methanol mixed solvent, and tin powder is added under ice cooling. After completion of the reaction, the reaction solution is made basic with an aqueous potassium carbonate solution and extracted with chloroform. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,
(6,7,8-Tetrahydroquinazolin-4-yl) benzamide is obtained.

Example 18 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) -4-nitrobenzamide and 4- (4-fluorobenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 17 to give N- (2- (4
-(4-fluorobenzoyl) piperidin-1-yl)
Ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-nitrobenzamide is obtained.
This compound was reacted in the same manner as in Example 17 to give 4-
Amino-N- (2- (4- (4-fluorobenzoyl)
Piperidin-1-yl) ethyl) -N- (5,6,7,
8-tetrahydroquinazolin-4-yl) benzamide is obtained. Example 19 4-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline and triethylamine were dissolved in chloroform, and cooled with ice. Add benzoyl chloride below. After completion of the reaction, the reaction solution was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain N- (2- (4- (4
-Fluorophenyl) piperazin-1-yl) ethyl)
-N- (5,6,7,8-tetrahydroquinazoline-
4-yl) benzamide is obtained. Example 20 N- (5,6,7,8-tetrahydroquinazoline-4
-Yl) benzamide is dissolved in dimethylformamide and at room temperature one equivalent of sodium hydride and a catalytic amount of sodium iodide are added. After stirring at room temperature for 30 minutes, 70 ° C
Then, a dimethylformamide solution of 4-benzoyl-1- (2-chloroethyl) piperidine is added dropwise. After completion of the reaction, the solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure,
Purification by silica gel column chromatography gives N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide. . Example 21 Example 19 was performed using 4-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline and 4-chlorobenzoyl chloride. In the same manner as described above, and N- (2-
(4- (4-Fluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) -4-chlorobenzamide is obtained. Example 22 4-chloro-N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide and 4-benzoyl-
1- (2-Chloroethyl) piperidine was reacted in the same manner as in Example 20 to give N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,7,8-
Tetrahydroquinazolin-4-yl) -4-chlorobenzamide is obtained.

Example 23 4-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydro-2-methylquinazoline was prepared in the same manner as in Example 23. 1 and reacted with N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (5,
6,7,8-tetrahydro-2-methylquinazoline-
4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N
-(2- (4- (4-fluorophenyl) piperazine-
1-yl) ethyl) -N- (5,6,7,8-tetrahydro-2-methylquinazolin-4-yl) benzamide is obtained. Example 24 N- (5,6,7,8-tetrahydro-2-methylquinazolin-4-yl) -4-nitrobenzamide and 4-
Benzoyl-1- (2-chloroethyl) piperidine was reacted in the same manner as in Example 17 to give N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,
6,7,8-tetrahydro-2-methylquinazoline-
4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-
N- (2- (4- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,7,8-tetrahydro-2-methylquinazolin-4-yl) benzamide is obtained. 25 4-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydro-2-phenylquinazoline was treated in the same manner as in Example 1. And N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydro-2-phenylquinazolin-4-yl) -4-nitrobenzamide is obtained.
This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7, 8-
Tetrahydro-2-phenylquinazolin-4-yl)
Obtain benzamide. Example 26 N- (5,6,7,8-tetrahydro-2-phenylquinazolin-4-yl) -4-nitrobenzamide and 4
-Benzoyl-1- (2-chloroethyl) piperidine was reacted in the same manner as in Example 17 to give N- (2- (4-
Benzoylpiperidin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydro-2-phenylquinazolin-4-yl) -4-nitrobenzamide is obtained.
This compound was reacted in the same manner as in Example 17 to give 4-
Amino-N- (2- (4- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,7,8-tetrahydro-2-phenylquinazolin-4-yl) benzamide is obtained.

Example 27 1-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroisoquinoline was prepared in the same manner as in Example 1. The reaction was carried out by operation and N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8
-Tetrahydroisoquinolin-1-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-
Fluorophenyl) piperazin-1-yl) ethyl)-
N- (5,6,7,8-tetrahydroisoquinoline-
1-yl) benzamide is obtained. Example 28 1-((2- (4-benzoylpiperidin-1-yl)
Ethyl) amino) -5,6,7,8-tetrahydroisoquinoline was reacted in the same manner as in Example 1 to give N-
(2- (4-Benzoylpiperidin-1-yl) ethyl) -N- (5,6,7,8-tetrahydroisoquinolin-1-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-benzoylpiperidine-1).
-Yl) ethyl) -N- (5,6,7,8-tetrahydroisoquinolin-1-yl) benzamide is obtained.

Example 29 4-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinoline was prepared in the same manner as in Example 1. The reaction was carried out by the operation, and N- (2- (4- (4-fluorophenyl) piperazin-4-yl) ethyl) -N- (5,6,7,8-tetrahydroquinolin-1-yl) -4- Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N-
(5,6,7,8-Tetrahydroquinolin-4-yl) benzamide is obtained. Example 30 N- (5,6,7,8-tetrahydroquinoline-4-
Yl) -4-nitrobenzamide and 4-benzoyl-1
-(2-Chloroethyl) piperidine was reacted in the same manner as in Example 17, and N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,7,8-tetrahydro (Quinolin-4-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-N- (2- (4- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,
7,8-Tetrahydroquinolin-4-yl) benzamide is obtained. Example 31 4-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroisoquinoline was reacted in the same manner as in Example 1. To give N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8
-Tetrahydroisoquinolin-4-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-
Fluorophenyl) piperazin-1-yl) ethyl)-
N- (5,6,7,8-tetrahydroisoquinoline-
4-yl) benzamide is obtained.

Example 32 N- (5,6,7,8-tetrahydroisoquinoline-
4-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 17 to give N- (2- (4-benzoylpiperidin-1-yl) ethyl ) -N- (5,6,7,8
-Tetrahydroisoquinolin-4-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 17 to give 4-amino-N- (2- (4- (4
-Benzoylpiperidin-1-yl) ethyl) -N-
(5,6,7,8-tetrahydroisoquinoline-4-
Il) to obtain benzamide. Example 33 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydro-1,2,4-triazolo [4 3-a]
Pyridine was reacted in the same manner as in Example 1 to give N- (2
-(4- (4-Fluorophenyl) piperazin-1-yl) ethyl) -N- (5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridine-3
-Yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N-
(2- (4- (4-fluorophenyl) piperazine-1
-Yl) ethyl) -N- (5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridin-3-yl) benzamide. Example 34 N- (5,6,7,8-tetrahydro-1,2,4-
Triazolo [4,3-a] pyridin-3-yl) -4-
Nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 17 to give N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (5, 6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridine-3
-Yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-N
-(2- (4- (4-benzoylpiperidin-1-yl) ethyl) -N- (5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridine- 3
-Yl) benzamide is obtained. Example 35 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2,1-benzisoxazole The reaction was conducted in the same manner as in Example 1 to obtain N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N
-(4,5,6,7-Tetrahydro-2,1-benzisoxazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-2,1-benzisoxazol-3-yl) benzamide is obtained. Example 36 Performed N- (4,5,6,7-tetrahydro-2,1-benzisoxazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine The reaction was carried out in the same manner as in Example 17, and N- (2-
(4-benzoylpiperidin-1-yl) ethyl) -N
-(4,5,6,7-Tetrahydro-2,1-benzisoxazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-N- (2- (4- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7
-Tetrahydro-2,1-benzisoxazole-3
-Yl) benzamide is obtained.

Example 37 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2,1-benzisoxa The sol was reacted with benzoyl chloride in the same manner as in Example 19,
-(2- (4- (4-fluorophenyl) piperazine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2,1-benzisoxazol-3-yl) benzamide is obtained. Example 38 As in Example 20, N- (4,5,6,7-tetrahydro-2,1-benzisoxazol-3-yl) benzamide and 4-benzoyl-1- (2-chloroethyl) piperidine were used. And N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-2,1-benzisoxazol-3-yl) benzamide is obtained. Example 39: 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-1-methyl-1H-indazole The reaction was carried out in the same manner as in Example 1, and N- (2- (4- (4-
Fluorophenyl) piperazin-1-yl) ethyl)-
N- (4,5,6,7-tetrahydro-1-methyl-
1H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-1-methyl-1H-indazol-3-yl) benzamide is obtained. Example 40 N- (4,5,6,7-tetrahydro-1-methyl-
1H-Indazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 17 to obtain N- (2
-(4-benzoylpiperidin-1-yl) ethyl)-
N- (4,5,6,7-tetrahydro-1-methyl-
1H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-N- (2- (4- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-1-methyl-1H-indazol-3-yl) benzamide is obtained. Example 41 Example of 3-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-1-phenyl-1H-indazole The reaction was carried out in the same manner as in Example 1, and N- (2- (4- (4
-Fluorophenyl) piperazin-1-yl) ethyl)
-N- (4,5,6,7-Tetrahydro-1-phenyl-1H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-1-phenyl-1
(H-indazol-3-yl) benzamide is obtained.

Example 42 N- (4,5,6,7-Tetrahydro-1-phenyl-1H-indazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine Was reacted in the same manner as in Example 17 to give N-
(2- (4-Benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-1-phenyl-1H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-N- (2- (4- (4-
Benzoylpiperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-1-phenyl-1
(H-indazol-3-yl) benzamide is obtained. Example 43 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-1-methyl-1H-indazole and benzoyl chloride Was reacted in the same manner as in Example 19,
N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-1-methyl-1H-indazol-3-yl) benzamide Get. Example 44 N- (4,5,6,7-tetrahydro-1-methyl-
1H-indazol-3-yl) benzamide was reacted with 4-benzoyl-1- (2-chloroethyl) piperidine in the same manner as in Example 20, to give N- (2- (4-benzoylpiperidin-1-yl) ethyl. ) -N- (4,
5,6,7-Tetrahydro-1-methyl-1H-indazol-3-yl) benzamide is obtained. Example 45 3-((2- (4-phenylpiperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-1
-Methyl-1H-indazole was reacted in the same manner as in Example 1 to give N- (2- (4-phenylpiperazine-1).
-Yl) ethyl) -N- (4,5,6,7-tetrahydro-1-methyl-1H-indazol-3-yl)-
4-nitrobenzamide is obtained. This compound was prepared in Example 1
The reaction was carried out in the same manner as described above, and 4-amino-N- (2- (4
-Phenylpiperazin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-1-methyl-1H
-Indazol-3-yl) benzamide. Example 46 Example 3 was performed using 3-((2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-1-methyl-1H-indazole. And N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-1-methyl-1H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-1-methyl-1H-indazol-3-yl) benzamide is obtained.

Example 47 3-((2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-1-methyl-1H-indazole Was reacted in the same manner as in Example 1 to give N- (2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-1-methyl-1H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-1-methyl-1H-indazol-3-yl) benzamide is obtained. Example 48 3-((2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-1-methyl-1H-indazole was prepared as an example. The reaction was carried out in the same manner as in Example 1, and N- (2- (4- (4-
Methoxyphenyl) piperazin-1-yl) ethyl)-
N- (4,5,6,7-tetrahydro-1-methyl-
1H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 1 to give 4-amino-N- (2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-1-methyl-1H-indazol-3-yl) benzamide is obtained. Example 49 N- (4,5,6,7-tetrahydro-1-methyl-
1H-indazol-3-yl) -4-nitrobenzamide and 4- (4-fluorobenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 17 to obtain N- (2- (4 -(4-fluorobenzoyl)
Piperidin-1-yl) ethyl) -N- (4,5,6,
7-tetrahydro-1-methyl-1H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-N- (2- (4- (4- (4-fluorobenzoyl)
Piperidin-1-yl) ethyl) -N- (4,5,6,
7-tetrahydro-1-methyl-1H-indazol-3-yl) benzamide is obtained. Example 50 N- (4,5,6,7-tetrahydro-1-methyl-
1H-indazol-3-yl) -4-nitrobenzamide and 4- (4-chlorobenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 17 to obtain N- (2- (4 -(4-chlorobenzoyl) piperidin-1-yl) ethyl) -N- (4,5,6,7-
Tetrahydro-1-methyl-1H-indazole-3
-Yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 17 to give 4-amino-N
-(2- (4- (4- (4-chlorobenzoyl) piperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-1-methyl-1H-indazole-3-
Il) to obtain benzamide.

Example 51 3-((2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole 2 0.0g
And triethylamine (2.3 ml) in methylene dichloride (40 m)
of 4-nitrobenzoyl chloride under ice-cooling.
5 g were added. After completion of the reaction, the reaction solution was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
(2- (4- (4-chlorophenyl) piperazine-1-
Yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4
2.2 g of nitrobenzamide were obtained. This compound is
It was dissolved in a mixed solvent of 5% hydrochloric acid (40 ml) and methanol (10 ml), and tin powder (1.5 g) was added thereto under ice cooling. After the reaction,
The reaction solution was made basic with an aqueous potassium carbonate solution and extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, and 4-amino-N- (2- (4- (4-
(4-chlorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide.
0.98 g of maleate was obtained. 170-171 ° C. Example 52 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H -Indazole was reacted in the same manner as in Example 51, and N- (2- (4- (4
-Fluorophenyl) piperazin-1-yl) ethyl)
-N- (4,5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide. Example 53 3-((2- (4- (4-bromophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole The reaction was carried out in the same manner as in Example 51, and N- (2- (4- (4-
Bromophenyl) piperazin-1-yl) ethyl) -N
-(4,5,6,7-tetrahydro-2-methyl-2
(H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51, and 4-amino-N- (2- (4- (4-bromophenyl) piperazin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained.

Example 54 3-((2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole Was reacted in the same manner as in Example 51, and N- (2- (4- (4-
Methylphenyl) piperazin-1-yl) ethyl) -N
-(4,5,6,7-tetrahydro-2-methyl-2
(H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4- (4-methylphenyl) piperazin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 55 3-((2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole The reaction was carried out in the same manner as in Example 51, and N- (2- (4- (4
-Methoxyphenyl) piperazin-1-yl) ethyl)
-N- (4,5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4- (4-methoxyphenyl) piperazin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide. Example 56 3-((2- (4- (3-Chlorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole was prepared in Example 51. And reacted with N- (2- (4- (3-
Chlorophenyl) piperazin-1-yl) ethyl) -N
-(4,5,6,7-tetrahydro-2-methyl-2
(H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51, and 4-amino-N- (2- (4- (3-chlorophenyl) piperazin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained.

Example 57 3-((2- (4- (2-Chlorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole was Reaction was carried out in the same manner as in Example 51, and N- (2- (4- (2-
Chlorophenyl) piperazin-1-yl) ethyl) -N
-(4,5,6,7-tetrahydro-2-methyl-2
(H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51, and 4-amino-N- (2- (4- (2-chlorophenyl) piperazin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 58 3-((2- (4-Phenylpiperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2
-Methyl-2H-indazole was reacted in the same manner as in Example 51 to give N- (2- (4-phenylpiperazine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
-4-Nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2-
(4- (4-phenylpiperazin-1-yl) ethyl)
-N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 59 3-((2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) amino) -4,
5,6,7-Tetrahydro-2-methyl-2H-indazole was reacted in the same manner as in Example 51 to give N-
(2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-
Tetrahydro-2-methyl-2H-indazole-3
-Yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N
-(2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl) -N- (4,5,6,
7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 60 3-((2- (4- (4-dimethylaminophenyl) piperazin-1-yl) ethyl) amino) -4,5,6.
7-Tetrahydro-2-methyl-2H-indazole was reacted in the same manner as in Example 51, and N- (2- (4
-(4-Dimethylaminophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4-
Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4-
(4-Dimethylaminophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 61 3-((2- (4- (3,4-difluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6.
7-Tetrahydro-2-methyl-2H-indazole was reacted in the same manner as in Example 51, and N- (2- (4
-(3,4-difluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4-
Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4-
(3,4-Difluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained.

Example 62 3-((2- (4- (2,4-difluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6
7-Tetrahydro-2-methyl-2H-indazole was reacted in the same manner as in Example 51, and N- (2- (4
-(2,4-difluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4-
Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4-
(2,4-Difluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 63 3-((2- (4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl) ethyl) amino) -4,5,6,7-tetra Hydro-2-
Methyl-2H-indazole was reacted in the same manner as in Example 51 to give N- (2- (4- (6-fluoro-1,2
-Benzisoxazol-3-yl) piperidin-1-
Yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4
Obtaining nitrobenzamide. This compound was prepared in Example 51
The reaction was carried out in the same manner as described above, and 4-amino-N- (2- (4
-(6-Fluoro-1,2-benzisoxazole-3
-Yl) piperidin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 64 3-((2- (4- (5-methyl-1-benzofuran-
3-yl) piperidin-1-yl) ethyl) amino)-
4,5,6,7-tetrahydro-2-methyl-2H-
Indazole was reacted in the same manner as in Example 51,
-(2- (4- (5-methyl-1-benzofuran-3-
Yl) piperidin-1-yl) piperidin-1-yl)
Ethyl) -N- (4,5,6,7-tetrahydro-2
-Methyl-2H-indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4- (5
-Methyl-1-benzofuran-3-yl) piperidine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
Obtain benzamide. Example 65 N- (4,5,6,7-tetrahydro-2-methyl-
900 mg of 2H-indazol-3-yl) -4-nitrobenzamide was dissolved in 10 ml of dimethylformamide, and 132 mg of sodium hydride and a catalytic amount of sodium iodide were added at room temperature. After stirring at room temperature for 30 minutes,
At ℃, 5 ml of a dimethylformamide solution of 754 mg of 4-benzoyl-1- (2-chloroethyl) piperidine was added dropwise. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6 , 7
-Tetrahydro-2-methyl-2H-indazole-
3-yl) -4-nitrobenzamide was obtained. This compound was dissolved in a mixed solvent of 5 ml of 35% hydrochloric acid-5 ml of methanol, and 356 mg of tin powder was added under ice cooling. After completion of the reaction, the reaction solution was made basic with an aqueous potassium carbonate solution and extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,
5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide was obtained. Melting point 157
-158 ° C

Example 66 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (4-fluorobenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 65, and N- (2- (4 -(4-fluorobenzoyl)
Piperidin-1-yl) ethyl) -N- (4,5,6,
7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (2- (4- (4-fluorobenzoyl) piperidin-1-yl) ethyl) -N- (4,5,6, 7-tetrahydro-2-methyl-2H-indazole-3-
Il) to obtain benzamide. Example 67 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (4-chlorobenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 65, and N- (2- (4 -(4-chlorobenzoyl) piperidin-1-yl) ethyl) -N- (4,5,6,7-
Tetrahydro-2-methyl-2H-indazole-3
-Yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N
-(2- (4- (4-chlorobenzoyl) piperidine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
Obtain benzamide. Example 68 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (4-methylbenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 65 to obtain N- (2- (4 -(4-methylbenzoyl) piperidin-1-yl) ethyl) -N- (4,5,6,7-
Tetrahydro-2-methyl-2H-indazole-3
-Yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N
-(2- (4- (4-methylbenzoyl) piperidine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
Obtain benzamide. Example 69 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (4-methoxybenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 65 to obtain N- (2- (4 -(4-methoxybenzoyl)
Piperidin-1-yl) ethyl) -N- (4,5,6,
7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (2- (4- (4-methoxybenzoyl) piperidin-1-yl) ethyl) -N- (4,5,6,6). 7-tetrahydro-2-methyl-2H-indazole-3-
Il) to obtain benzamide.

Example 70 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (2-chlorobenzoyl) -1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 65 to obtain N- (2- (4 -(2-chlorobenzoyl) piperidin-1-yl) ethyl) -N- (4,5,6,7-
Tetrahydro-2-methyl-2H-indazole-3
-Yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N
-(2- (4- (2-chlorobenzoyl) piperidine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
Obtain benzamide. Example 71 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (3-trifluoromethylbenzoyl) -1
-(2-Chloroethyl) piperidine was reacted in the same manner as in Example 65 to give N- (2- (4- (3-trifluoromethylbenzoyl) piperidin-1-yl) ethyl)
-N- (4,5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65, and 4-amino-N- (2- (4- (3-trifluoromethylbenzoyl) piperidin-1-yl) ethyl) -N- (4,5, 6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 72 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (4-dimethylaminobenzoyl) -1-
(2-Chloroethyl) piperidine was reacted in the same manner as in Example 65 to give N- (2- (4- (4-dimethylaminobenzoyl) piperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (2- (4- (4-dimethylaminobenzoyl) piperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide. Example 73 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (3,4-difluorobenzoyl) -1-
(2-Chloroethyl) piperidine was reacted in the same manner as in Example 65 to give N- (2- (4- (3,4-difluorobenzoyl) piperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (2- (4- (3,4-difluorobenzoyl) piperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide.

Example 74 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide and 4- (2,4-difluorobenzoyl) -1-
(2-Chloroethyl) piperidine was reacted in the same manner as in Example 65 to give N- (2- (4- (2,4-difluorobenzoyl) piperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (2- (4- (2,4-difluorobenzoyl) piperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide. Example 75 3-((2- (4-Phenylpiperidin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2
-Methyl-2H-indazole was reacted in the same manner as in Example 51 to give N- (2- (4-phenylpiperidine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
-4-Nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2-
(4-phenylpiperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide. Example 76 Example 3-((2- (4- (4-fluorophenyl) piperidin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole The reaction was carried out in the same manner as in Example 51, and N- (2- (4- (4
-Fluorophenyl) piperidin-1-yl) ethyl)
-N- (4,5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4- (4-fluorophenyl) piperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide. Example 77 3-((2- (1,2,3,6-tetrahydro-4-
Phenylpyridin-1-yl) ethyl) amino) -4,
5,6,7-Tetrahydro-2-methyl-2H-indazole was reacted in the same manner as in Example 51 to give N-
(2- (1,2,3,6-tetrahydro-4-phenylpyridin-1-yl-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (1,2,3,6-tetrahydro-4-phenylpyridin-1-yl) ethyl)
-N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained.

Example 78 3-((2- (4- (4-fluorophenyl) -1,1
2,3,6-tetrahydropyridin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-
Methyl-2H-indazole was reacted in the same manner as in Example 51 to give N- (2- (4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine-1-).
Yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4
Obtaining nitrobenzamide. This compound was prepared in Example 51
The reaction was carried out in the same manner as described above, and 4-amino-N- (2- (4
-(4-Fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl) -N- (4
5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 79 3-((2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole 1.5 g
And 1.7 ml of triethylamine in 30 m of methylene dichloride
Then, 0.84 g of benzoyl chloride was added under ice cooling. After completion of the reaction, the reaction solution was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain N- (2-
(4- (4-chlorophenyl) piperazin-1-yl)
Ethyl) -N- (4,5,6,7-tetrahydro-2
-Methyl-2H-indazol-3-yl) benzamide (0.68 g) was obtained. Melting point 138-139 ° C Example 80 N- (4,5,6,7-tetrahydro-2-methyl-
1.0 g of 2H-indazol-3-yl) benzamide
Was dissolved in 10 ml of dimethylformamide, and 176 mg of sodium hydride and a catalytic amount of sodium iodide were added at room temperature. After stirring at room temperature for 30 minutes, 5 ml of a dimethylformamide solution of 1.0 g of 4-benzoyl-1- (2-chloroethyl) piperidine was added dropwise at 70 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,6). 0.4 g of 7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide was obtained. Melting point 162-164 ° C Example 81 3-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H -Indazole and 2-
Pyridinecarbonyl chloride was reacted in the same manner as in Example 79, and N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -2-pyridinecarboxamide is obtained. Example 82 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -2-pyridinecarboxamide and 4-benzoyl-1- (2-chloroethyl)
Piperidine was reacted in the same manner as in Example 80, and N-
(2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -2-pyridinecarboxamide is obtained.

Example 83 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole And 4-
Chlorobenzoyl chloride was reacted in the same manner as in Example 79 to give N- (2- (4- (4-fluorophenyl)
Piperazin-1-yl) ethyl) -N- (4,5,6,
7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-chlorobenzamide is obtained. Example 84 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-chlorobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 80 to obtain N- (2
-(4-benzoylpiperidin-1-yl) ethyl)-
N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-chlorobenzamide is obtained. Example 85 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole and 4-
Methoxybenzoyl chloride was reacted in the same manner as in Example 79, and N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-methoxybenzamide is obtained. Example 86 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-methoxybenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 80 to give N-
(2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4-methoxybenzamide is obtained. Example 87 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole and 3-
Pyridinecarbonyl chloride was reacted in the same manner as in Example 79, and N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -3-pyridinecarboxamide is obtained.

Example 88 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -3-pyridinecarboxamide and 4-benzoyl-1- (2-chloroethyl)
Piperidine was reacted in the same manner as in Example 80, and N-
(2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -3-pyridinecarboxamide is obtained. Example 89 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole and 4-
Fluorobenzoyl chloride was reacted in the same manner as in Example 79, and N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-fluorobenzamide is obtained. Example 90 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-fluorobenzamide was reacted with 4-benzoyl-1- (2-chloroethyl) piperidine in the same manner as in Example 80 to give N-
(2- (4-Benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4-fluorobenzamide is obtained. Example 91 4-amino-N- (2- (4-benzoylpiperidine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
Dissolve benzamide in methanol and add sodium borohydride under ice cooling. After completion of the reaction, the reaction solution is poured into ice water, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 4-amino-N- (2- (4-
(Phenylhydroxymethyl) piperidin-1-yl)
Ethyl) -N- (4,5,6,7-tetrahydro-2
-Methyl-2H-indazol-3-yl) benzamide is obtained.

Example 92 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide was reacted with 4-benzyl-1- (2-chloroethyl) piperidine in the same manner as in Example 65 to obtain N- (2-
(4-benzylpiperidin-1-yl) ethyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 65, and 4-amino-N- (2- (4-benzylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro- 2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 93 3-((3- (4- (4-fluorophenyl) piperazin-1-yl) propyl) amino) -4,5,6,7-
Tetrahydro-2-methyl-2H-indazole was reacted in the same manner as in Example 51, and N- (3- (4-
(4-Fluorophenyl) piperazin-1-yl) propyl) -N- (4,5,6,7-tetrahydro-2-
Methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (3- (4- (4-
Fluorophenyl) piperazin-1-yl) propyl)
-N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 94 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide was reacted with 4-benzoyl-1- (3-chloropropyl) piperidine in the same manner as in Example 65 to give N-
(3- (4-Benzoylpiperidin-1-yl) propyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (3- (4-benzoylpiperidin-1-yl) propyl) -N- (4,5,
6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) benzamide is obtained. Example 95 3-((4- (4- (4-Fluorophenyl) piperazin-1-yl) butyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole was prepared. The reaction was carried out in the same manner as in Example 51, and N- (4- (4- (4
-Fluorophenyl) piperazin-1-yl) butyl)
-N- (4,5,6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (4- (4- (4-fluorophenyl) piperazin-1-yl) butyl) -N-
(4,5,6,7-tetrahydro-2-methyl-2H
-Indazol-3-yl) benzamide.

Example 96 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide was reacted with 4-benzoyl-1- (4-chlorobutyl) piperidine in the same manner as in Example 65 to obtain N- (4
-(4-benzoylpiperidin-1-yl) butyl)-
N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (4- (4-benzoylpiperidin-1-yl) butyl) -N- (4,5,6,7-
Tetrahydro-2-methyl-2H-indazole-3
-Yl) benzamide is obtained. Example 97 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-phenyl-2H-indazole The reaction was carried out in the same manner as in Example 51, and N- (2- (4-
(4-Fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4- (4-
Fluorophenyl) piperazin-1-yl) ethyl)-
N- (4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl) benzamide is obtained. Example 98 N- (4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine Reaction was carried out in the same manner as in Step 65, and N-
(2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,
6,7-Tetrahydro-2-phenyl-2H-indazol-3-yl) benzamide is obtained.

Example 99 N- (4,5,6,7-tetrahydro-2-tert-butyloxycarbonyl-2H-indazol-3-yl) -4-nitrobenzamide and 4- (4-fluorophenyl ) -1- (2-chloroethyl) piperazine was reacted in the same manner as in Example 65 to give N- (2- (4- (4
-Fluorophenyl) piperazin-1-yl) ethyl)
-N- (4,5,6,7-tetrahydro-2-tert-butyloxycarbonyl-2H-indazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65 to give 4-amino-N-
(2- (4- (4-fluorophenyl) piperazine-1
-Yl) ethyl) -N- (4,5,6,7-tetrahydro-2-tert-butyloxycarbonyl-2H-indazol-3-yl) benzamide. This compound is dissolved in methylene dichloride, and trifluoroacetic acid is added under ice cooling. After completion of the reaction, the reaction solution is poured into ice water, made basic with potassium carbonate, and extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl. ) -N- (4,5,6,7-tetrahydro-2H-indazol-3-yl) benzamide is obtained. Example 100 N- (4,5,6,7-tetrahydro-2-tertiarybutyloxycarbonyl-2H-indazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1-
(2-Chloroethyl) piperidine was reacted in the same manner as in Example 65, and N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro- 2-tert-butyloxycarbonyl-2H
-Indazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 65, and 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro- 2-tert-butyloxycarbonyl-2H
-Indazol-3-yl) benzamide. This compound was reacted in the same manner as in Example 99 to give 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro- 2H-indazol-3-yl) benzamide is obtained. Example 101 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole and cyclohexanecarbonyl The chloride was reacted in the same manner as in Example 79, and N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,
(6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) cyclohexanecarboxamide is obtained.

Example 102 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) cyclohexanecarboxamide and 4-benzoyl-1- (2-chloroethyl)
Piperidine was reacted in the same manner as in Example 80, and N-
(2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) cyclohexanecarboxamide is obtained. Example 103 3-((2- (4- (4-Chlorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2-methyl-2H-indazole and acetyl chloride The reaction was conducted in the same manner as in Example 79, and N-
(2- (4- (4-chlorophenyl) piperazine-1-
(Yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl) acetamide dioxalate monohydrate was obtained. Melting point 155-
156 ° C. Example 104 N- (4,5,6,7-tetrahydro-2-methyl-
2H-indazol-3-yl) acetamide and 4-benzoyl-1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 80 to give N- (2- (4-benzoylpiperidin-1-yl) ethyl. ) -N- (4,5,
(6,7-Tetrahydro-2-methyl-2H-indazol-3-yl) acetamide is obtained. Example 105 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -2,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reaction was conducted in the same manner as in Example 51, and N- (2- (4- (4-
Fluorophenyl) piperazin-1-yl) ethyl)-
N- (2,4,6,7-tetrahydropyrano [4,3
-C] pyrazol-3-yl) -4-nitrobenzamide. This compound was reacted in the same manner as in Example 51, and 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (2,
4,6,7-Tetrahydropyrano [4,3-c] pyrazol-3-yl) benzamide is obtained. Example 106 N- (2,4,6,7-tetrahydropyrano [4,3
-C] Pyrazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine were reacted in the same manner as in Example 65 to give N- (2-
(4-benzoylpiperidin-1-yl) ethyl) -N
-(2,4,6,7-tetrahydropyrano [4,3-
c] Pyrazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65, and 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (2,4,6,7-tetrahydropyra No [4,3-c] pyrazol-3-yl) benzamide is obtained.

Example 107 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -2,4,6,7-tetrahydrothiopyrano [4,3- c] Pyrazole was reacted in the same manner as in Example 51, and N- (2- (4-
(4-Fluorophenyl) piperazin-1-yl) ethyl) -N- (2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) -4-nitrobenzamide obtain. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4- (4-
Fluorophenyl) piperazin-1-yl) ethyl)-
N- (2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) benzamide is obtained. Example 108: N- (2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl) piperidine Was reacted in the same manner as in Example 65,
N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) -4- Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 65, and 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (2,
4,6,7-tetrahydrothiopyrano [4,3-c]
Pyrazol-3-yl) benzamide is obtained. Example 109 4-amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (2,4,
6,7-Tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) benzamide is dissolved in formic acid, 30% hydrogen peroxide is added dropwise under ice cooling, and the mixture is stirred at 5 ° C or lower.
After completion of the reaction, the reaction solution is poured into ice water, made basic with potassium carbonate, and then extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-amino-N- (2-
(4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazole-5-oxide-
3-yl) benzamide is obtained.

Example 110 4-amino-N- (2- (4-benzoylpiperidine-
1-yl) ethyl) -N- (2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazol-3-yl) benzamide was reacted in the same manner as in Example 109 to give 4 -Amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (2,4,6,7-tetrahydrothiopyrano [4,3-c] pyrazole-5-
Oxid-3-yl) benzamide is obtained. Example 111 3-((2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2H-2,5-dimethylpyrido [4 3
-C] pyrazole was reacted in the same manner as in Example 51, and N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7- Tetrahydro-2H-2,5-dimethylpyrido [4,3
-C] pyrazole) -4-nitrobenzamide.
This compound was reacted in the same manner as in Example 51 to give 4-
Amino-N- (2- (4- (4-fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7
-Tetrahydro-2H-2,5-dimethylpyrido [4,3-c] pyrazole) benzamide. Example 112 N- (4,5,6,7-tetrahydro-2H-2,5
-Dimethylpyrido [4,3-c] pyrazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1-
(2-Chloroethyl) piperidine was reacted in the same manner as in Example 65, and N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro- 2H-2,5-dimethylpyrido [4,3-
c] Pyrazol-3-yl) -4-nitrobenzamide is obtained. This compound was reacted in the same manner as in Example 65, and 4-amino-N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro- 2H-2,5-dimethylpyrido [4,3-
c] Pyrazol-3-yl) benzamide is obtained. Example 113 3-((2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl) amino) -4,5,6,7-tetrahydro-2,5-dimethyl-2H-indazole The reaction was conducted in the same manner as in Example 51, and N- (2- (4
-(4-Fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2,
5-dimethyl-2H-indazol-3-yl) -4-
Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 51 to give 4-amino-N- (2- (4-
(4-Fluorophenyl) piperazin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2,5
-Dimethyl-2H-indazol-3-yl) benzamide.

Example 114 N- (4,5,6,7-Tetrahydro-2,5-dimethyl-2H-indazol-3-yl) -4-nitrobenzamide and 4-benzoyl-1- (2-chloroethyl ) Piperidine was reacted in the same manner as in Example 65,
N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2,
5-dimethyl-2H-indazol-3-yl) -4-
Obtain nitrobenzamide. This compound was reacted in the same manner as in Example 65 to give 4-amino-N- (2- (4-
Benzoylpiperidin-1-yl) ethyl) -N-
(4,5,6,7-Tetrahydro-2,5-dimethyl-2H-indazol-3-yl) benzamide is obtained. Example 115 0.9 g of 4-((2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline and 1 m of triethylamine
was dissolved in 10 ml of methylene chloride, and 570 mg of acetyl chloride was added under ice cooling. After completion of the reaction, the reaction solution was washed with an aqueous solution of potassium carbonate and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and the effluent was concentrated to obtain an oily substance. This substance was dissolved in isopropyl alcohol, isopropyl alcohol-hydrochloric acid was added, and the mixture was purified as a hydrochloride. N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N- (5,6 ,
390 mg of 7,8-tetrahydroquinazolin-4-yl) acetamide monohydrochloride monohydrate was obtained. Melting point 19
8-201 ° C Example 116 4-((2- (4- (4-Chlorophenyl) piperazin-1-yl) ethyl) amino) -5,6,7,8-tetrahydroquinazoline 0.7 g and benzoyl chloride 0 .8 g was reacted in the same manner as in Example 115, and N- (2-
(4- (4-chlorophenyl) piperazin-1-yl)
0.98 g of ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide monohydrochloride 0.3 hydrate was obtained. Melting point 192-194 ° C / decomposition

Example 117 4-((2- (4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl) ethyl) amino) -5,6,7, 0.7 g of 8-tetrahydroquinazoline and 0.27 ml of benzoyl chloride were reacted in the same manner as in Example 115 to obtain N- (2- (4- (6-
Fluoro-1,2-benzisoxazol-3-yl)
Piperidin-1-yl) ethyl) -N- (5,6,7,
0.59 g of 8-tetrahydroquinazolin-4-yl) benzamide / 1 oxalic acid was obtained. Melting point 184-186
° C / decomposition Example 118 N- (2-chloroethyl) -N- (2-methyl-4,
5,6,7-tetrahydro-2H-indazole-3
-Yl) benzamide and 4- (2,3-dimethoxybenzoyl) piperidine are dissolved in dimethylformamide, and potassium carbonate and a catalytic amount of potassium iodide are added thereto.
Heat and stir at 0 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure.
Water is added to the residue and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give N- (2-
(4- (2,3-dimethoxybenzoyl) piperidine-
1-yl) ethyl) -N- (2-methyl-4,5,6,
7-tetrahydro-2H-indazol-3-yl)
Obtain benzamide. Example 119 N- (2- (4- (2,3-dimethoxybenzoyl) piperidin-1-yl) ethyl) -N- (2-methyl-
4,5,6,7-Tetrahydro-2H-indazol-3-yl) benzamide is dissolved in methanol and sodium borohydride is added at room temperature. After completion of the reaction, the solvent is distilled off under reduced pressure, water is added to the residue, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure,
The residue is purified by silica gel chromatography to give N- (2- (4- (2,3-dimethoxyphenylhydroxymethyl) piperidin-1-yl) ethyl)
-N- (2-Methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl) benzamide is obtained. The structural formulas of the compounds obtained in the above Examples are
Shown in

[0121]

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[0122]

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[0123]

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[0124]

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[0125]

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[0126]

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[0127]

Embedded image

[0128]

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[0129]

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[0130]

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[0131]

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[0132]

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Formulation Formulation Example 1 0.5 part of the compound of Example 1, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of corn starch were thoroughly mixed and kneaded well with a binder made with 2 parts of corn starch. The kneaded mixture is sieved through 16 mesh and placed in an oven for 5 minutes.
After drying at 0 ° C., the mixture is sieved with 24 mesh. The kneaded powder thus obtained, 8 parts of corn starch, 11 parts of crystalline cellulose and 9 parts of talc were mixed well, and then compressed and compressed to obtain 1 part.
Tablets containing 0.5 mg of active ingredient per tablet are obtained. Formulation Example 2 1.0 mg of the compound of Example 1 and 9.0 m of sodium chloride
g in water for injection and filtered to remove pyrogens,
The filtrate is aseptically transferred to an ampoule, sterilized, and melt-sealed to give an injection containing 1.0 mg of the active ingredient.

The excellent pharmacological activity of the compounds of the general formula (I) is proved by the following series of tests. Experimental Example 1: affinity for 5-HT ₂ receptor ⁽³ H- ketanserin binding) crude synaptic membrane preparation and binding experiments Rijssen (Leys
en J. En. E. FIG. [Molecular Pharmacology, Vol. 21, p. 301 (1982)]. A crude synaptic membrane was prepared from the cryopreserved rat cerebral cortex, and the membrane specimen and ³ H-ketanserin were incubated at 37 ° C. for 20 minutes in the presence of the test compound. Immediately after the reaction, Whatman GF / B filter (trade name)
And the radioactivity on the filter was measured with a liquid scintillation counter. Non-specific binding is 1
It was determined in the presence of 0 μM mianserin. 50 of test compound
The% inhibitory concentration (IC ₅₀ ) was calculated by nonlinear regression, and the inhibition constant (Ki value) was determined.

Experimental Example 2: Platelet Aggregation Inhibitory Activity Platelet-rich plasma preparation and platelet aggregation
rn, G .; V. R. ) (Journal of Physiology, vol. 168, p. 178 (1963)). From the carotid artery of a male Japanese white rabbit local anesthetized with xylocaine, 1
Blood was collected with a syringe previously added with a / 10 volume of 3.8% sodium citrate solution. 1000 revolutions of this blood
The supernatant obtained by centrifugation at room temperature for 10 minutes at room temperature was collected as platelet-rich plasma (PRP), and the supernatant obtained by centrifugation at 3000 rpm for 10 minutes was collected as platelet-poor plasma (PPP). . The platelet aggregation rate (%) was calculated assuming that the values measured by PRP and PPP were 0% aggregation and 100% aggregation, respectively. 3 μl of the test compound was added to 300 μl of PRP and incubated at 37 ° C. for 5 minutes. Collagen at a concentration that does not induce aggregation by itself and 5-HT at a final concentration of 3 μM were added thereto as an aggregation-inducing substance, and the aggregation reaction was recorded for 7 minutes. The effect of the test compound was determined by controlling the maximum agglutination value as an index with respect to the control group. The 50% inhibitory concentration (IC ₅₀ ) of the test compound was calculated by non-linear regression. As a result, the IC ₅₀ value of sarpogrelate was 0.26.
μM, and the compound of Example 80 was 0.026 μM
Met.

[0136]

The compound of the present invention of formula (I), an optical isomer or a pharmaceutically acceptable salt thereof is a strong and selective compound.
-HT ₂ receptor has an antagonism, addition of platelet aggregation inhibitory action, both the peripheral circulation improving action. Therefore, the compound of the present invention has thromboembolism, chronic arterial occlusion, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disorder, migraine, diabetic peripheral neuropathy with less side effects such as an action on the extrapyramidal system and a blood pressure lowering action. It is useful as a therapeutic agent for postherpetic neuralgia.

──────────────────────────────────────────────────の Continued on front page (51) Int.Cl. ⁶ Identification code FI C07D 217/22 C07D 217/22 231/56 231/56 F 239/94 239/94 261/20 261/20 401/12 211 401 / 12 211 231 231 239 239 239 403/12 239 403 403 239 405/14 211 405/14 211 413/12 211 413/12 211 413/14 211 413/14 211 471/04 101 471/04 101 106 106H 491 / 052 491/052 495/04 111 495/04 111 (72) Inventor Haruhito Nakagawa 955 Koiji, Yoshitomi-cho, Chikugami-gun, Fukuoka Prefecture Yoshitomi Pharmaceutical Co., Ltd.

Claims (10)

[Claims] 1. A compound of the general formula (I)[Wherein, R represents the following formula (1), (2), (3),
Select from (4), (5), (6), (7) and (8)
Represents a group to be Embedded imageR¹Is hydrogen, alkyl, hydroxy, amino, aryl
Alkyl, or phenyl which may have a substituent or
Represents a heteroaryl. R^TwoIs hydrogen, alkyl, reed
, Arylalkyl, or an optionally substituted
Represents nyl or heteroaryl. A can be placed anywhere
Substituent R^Three(R^ThreeIs hydrogen, alkyl, hydroxy, alcohol
Represents xy, amino or dialkylamino. Have)
Straight or branched having 1 to 4 carbon atoms
Shows a chain alkylene. Y is absent or oxygen
Atom, sulfur atom, SO, SO_TwoOr NR ^Four(R^Four
Is hydrogen, alkyl, aryl, heteroaryl, aryl
Represents alkyl or acyl. ). B is arbitrary
A substituent R at the position^Threea (R^Threea is hydrogen, alkyl, hydroxy
Represents alkoxy, alkoxy, amino or dialkylamino
You. ) Having 1 to 4 carbon atoms
Shows a chain or branched alkylene. Z is 1-8 carbon atoms
Alkyl, cycloalkyl having 3 to 8 carbon atoms
Alkyl, phenyl or heteroaryl optionally having substituent (s)
Indicates a reel. D is a straight chain having 1 to 8 carbon atoms or
Shows a branched alkylene chain. QT is CH, CH_Two−
N, (CH_Two)_Two-N, CH_TwoRepresents -CH or CH = C
You. G is absent or a straight chain having 1 to 8 carbon atoms.
Or branched alkylene chain, carbonyl or CH (O
H). However, QT is CH_Two-N, (CH_Two) _Two−
When indicating N, G does not exist or has 1 to 8 carbon atoms.
Linear or branched alkylene chain or carbonyl
Is shown. R is the formula (7) or (8), and
R^TwoRepresents hydrogen, and QT represents CH_TwoIndicates -N
G is a straight or branched chain having 1 to 8 carbon atoms
Shows an alkylene chain or carbonyl. Ar represents a substituent
Aryl, heteroaryl or fused hetero
Represents a loaryl. A heterocyclic compound represented by the formula
Or an optical isomer or a pharmaceutically acceptable salt thereof. 2. In the general formula (I), R is a group represented by the formula (1):
Selected from the group of (5), (6), (7) and (8)
R represents a group¹Is hydrogen, alkyl, hydroxy, amino, aryl
Alkyl, or phenyl which may have a substituent or
Represents heteroaryl, R^TwoIs hydrogen, alkyl, acyl, arylalkyl or
Is phenyl or heteroaryl which may have a substituent
A represents a substituent R at any position^Three(R^ThreeIs hydrogen, alkyl,
Hydroxy, alkoxy, amino or dialkylamido
No. ) Having 1 to 4 carbon atoms.
Y is absent or represents an oxygen atom, a sulfur atom, SO,
SO_TwoOr NR ^Four(R^FourIs hydrogen, alkyl, ant
, Heteroaryl, arylalkyl or acyl
Is shown. And B represents a substituent R at any position.^Threea (R^Threea is hydrogen, alkyl,
Hydroxy, alkoxy, amino or dialkylamido
No. ) Having 1 to 4 carbon atoms.
Z is an alkyl having 1 to 8 carbons, 3 to 8 carbons
A phenyl which may have a substituent
And D represents a straight-chain or branched alkyl having 1 to 8 carbon atoms.
QT represents CH, CH_Two-N, (CH_Two)_Two-N, CH_Two−
G represents CH or CH = C, G is absent, straight chain having 1 to 8 carbon atoms, or
Branched alkylene chain, carbonyl or CH (OH)
Where QT is CH_Two-N or (CH_Two)_Two−
When indicating N, G does not exist or has 1 to 8 carbon atoms.
Linear or branched alkylene chain or carbonyl
And R is the formula (7) or (8), and
R^TwoRepresents hydrogen, and QT represents CH_TwoIndicates -N
G is a straight or branched chain having 1 to 8 carbon atoms
Represents an alkylene chain or a carbonyl, and Ar is an aryl or heteroaryl which may have a substituent.
Or a fused heteroaryl.
A fused heterocyclic compound, an optical isomer thereof or a pharmaceutical thereof
Above acceptable salts. 3. In the general formula (I), R is a group represented by the formula (1):
Selected from the group of (5), (6), (7) and (8)
R represents a group¹Represents hydrogen or alkyl;^TwoIs hydrogen, alkyl, acyl, arylalkyl or
Is phenyl or heteroaryl which may have a substituent
A represents a substituent R at any position^Three(R^ThreeIs hydrogen or alk
Show ) Having 1 to 4 carbon atoms.
Y is absent, B is a substituent R at any position^Threea (R^Threea is hydrogen or alk
Show ) Having 1 to 4 carbon atoms.
Z is an alkyl having 1 to 8 carbons, 3 to 8 carbons
A phenyl which may have a substituent
And D represents a straight-chain or branched alkyl having 1 to 8 carbon atoms.
QT represents CH, CH_Two-N, (CH_Two)_Two-N, CH_Two−
CH or CH = C, G is absent, methylene, carbonyl or CH
(OH), where QT is CH_Two-N or (C
H_Two)_TwoWhen -N is indicated, G is absent or methylene or
Or R represents a carbonyl and R is a group represented by the formula (7) or (8)
And R ^TwoRepresents hydrogen, and QT represents C
H_TwoWhen -N is indicated, G represents methylene or carbonyl.
In the formula, Ar is aryl or heteroaryl which may have a substituent.
Or a fused heteroaryl.
A fused heterocyclic compound, an optical isomer thereof or a pharmaceutical thereof
Above acceptable salts. 4. In the general formula (I), R is a group represented by the formula (1):
A group selected from the group consisting of (7) and (8); R ¹ represents hydrogen or alkyl; R ² represents hydrogen, alkyl, arylalkyl or phenyl or heteroaryl which may have a substituent; A represents a linear or branched alkylene having 1 to 4 carbon atoms which can have a substituent R ³ (R ³ represents hydrogen or alkyl) at an arbitrary position; , B is a substituted group R ³ a to an arbitrary position (R ³ a is. represents a hydrogen or alkyl) indicates a straight or branched chain alkylene having from 1 to 4 carbon atoms which can have, Z is Represents alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons, phenyl or heteroaryl which may have a substituent, D represents ethylene, QT represents CH, CH ₂ -N, (CH _{2) 2} -N CH ₂ -
G represents CH or CH = C, G is absent, represents methylene or carbonyl,
Provided that when R is the formula (7) or (8), R ² represents hydrogen, and QT represents CH ₂ —N,
G represents methylene or carbonyl; and Ar represents optionally substituted aryl, heteroaryl or fused heteroaryl; the fused heterocyclic compound according to claim 1, its optical isomer or its pharmaceutically acceptable. Possible salt. 5. In the general formula (I), R is a group represented by the formula (1):
(7) or (8), R ¹ represents hydrogen, R ² represents methyl, A represents ethylene, Y does not exist, B represents ethylene, and Z has a substituent. Represents phenyl or heteroaryl, D represents ethylene, QT represents CH ₂ —N or CH ₂ —CH, G represents absent or represents methylene or carbonyl, and Ar represents a substituent. A fused heterocyclic compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, which represents aryl, heteroaryl or fused heteroaryl which may be substituted. 6. Amino-N- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -N-
(5,6,7,8-tetrahydroquinazolin-4-yl) benzamide, 4-amino-N- (2- (4- (4-chlorophenyl)
Piperazin-1-yl) ethyl) -N- (4,5,6,
7-tetrahydro-2-methyl-2H-indazol-3-yl) benzamide, 4-amino-N- (2- (4-benzoylpiperidine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
Benzamide, N- (2- (4- (4-chlorophenyl) piperazine-
1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)
Benzamide, N- (2- (4-benzoylpiperidin-1-yl) ethyl) -N- (4,5,6,7-tetrahydro-2-
Methyl-2H-indazol-3-yl) benzamide, and N- (2- (4- (4-chlorophenyl) piperazine-
The fused heterocyclic compound according to claim 1, which is selected from 1-yl) ethyl) -N- (5,6,7,8-tetrahydroquinazolin-4-yl) benzamide, or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising the fused heterocyclic compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. 8. A medicament comprising the fused heterocyclic compound according to claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof. 9. A compound comprising the fused heterocyclic compound according to claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
-HT ₂ receptor antagonists. 10. The fused heterocyclic compound according to claim 1,
A platelet aggregation inhibitor comprising the optical isomer or a pharmaceutically acceptable salt thereof.