JPH07242629A - Substituted cyclic amine compound, its production and medicine for circulatory organ containing the same compound - Google Patents

Abstract

PURPOSE:To obtain a new substituted cyclic amine compound having a strong and selective serotonin 2 receptor antagonistic effect and useful for prevention and therapy of hypertension, ischemic heart diseases, cerebrovascular diseases, etc. CONSTITUTION:A compound is expressed by formula I [A is CONR<4> or SO2NR<4> (R<4> is an alkyl, an alkenyl, an aralkyl, an acyl, phenyl, naphthyl, etc.); B is a single bond, CHOH or CO; D is CH, H or N(0); Q is CH or N; R<1> and R<2> are H, a halogen, an alkyl, an alkenyl, an alkoxy, a hydroxyalkyl, an alkyl- substituted or non-substituted amino, an acylamino, an amidino which may be substituted, a (thio)ureido which may be substituted, an azole, a carboxyl, formyl, etc.; R<3> is H, a halogen, a mono- or di-alkylamino; (n) is 2 to 6] or its salt, e.g. N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-3-methoxy-N-(2- methoxyphenyl)benzamide oxalic acid salt. This compound can be synthesized by reacting a compound of formula II with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel substituted cyclic amine compound and a drug containing the same. The substituted cyclic amine compound and the salt thereof of the present invention are strong serotonin 2
A compound which exhibits a receptor antagonistic action and is separated from the central action, and is a pharmaceutical for the prevention and treatment of cardiovascular diseases such as hypertension, ischemic heart disease, cerebrovascular disorders or peripheral circulatory disorders. Is useful as

[0002]

2. Description of the Related Art In recent years, attention has been focused on the mechanism of occurrence of unstable angina and myocardial infarction due to coronary atherosclerotic lesions, and the involvement of serotonin in hypertension. That is, platelet aggregation is more likely to occur in blood vessels with arteriosclerotic lesions or endothelial damage, and high concentrations of serotonin are released from platelets in the agglomerated vascular regions, and the released serotonin enhances platelet aggregation. It is thought that a strong vasospasm is induced via the serotonin 2 receptor together with the formation of a blood clot. Therefore, peripherally selective serotonin 2 receptor antagonists are considered to suppress these phenomena, and studies have been conducted from this direction. It is disclosed. However, many conventional serotonin 2 receptor antagonists have a central action in addition to peripheral serotonin 2 antagonism, which is problematic for use as a circulatory organ agent.

[0003]

DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION As a result of intensive investigations by the present inventors, a novel serotonin 2 receptor antagonist showing a strong serotonin 2 receptor antagonistic action and being separated from the central action was obtained. The present invention has been completed.

[0004]

The present invention is based on the general formula (1)

[Chemical 12] (In the formula, A is a group represented by a member of the group consisting of —CONR ⁴ — or —SO ₂ NR ⁴ —, and B is a single bond or —CHOH.
-Or a carbonyl group, D represents a methine group, a nitrogen atom or = N (→ O)-, Q represents a methine group or a nitrogen atom, R ¹ and R ² may be the same or different, and a hydrogen atom or a halogen atom. Atom, linear or branched lower alkyl group, lower alkenyl group, lower alkoxy group, lower hydroxyalkyl group, lower alkoxy substituted alkyl group, lower alkyl substituted or unsubstituted amino group, lower acylamino group, substituted sulfonylamino group, Lower alkoxycarbonylamino group, lower alkyl substituted or unsubstituted aminoalkyl group, lower acylaminoalkyl group, substituted sulfonylaminoalkyl group, lower alkoxycarbonylaminoalkyl group, substituted or unsubstituted amidino group,
It represents a substituted or unsubstituted ureido group, a substituted or unsubstituted thioureido group, an azole group, a carboxyl group, a lower alkoxycarbonyl group, a formyl group, a lower alkyl substituted or unsubstituted carbamoyl group, a cyano group, an oxime group or a nitro group. , R ³ represents a hydrogen atom, a halogen atom or a mono- or di-substituted alkylamino group of a lower alkyl group, R ⁴ represents a lower alkyl group, a lower alkenyl group, a lower alkoxy substituted alkyl group, a lower alkoxycarbonyl substituted alkyl group, a substituted or Unsubstituted aralkyl group, lower acyl group, substituted or unsubstituted aryloyl group, halogen atom as a substituent, lower alkyl group, halogenated lower alkyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, lower acylamino group, cyano Group, lower Represents a phenyl group which may contain 1 or 2 rukylthio groups, a naphthyl group or a 5- or 6-membered aromatic heterocycle, and n represents an integer of 2 to 6)
Is a substituted cyclic amine compound or a salt thereof.

The present invention further provides a method for producing the compound of the general formula (1) and use as a circulatory organ agent, the general formula (2)

[Chemical 13] (In the formula, R ⁵ is a halogen atom, a hydroxyl group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group,
Represents a P-toluenesulfonyloxy group, a tetrahydropyranyloxy group, a lower alkoxy group, a lower acyloxy group or a trimethylsilyloxy group, and represents A, D, R ¹ , R ² ,
And n are the same as defined above, a synthetic intermediate of the compound (1), or the general formula (3)

[Chemical 14] (Wherein A, D, R ¹ , R ² and n have the same meanings as defined above), and relates to a synthetic intermediate of the compound (1).

Examples of the halogen atom of the substituents R ¹ , R ² and R ³ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and the lower alkyl group of R ¹ , R ² and R ⁴ is directly Both linear and branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like having 1 to 4 carbon atoms.
And a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. R ¹ , R ² and R ⁴
Examples of the lower alkenyl group include those having 1 to 4 carbon atoms such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl and 2-butenyl. The lower alkoxy group for R ¹ and R ² means either linear or branched, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s.
Examples thereof include those having 1 to 4 carbon atoms such as ec-butoxy and tert-butoxy.

Examples of the hydroxyalkyl group for R ¹ and R ² include carbon such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl and 3-hydroxybutyl. The lower alkoxy group in the lower alkoxy-substituted alkyl group of R ¹ , R ² and R ⁴ is a hydroxyalkyl group of 1 to 4 and includes methoxy, ethoxy, propoxy, benzyloxy, tetrahydropyranyloxy and the like. . Substituents R ¹ , R ² and R ³
The amino group may be an unsubstituted, mono- or di-substituted amino group, and examples of the substituent include a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl, and R ¹ and R ² Further as the substituent in,
Acyl group such as acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, pivaloyl or benzoyl, amino acid residue such as glycyl, alanyl or phenylalanyl, sulfonyl group such as methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, methoxycarbonyl , Ethoxycarbonyl or tert
Lower alkoxycarbonyl groups such as -butoxycarbonyl may be mentioned, and two substituents may be bonded to each other to form a ring, which may be pyrrolidinyl, piperidino, morpholino, piperazinyl, succinimide or phthalimide.

The aminoalkyl group for R ¹ and R ² is
Aminomethyl, 2-aminoethyl, 1-aminoethyl,
An aminoalkyl group having 1 to 4 carbon atoms such as 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 3-aminobutyl, etc., wherein the amino group of the aminoalkyl group is unsubstituted, monosubstituted or disubstituted amino It may be a group, and as the substituent, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl, acetyl, trifluoroacetyl, propionyl,
n-butyryl, isobutyryl, sec-butyryl, te
Acyl group such as rt-butyryl or benzoyl, amino acid residue such as glycyl, alanyl or phenylalanyl, sulfonyl group such as methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl etc. An alkoxycarbonyl group of
Two substituents may be bonded to each other to form a ring, which may be pyrrolidinyl, piperidino, morpholino, piperazinyl, succinimide or phthalimide.

The amidino group of R ¹ and R ² may have one or two nitrogen atoms substituted, and the substituents are methyl, ethyl, benzyl, acetyl, trifluoroacetyl, propionyl, methoxycarbonyl and ethoxy. Alkoxycarbonyl such as carbonyl, cyano, nitro,
Examples include methanesulfonyl, p-toluenesulfonyl and the like. The ureido group of R ¹ and R ² may have one or two nitrogen atoms substituted, and examples of the substituent include methyl, ethyl, propyl, tert-butyl and the like. R
The thioureido group of ¹ and R ² may have one or two nitrogen atoms substituted, and examples of the substituent include methyl, ethyl, propyl, tert-butyl and the like.

[0010] The azole group of R ¹ and R ^2, pyrrole, imidazole, triazole, N- methyl triazole, tetrazole, N- methyl tetrazole, oxazole, 5-membered ring aromatic heterocyclic thiazole and the like, R ¹ Examples of the lower alkoxycarbonyl group of R ² and R ² include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl and the like. The carbamoyl group of R ¹ and R ² is an unsubstituted group obtained by condensing an amine and a carboxyl group such as ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, aniline and morpholine,
Examples include mono- or di-substituted carbamoyl groups.

The alkyl group in the lower alkoxycarbonyl-substituted alkyl group for R ⁴ is a methyl group, an ethyl group, a propyl group or a butyl group, and the lower alkoxycarbonyl group as a substituent is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, n-butoxycarbonyl or tert
-Butoxycarbonyl and the like. Examples of the aralkyl group of R ⁴ include optionally substituted benzyl, phenethyl, pyridylmethyl, pyridylethyl, imidazomethyl and the like, and the substituents include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Groups, alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, cyano groups, nitro groups, amino,
Amino group such as methylamino, dimethylamino, morpholino, carboxyl group, alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, trihalogenomethyl group such as trichloromethyl or trifluoromethyl, hydroxyl group, optionally protected hydroxymethyl or Lower hydroxyalkyl group such as hydroxyethyl, mercapto group, lower alkylthio group such as methylthio or ethylthio, optionally protected mercaptomethyl, lower mercaptoalkyl group such as mercaptoethyl, fluorine atom, chlorine atom, bromine atom, iodine atom Can be given.

As the lower acyl group for R ⁴ , acetyl,
Examples thereof include trifluoroacetyl, propionyl, butyryl, isobutyryl, and pivaloyl groups. Examples of the substituted or unsubstituted aryloyl group for R ⁴ include benzoyl group and naphthoyl group, and examples of the substituents include methyl, ethyl, propyl and isopropyl. , A lower alkyl group such as butyl and isobutyl, an alkoxy group such as methoxy, ethoxy, propoxy and isopropoxy, a cyano group and a nitro group,
Examples thereof include amino groups such as amino, methylamino, dimethylamino and morpholino, carboxyl groups, alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, trihalogenomethyl groups such as trichloromethyl and trifluoromethyl, and hydroxyl groups. The phenyl group which may be substituted for R ⁴ is a mono- or di-substituted phenyl group, and examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl, ethyl, propyl,
Even if a lower alkyl group such as isopropyl, a trihalogenomethyl group such as trichloromethyl or trifluoromethyl, a hydroxyl group, a lower alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, or two substituents are combined. Well an alkoxy group such as methylenedioxy group, ethylenedioxy group, an alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl,
Examples thereof include amino groups such as amino, methylamino, dimethylamino and morpholino, acylamino groups such as acetylamino, propionylamino and butyrylamino, cyano groups, and lower alkylthio groups such as methylthio and ethylthio.

The 5- or 6-membered aromatic heterocycle of R ⁴ may be substituted and may be furan, thiophene, pyrrole, imidazole, triazole, tetrazole, oxazole, thiazole, pyridine, pyrimidine, pyrazine, indole, benzimidazole. , Quinoline, isoquinoline, etc., the substituents include methyl,
Lower alkyl groups such as ethyl, propyl and isopropyl,
Alkoxy group such as methoxy, ethoxy, propoxy and isopropoxy, cyano group, amino group such as amino, methylamino, dimethylamino and morpholino, nitro group, carboxyl group, alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, trichloromethyl or Examples thereof include trihalogenomethyl group such as trifluoromethyl, hydroxyl group, mercapto group, lower alkylthio group such as methylthio or ethylthio, and halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom.

Examples of the salt of the compound (1) include acid addition of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid and acetic acid, tartaric acid and maleic acid. Examples thereof include acid addition salts with physiologically acceptable mineral acids or organic acids such as acid addition salts of organic carboxylic acids such as fumaric acid, oxalic acid, lactic acid and citric acid.

The method for producing the object compound (1) of the present invention and its synthetic intermediates (2) and (3) will be described in detail below.
The novel substituted cyclic amine compound represented by the general formula (1) and salts thereof of the present invention can be produced by the production method described in the following reaction scheme. [Production method 1]

[Chemical 15] (X is a halogen atom, p-toluenesulfonyloxy group,
A methanesulfonyloxy group or a trifluoromethanesulfonyloxy group, R ¹ , R ² , R ³ , A, B,
(D, Q and n have the same meanings as above)

[Manufacturing Method 2]

[Chemical 16] (R ¹ , R ² , A, D, and n are as defined above)

[Manufacturing Method 3]

[Chemical 17] (Y is a halogen atom, p-toluenesulfonyloxy group,
A methanesulfonyloxy group or a trifluoromethanesulfonyloxy group, R ¹ , R ² , R ³ , A, B,
(D, Q and n have the same meanings as above)

[Production Method 4]

[Chemical 18] (A 'is -CO- or -SO ₂ - and represented by group, X
Represents a hydroxyl group or a halogen atom, and R ¹ , R ² , R ³ ,
R ⁴ , B, D, Q, and n have the same meanings as above.)

[Production Method 1] Compound (1) is prepared by converting compound (2)
It can be produced by reacting a) with the compound (4). Examples of the base used in the reaction include organic bases such as triethylamine, alkali metal salts such as sodium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, tert-butoxypotassium, and alkali metals such as potassium carbonate. Carbonates and the like can be used. As the solvent used in the reaction,
Tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMS)
O), methylene chloride, benzene, toluene, acetone,
The reaction temperature is 0 ° C to 1 such as methyl ethyl ketone.
The range of 00 ° C can be selected and the reaction is 2 to 2
It will be completed in 4 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

[Production Method 2] The compound (1) can be produced by reacting the compound (3) with the compound (4). The reaction is carried out, for example, in an alcohol such as methanol or ethanol, a solvent such as methylene chloride, chloroform or THF, an alkali metal cyanoborohydride such as sodium cyanoborohydride, an alkali metal borohydride such as sodium borohydride or diborane. Or a boron-based reducing agent or a transition metal catalyst such as palladium carbon, palladium black or rhodium carbon in a hydrogen atmosphere. The reaction temperature can be selected in the range of 0 ° C. to room temperature, and if necessary, a catalytic amount of an organic acid such as acetic acid or p-toluenesulfonic acid or a dehydrating agent such as molecular sieves or magnesium sulfate can be added. Reaction is 1
It will be completed in 4 hours. In addition, this reaction is an inert gas,
For example, it is preferably performed in an atmosphere of argon gas or nitrogen gas.

[Production Method 3] Compound (1) can be produced by reacting compound (5) with compound (6). Examples of the base used in the reaction include organic bases such as triethylamine, sodium hydride, lithium diisopropylamide (LDA), amide bases such as sodium amide, n-butyllithium, sec-butyllithium, tert-butyllithium, tert- It is possible to use alkali metal salts such as potassium butoxy, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkali metal carbonates such as potassium carbonate. The solvent used in the reaction is diethyl ether, THF, DMF, DMSO, methylene chloride, benzene, toluene, acetone, methyl ethyl ketone, etc., and the reaction temperature can be selected in the range of 0 ° C to 100 ° C, and the reaction is 2 to 24. Complete in time. In addition,
This reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas, and an alkali metal halide such as sodium iodide or potassium iodide can be added if necessary.

[Production Method 4] Compound (1) can be produced by reacting compound (7) with compound (8). When X is a hydroxyl group, N, N′-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (E
It is possible to condense using a condensing agent such as DC). Solvents used for the reaction are diethyl ether, THF, DMF, D
It is MSO, methylene chloride, benzene, toluene, acetone, methyl ethyl ketone, etc. The reaction temperature can be selected in the range of 0 ° C to 100 ° C, and the reaction is completed in 2 to 24 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas. When X is a hydroxyl group, carbonic acid esters such as ethyl chlorocarbonate and isobutyl chlorocarbonate and organic bases such as triethylamine and morpholine are used. ) And can be manufactured. The solvent used for the reaction is diethyl ether, THF, DMF, DMSO,
It is methylene chloride, benzene, toluene, acetone, methyl ethyl ketone, etc., and the reaction temperature is -15 ° C to 10 ° C.
The range of 0 ° C can be selected, and the reaction is 1 to 12
Complete in time. In addition, this reaction is an inert gas, for example,
It is preferably carried out under an atmosphere of argon gas or nitrogen gas. When X is a halogen atom, examples of the base used in the reaction include organic bases such as triethylamine, amide bases such as sodium hydride, LDA and sodium amide, n-butyllithium, sec-butyllithium,
Alkali metal salts such as tert-butyllithium and tert-butoxypotassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkali metal carbonates such as potassium carbonate can be used. The solvent used for the reaction is diethyl ether, TH
F, DMF, DMSO, methylene chloride, benzene, toluene, acetone, methyl ethyl ketone, etc., and the reaction temperature can be selected in the range of 0 ° C to 100 ° C.
The reaction is completed in 2 to 24 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

The synthetic intermediate of the compound (1) represented by the general formula (2) of the present invention can be produced by the production method described by the following reaction formula. [Production method 5]

[Chemical 19] (R ⁵ represents a halogen atom, a hydroxyl group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a P-toluenesulfonyloxy group, a tetrahydropyranyloxy group, a lower alkoxy group, a lower acyloxy group or a trimethylsilyloxy group, and Y ′ is A chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a P-toluenesulfonyloxy group, wherein A, D, R ¹ , R ² and n have the same meanings as above)

[Production Method 6]

[Chemical 20] (A, D, R ¹ , R ² and n are as defined above)

[Production Method 7]

[Chemical 21] (A, D, R ¹ , R ² and n are as defined above)

[Production Method 5] Compound (2) can be produced by reacting compound (5) with compound (9). Examples of the base used in the reaction include organic bases such as triethylamine and pyridine, LDA, amide bases such as sodium amide, sodium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, and tert-butoxypotassium. And alkali metal carbonates such as alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, or potassium carbonate. The solvent used in the reaction is diethyl ether, THF, dioxane, DMF, DMSO, methylene chloride, benzene, toluene, acetone, methyl ethyl ketone, etc., and the reaction temperature can be selected in the range of 0 ° C to 100 ° C. Is completed in 2 to 24 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas, and an alkali metal halide such as sodium iodide or potassium iodide can be added if necessary.

[Production Method 6] The compound (2b) can be produced by reducing the compound (3). For the reduction reaction, a borohydride-based reducing agent such as sodium borohydride or sodium cyanoborohydride is used in an alcohol solvent such as methanol or ethanol, with toluene or TH.
In a solvent such as F, diethyl ether or ethylene glycol dimethyl ether (DME), a lithium hydride-based reducing agent such as lithium hydride or diisobutylaluminum hydride (DIBAH) can be used.
The reaction temperature can be selected in the range of -78 ° C to the boiling point, and the reaction is completed in 1 to 4 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas. Further, the compound (2a) can be produced by substituting the hydroxyl group of the compound (2b) with a halogen atom or sulfonylating the compound. When carrying out a substitution reaction with a halogen atom, hydrogen chloride as a reactant, hydrogen halide such as hydrogen bromide and an aqueous solution thereof, thionyl chloride, thionyl halide such as thionyl bromide, acid halide such as oxalyl chloride, Phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, etc., halogenated phosphorus, carbon tetrachloride, carbon tetrabromide, etc. can be used, and sulfonylation reaction is carried out. If
In the presence of a tertiary amine such as triethylamine or pyridine, a sulfonic acid chloride such as methanesulfonyl chloride or p-toluenesulfonyl chloride, or a sulfonic acid anhydride such as trifluoromethanesulfonic anhydride can be used. For the reaction, no solvent or methylene chloride, chloroform, benzene, toluene, THF, DMF, DME or the like can be used. The reaction temperature can be selected in the range of -20 ° C to the boiling point, and the reaction is completed in 1 to 24 hours.

[Production Method 7] Compound (2c) can also be produced by hydroborating compound (10) and then oxidizing it with hydrogen peroxide under alkaline conditions. Examples of the hydroborating agent include diborane, 9-borabicyclo [3.3.1] nonane (9-B
BN), disiamilborane and the like can be used.
The solvent used in the reaction may be THF, diethyl ether or the like, and the reaction temperature may be selected in the range of −78 ° C. to room temperature. The reaction is completed in 3 to 6 hours, and the subsequent oxidation reaction is completed in 1 to 5 hours.
The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

The synthetic intermediate of the compound (1) represented by the general formula (3) of the present invention can be produced by the production method described by the following reaction formula. [Production method 8]

[Chemical formula 22] (A, D, R ¹ , R ² and n are as defined above)

[Manufacturing Method 9]

[Chemical formula 23] (A, D, R ¹ , R ² and n are as defined above)

[Manufacturing Method 10]

[Chemical formula 24] (R ⁶ and R ⁷ may be the same or different and may be a linear or branched lower alkyl group or R ⁶ and R ⁷ may be bonded to each other to form a lower alkyl chain represented by —C ₂ H ₄ —. Good, A, D, R ¹ , R ² and n are as defined above.

[Production Method 8] Compound (3) is prepared by converting compound (2)
It can be produced by subjecting b) to an oxidation reaction. For the oxidation reaction, a chromic acid-based oxidizing agent such as Collins reagent or pyridinium chlorochromate is used in a halogenated hydrocarbon solvent such as methylene chloride, and an oxidizing agent such as Swern oxidation or sulfur trioxide / pyridine complex is used in a DMSO solvent. The reaction temperature is -78 ° C.
To room temperature can be selected. The reaction is completed in 1 to 12 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

[Production Method 9] Compound (3) is prepared by converting compound (1)
It can be produced by reducing 1) to an iminium salt and then subjecting it to a hydrolysis reaction. In the reduction reaction, lithium hydride aluminum hydride, hydrogenated alumina type reducing agent such as DIBAH in a hydrocarbon solvent such as hexane or toluene can be used, and sulfuric acid, hydrochloric acid or the like can be used in the subsequent hydrolysis reaction. Any mineral acid can be used. The reaction temperature can be selected from -78 ° C to room temperature, and the reaction is completed in 1 to 12 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

[Production Method 10] Compound (3) can be produced by deprotecting the acetal portion of compound (12). In the reaction, in a polar solvent such as THF, acetone, and water, a mineral acid such as hydrochloric acid and sulfuric acid, an organic acid such as acetic acid and trifluoroacetic acid, or a Lewis acid such as aluminum chloride, silica gel, and trimethylsilane iodide can be used. it can. The reaction temperature can be selected from -20 ° C to boiling point,
The reaction is completed in 30 minutes to 24 hours.

[Production Method 11]

[Chemical 25] (A, D, R ¹ , R ² and n are as defined above)

[Production Method 11] The compound (10) can be produced by subjecting the compound (3) to a methyleneation reaction. The reaction is carried out in an ether solvent such as THF or diethyl ether using an ylide obtained from methyltriphenylphosphonium bromide and a base such as potassium tert-butoxide. The reaction temperature can be selected in the range of −78 ° C. to room temperature, and the reaction is completed in 30 minutes to 3 hours. The reaction is preferably carried out in an atmosphere of an inert gas such as argon gas or nitrogen gas.

[Action and Effect of the Invention] The serotonin 2 receptor antagonistic action, platelet aggregation inhibitory action, and serotonin (5-hy
The inhibitory effect on droxy-L-tryptophan: 5-HTP) -induced Head-Twitch is described in detail below. N- {2- [4- (4-Fluorobenzoyl) piperidino] ethyl} -3-methoxy-N- (2-methoxyphenyl) benzamide oxalate (Compound A: Example 191) N- {2- [4- (4-Fluorobenzoyl) piperidino] ethyl} -4-methoxy-N- (2-methoxyphenyl) benzenesulfonamide oxalate (Compound B: Example 192) 4-Fluoro-N- {2- [4- (4 -Fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzenesulfonamide oxalate (Compound C: Example 193) N-cyclohexyl-N- {2- [4- (4-fluorobenzoyl) piperidino] Ethyl} -4-methoxybenzenesulfonamide oxalate (Compound D: Example 207) N- {2- [4- (4-fluorobenzoyl) pi] Peridino] ethyl} -4-hydroxymethyl-N- (2-methoxyphenyl) benzenesulfonamide oxalate (Compound E: Example 216) N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl}- 4-Hydroxymethyl-N- (2-methoxyphenyl) benzamide oxalate (Compound F: Example 217) 4-Aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-Methoxyphenyl) benzamide oxalate (Compound G: Example 22)
5) 4-Acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide fumarate (Compound H: Example 244) 4-Acetylamino -N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (phenyl)
Benzamide fumarate (Compound I: Example 264) Ketanserin (Comparative Control Compound)

[Measurement of Serotonin 2 Receptor Antagonistic Activity] Wi
male star-KY rats (weight approximately 220 to 370 g)
After bruising, the patient was exsanguinated and the ventral tail artery was removed. A spiral strip sample (about 1.5 × 30 mm) was prepared by passing a wire through the excised blood vessel. This sample was suspended by applying a load of 500 mg to a Magnus tube (10 ml) filled with a Krebs-Hensereit solution at 37 ° C. and suspended, and a mixed gas of 95% O ₂ + 5% CO ₂ was aerated. The tension was measured by using a tension transducer (TB-621T, Nihon Kohden) and drawing on an ink writing recorder (FBR-253A, Toa Denpa) via a pressure amplifier (AP-621G, Nihon Kohden). The tension was measured by contracting with serotonin 10 ^-5 M after the equilibration time of 1 hour, and recording the contraction of serotonin 10 ^-8 to 3 × 10 ^-5 M cumulative administration twice at 45 minute intervals after washing. The second time was used as a control. Then, when recording the serotonin contraction, the test drug was administered 10 minutes before the start of the accumulation of serotonin, and the serotonin antagonism was examined. The antagonism of these test drugs on the contraction of serotonin is IC for the contraction of serotonin 3 × 10 ⁻⁶ M.
_{The 50} values are shown in Table 1. The display shows an IC ₅₀ value of 1.0 × 10 ^-7
+, 9.9 × 10 ^-8 to 1.0 × 10 when M or more
++ for ^-8 M, ++ for 9.9 × 10 ^-9 M or less
It was set to +.

[0039]

[Table 1]

[Measurement of Platelet Aggregation Inhibitory Action] Platelet aggregation is measured by a platelet aggregability measuring device NSB Hematracer 601
Was performed. Male Japanese white rabbit (2-3k
Using g), blood was collected from the auricular artery using a syringe containing 3.8% sodium citrate, which was 1 volume to 9 volumes of blood.
Centrifugation was performed at 0 rpm for 10 minutes. After collecting the supernatant platelet-rich plasma (PRP), the lower layer was centrifuged at 3000 rpm for 10 minutes to obtain platelet-poor plasma (PPP). Obtained PRP
Microplate counter (Sysmex F-800,
30 × 10 ⁴ / measured by Toa Medical Electronics Co., Ltd.
It was diluted with PPP to give a volume of μl. First, diluted P
The aggregation of RP by collagen alone was examined, and the concentration of collagen that did not cause aggregation by itself was confirmed. PRP 220
Add 5 μl of 104 mM CaCl _{2 to} μl and add 1 at 37 ° C.
Incubate for 5 minutes and add 5 mg of test drug or physiological saline as a control.
μl was added. Two minutes later, 5 μl of 5-HTP (final concentration 3 μM) was added, and one minute later, collagen was added at a concentration not causing aggregation by itself to induce the platelet aggregation reaction.
The inhibitory effect on this agglutination reaction was measured, and the 50% inhibitory concentration (IC ₅₀ ) was measured by probit analysis (Table 2).
The display shows + when the IC ₅₀ value is 1.0 × 10 ^-6 M or more.
In the case of 9.9 × 10 ^-7 to 1.0 × 10 ^-7 M, ++,
In the case of 9.9 × 10 ^-8 M or less, it was set as +++.

[0041]

[Table 2]

[Measurement of inhibitory effect on 5-HTP-induced Head-Twitch] 5-HTP30 was added to 4-week-old ICR male mice.
Administer 0 mg / kg intraperitoneally (ip), further administer 0.03 to 3 mg / kg of the test drug intravenously 25 minutes later, and measure the number of Head-Twitch that appears 5 minutes after administration (20 minutes) Then, the ID ₅₀ value was calculated (Table 3). The display shows ID ₅₀
The value was + when the value was 1000 μg / kg or more, ++ when the value was 100 to 999 μg / kg, and ++ when the value was 99 μg / kg or less.

[0043]

[Table 3]

As is clear from the results of the above pharmacological tests,
The substituted cyclic amine compound represented by the general formula (1) and its salt are equivalent to ketanserin, which is a comparative drug, in the test of serotonin 2 antagonistic activity using isolated rat blood vessels and the inhibitory effect on serotonin-induced agglutination of rabbit platelets. It shows that the activity is higher than that, and that it has a strong serotonin 2 receptor antagonistic action. On the other hand, the inhibitory effect on serotonin-induced Head-Twitch in mice is weaker than that of ketanserin, and it is recognized that the effect on the central nervous system is separated.

The substituted cyclic amine compound represented by the general formula (1) and salts thereof of the present invention have a strong serotonin 2 antagonistic action and, in addition, show excellent action selectivity, and therefore have cardiovascular diseases such as hypertension. It is useful as a prophylactic and therapeutic drug for diseases such as illness, ischemic heart disease, cerebrovascular disorder, and peripheral circulatory disorder. The compound (1) and a salt thereof are themselves or a suitable pharmacologically acceptable carrier,
It can be mixed with excipients and diluents and administered orally or parenterally in the form of powder, granules, tablets, capsules, injections and the like. The dose varies depending on the target disease, symptom, administration subject and administration method. For example, when administered to an adult, the daily dose is 1 to 200 mg by oral administration and 1 by intravenous injection.
The daily dose is 0.5 to 50 mg, which is preferably administered in 1 to 3 divided doses.

[0046]

EXAMPLES The present invention will be described below with reference to reference examples and examples, but the present invention is not limited thereto. Reference Example 1 N- (2-methoxyphenyl) -3-pyridy
Emissions sulfonamide o- anisidine (377 mg, 3.0 mmol) was dissolved in toluene (10 ml), pyridine (0.48 ml,
6.0 mmol) and 3-pyridinesulfonyl chloride hydrochloride (642 mg, 3.0 mmol) were added at room temperature.
After stirring at 100 ° C for 1 hour and 30 minutes, water (20 ml)
Was added, the pH was adjusted to 7-8 with anhydrous sodium carbonate, extraction was performed with ethyl acetate, and the extract was washed with water and saturated brine. After drying over anhydrous sodium carbonate, the solvent was distilled off to obtain an orange solid. Silica gel column chromatography (ether:
Purification with hexane = 3: 1) gave a pale orange solid, followed by washing with a mixed solution of ether-hexane (1: 3) to give 662 m of the title compound as colorless prism crystals.
g (83.5%) was obtained. Melting point: 101.5 to 103 ° C IR (KBr): 3008, 2712, 1586, 14
98, 1420, 1336, 1320, 1280, 12
56, 1194, 1110, 1020, 762, 74
4,600,578,544 cm ^-1 . NMR (CDCl ₃ ) δ: 3.58 (3H, s), 6.
71 (1H, dd, J = 7.5Hz, 2Hz), 6.8
0 to 7.14 (3H, m), 7.31 (1H, dd, J
= 8 Hz, 5 Hz), 7.54 (1H, dd, J = 7.
5Hz, 2Hz), 7.96 (1H, dd, J = 8H
z, 2 Hz), 8.70 (1H, dd, J = 5 Hz, 2
Hz), 8.93 (1H, d, J = 2Hz).

Reference Example 2 N- (2-methoxyphenyl)
-P -Toluenesulfonamide o-anisidine (2.34 ml, 20 mmol) was dissolved in toluene (60 ml), and pyridine (4.58 ml,
60 mmol), p-toluenesulfonyl chloride (3.89 g, 20 mmol) and a catalytic amount of 4-dimethylaminopyridine were added under ice cooling. 2 hours 30 at room temperature
After stirring for 1 minute, water (50 ml) was added, extraction was performed with ethyl acetate, and the mixture was washed successively with water, 10% aqueous sodium hydroxide solution, 1N hydrochloric acid, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain an orange solid. This was dissolved in ethyl acetate (50 ml), adsorbed on anhydrous magnesium sulfate (20 g) and eluted with ether, and the solvent was distilled off to obtain a colorless solid, followed by ether-hexane (1:
1) By washing with the mixed solution, 3.44 g (62.0%) of the title compound was obtained as colorless prism crystals. Melting point: 126.5 to 128.5 ° C IR (KBr): 3336, 1594, 1498, 14
40, 1286, 1256, 1158, 1112, 10
88, 1024, 822, 752, 660, 554, 5
34 cm ^-1 . NMR (CDCl ₃ ) δ: 2.35 (3H, s), 3.
63 (3H, s), 6.58 to 7.34 (7H, m),
7.35-7.75 (2H, m).

Reference Example 3 4-methoxy-N- (2-meth
Xyphenyl) benzenesulfonamide o-anisidine (1.0 ml, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78).
g, 8.55 mmol) and the same operation as in Reference Example 2 was carried out to give the title compound as a colorless powder (2.
26 g (90.1%) was obtained. Melting point: 85.5-87 ° C IR (KBr): 3620, 3540, 3248, 15
94, 1500, 1448, 1342, 1286, 12
46, 1156, 1114, 1094, 1024, 91
0,836,754,678,582,568,546
cm ^-1 . NMR (CDCl ₃ ) δ: 3.63, 3.77 (eac
h 3H, s), 6.55 to 7.15 (6H, m),
7.35-7.90 (3H, m).

Reference Example 4 4-Fluoro-N- (2-meth
Xyphenyl) benzenesulfonamide o-anisidine (1.0 ml, 8.55 mmol) and 4-fluorobenzenesulfonyl chloride (1.7 g,
By performing the same operation as in Reference Example 2 using 8.55 mmol), 2.24 g (93.1%) of the title compound was obtained as colorless prism crystals. Melting point: 101 to 102.5 ° C IR (KBr): 3272, 1598, 1494, 13
96, 1342, 1254, 1222, 1178, 11
54, 1112, 1088, 840, 754, 690,
552,538 cm ^-1 . NMR (CDCl ₃ ) δ: 3.60 (3H, s), 6.
60 to 7.25 (6H, m), 7.37 to 7.94 (3
H, m).

Reference Example 5 N- (2-methoxyphenyl)
-3-Nitrobenzenesulfonamide o-anisidine (1.0 ml, 8.55 mmol) and 3-nitrobenzenesulfonyl chloride (1.95 g,
(8.55 mmol) was used to perform the same operation as in Reference Example 2 to give the title compound as 2.
36 g (89.5%) were obtained. Melting point: 130 to 131.5 ° C. IR (KBr): 3252, 1608, 1532, 14
96, 1406, 1354, 1258, 1154, 11
12,746,684,668 cm ^-1 . NMR (CDCl ₃ ) δ: 3.63 (3H, s), 6.
65 to 7.15 (4H, m), 7.56 (1H, d, J
= 7.5 Hz), 7.63 (1H, d, J = 7.5H)
z), 8.05 (1H, d, J = 7.5 Hz), 8.3
3 (1H, d, J = 7.5Hz), 8.60 (1H, b
r-s).

Reference Example 6 4-methoxy-N- (2-thia
Zolyl) benzenesulfonamide 2-aminothiazole (883 mg, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol) were used to carry out the same operation as in Reference Example 2 to give 1.47 g (63.6%) of the title compound was obtained as yellow needle crystals. Melting point: 162 to 164 ° C IR (KBr): 1594, 1580, 1518, 14
98, 1372, 1290, 1270, 1170, 11
44, 1134, 1084, 834, 688, 656,
556 cm ^-1 . NMR (CDCl ₃ ) δ: 3.84 (3H, s), 6.
37 (1H, d, J = 5Hz), 6.86 (1H, d,
J = 9 Hz), 6.89 (1H, d, J = 9 Hz),
7.44 (1H, d, J = 5Hz), 7.84 (1H,
d, J = 9 Hz), 7.91 (1H, d, J = 9H
z).

Reference Example 7 4-methoxy-N- (3-meth
X-phenyl) benzenesulfonamide m-anisidine (0.99 ml, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78).
g, 8.55 mmol) and the same procedure as in Reference Example 2 was carried out to obtain 2.50 g (99.7%) of the title compound as a pale yellow oily substance. IR (neat): 3268, 1596, 1500, 1
328, 1262, 1152, 1094, 834, 69
2,570,550 cm ^-1 . NMR (CDCl ₃ ) δ: 3.72, 3.81 (eac
h 3H, s), 6.45 to 7.40 (7H, m),
7.74 (2H, d, J = 9 Hz).

Reference Example 8 N- (2-cyanophenyl)-
4-Methoxybenzenesulfonamide 2-aminobenzonitrile (1.03 g, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol) were used to carry out the same operation as in Reference Example 2. This gave 1.57 g (63.7%) of the title compound as a colorless solid. Melting point: 102 to 103 ° C IR (KBr): 3252, 2228, 1596, 15
78, 1496, 1456, 1416, 1340, 13
10, 1180, 1162, 1092, 1024, 90
8,834,762,670,592 cm ^-1 . NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.
92 (2H, d, J = 9 Hz), 7.50 to 7.29
(2H, m), 7.35 to 7.90 (5H, m).

Reference Example 9 N- (2-trifluoromethyl)
Phenyl) -4-methoxybenzenesulfonamide Reference example 2 using 2-trifluoroaniline (1.39 g, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol).
By performing the same operation as above, 2.14 g (75.5%) of the title compound was obtained as a colorless solid. Melting point: 92-93 ° C IR (KBr): 3292, 1596, 1494, 14
16, 1346, 1318, 1270, 1254, 11
64, 1112, 1094, 1026, 834, 75
8,670,556 cm ^-1 . NMR (CDCl ₃ ) δ: 3.82 (3H, s), 6.
65 to 7.00 (3H, m), 7.03 to 7.30 (1
H, m), 7.35-7.90 (5H, m).

Reference Example 10 4-methoxy-N-cyclohexyl
Hexyl benzenesulfonamide cyclohexylamine (1.98 ml, 17.1 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol) Reference Examples Example 2 using
By performing the same operation as above, 2.30 g (100%) of the title compound was obtained as a pale yellow oil. IR (neat): 3248, 2936, 2856, 1
598, 1580, 1452, 1324, 1258, 1
156, 1096, 1080, 1026, 834, 67
2,576,556 cm ^-1 . NMR (CDCl ₃ ) δ: 0.76 to 1.95 (10
H, m), 3.05 (1H, br-s), 3.85 (3
H, s), 4.95 (1H, br-s), 6.95 (2
H, d, J = 9Hz), 7.83 (2H, d, J = 9H)
z).

Reference Example 11 4-[(2-methoxyanili)
No) sulfonyl] benzoic acid o-anisidine (0.585 ml, 5.0 mmol) and 4- (chlorosulfonyl) benzoic acid (1.15 g,
5.0 mmol) and the same procedure as in Reference Example 2 was carried out to give 1.4% of the title compound as a pink powder.
7 g (95.5%) was obtained. Melting point: 202-205 ° C IR (KBr): 3268, 1688, 1502, 14
06, 1346, 1314, 1286, 1258, 11
66,744,724 cm ^-1 . NMR (CDCl ₃ ) δ: 3.57 (3H, s), 6.
55 to 7.20 (3H, m), 7.25 to 7.60 (2
H, m), 7.76 (2H, m, J = 8.5 Hz),
8.07 (2H, m, J = 8.5Hz), 8.35 (1
H, br-s).

Reference Example 12 3-methoxy-N- (2-me
Toxyphenyl) benzamide o-anisidine (1.0 ml, 8.55 mmol) and m-anisoyl chloride (1.2 ml, 8.55 mmol) were used to carry out the same operation as in Reference Example 2 to give a brown oil. 2.2 g of the title compound (100 g
%)Obtained. IR (neat): 3436, 2940, 1674, 1
600, 1526, 1482, 1460, 1434, 1
336, 1288, 1274, 1250, 1220, 1
120, 1046, 1028, 748 cm ^-1 . NMR (CDCl ₃ ) δ: 3.88, 4.02 (eac
h 3H, s), 6.80 to 7.20 (5H, m),
7.30 to 7.55 (3H, m), 8.50 (1H, b
r-s).

Reference Example 13 4-Cyano-N- (2-meth
(Xyphenyl) benzamide 4-cyanobenzoic acid (1.5 g, 10 mmol) was dissolved in benzene (5 ml) in dry air, and DMF (0.1 mg) was added.
ml) and thionyl chloride (2.2 ml, 30 mmol)
Was added dropwise at room temperature and then refluxed for 30 minutes. The solvent was distilled off, and azeotropic distillation of benzene (10 ml × 2) was performed to dissolve the obtained yellow solid in methylene chloride (10 ml).
-Anisidine (1.16 ml, 10 mmol) and 20
Aqueous sodium hydroxide solution (4 ml) was added under ice cooling. After stirring at the same temperature for 20 minutes, methylene chloride extraction was performed, and the mixture was washed successively with 1N hydrochloric acid, water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was evaporated to obtain a pale yellow solid, which was purified by recrystallization (methylene chloride-ether) to give the title compound as a cream-colored crystal in 2.3.
Obtained 6 g (93.6%). Melting point: 157.5 to 160 ° C. IR (KBr): 3312, 2228, 1666, 16
44, 1600, 1534, 1486, 1460, 14
34, 1334, 1288, 1256, 1218, 10
22,742 cm ^-1 . NMR (CDCl ₃ ) δ: 3.93 (3H, s), 6.
81 to 7.20 (3H, m), 7.77 (2H, d, J
= 8.5 Hz), 7.98 (2H, d, J = 8.5H)
z), 8.32 to 8.58 (2H, m).

Reference Example 14 4-[(2-methoxyanili)
No. carbonyl] pyridine o-anisidine (2.34 g, 19.0 mmol) and 4-carboxypyridine (2.29 g, 19.0 mmol) were used to carry out the same operation as in Reference Example 13 to give colorless. As a powder, 4.22 g (9
7.2%) was obtained. Melting point: 79-80 ° C IR (KBr): 3316, 1665, 1596, 15
33, 1485, 1464, 1440, 747 cm ^-1 NMR (CDCl ₃ ) δ: 3.92 (3H, s), 6.
85-7.16 (3H, m), 7.72 (2H, d, J
= 6.0 Hz), 8.36-8.60 (2H, m),
8.78 (2H, d, J = 6.0 Hz).

Reference Example 15 4-chloromethyl-N- (2
-Methoxyphenyl) benzamide o-anisidine (0.69 ml, 6.0 mmol) was dissolved in methylene chloride (10 ml), 20% aqueous sodium hydroxide solution (5 ml) and 4-chloromethylbenzoyl chloride (1.17 g, 6). 0.0 mmol) was added under ice cooling. After stirring at the same temperature for 30 minutes, methylene chloride extraction was performed, and the mixture was washed successively with 1N hydrochloric acid, water and saturated saline.
After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a light beige solid, which was purified by recrystallization (ether-hexane) to give the title compound as colorless needle crystals in an amount of 1.5.
6 g (94.2%) was obtained. Melting point: 101 to 103 ° C. IR (KBr): 3448, 1668, 1600, 15
36, 1510, 1484, 1460, 1438, 13
44, 1290, 1248, 1220, 1022, 75
0,702,592,556 cm ^-1 . NMR (CDCl ₃ ) δ: 3.93 (3H, s), 4.
64 (2H, s), 6.80 to 7.16 (3H, m),
7.51 (2H, d, J = 8.5Hz), 7.98 (2
H, d, J = 8.5 Hz), 8.33 to 8.66 (2
H, m).

Reference Example 16 3-methoxy-N- (2-pi-
Lysyl) benzamido 2-aminopyridine (670 mg, 7.12 mmol)
And m-anisoyl chloride (1.2 ml, 8.55 mmol) were subjected to the same operations as in Reference Example 15 to give 341 mg of the title compound as a pale yellow oily substance.
(21.0%) was obtained. IR (neat): 3250, 1676, 1580, 1
526, 1488, 1464, 1432, 1306, 1
272, 1226, 1042, 778 cm ^-1 . NMR (CDCl ₃ ) δ: 3.80 (3H, s), 6.
85 to 7.17 (2H, m), 7.20 to 7.57 (3
H, m), 7.72 (1H, dd, J = 7.5 Hz,
7.5 Hz), 8.11 (1H, br-s), 8.40
(1H, d, J = 8Hz), 9.37 (1H, br-
s).

Reference Example 17 4-chloromethyl-N- (3
-Methoxybenzyl) benzamido Using 3-methoxybenzylamine (754 mg, 5.39 mmol) and 4-chloromethylbenzoyl chloride (1.17 g, 6.0 mmol) in the same manner as in Reference Example 15, 1.31 g (83.9%) of the title compound was obtained as colorless crystals. Melting point: 108-109.5 ° C. IR (KBr): 3292, 1634, 1612, 15
84, 1572, 1552, 1438, 1304, 12
66,1234,1052,784,740,700,
678 cm ^-1 . NMR (CDCl ₃ ) δ: 3.78 (3H, s), 4.
57 (2H, s), 4.62 (2H, d, J = 5H
z), 6.16 to 6.55 (1H, m), 6.66 to
7.03 (3H, m), 7.10 to 7.31 (1H,
m), 7.43 (2H, d, J = 8Hz), 7.78
(2H, d, J = 8Hz).

Reference Example 18 4-chloromethyl-N- (2
-Methoxyethyl) benzamide 2-methoxyethylamine (0.53 ml, 6.0 mmol) and 4-chloromethylbenzoyl chloride (78
By performing the same operation as in Reference Example 15 using 0 mg (4.0 mmol), 878 mg (96.4%) of the title compound was obtained as colorless crystals. Melting point: 125-126 ° C IR (KBr): 3348, 2900, 1638, 15
60, 1510, 1446, 1340, 1296, 12
66, 1156, 1122, 1114, 956, 67
2,640 cm ^-1 . NMR (CDCl ₃ ) δ: 3.39 (3H, s), 3.
46-3.79 (4H, m), 4.60 (2H, s),
6.50 (1H, br-s), 7.43 (2H, d, J
= 8 Hz), 7.76 (2H, d, J = 8 Hz).

Reference Example 19 4-Nitro-N- (2-meth
Xyphenyl) benzamide o-anisidine (368 mg, 2.99 mmol) and 4-nitrobenzoic acid (500 mg, 2.99 mmol).
In a solution of 15 ml of methylene chloride in 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) (630 mg, 3.29 mmol).
Was added under ice cooling. After stirring at the same temperature for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to about 8, methylene chloride extraction was performed, and the mixture was washed successively with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a solid. Purification by silica gel column chromatography (methylene chloride) gave 712 mg (87.4%) of the title compound as a yellow powder. Melting point: 146 to 147 ° C IR (KBr): 3322, 1647, 1599, 15
45, 1521, 1461, 1338, 1266, 74
1 cm ^-1 .NMR (CDCl ₃ ) δ: 3.93 (3H, s), 6.
81-7.18 (3H, m), 8.03 (2H, d, J
= 10.0 Hz), 8.34 (2H, d, J = 10.0)
Hz), 8.40 (1H, m)

Reference Example 20 4-Nitro-N- (3-meth
Xyphenyl) benzamide m-anisidine (2.50 g, 15.0 mmol) and 4
By performing the same operation as in Reference Example 19 using -nitrobenzoic acid (2.03 g, 16.5 mmol), 3.80 g (93.2 g) of the title compound was obtained as pale yellow needle crystals.
%)Obtained. Melting point: 189 to 191 ° C IR (KBr): 3316, 1642, 1598, 15
36, 1522, 1434, 1320, 1296, 11
62, 1046, 970 cm ^-1 · NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.
60-6.80 (1H, m), 7.10-7.43 (4
H, m), 8.05 (2H, d, J = 9.0 Hz),
8.33 (2H, d, J = 9.0 Hz).

Reference Example 21 4-Nitro-N- (4-meth
Xyphenyl) benzamide p-anisidine (492.6 mg, 4.0 mmol) and 4-nitrobenzoic acid (668.5 mg, 4.0 mmol) were used in the same manner as in Reference Example 19 to give a pale yellow powder. As the title compound as 904.9 mg (8
3.2%) was obtained. Melting point: 199 to 200 ° C IR (KBr): 3296, 1644, 1600, 15
30, 1516, 1462, 1348, 1322, 13
02, 1248, 1104, 1028, 872, 82
8,704,690 cm ^-1 · NMR (CDCl ₃ ) δ: 3.82 (3H, s), 6.
62 (2H, d, J = 9.0 Hz), 7.53 (2H,
d, 9.0 Hz), 8.01 (2H, d, J = 8.7H
z), 8.33 (2H, d, J = 8.7Hz).

Reference Example 22 4-Nitro-N- (2,5-
Dimethoxyphenyl) benzamide 2,5-dimethoxyaniline (2.53 g, 16.5 mmol) and 4-nitrobenzoic acid (2.51 g, 15.
(0 mmol) in the same manner as in Reference Example 19 to obtain 3.50 of the title compound as orange needle crystals.
g (77.2%) was obtained. Melting point: 184-186 ° C IR (KBr): 3424, 1686, 1604, 15
36, 1346, 1220, 1042, 850, 614
cm ^-1 NMR (CDCl ₃ ) δ: 3.83 (3H, s), 3.
91 (3H, s), 6.65 (1H, dd, J = 2.
9, 9.0 Hz), 6.85 (1H, d, 9.0H
z), 8.06 (2H, dd, J = 7.0, 2.0H
z), 8.21-8.65 (3H, m).

Reference Example 23 3-Nitro-N- (3-meth
Xyphenyl) benzamide m-anisidine (2.03 g, 16.5 mmol) and 3
By performing the same operation as in Reference Example 19 using -nitrobenzoic acid (2.51 g, 15.0 mmol), 3.72 g (91.3%) of the title compound was obtained as a colorless powder. Melting point: 120 to 121.5 ° C IR (KBr): 3300, 1648, 1608, 16
00, 1534, 1452, 1432, 1358, 12
72, 1156 cm ^-1 · NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.
66-6.83 (1H, m), 7.06-7.33 (3
H, m), 7.33-7.45 (1H, m), 7.68.
(1H, dd, eachchJ = 9.0Hz), 8.20-
8.46 (2H, m), 8.70-8.88 (1H,
m).

Reference Example 24 4-nitro-N- (2,4-
Dimethoxyphenyl) benzamide 2,4-dimethoxyaniline (2.53 g, 16.0 mmol) and 4-nitrobenzoic acid (2.50 g, 14.
(8 mmol) in the same manner as in Reference Example 19 to give 3.72 of the title compound as yellow needle crystals.
g (91.3%) was obtained. Melting point: 172-174 ° C IR (KBr): 1680, 1522, 1502, 14
22,1342,1286,1252,1212,11
56, 1136, 1032, 852, 836, 708,
550 cm ^-1 · NMR (CDCl ₃ ) δ: 3.82 (3H, s), 3.
91 (3H, s), 6.51-6.85 (2H, m),
7.76-8.29 (1H, m), 8.03 (2H, d
d, eachJ = 8.8 Hz), 8.34 (2H, d,
J = 8.8 Hz), 8.39 (1H, d, J = 4.2H)
z).

Reference Example 25 4-nitro-N- (3-methyl
Luphenyl) benzamide m-toluidine (1.61 g, 15.0 mmol) and 4-nitrobenzoic acid (2.76 g, 16.5 mmol)
By performing the same operation as in Reference Example 19 using
3.34 g (84.3) of the title compound as colorless needle crystals.
%)Obtained. Melting point: 140.5 to 146.5 ° C IR (KBr): 3298, 1641, 1599, 15
33, 1515, 1449, 1347, 1320, 13
02, 1260, 867, 708 cm ^-1 · NMR (CDCl ₃ ) δ: 2.37 (3H, s), 6.
87-7.53 (4H, m), 7.64-8.10 (1
H, m), 7.99 (2H, dd, eachJ = 9.0)
Hz), 8.32 (2H, d, J = 9.0 Hz).

Reference Example 26 4-nitro-N- (phenylene
) Benzamidoaniline (1.50 ml, 16.5 mmol) and 4-
By performing the same operation as in Reference Example 19 using nitrobenzoic acid (1.77 g, 10.5 mmol), 2.48 g (97.5%) of the title compound was obtained as a colorless powder. Melting point: 90-93 ° C IR (KBr): 3324, 1652, 1598, 15
30, 1494, 1440, 1348, 1324, 13
00, 1264, 852, 758, 722, 694 cm
^-1. NMR (CDCl ₃ ) δ: 7.25 (1H, t, J =
5.7 Hz), 7.41 (2H, dd, J = 5.7H)
z), 7.64 (2H, d, J = 7.9 Hz), 7.6
8-7.99 (1H, s), 8.03 (2H, d, J =
8.8 Hz), 8.35 (2H, d, J = 8.8H)
z).

Reference Example 27 4-nitro-N- (3-methyl
Luthiophenyl ) benzamide 3-methylthioaniline (1.40 ml, 11.0 mmol) and 4-nitrobenzoic acid (1.67 g, 10.0
Was carried out in the same manner as in Reference Example 19 to give 2.46 g (8%) of the title compound as a yellow powder.
(5.2%) was obtained. Melting point: 158 to 161 ° C IR (KBr): 3280, 1648, 1598, 15
40, 1518, 1476, 1344, 1326, 13
10, 1300, 1264, 868, 848, 716
684 cm ^-1 · NMR (CDCl ₃ ) δ: 2.51 (3H, s), 7.
08-7.35 (3H, m), 7.63 (1H, s),
7.81 (1H, s), 8.02 (2H, d, J = 8.
8 Hz), 8.35 (2H, d, J = 8.8 Hz).

Reference Example 28 4-nitro-N- (2-tri
Fluoromethylphenyl) benzamide 2-trifluoromethylaniline (1.77 g, 11.
0 mmol) and 4-nitrobenzoic acid (1.67 g, 1
(0.0 mmol) in the same manner as in Reference Example 19 to obtain 474 m of the title compound as a colorless powder.
g (15.3%) was obtained. Melting point: 125.6-126.1 ° C IR (KBr): 3308, 1660, 1524, 13
48, 1318, 1294, 1164, 1114, 76
2 cm ^-1 .NMR (CDCl ₃ ) δ: 7.53 (1H, d, J =
7.7 Hz), 7.66 (2H, t, J = 7.7H
z), 7.98-8.43 (5H, m).

Reference Example 29 4-nitro-N- (3-tri
Fluoromethylphenyl) benzamide 3-trifluoromethylaniline (1.77 g, 11.
0 mmol) and 4-nitrobenzoic acid (1.67 g, 1
(0.0 mmol) and the same operation as in Reference Example 19 was conducted to obtain 2.48 of the title compound as a colorless powder.
g (80.0%) was obtained. Melting point: 209.6 to 210.3 ° C IR (KBr): 3304, 1658, 1652, 13
50,1332,714,698 cm ^-1 · NMR (CDCl ₃ ) δ: 7.50 (1H, dd, J =
2.0, 6.8 Hz), 7.83-8.09 (4H,
m), 8.36 (2H, m, J = 2.0, 6.8H
z).

Reference Example 30 4-nitro-N- (3-pyri
Zyl) benzamido 3-aminopyridine (1.55 g, 16.5 mmol)
And 4-nitrobenzoic acid (2.5 g, 15.0 mmol) were subjected to the same operations as in Reference Example 19 to give 1.81 g (49.6 g) of the title compound as a colorless powder.
%)Obtained. Melting point: 191-1945C IR (KBr): 3305, 3025, 1665, 16
02,1539,1521,1422,1353,13
05,1281,1236,711 cm ^-1 · NMR (CDCl ₃ -CD ₃ OD) δ: 7.15-7.4
7 (2H, m), 8.08 (2H, d, J = 9.0H
z), 8.36 (2H, d, J = 9.0Hz), 8.1
9-8.54 (2H, m), 8.58-8.82 (1
H, m).

Reference Example 31 2-Nitro-N- (3-meth
Xyphenyl) benzamide m-anisidine (2.03 g, 16.5 mmol) and 2
By performing the same operation as in Reference Example 19 using -nitrobenzoic acid (2.51 g, 15.0 mmol), 3.47 g (84.9 g) of the title compound was obtained as pale yellow needle crystals.
%)Obtained. Melting point: 156-158 ° C IR (KBr): 3252, 1656, 1612, 15
98, 1488, 1470, 1350, 1266, 12
02,1030 cm ^-1 · NMR (CDCl ₃ -CD ₃ OD) δ: 3.80 (3H,
s), 6.58-6.80 (1H, m), 7.00-
7.40 (3H, m), 7.43-7.75 (4H,
m), 7.96-8.18 (1H, m).

Reference Example 32 4-nitro-N- (3-nit
Rophenyl) benzamide 3-nitroaniline (2.76 g, 16.5 mmol)
And 4-nitrobenzoic acid (2.51 g, 15.0 mmol) were subjected to the same operations as in Reference Example 19 to give 3.58 g (83.
2%) was obtained. Melting point: 229.2 to 232 ° C IR (KBr): 3394, 3106, 3076, 16
80, 1602, 1548, 1518, 1428, 13
44,1281,1086,870 cm ^-1 · NMR (CDCl ₃ -CD ₃ OD) δ: 7.40-7.8
3 (3H, m), 8.11 (2H, d, J = 9.0H
z), 8.36 (2H, d, J = 9.0 Hz), 7.9
2-8.60 (2H, m).

Reference Example 33 4-Nitro-N- (2-meth
By performing the same operation as in Reference Example 19 using methyl xycarbonylphenyl ) benzamido anthranilate (3.02 g, 20.0 mmol) and 4-nitrobenzoic acid (3.67 g, 22.0 mmol), The title compound was 4.20 as yellow prism crystals.
g (72.9%) was obtained. Melting point: 196-199 ° C IR (KBr): 3368, 1676, 1606, 15
20, 1346, 1276, 758, 697 cm ^-1 · NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.
18 (1H, t, J = 7.3 Hz), 7.64 (1H,
t, J = 7.3 Hz), 8.06-8.44 (5H,
m), 8.89 (1H, d, J = 8.4 Hz).

Reference Example 34 4-Cyano-N- (4-meth
Xyphenyl) benzamide p-anisidine (1.35 g, 11.0 mmol) and 4-cyanobenzoic acid (1.47 g, 10.0 mmol)
By performing the same operation as in Reference Example 19 using
2.31 g (91.7) of the title compound as colorless needle crystals.
%)Obtained. Melting point: 154.6-157.3 ° C IR (KBr): 3440, 2945, 1646, 13
48,1258,973,850,715,601cm
_{^{-1 · NMR (CDCl 3) δ}} : 3.82 (3H, s), 6.
91 (2H, t, J = 9.0Hz), 7.51 (2H,
d, J = 9.0 Hz), 7.77 (2H, d, J = 8.
6 Hz), 7.94 (2H, d, J = 8.6 Hz).

Reference Example 35 3-Methyl-4-nitro-N
-(4-Methoxyphenyl) benzamide p-anisidine (738 mg, 6.0 mmol) and 3
By performing the same operation as in Reference Example 19 using -methyl-4-nitrobenzoic acid (906 mg, 5.0 mmol), 1.33 g (9%) of the title compound was obtained as a yellow powder.
3.0%) was obtained. Melting point: 167.8-169.1 ° C IR (KBr): 3276, 1642, 1534, 15
14,135,1248,1031,826,71
3,522 cm ^-1 · NMR (CDCl ₃ ) δ: 2.63 (3H, s), 3.
81 (3H, s), 6.90 (2H, dd, J = 2.
2,6.8 Hz), 7.42 (2H, dd, J = 2.
2, 6.8 Hz), 7.71-8.04 (3H, m).

Reference Example 36 3-Methoxy-4-nitro-
N- (4-methoxyphenyl) benzamide p-anisidine (738 mg, 6.0 mmol) and 3
-Methoxy-4-nitrobenzoic acid (986 mg, 5.0
(40 mmol) to carry out the same operation as in Reference Example 19 to obtain 1.40 g (9%) of the title compound as a colorless powder.
2.7%) was obtained. Melting point: 168 to 169.3 ° C IR (KBr): 3312, 1650, 1526, 15
14, 1238, 1028, 803, 680 cm ^-1 · NMR (CDCl ₃ ) δ: 3.82 (3H, s), 4.
01 (3H, s), 6.92 (2H, d, J = 9.0H
z), 7.31-7.65 (3H, m), 7.84 (2
H, d, J = 8.1 Hz).

Reference Example 37 4-Nitro-N- (3-methyl
Luphenyl) benzamide p-toluidine (1.19 g, 11.0 mmol) and 4-nitrobenzoic acid (1.77 g, 10.5 mmol)
By performing the same operation as in Reference Example 19 using
2.68 g (99.
6%) was obtained. Melting point: 140.5 to 146.5 ° C IR (KBr): 3298, 1641, 1599, 15
33, 1515, 1449, 1347, 1320, 13
02, 1260, 867, 708 cm ^-1 · NMR (CDCl ₃ ) δ: 2.37 (3H, s), 6.
87 to 7.53 (4H, m), 7.64 to 8.10 (1
H, m), 7.99 (2H, d, J = 9.0 Hz),
8.32 (2H, d, J = 9.0 Hz).

Reference Example 38 4-nitro-N- (4-full
Orophenyl) benzamide 4-fluoroaniline (1.0 ml, 9.93 mmol) and 4-nitrobenzoic acid (1.58 g, 9.36 mmol) were used to carry out the same operation as in Reference Example 19 to give a pale yellow color. 1.60 g of the title compound as needle crystals
(65.8%) was obtained. Melting point: 143-146 ° C IR (KBr): 3280, 1648, 1598, 15
54, 1524, 1504, 1348, 1322, 12
44, 1212, 838, 824 cm ^-1 · NMR (CDCl ₃ ) δ: 7.09 (2H, t, J =
8.8 Hz), 7.63 (2H, dd, J = 4.6)
8.8 Hz), 8.05 (2H, d, J = 8.6H
z), 8.10 (1H, s), 8.34 (2H, d, J
= 8.6 Hz).

Reference Example 39 3-Nitro-N- (phenylene
Le) benzamido aniline (1.50 ml, 16.5 mmol) and 3-
By performing the same operation as in Reference Example 19 using nitrobenzoic acid (2.64 g, 15.0 mmol), 2.84 g (78.2) of the title compound was obtained as pale yellow needle crystals.
%)Obtained. Melting point: 153-154 ° C IR (KBr): 1654, 1600, 1528, 14
94, 1444, 1348, 1326, 1304, 12
60,756,714 cm ⁻¹ · NMR (CDCl ₃ ) δ: 7.19-7.48 (2H,
m), 7.60-7.79 (4H, m), 7.86 (1
H, brs), 8.25 (1H, d, J = 7.7H
z), 8.40 (1H, d, J = 7.7 Hz), 8.6
9 (1H, s).

Reference Example 40 3-Nitro-N- (4-methyi)
Luphenyl) benzamide p-toluidine (1.19 g, 11.0 mmol) and 3-nitrobenzoic acid (1.76 g, 10.0 mmol)
By performing the same operation as in Reference Example 19 using
2.27 g (88.3) of the title compound as colorless needle crystals.
%)Obtained. Melting point: 160 to 162 ° C IR (KBr): 3304, 1648, 1522, 13
50,1322,814 cm ^-1 · NMR (CDCl ₃ ) δ: 2.37 (3H, s), 7.
18-7.28 (3H, m), 7.51-7.81 (4
H, m), 8.28 (1H, d, J = 8.6 Hz),
8.43 (1H, d, J = 8.6Hz), 8.72 (1
H, s).

Reference Example 41 3-Nitro-N- (4-full
Orophenyl) benzamide 4-fluoroaniline (1.1 ml, 10.9 mmol) and 3-nitrobenzoic acid (1.76 g, 10.0 mmol) were used to carry out the same operation as in Reference Example 19 to give a pale yellow color. 1.98 g of the title compound as needle crystals
(76.0%) was obtained. Melting point: 167 to 168 ° C IR (KBr): 3312, 1650, 1614, 15
28, 1504, 1408, 1350, 1322, 12
64, 1240, 1210, 1098, 832, 71
2,518 cm ^-1 · NMR (CDCl ₃ ) δ: 6.98-7.18 (3H,
m), 7.53-7.79 (3H, m), 7.79-
7.98 (1H, m), 8.24 (1H, d, J = 7.
8Hz), 8.40 (1H, d, J = 7.8Hz),
8.68 (1H, s).

Reference Example 42 3-Nitro-N- (3-methyi)
Luthiophenyl) benzamide 3-methylthioaniline (2.1 ml, 16.5 mmol) and 3-nitrobenzoic acid (2.64 g, 15.0 mmol) were used to carry out the same operation as in Reference Example 19 to give 4.09 g of the title compound as yellow needle crystals
(94.6%) was obtained. Melting point: 145 ° C IR (KBr): 3300, 1658, 1596, 15
28, 1476, 1432, 1404, 1350, 13
16, 1304, 832 cm ^-1 · NMR (CDCl ₃ ) δ: 2.51 (3H, s), 7.
04-7.35 (3H, m), 7.62 (1H, s),
7.73 (1H, d, J = 8.7 Hz), 7.70-
7.98 (1H, m), 8.24 (1H, d, J = 7.
8Hz), 8.40 (1H, d, J = 7.8Hz),
8.68 (1H, s).

Reference Example 43 4-nitro-N- (3,4-
Dimethylphenyl) benzamide 3,4-xylidine (1.35 g, 11.0 mmol)
Using 4-nitrobenzoic acid (1.69 g, 10.0 mmol) and performing the same operation as in Reference Example 19, 2.70 g (quantitative) of the title compound was obtained as pale yellow crystals. Melting point: 221-223 ° C IR (KBr): 3292, 1650, 1600, 15
40, 1514, 1500, 1414, 1342, 13
26, 1312, 1300, 1288, 1262, 84
8,812,706 cm ⁻¹ · NMR (CDCl ₃ ) δ: 2.27 (6H, s), 7.
09-7.41 (3H, m), 7.80-7.81 (1
H, m), 8.02 (2H, d, J = 8.6 Hz),
8.33 (2H, d, J = 8.6Hz).

Reference Example 44 4-nitro-N- (3,5-
By performing the same operation as in Reference Example 19 using dimethylphenyl) benzamide 3,5-xylidine (1.42 ml, 11.0 mmol) and 4-nitrobenzoic acid (1.76 g, 10.4 mmol), 2.72 g (quantitative) of the title compound was obtained as pale yellow crystals. Melting point: 206-210 ° C IR (KBr): 3296, 1648, 1618, 16
00, 1562, 1522, 1462, 1344, 13
26, 1290, 1254, 864, 850, 838,
704,682 cm ^-1 .NMR (CDCl ₃ ) δ: 2.33 (6H, s), 6.
84 (1H, s), 7.26 (2H, s), 8.00
(2H, d, J = 8.8Hz), 8.33 (2H, d,
J = 8.8 Hz).

Reference Example 45 4-nitro-N- (4-chloro
Rophenyl) benzamide 4-chloroaniline (1.42 g, 11.0 mmol)
And 4-nitrobenzoic acid (1.76 g, 10.4 mmol) were used to perform the same operation as in Reference Example 19 to give 2.84 g (98.5 g) of the title compound as yellow crystals.
%)Obtained. Melting point: 233-235 ° C IR (KBr): 3424, 1680, 1604, 15
32, 1512, 1492, 1394, 1346, 13
28, 1310, 1300, 1248 cm ^-1 · NMR (CDCl ₃ ) δ: 7.36 (2H, d, J =
9.0 Hz), 7.67 (2H, d, J = 9.0H
z), 7.84-7.88 (1H, m), 8.04 (2
H, d, J = 8.8 Hz), 8.35 (2H, d, J =
8.8 Hz).

Reference Example 46 4-nitro-N- (3,4-
Methylenedioxyphenyl) benzamide 3,4-methylenedioxyaniline (1.44 g, 1
0.5 mmol) and 4-nitrobenzoyl chloride (1.86 g, 10.0 mmol) in Reference Example 13
By performing the same operation as above, 2.49 g (87.2%) of the title compound was obtained as yellow crystals. Melting point: 231-234 ° C IR (KBr): 3316, 1650, 1599, 15
33, 1512, 1494, 1452, 1344, 13
20, 1278, 1245, 1200, 1035, 92
4,864,852 cm ^-1 · NMR (CDCl ₃ ) δ: 5.98 (2H, s), 6.
80 (2H, d, J = 8.1Hz), 7.06 (1H,
dd, J = 8.1, 1.9 Hz), 8.07 (2H,
d, J = 8.7 Hz), 8.32 (2H, d, J = 8.
7 Hz).

Reference Example 47 4-Nitro-N- (1-naphth
Cyl ) benzamido 1-aminonaphthalene (751.7 mg, 5.25 mmol) and 4-nitrobenzoyl chloride (927.9).
The title compound was obtained as pale yellow crystals in an amount of 1.57 g (quantitative) by performing the same operation as in Reference Example 13 using (mg, 5.00 mmol). Melting point: 197 to 203 ° C IR (KBr): 3232, 3064, 1644, 16
02, 1545, 1518, 1485, 1443, 14
04, 1344, 1320, 1287, 1104, 86
4,849,789,762 cm ⁻¹ · NMR (CDCl ₃ ) δ: 7.40 to 7.63 (3H,
m), 7.70 to 8.00 (4H, m), 8.14 (2
H, d, J = 8.0 Hz), 8.36 (2H, d, J =
8.0 Hz).

Reference Example 48 3-[(2-methoxyanili)
No) sulfonyl] pyridine- N -oxide N- (2-methoxyphenyl) -3-pyridinesulfonamide (132 mg, 0.5 mmol) was dissolved in methylene chloride (5 ml) to give m-chloroperbenzoic acid (185 m).
g, 70%, 0.75 mmol) was added at room temperature. After stirring at the same temperature for 7 hours, saturated aqueous sodium thiosulfate solution (5 ml) and saturated aqueous sodium hydrogen carbonate solution (5 ml) were added to saturate the sodium chloride, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium carbonate, the solvent was evaporated to give a yellow solid, which was washed with ethyl acetate to give the title compound (124 mg, 88.5%) as a cream-colored powder. IR (KBr): 3000, 2710, 1605, 14
96, 1446, 1426, 1342, 1290, 12
60, 1236, 1168, 1158, 1110, 60
6,592 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 3.66 (3H,
s), 6.70 to 7.65 (6H, m), 8.26 (1
H, d, J = 6 Hz), 8.60 (1H, br-s).

Reference Example 49 4-[(2-methoxyanili)
No. carbonyl] pyridine-N-oxide 4-{(2-methoxyanilino) carbonyl} pyridine (500 mg, 2.19 mmol) and 89% m-chloroperbenzoic acid (637 mg, 3.28 mmol). By the same procedure as in Reference Example 48, 501 mg (93.6%) of the title compound was obtained as a colorless powder. Melting point: 182-184 ° C IR (KBr): 3610, 2998, 1665, 16
14,1596,1536,1503,1479,14
64, 1260, 1176 cm ^-1 NMR (CDCl ₃ ) δ: 3.94 (3H, s), 6.
83-7.19 (3H, m), 7.76 (2H, d, J
= 6.0 Hz), 8.27 (2H, d, J = 6.0H)
z), 8.35-8.55 (2H, m).

Reference Example 50 4-Hydroxymethyl-N-
(2-methoxyphenyl) benzenesulfonamide Under argon atmosphere, 4-[(2-methoxyanilino) sulfonyl] benzoic acid (150 mg, 0.488 mmol) was dissolved in THF (5 ml), and triethylamine (0.14 ml, 1.0 mmol) and ethyl chloroformate (50 μl, 0.509 mmol) were added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, the precipitate was filtered off. The residue obtained by concentrating the filtrate was dissolved in 5 ml of THF, and sodium borohydride (46.5 mg, 1.22 mmol) and water (1 ml) were added under ice cooling. 40 at the same temperature
After stirring for 2 minutes, 2N hydrochloric acid was added to adjust the pH to 4 to 5, and ether extraction was performed. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a colorless oil, which was purified by silica gel column chromatography (ether) to give 99.6 mg of the title compound as a colorless solid. (69.6%) was obtained. Melting point: 101 to 104 ° C. IR (KBr): 3528, 3180, 1598, 15
02, 1448, 1412, 1332, 1254, 11
82, 1154, 1114, 1088, 1052, 92
2,754,590,544 cm ^-1 . NMR (CDCl ₃ ) δ: 1.79 (1H, t, J = 6
Hz), 3.63 (3H, s), 4.72 (2H, d,
J = 6 Hz), 6.72 (1 H, dd, J = 8 Hz, 2
Hz), 6.83 to 7.16 (3H, m), 7.38
(2H, d, J = 9Hz), 7.51 (1H, dd, J
= 8 Hz, 2 Hz), 7.74 (2H, d, J = 9H
z).

Reference Example 51 4-methoxymethyl-N-
(2-Methoxyphenyl) benzamide 4-chloromethyl-N- (2-methoxyphenyl) benzamide (138 mg, 0.50 mmol) was dissolved in a mixed solution of methanol-THF (1: 1) (6 ml) to give 1
A 0% aqueous sodium hydroxide solution (3 ml) was added at room temperature. After stirring at the same temperature for 14 hours, ultrasonic waves were applied for 3 hours. After distilling off the organic solvent, extraction with methylene chloride was performed, and the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a colorless oily substance, which was purified by silica gel column chromatography (ether: hexane = 1: 2). 126 mg (92.9%) of the title compound was obtained as a colorless oil. IR (neat): 3440, 2930, 1674, 1
602, 1530, 1510, 1482, 1460, 1
434, 1252, 1102, 748 cm ^-1 . NMR (CDCl ₃ ) δ: 3.41 (3H, s), 3.
92 (3H, s), 4.52 (2H, s), 6.80-
7.14 (3H, m), 7.45 (2H, d, J = 8.
5Hz), 7.88 (2H, d, J = 8.5Hz),
8.35-8.68 (2H, m).

Reference Example 52 3-Hydroxymethyl-N-
(2-Methoxyphenyl) benzamide N-bromosuccinimide (1.29 g, 7.2 mmol) and AIBN (50 mg, 0.30 mmol) were suspended in carbon tetrachloride (80 ml) and m-toluyl chloride (0.8 ml). , 6.0 mmol) was added and 4 under light irradiation.
Reflux for hours. The reaction mixture was concentrated to 1/3, the insoluble material was filtered off, and o-anisidine (0.69 ml, 6 mmol) was added.
And 20% aqueous sodium hydroxide solution (5 ml) were sequentially added dropwise under ice cooling. After stirring at room temperature for 20 minutes, methylene chloride extraction was performed, and the mixture was washed successively with a 10% aqueous citric acid solution, water, and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a light beige solid, and 20 g of silica gel.
Silica gel column chromatography (ether: hexane = 1: 1) was carried out to obtain a cream powder. Precipitated calcium carbonate (2.34 g, 23.
4 mmol) and dioxane-water (1: 1) mixed solution (20 ml) were added and the mixture was refluxed for 6 hours. THF (50m
l) was added, the insoluble matter was filtered off, and then the organic solvent was distilled off. The residue was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give an orange oil. This was dissolved in methanol (15 ml) and sodium borohydride (90 mg, 2.34) was added.
Mmol) at -15 ° C. After stirring at the same temperature for 1 hour, acetone (1 ml) was added, the temperature was raised to room temperature, and a saturated ammonium chloride aqueous solution (10 ml) was added. After distilling off methanol, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (ether: hexane = 3). : 1).
The obtained colorless solid was washed with a mixed solution of ether-hexane (2: 1) to obtain 1.02 g (66.1%) of the title compound as a colorless powder. Melting point: 101.5 to 102.5 ° C IR (KBr): 3312, 1650, 1594, 15
34, 1494, 1462, 1434, 1332, 12
88, 1256, 1224, 1030 cm ^-1 . NMR (CDCl ₃ ) δ: 1.95 (1H, t, J = 5
Hz), 3.93 (3H, s), 4.79 (2H, d,
J = 5 Hz), 6.76 to 7.18 (3H, m), 7.
35 to 7.65 (2H, m), 7.67 to 8.00 (2
H, m), 8.35-8.70 (2H, m).

Reference Example 53 4-Hydroxymethyl-N-
(2-Methoxyphenyl) benzamide 4-chloromethyl-N- (2-methoxyphenyl) benzamide (500 mg, 1.81 mmol) and precipitated calcium carbonate (970 mg, 9.7 mmol) in dioxane-water (1: 1). ) Suspended in mixed solution (9 ml) for 2
Refluxed for 5 hours. After adding THF (25 ml), the insoluble matter was filtered off and the organic solvent was distilled off. The residue was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a colorless solid, which was subjected to silica gel column chromatography (ether: hexane = 3: 1). Purification yielded 411 mg (88.3%) of the title compound as colorless crystals. Melting point: 104 to 105.5 ° C IR (KBr): 3428, 1648, 1604, 15
36, 1510, 1488, 1456, 1438, 13
46,1292,1254,1038,744,614
cm ^-1 . NMR (CDCl ₃ ) δ: 1.88 (1H, t, J = 5
Hz), 3.93 (3H, s), 4.80 (2H, d,
J = 5 Hz), 6.76 to 7.16 (3H, m), 7.
49 (2H, d, J = 8Hz), 7.89 (2H, d,
J = 8 Hz), 8.30-8.70 (2H, m).

Reference Example 54 4-hydroxymethyl-N-
(3-Methoxybenzyl) benzamide 4-chloromethyl-N- (3-methoxybenzyl) benzamide (500 mg, 1.73 mmol) was used to perform the same operation as in Reference Example 53 to give the title compound as a colorless powder. Obtained 389 mg (82.9%). Melting point: 63 to 67.5 ° C IR (KBr): 3320, 1640, 1614, 15
46, 1492, 1454, 1436, 1308, 12
64, 1048, 734, 694 cm ^-1 . NMR (CDCl ₃ ) δ: 2.04 (1H, t, J = 6
Hz), 3.79 (3H, s), 4.60 (2H, d,
J = 6Hz), 4.73 (2H, d, J = 4.5H)
z), 6.20 to 6.58 (1H, m), 6.68 to
7.04 (3H, m), 7.10 to 7.32 (1H,
m), 7.39 (2H, d, J = 8Hz), 7.76
(2H, d, J = 8Hz).

Reference Example 55 4-hydroxymethyl-N-
(2- Methoxyethyl ) benzamide 4-chloromethyl-N- (2-methoxyethyl) benzamide (228 mg, 1.0 mmol) was used to perform the same operation as in Reference Example 53 to give the title compound as a colorless solid. Obtained 209 mg (100%). Melting point: 84 to 86 ° C IR (KBr): 3300, 2888, 1634, 15
54, 1510, 1334, 1308, 1120, 10
34,748,658 cm ^-1 . NMR (CDCl ₃ ) δ: 2.07 (1H, t, J =
5.2 Hz), 3.39 (3H, s), 3.47-3.
88 (4H, m), 4.72 (2H, d, J = 5.2H
z), 6.52 (1H, br-s), 7.40 (2H,
d, J = 8 Hz), 7.76 (2H, d, J = 8H)
z).

Reference Example 56 4-Tetrahydropyranylo
Xymethyl-N- (2-methoxyphenyl) benzenes
Rufonamide 4-hydroxymethyl-N- (2-methoxyphenyl)
Benzenesulfonamide (99.6 mg, 0.34 mmol) was dissolved in methylene chloride (3 ml) and 3,4-dihydro-2H-pyran (48 μl, 0.51 mmol) was added.
And a catalytic amount of p-toluenesulfonic acid monohydrate were added under ice cooling. After stirring at the same temperature for 90 minutes, saturated sodium hydrogen carbonate solution (5 ml) was added and ether extraction was performed. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a pale yellow oily substance, which was purified by silica gel column chromatography (ether: hexane = 1: 1) to give a colorless solid. The title compound as 117 m
g (91.2%) was obtained. Melting point: 67 to 70 ° C. IR (KBr): 3272, 2932, 1598, 15
02, 1398, 1342, 1256, 1168, 11
14,1090,1028,972,908,752
696,548 cm ^-1 . NMR (CDCl ₃ ) δ: 1.34 to 2.10 (6H,
m), 3.30 to 4.10 (2H, m), 3.63 (3
H, s), 4.46 (1H, d, J = 13.2 Hz),
4.65 (1H, br-s), 4.78 (1H, d, J
= 13.2 Hz), 6.56 to 7.14 (4H, m),
7.19 to 7.60 (1H, m), 7.36 (2H,
d, J = 8 Hz), 7.74 (2H, d, J = 8H)
z).

Reference Example 57 4-Tetrahydropyranylo
Xymethyl-N- (2-methoxyphenyl) benzami
De 4-hydroxymethyl-N- (2-methoxyphenyl)
By performing the same operation as in Reference Example 56 using benzamide (129 mg, 0.5 mmol), 166 mg (97.2%) of the title compound was obtained as a colorless solid. Melting point: 67 to 70 ° C IR (KBr): 3445, 2944, 1676, 16
02, 1528, 1510, 1482, 1460, 14
34, 1340, 1288, 1124, 1032, 74
8 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.10 (6H,
m), 3.40 to 3.72 (1H, m), 3.73 to
4.15 (1H, m), 3.92 (3H, s), 4.5
7 (1H, d, J = 12.5Hz), 4.73 (1H,
br-s), 4.85 (1H, d, J = 12.5H
z), 6.80 to 7.15 (3H, m), 7.49 (2
H, d, J = 8Hz), 7.87 (2H, d, J = 8H)
z), 8.35-8.67 (2H, m).

Reference Example 58 3-Tetrahydropyranylio
Xymethyl-N- (2-methoxyphenyl) benzami
De 3-hydroxymethyl-N- (2-methoxyphenyl)
By performing the same operation as in Reference Example 56 using benzamide (129 mg, 0.5 mmol), 159 mg (93.1%) of the title compound was obtained as a colorless oil. IR (neat): 3435, 2944, 1676, 1
602, 1526, 1460, 1432, 1338, 1
288, 1250, 1120, 1030, 746c
m ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 2.00 (6H,
m), 3.40 to 3.70 (1H, m), 3.78 to
4.11 (1H, m), 3.92 (3H, s), 4.5
7 (1H, d, J = 12.5Hz), 4.75 (1H,
br-s), 4.89 (1H, d, J = 12.5H
z), 6.80 to 7.15 (3H, m), 7.40 to
7.64 (2H, m), 7.67 to 7.98 (2H,
m), 8.35-8.66 (2H, m).

Reference Example 59 4-Tetrahydropyranylio
Xymethyl-N- (3-methoxybenzyl) benzami
De 4-hydroxymethyl-N- (3-methoxybenzyl)
By performing the same operation as in Reference Example 56 using benzamide (136 mg, 0.5 mmol), 178 mg (100%) of the title compound was obtained as a colorless solid. Melting point: 66 to 68.5 ° C IR (KBr): 3308, 2944, 1640, 15
52, 1492, 1352, 1320, 1260, 11
40, 1116, 1032, 980, 770, 674c
m ^-1 . NMR (CDCl ₃ ) δ: 1.35 to 2.23 (6H,
m), 3.37 to 4.13 (2H, m), 3.79 (3
H, s), 4.35 to 4.97 (5H, m), 6.15
~ 6.55 (1H, m), 6.67 ~ 7.06 (3H,
m), 7.12 to 7.33 (1H, m), 7.42 (2
H, d, J = 8Hz), 7.77 (2H, d, J = 8H)
z).

Reference Example 60 4-Tetrahydropyranilio
Xymethyl-N- (2-methoxyethyl) benzamide 4-hydroxymethyl-N- (2-methoxyethyl) benzamide (209 mg, 1.0 mmol) was used to perform the same operation as in Reference Example 56 to give a colorless oil. As a substance, 268 mg (91.4%) of the title compound was obtained. IR (neat): 3336, 2940, 2872, 1
640, 1544, 1504, 1304, 1198, 1
120, 1078, 1064, 1034 cm ^-1 . NMR (CDCl ₃ ) δ: 1.35 to 2.10 (6H,
m), 3.38 (3H, s), 3.42 to 4.06 (6
H, m), 4.54 (1H, d, J = 13 Hz), 4.
70 (1H, br-s), 4.83 (1H, d, J = 1
3 Hz), 6.49 (1 H, br-s), 7.40 (2
H, d, J = 8Hz), 7.75 (2H, d, J = 8H)
z).

Reference Example 61 N- (2-methoxyphenyl)
) -4- phthalimidomethylbenzamide under an atmosphere of argon, phthalimide (150 mg, 1.0
Mmol) was dissolved in THF (10 ml) and sodium hydride (44 mg, 60%, 1.1 mmol) was added at room temperature. After stirring for 40 minutes at the same temperature, 4-chloromethyl-N- (2-methoxyphenyl) benzamide (27
6 mg, 1.0 mmol) and a catalytic amount of sodium iodide dissolved in DMF (5 ml) were added. After stirring at 80 ° C. for 2 hours, the solvent was evaporated, water (10 ml) was added,
Extraction was performed using a mixed solution of ethyl acetate-methylene chloride (1: 2). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (methylene chloride-ether: hexane = 2: 1). Washing with ether afforded 300 mg (77.6%) of the title compound as a colorless solid. Melting point: 176.5 to 179.5 ° C. IR (KBr): 3350, 1710, 1658, 15
22, 1462, 1432, 1394, 1288, 93
8,748,724 cm ^-1 . NMR (CDCl ₃ ) δ: 3.90 (3H, s), 4.
91 (2H, s), 6.80 to 7.14 (3H, m),
7.54 (2H, d, J = 8.5Hz), 7.65
8.10 (6H, m), 8.30 to 8.67 (2H,
m).

Reference Example 62 N- (2-methoxyphenyl)
) -4- morpholino-methylbenzamide argon atmosphere, morpholine dissolved in ether (5 ml) (192 mg, 2.2 mmol) in n- butyl lithium (1.45 ml, 1.52M, 2.2 mmol)
Was added dropwise under ice cooling. After stirring at room temperature for 5 minutes, 4-chloromethyl-N- (2-methoxyphenyl) benzamide (276 mg, 1.0 mmol) was added at the same temperature.
After adding THF (5 ml) and stirring at 60 ° C. for 2 hours and 30 minutes, water (20 ml) was added and extraction with ethyl acetate was performed. After the insoluble matter was removed by filtration, the organic layer was washed with water and saturated brine, dried over anhydrous sodium carbonate and the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ether). 128 mg (39.2%) of the title compound was obtained as a pale yellow solid. Melting point: 90 to 93.5 ° C IR (KBr): 3440, 1666, 1600, 15
30, 1510, 1486, 1460, 1440, 13
40,1292,1252,1112,1020,86
6,754 cm ^-1 . NMR (CDCl ₃ ) δ: 2.46 (4H, t, J = 5
Hz), 3.56 (2H, s), 3.72 (4H, t,
J = 5 Hz), 3.92 (3H, s), 6.70 to 7.
14 (3H, m), 7.45 (2H, d, J = 8.5H
z), 7.85 (2H, d, J = 8.5Hz), 8.3
3-8.70 (2H, m).

Reference Example 63 N- (2-methoxyphenyl)
25 ) -4-dimethylaminomethylbenzamide under argon atmosphere and equipped with a cold finger 25
4-Chloromethyl-N- (2-methoxyphenyl) benzamide (276 mg, 1.0 mmol) was taken in a ml eggplant-shaped flask and dissolved in dioxane (3 ml) to give 50%.
Aqueous dimethylamine solution (3 ml) was added at room temperature. 80
After stirring for 2 hours and 30 minutes at ℃, dioxane was distilled off,
Diluted with ethyl acetate (30 ml). The residue obtained by drying over anhydrous sodium carbonate and distilling off the solvent was purified by silica gel column chromatography (ether-ethyl acetate-ethyl acetate: methanol = 10: 1) to give 284 mg of the title compound as a colorless oil. (100
%)Obtained. IR (neat): 3440, 2944, 2816, 2
772, 1676, 1602, 1530, 1482, 1
460, 1434, 1338, 1290, 1250, 1
028,748 cm ^-1 . NMR (CDCl ₃ ) δ: 2.25 (6H, s), 3.
48 (2H, s), 3.93 (3H, s), 6.80-
7.13 (3H, m), 7.42 (2H, d, J = 8.
5Hz), 7.84 (2H, d, J = 8.5Hz),
8.35-8.66 (2H, m).

Reference Example 64 N- (2-methoxyphenyl)
) -4- (Methylamino) methylbenzamide 4-chloromethyl-N- (2-methoxyphenyl) benzamide (400 mg, 1.45 mmol) was dissolved in dioxane (4 ml) and a 50% aqueous methylamine solution (4
ml) was added at room temperature. After stirring at the same temperature for 1 hour, dioxane was distilled off and the residue was diluted with methylene chloride (10 ml). After drying over anhydrous sodium carbonate, the solvent was evaporated to give 500 mg (1 mg) of the title compound as a colorless oil.
00%) was obtained. IR (neat): 3436, 2956, 2848, 1
674, 1602, 1527, 1485, 1461, 1
251, 1122, 747 cm ^-1 . NMR (CDCl ₃ ) δ: 1.51 (1H, s), 2.
47 (3H, s), 3.84 (2H, s), 3.92
(3H, s), 6.81 to 7.10 (3H, m), 7.
42 (2H, d, J = 8.5 Hz), 7.83 (2H,
d, J = 8.5 Hz), 8.42 to 8.58 (2H,
m).

Reference Example 65 4- (N-tert-butoki)
Cycarbonyl-N-methylamino) methyl-N- (2-
Methoxyphenyl) benzamide N- (2-methoxyphenyl) -4- (methylamino)
Methylbenzamide (500 mg, 1.45 mmol)
Was dissolved in a mixed solution of dioxane-water (2: 1) (5 ml), 1N aqueous sodium hydroxide solution (2 ml) and di-t were added.
ert-Butyl dicarbonate (380 mg, 1.74
(Mmol) was added under ice cooling. The mixture was stirred at room temperature for 14 hours, extracted with methylene chloride, and washed with saturated saline.
The organic layer was dried over anhydrous sodium carbonate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 537 mg of the title compound as a colorless oil. (1
00%) was obtained. IR (neat): 2974, 2932, 1689, 1
605, 1527, 1485, 1461, 1395, 1
248,1146 cm ^-1 . NMR (CDCl ₃ ) δ: 1.57 (9H, s), 2.
85 (3H, s), 3.93 (3H, s), 4.49
(2H, s), 6.89 to 7.12 (3H, m), 7.
33 (2H, d, J = 8.5 Hz), 7.85 (2H,
d, J = 8.5 Hz), 8.42 to 8.55 (2H,
m).

Reference Example 66 4-chloromethyl-N- (2
-Methoxyphenyl) -N- (1,3-dioxolane-
2-yl) methylbenzamide o-anisidine (500 mg, 4.
06 mmol), triethylamine (1.6 ml, 1
1.5 mmol) and 2-bromomethyl-1,3-dioxolane (0.96 ml, 8.18 mmol) were stirred at 80 ° C. for 4 days and then methylene chloride (8 ml).
Dissolved in 20% aqueous sodium hydroxide solution (4 ml) and 4-chloromethylbenzoyl chloride (768 mg,
(4.06 mmol) was added under ice cooling. After stirring at the same temperature for 1 hour, methylene chloride extraction was performed, and the mixture was washed with 10% citric acid aqueous solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 5) to give 704 mg (47. 9%) was obtained. Melting point: 126 to 129 ° C IR (KBr): 1644, 1500, 1418, 13
84, 1306, 1276, 1162, 1134, 10
74,1030,746 cm ^-1 . NMR (CDCl ₃ ) δ: 3.68 (3H, s), 3.
80-4.02 (1H, m), 3.91 (4H, d, J
= 3 Hz), 4.20 to 4.65 (1 H, m), 4.4
5 (2H, s), 5.25 (1H, t, J = 5Hz),
6.74 (1H, d, J = 8.5Hz), 6.85 (1
H, d, J = 7.5 Hz), 6.96 to 7.43 (6
H, m).

Reference Example 67 N- (2-methoxyphenyl)
R) -N- (1,3-dioxolan-2-yl) methyl
-4-phthalimidomethylbenzamide 4-chloromethyl-N- (2-methoxyphenyl) -N
By performing the same operation as in Reference Example 61 using-(1,3-dioxolan-2-yl) methylbenzamide (556 mg, 1.54 mmol), 546 mg (75.1%) of the title compound was obtained as a colorless solid. Obtained. Melting point: 150 to 152 ° C. IR (KBr): 1716, 1641, 1503, 14
22, 1392, 1347, 1308, 1278, 12
51, 1134, 1122, 1086, 1035, 10
14,942,744,720 cm ^-1 . NMR (CDCl ₃ ) δ: 3.47 to 4.02 (1H,
m), 3.66 (3H, s), 3.88 (4H, d, J
= 3 Hz), 4.20 to 4.55 (1 H, m), 4.7
2 (2H, s), 5.23 (1H, t, J = 5Hz),
6.71 (1H, d, J = 8Hz), 6.81 (1H,
d, J = 7.5 Hz), 6.96 to 7.38 (6H,
m), 7.55 to 7.93 (4H, m).

Reference Example 68 4- (4-fluorobenzoi)
L) -1- (2-hydroxyethyl) piperidine Under an argon atmosphere, 4- (4-fluorobenzoyl) piperidine (2.07 g, 10 mmol) was dissolved in triethylamine (30 ml), and 2-bromoethanol (1.1 ml). , 14.7 mmol) was added dropwise at room temperature.
After refluxing for 1 hour, triethylamine was distilled off, saturated aqueous sodium carbonate solution (40 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium carbonate, the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate-methylene chloride: methanol = 1).
Purification by 0: 1) gave 1.96 g (78.0%) of the title compound as a pale yellow solid. Melting point: 45 to 47 ° C IR (KBr): 3428, 2944, 1680, 15
96, 1278, 1238, 1204 cm ^-1 . NMR (CDCl ₃ ) δ: 1.71-1.95 (4H,
m), 2.01 to 2.43 (3H, m), 2.54 (2
H, t, J = 6 Hz), 2.83 to 3.38 (3H,
m), 3.60 (2H, t, J = 6Hz), 7.12
(2H, dd, J = 9Hz, 9Hz), 7.93 (2
H, dd, J = 9 Hz, 6 Hz).

Reference Example 69 4- (4-fluorophenyl)
) -1- (3-hydroxypropyl) piperazine 4- (4-fluorophenyl) piperazine (3.68)
g, 20 mmol) and 3-bromopropanol (3.
By performing the same operation as in Reference Example 68 using 42 ml, 36.0 mmol, 3.87 g (81.2%) of the title compound was obtained as a pale yellow solid. Melting point: 77 to 79 ° C IR (KBr): 3406, 3262, 2938, 28
36, 1512, 1452, 1269, 1242, 11
52, 1122, 1053 cm ^-1 . NMR (CDCl ₃ ) δ: 1.69 to 1.88 (2H,
m), 2.51 to 2.76 (6H, m), 2.98 to
3.20 (4H, m), 3.80 (2H, t, J = 6.
6 Hz), 4.60 (1 H, br-s), 6.70-
7.00 (4H, m).

Reference Example 70 1- (2-chloroethyl)-
4- (4-fluorobenzoyl) piperidine hydrochloride in dry air, 4- (4-fluorobenzoyl) -1-
(2-hydroxyethyl) piperidine (1.96 g,
7.8 mmol) was dissolved in methylene chloride (10 ml), and DMF (0.1 ml) and thionyl chloride (2.5 ml, 34.2 mmol) were added dropwise under ice cooling. After stirring at room temperature for 7 hours, the solvent was distilled off, and benzene (1
The residue obtained by azeotropic distillation using 5 ml × 2) was washed with a mixed solution of ether-methylene chloride (4: 1) (30 ml) to give 2.3 g of the title compound as a light beige powder ( 96.3%). IR (KBr): 2620, 2520, 1678, 15
98, 1506, 1446, 1408, 1278, 12
24, 1158, 950, 840, 606 cm ^-1 . NMR (CDCl ₃ ) δ: 1.75 to 2.90 (4H,
m), 2.90-4.50 (9H, m), 6.90-
7.40 (2H, m), 7.65-8.30 (2H,
m).

Reference Example 71 1- (3-Bromopropyl)
-4- (4-Fluorophenyl) piperazine dihydrogen bromide
Acid salt 4- (4-fluorophenyl) -1- (3-hydroxypropyl) piperazine (1.0 g, 4.20 mmol)
47% aqueous hydrogen bromide (10 ml) was added to the mixture, the mixture was refluxed for 4 hours, and the solvent was evaporated. Further, the residue obtained by azeotropic distillation using a benzene-methanol (1: 1) mixed solution (40 ml × 2) was ether-methylene chloride (4: 1).
By washing with a mixed solution (30 ml), 1.76 g of the title compound was obtained as a beige powder insoluble in ether, methylene chloride, methanol, DMSO and acetone.
(93.2%) was obtained. IR (KBr): 2980, 2620, 2508, 24
28, 1508, 1476, 1454, 1232, 84
6,544 cm ^-1 .

Reference Example 72 1- (2-chloroethyl)-
4- (4-Fluorobenzoyl) piperidine 1- (2-chloroethyl) -4- (4-fluorobenzoyl) piperidine hydrochloride (800 mg, 2.61 mmol) was suspended in ether (20 ml) and saturated aqueous sodium hydrogen carbonate (5
(ml) was added dropwise under ice cooling. The reaction solution is extracted with ether,
The organic layer was washed with saturated brine and dried over anhydrous sodium carbonate. The organic layer was filtered through silica gel (5 g), the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (ether) to give 650 mg (92.
3%) was obtained. Melting point: 33 to 37 ° C IR (KBr): 2944, 2812, 1666, 15
98, 1446, 1412, 1376, 1298, 12
64, 1230, 1208, 1164, 1132, 11
04, 976, 852 cm ^-1 . NMR (CDCl ₃ ) δ: 1.67 to 1.96 (4H,
m), 2.07 to 2.43 (2H, m), 2.75 (2
H, t, J = 7.5 Hz), 2.86 to 3.30 (3
H, m), 3.60 (2H, d, J = 7.5 Hz),
7.12 (2H, dd, J = 9Hz, 9Hz), 7.9
3 (2H, dd, J = 9Hz, 6Hz).

Reference Example 73 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} phthalimide Under an argon atmosphere, 4- (4-fluorobenzoyl) piperidine (3.11 g, 15 mmol) was dissolved in triethylamine (15 ml) to give N- (2-bromoethyl).
Phthalimide (6.08 g, 22.5 mmol) was added at room temperature. After refluxing for 2 hours, triethylamine was distilled off, water (30 ml) was added, and the mixture was extracted with methylene chloride.
The organic layer was washed with water and saturated brine, dried over anhydrous sodium carbonate, and the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification by 2-2: 3) gave 2.72 g (47.7%) of the title compound as a pale yellow solid. Melting point: 143-147 ° C IR (KBr): 2940, 2812, 1776, 17
12, 1666, 1596, 1396, 1376, 12
86, 1228, 1210, 1166, 1098, 71
0 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.95 (4H,
m), 1.95 to 2.40 (2H, m), 2.67 (2
H, t, J = 6.5 Hz), 2.86 to 3.38 (3
H, m), 3.83 (2H, t, J = 6.5Hz),
7.11 (2H, dd, J = 9Hz, 9Hz), 7.5
5 to 8.08 (6H, m).

Reference Example 74 N- {3- [4- (4-full
Orophenyl) piperazinyl] propyl} phthalimide 4- (4-fluorophenyl) piperazine (1.0 g,
5.55 mmol) and N- (3-bromopropyl) phthalimide (1.59 g, 5.55 mmol) were carried out in the same manner as in Reference Example 73 to give 1.85 g of the title compound as a pale yellow solid. (90.5%) was obtained. Melting point: 94 to 96 ° C IR (KBr): 2820, 1698, 1508, 13
98,1232,1148,1022,818,716
cm ^-1 . NMR (CDCl ₃ ) δ: 1.73 to 2.15 (2H,
m), 2.35 to 2.70 (6H, m), 2.84 to
3.10 (4H, m), 3.77 (2H, t, J = 7H
z), 6.55 to 7.05 (4H, m), 7.53 to
7.89 (4H, m).

Reference Example 75 1- (2-aminoethyl)-
4- (4-fluorobenzoyl) piperidine N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} phthalimide (190 mg, 0.50 mmol) in methanol-THF (3: 2) mixed solution (2.
5 ml) and hydrazine hydrate (1.5 ml) was added dropwise under ice cooling. After stirring at room temperature for 20 minutes, the solvent was distilled off, the obtained residue was dissolved in methylene chloride, and then washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium carbonate and the solvent was evaporated to give the title compound as a pale yellow solid (125 mg).
Obtained mg (100%). IR (KBr): 3365, 2944, 2804, 16
80, 1598, 1506, 1300, 1262, 12
28, 1158, 976, 854 cm ^-1 . NMR (CDCl ₃ ) δ: 1.49 (2H, br-
s), 1.63 to 2.30 (6H, m), 2.43 (2
H, t, J = 6 Hz), 2.61 to 3.40 (5H,
m), 7.13 (2H, dd, J = 9Hz, 9Hz),
7.97 (2H, dd, J = 9Hz, 6Hz).

Reference Example 76 1- (3-aminopropyl)
-4- (4-Fluorophenyl) piperazine N- {3- [4- (4-fluorophenyl) piperazinyl] propyl} phthalimide (1.10 g, 2.99 mmol) was used to carry out the same operation as in Reference Example 75. By performing 702 mg (9%) of the title compound as a yellow oil.
8.9%). IR (neat): 2938, 2818, 1512, 1
455, 1380, 1302, 1287, 1233, 1
161, 1143, 819 cm ^-1 . NMR (CDCl ₃ ) δ: 1.38 (2H, s), 1.
50 to 2.00 (2H, m), 2.30 to 2.90 (8
H, m), 2.90 to 3.55 (4H, m), 6.74
~ 7.12 (4H, m).

Reference Example 77 1- (2,2-diethoxyethane
Cyl) -4- (4-fluorobenzoyl) piperidine 4- (4-fluorobenzoyl) piperidine (207m
g, 1.0 mmol) was dissolved in methylene chloride (5 ml), and bromoacetaldehyde diethyl acetal (30
5 mg, 1.5 mmol) and triethylamine (0.
5 ml) was added. After refluxing for 12 hours, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (ether) to give 81 mg (25.0%) of the title compound as an orange oil. IR (neat): 2976, 2944, 1682, 1
598, 1278, 1230, 1206, 1156, 1
120, 1062, 976, 852 cm ^-1 . NMR (CDCl ₃ ) δ: 1.21 (6H, t, J = 7
Hz), 1.50 to 1.98 (4H, m), 2.02
2.44 (2H, m), 2.56 (2H, d, J = 5.
6Hz), 2.85 to 3.30 (3H, m), 3.5
8, 3.66 (each 2H, q, J = 7Hz),
4.65 (1H, t, J = 5.6Hz), 7.12 (2
H, dd, J = 9 Hz, 9 Hz), 7.95 (2H, d
d, J = 9 Hz, 6 Hz).

Reference Example 78 4- (4-Fluorobenzoi
) -1- [2- (2-Methoxyanilino) ethyl] pi
Peridine 1- (2,2-diethoxyethyl) -4- (4-fluorobenzoyl) piperidine (81 mg, 0.25 mmol) was dissolved in THF (3 ml) and 10% hydrochloric acid (2 m
l) was added at room temperature. After stirring at the same temperature for 1 hour, the solvent was distilled off, and then benzene (5 ml × 4) was azeotropically distilled off to obtain an orange candy. The obtained residue was dissolved in methanol (2 ml), and o-anisidine (29 μl,
0.25 mmol) and sodium cyanoborohydride (11 mg, 0.166 mmol) were added at room temperature. After stirring at the same temperature for 2 hours, saturated aqueous sodium hydrogen carbonate (10 ml) was added, extraction was performed with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium carbonate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (ether: hexane = 2: 1 to ether) to give 59 mg of the title compound as a colorless solid.
(66.2%) was obtained. Melting point: 116 to 120 ° C IR (KBr): 3410, 2956, 2810, 16
78, 1600, 1510, 1450, 1288, 12
68, 1234, 1224, 1204, 1154, 10
22,728 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.38 (7H,
m), 2.70 (2H, t, J = 6Hz), 2.83-
3.45 (5H, m), 3.85 (3H, s), 6.4
7 to 6.92 (4H, m), 7.13 (2H, dd, J
= 9 Hz, 9 Hz), 7.96 (2H, dd, J = 9H
z, 6 Hz).

Example 1 N- (2-tetrahydropyrani
Luoxyethyl) -3-methoxy-N- (2-methoxy
(Phenyl) benzamide Under an argon atmosphere, 3-methoxy-N- (2-methoxyphenyl) benzamide (500 mg, 1.94 mmol) was dissolved in DMF (10 ml) and sodium hydride (85 mg, 60%, 2.13 mmol) was added. ) Was added at room temperature and stirred for 20 minutes and under ultrasonic irradiation for 5 minutes, and then 2-tetrahydropyranyloxyethyl bromide (44
6 mg, 2.13 mmol) was added. 1 hour at room temperature,
After stirring at 70 ° C. for 6 hours, DMF was distilled off and water (20
(ml) was added, extraction with ether was performed, the extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an orange oily substance. The residue was purified by silica gel column chromatography (ether: hexane = 2: 1) to give 501 mg of the title compound as a yellow oil.
(67.0%) was obtained. IR (neat): 2944, 1650, 1586, 1
502, 1456, 1434, 1384, 1318, 1
286, 1252, 1122, 1074, 1034, 7
50 cm ^-1 . NMR (CDCl ₃ ) δ: 1.20 to 2.00 (6H,
m), 3.25 to 4.40 (6H, m), 3.63,
3.66 (each 3H, s), 4.57 (1H, b
r-s), 6.58 to 7.30 (8H, m).

Example 2 4-Methoxy-N- (2-hydr
Roxyethyl) -N- (2-methoxyphenyl) benze
Emissions sulfonamide Under argon atmosphere, 4-methoxy-N-(2-methoxyphenyl) benzenesulfonamide (300 mg, 1.
(02 mmol) was dissolved in DMF (6 ml), sodium hydride (49 mg, 60%, 1.23 mmol) was added at room temperature and the mixture was stirred for 1 hr, and then 2-tetrahydropyranyloxyethyl bromide (258 mg, 1.23
Mmol) was added. After stirring at 70 ° C for 4 hours, DM
F was distilled off, and saturated ammonium chloride aqueous solution (10 ml)
Was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated to give a pale yellow oil. The residue was dissolved in methanol (5 ml), a catalytic amount of p-toluenesulfonic acid monohydrate was added at room temperature, and the mixture was stirred for 3 hours. After the methanol was distilled off, saturated aqueous sodium hydrogen carbonate (10 ml) was added to the reaction solution, extraction with ethyl acetate was performed, and the mixture was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a pale yellow oily substance, which was purified by silica gel column chromatography (ether: hexane = 4: 1) to give 235 mg of the title compound as a colorless oily substance ( 68.3%) was obtained. IR (neat): 3532, 2944, 1596, 1
498, 1462, 1342, 1302, 1260, 1
156, 1116, 1072, 1042, 1024, 5
86,562 cm ^-1 . NMR (CDCl ₃ ) δ: 2.65-2.97 (1H,
m), 3.38 to 3.85 (4H, m), 3.63,
3.87 (each 3H, s), 6.70-7.45
(6H, m), 7.67 (2H, d, J = 9Hz).

Example 3 4-Fluoro-N- (2-hydr
Roxyethyl) -N- (2-methoxyphenyl) benze
The same procedure as in Example 2 was carried out using 4-fluoro-N- (2-methoxyphenyl) benzenesulfonamide (282 mg, 1.0 mmol) to give 302 mg of the title compound as a colorless oil ( 92.8%) was obtained. IR (neat): 3536, 2940, 1592, 1
494, 1344, 1290, 1234, 1166, 1
118, 1088, 1072, 1042, 1024, 8
38,756,586,554 cm ^-1 . NMR (CDCl ₃ ) δ: 2.44 to 2.73 (1H,
m), 3.30 to 3.83 (4H, m), 3.56 (3
H, s), 6.65 to 7.43 (6H, m), 7.73
(2H, dd, J = 9Hz, 6Hz).

Example 4 N- (2-hydroxyethyl)
-3-Methoxy-N- (2-methoxyphenyl) benz
Amido 3-methoxy-N- (2-methoxyphenyl) -N-
(2-Tetrahydropyranyloxyethyl) benzamide (501 mg, 1.30 mmol) was added to methanol (4
ml), a catalytic amount of p-toluenesulfonic acid monohydrate was added at room temperature, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate (10 ml) was added to the reaction solution, which was then extracted with ether and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated to give a colorless oily substance, which was subjected to silica gel column chromatography (ether: hexane = 3: 3).
Purification in 1) gave 340 mg (86.8%) of the title compound as a pale yellow oil. IR (neat): 3432, 1638, 1580, 1
502, 1458, 1434, 1396, 1320, 1
288, 1250, 1046, 1026, 750c
m ^-1 . NMR (CDCl ₃ ) δ: 3.30 to 4.13 (5H,
m), 3.63, 3.73 (each 3H, s),
6.60-7.30 (8H, m).

Example 5 N-formylmethyl-3-meth
Xy-N- (2-methoxyphenyl) benzamide N- (2-hydroxyethyl) -3 under argon atmosphere.
-Methoxy-N- (2-methoxyphenyl) benzamide (339 mg, 1.12 mmol) in DMSO (4 m).
l) and dissolved in triethylamine (0.724 ml,
5.20 mmol) and sulfur trioxide / pyridine complex (844 mg, 5.20 mmol) dissolved in DMSO (4 ml) were added dropwise at room temperature. After stirring at the same temperature for 20 minutes, ice water (20 ml) was added, extraction was performed with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain 220 mg (65.6%) of the title compound as a pale yellow solid, which was used in the next reaction without purification. Melting point: 77 to 81 ° C IR (KBr): 1732, 1648, 1588, 15
02,1462,1432,1372,1322,12
80, 1252, 1044, 1026 cm ^-1 . NMR (CDCl ₃ ) δ: 3.64, 3.77 (eac
h 3H, s), 4.40 (2H, s), 6.55
7.30 (8H, m), 9.76 (1H, s).

Example 6 N-formylmethyl-N- (2
-Methoxyphenyl) -4-phthalimidomethylbenzua
Mido N- (2-methoxyphenyl) -N- (1,3-dioxolan-2-yl) methyl-4-phthalimidomethylbenzamide (450 mg, 0.953 mmol) in THF
It was dissolved in (6 ml) and 10% hydrochloric acid (4 ml) was added at room temperature. After stirring at 60 ° C. for 2 hours, the mixture was extracted with chloroform and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was washed with chloroform 5
300 ml (73.5%) of the title compound was obtained as a yellow oil by adding ml and filtering off the insoluble matter, which was used in the next reaction without purification. IR (neat): 1716, 1644, 1500, 1
428, 1392, 1248, 747, 717 cm ^-1 . NMR (CDCl ₃ ) δ: 3.73 (3H, s), 4.
35 (2H, s), 4.72 (2H, s), 6.63-
7.35 (8H, m), 7.60 to 7.88 (4H,
m), 9.61 (1H, s).

Example 7 N- {2- [4- (4-fluor
Robenzoyl) piperidino] ethyl} -3-methoxy-
N- (2-Methoxyphenyl) benzamide N-formylmethyl-3-methoxy-N- (2-methoxyphenyl) benzamide (141 mg, 0.473 mmol) and 4- (4-fluorobenzoyl) piperidine (125 mg, 0. 60 mmol) was dissolved in methanol (4.5 ml) and molecular sieves 4A was added.
(300 mg) was added at room temperature. After stirring at the same temperature for 1 hour, sodium cyanoborohydride (12 mg, 0.
191 mmol) was added and the mixture was stirred for 45 minutes, and acetone (2 ml) was added. The reaction mixture was diluted with ether (15 ml) and filtered through Celite, and the solvent was evaporated to give a colorless oil. Ether (7 ml) was added and dissolved in this, and saturated hydrogen chloride / ether solution (7 ml) was added to add 5
Stir for minutes. After removing the ether layer, water (7 m
l) and potassium carbonate (1.5 g) were added for ether extraction, the organic layer was dried over potassium carbonate and the solvent was evaporated to give a colorless oil. Purification by silica gel column chromatography (ether: hexane = 3: 2) gave 107 mg (46.1) of the title compound as a pale yellow oil.
%)Obtained. IR (neat): 2944, 1678, 1638, 1
596, 1500, 1458, 1390, 1278, 1
248, 1156, 1046, 748 cm ^-1 . NMR (CDCl ₃ ) δ: 1.58 to 1.93 (4H,
m), 2.00 to 2.36 (2H, m), 2.63 (2
H, t, J = 7.5 Hz), 2.80 to 3.30 (3
H, m), 3.64, 3.70 (each 3H,
s), 3.90-4.40 (2H, m), 6.55-
7.30 (10H, m), 7.95 (2H, dd, J =
9 Hz, 6 Hz).

Example 8 N- {2- [4- (4-fluor
Robenzoyl) piperidino] ethyl} -4-methoxy-
N- (2-methoxyphenyl) benzenesulfonamide N-hydroxyethyl-4-methoxy-N- (2-methoxyphenyl) benzenesulfonamide (235 mg, 0.697 mmol) was added to DMSO under an argon atmosphere.
(3 ml), triethylamine (0.48 m
1,3.44 mmol) and sulfur trioxide / pyridine complex (558 mg, 3.4) dissolved in DMSO (3 ml).
4 mmol) was added dropwise at room temperature. 20 at the same temperature
After stirring for 1 minute, ice water (10 ml) was added to perform extraction with ethyl acetate, and the extract was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a pale yellow oily substance. The residue was dissolved in methanol (5 ml), 4-
(4-fluorobenzoyl) piperidine (108 mg,
0.52 mmol) and molecular sieves 4A (2
00 mg) was added at room temperature. After stirring at the same temperature for 45 minutes, sodium cyanoborohydride (11 mg, 0.1
66 mmol) was added and stirred for 30 minutes, and acetone (1
ml) was added. The reaction mixture was diluted with ether (10 ml) and filtered through Celite, and the solvent was evaporated to give a colorless oil. Ether (10 ml) was added and dissolved,
It was extracted with 2N hydrochloric acid (10 ml). After removing the ether layer, the pH was adjusted to 9 to 10 with a 10% aqueous sodium hydroxide solution, methylene chloride extraction was performed, the organic layer was dried over potassium carbonate, and the solvent was evaporated to give a yellow oil. The residue was purified by silica gel column chromatography and PTLC (ether: hexane = 7: 1) to give 56.7 mg (15.4 mg) of the title compound as a colorless oil.
%)Obtained. IR (neat): 2944, 1680, 1598, 1
498, 1342, 1258, 1158, 732, 58
8,562 cm ^-1 . NMR (CDCl ₃ ) δ: 1.53 to 2.30 (6H,
m), 2.52 (2H, t, J = 7.5Hz), 2.7
3 to 3.30 (3H, m), 3.43 (3H, s),
3.72 (2H, t, J = 7.5Hz), 3.84 (3
H, s), 6.67 to 7.40 (8H, m), 7.62
(2H, d, J = 9 Hz), 7.93 (2H, dd, J
= 9 Hz, 6 Hz).

Example 9 4-Fluoro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-methoxyphenyl) benzenesulfonamide 4-fluoro-N-hydroxymethyl-N- (2-methoxyphenyl) benzenesulfonamide (302 mg,
The title compound was obtained as a yellow oil by the same procedure as in Example 8 (0.928 mmol).
mg (16.9%) was obtained. IR (neat): 2948, 1680, 1596, 1
494, 1344, 1234, 1156, 1094, 8
38,732,586,554 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.31 (6H,
m), 2.51 (2H, t, J = 7.5Hz), 2.7
2-3.30 (3H, m), 3.39 (3H, s),
3.66-3.90 (2H, m), 6.60-7.50
(8H, m), 7.69, 7.93 (each 2H,
dd, J = 9 Hz, 6 Hz).

Example 10 4-Chloromethyl-N- {2
-[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzamide under argon atmosphere, 4- (4-fluorobenzoyl)-
1- [2- (2-Methoxyanilino) ethyl] piperidine (264 mg, 0.741 mmol) was dissolved in methylene chloride (7.5 ml) and triethylamine (0.42) was added.
ml, 3.0 mmol), p-toluenesulfonyl chloride (158 mg, 0.83 mmol) and a catalytic amount of 4
-Dimethylaminopyridine was added to each at room temperature. After stirring at the same temperature for 15 hours, 4-chloromethylbenzoyl chloride (145 mg, 0.741 mmol) was added, and the mixture was refluxed for 2.5 days. After adding water (10 ml),
2N hydrochloric acid (5 ml) was added to perform methylene chloride extraction,
The extract was washed with 5% aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain an orange oily substance. Purification by silica gel column chromatography (methylene chloride: ether = 1: 1) gave 314 mg (83.
2%) was obtained. IR (KBr): 2944, 1680, 1644, 15
96, 1502, 1440, 1392, 1278, 12
38,1156,750 cm ^-1 . NMR (CDCl ₃ ) δ: 1.57 to 2.00 (4H,
m), 2.00-2.45 (2H, m), 2.48-
2.80 (2H, m), 2.80 to 3.38 (3H,
m), 3.48 to 3.94 (1H, m), 3.66 (3
H, s), 3.96 to 4.32 (1H, m), 4.44.
(2H, s), 6.73 (1H, d, J = 7.5H
z), 6.84 (1H, d, J = 8 Hz), 6.92-
7.43 (8H, m), 7.94 (2H, dd, J = 9
Hz, 6 Hz).

Example 11 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-methoxy
Benzenesulfonamide 1- (2-aminoethyl) -4-under argon atmosphere
(4-fluorobenzoyl) piperidine (125 mg,
0.50 mmol) was dissolved in methylene chloride (3 ml) and 4-methoxybenzenesulfonyl chloride (104 mg, 0.50 mmol) and triethylamine (0.07 ml, 0.50 mmol) were added at room temperature. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate (0.5 ml) was added and the mixture was stirred for 30 minutes. After diluting with methylene chloride (15 ml), it was dried over anhydrous sodium carbonate and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: methylene chloride = 3: 1) to give 177 mg (84.2) of the title compound as a colorless solid.
%)Obtained. Melting point: 140 to 142 ° C IR (KBr): 3288, 2948, 2816, 16
80, 1598, 1500, 1322, 1260, 11
58, 1096, 834, 560 cm ^-1 . NMR (CDCl ₃ ) δ: 1.55 to 2.23 (6H,
m), 2.42 (2H, t, J = 5Hz), 2.55
2.82 (2H, m), 2.85 to 3.40 (1H,
m), 2.99 (2H, t, J = 5Hz), 3.85
(3H, s), 5.10 (1H, br-s), 6.83
~ 7.30 (4H, m), 7.60-8.10 (4H,
m).

Example 12 N- {3- [4- (4-full
Orophenyl) piperazinyl] propyl} -4-methoki
Shi benzenesulfonamide 1- (3-aminopropyl) -4- (4-fluorophenyl) piperazine (122 mg, 0.514 mmol)
And 4-methoxybenzenesulfonyl chloride (107
The title compound was obtained as a colorless solid in an amount of 207 mg (98.8%) by performing the same operation as in Example 11 by using (mg, 0.514 mmol). Melting point: 127 to 128.5 ° C IR (KBr): 3060, 2960, 2840, 16
00, 1508, 1326, 1262, 1218, 11
56,1084,838,576,558 cm ^-1 . NMR (CDCl ₃ ) δ: 1.46 to 1.87 (2H,
m), 2.25 to 2.76 (6H, m), 2.90 to
3.30 (7H, m), 3.86 (3H, s), 6.6
6 to 7.13 (6H, m), 7.78 (2H, d, J =
9 Hz).

Example 13 N-benzoyl-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
L} -4-methoxybenzenesulfonamide under an argon atmosphere, N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (42 mg, 0.10 mmol) was added as D.
Dissolve in MF (2 ml) and add sodium hydride (10 m
g, 60%, 0.25 mmol) was added at room temperature and stirred for 45 minutes under ultrasonic irradiation, and then benzoyl chloride (21 μm) was added.
1, 0.18 mmol) was added dropwise. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate (10 ml) was added, extraction was performed with ethyl acetate, and the mixture was washed with water and saturated brine. After drying over anhydrous sodium carbonate, the solvent was distilled off to obtain a yellow oily substance, PTLC
Purification with (ether: hexane = 5: 1) gave 23.7 mg (45.
2%) was obtained. IR (neat): 2948, 1680, 1596, 1
580, 1500, 1448, 1352, 1314, 1
262, 1160, 1090, 1014, 976, 83
4,730,578,556 cm ^-1 . NMR (CDCl ₃ ) δ: 1.47 to 1.82 (4H,
m), 1.93 to 2.28 (2H, m), 2.43 to
2.90 (4H, m), 2.90 to 3.25 (1H,
m), 3.87 (3H, s), 3.94 (2H, t, J
= 7.5 Hz), 6.80 to 7.65 (9H, m),
7.70-8.10 (4H, m).

Example 14 N-acetyl-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -4-methoxybenzenesulfonamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (42 mg, 0.10 mmol) and acetic anhydride (25 μm).
(1, 0.18 mmol) in the same manner as in Example 13 to give the title compound (2) as a colorless oil.
Obtained 7.6 mg (59.7%). IR (neat): 2940,1682,1596,1
500,1352,1310,1262,1160,1
090,974,834,730,578,558cm
^-1 . NMR (CDCl ₃ ) δ: 1.63 to 2.00 (4H,
m), 2.00 to 2.45 (2H, m), 2.31 (3
H, s), 2.67 (2H, t, J = 7.5 Hz),
2.88-3.40 (3H, m), 3.89 (3H,
s), 3.92 (2H, t, J = 6Hz), 6.83-
7.30 (4H, m), 7.73 to 8.10 (4H,
m).

Example 15 N-benzyl-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -4-methoxybenzenesulfonamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (42 mg, 0.10 mmol) and benzyl chloride (2
By performing the same operation as in Example 13 using 1 μl (0.18 mmol), 22.8 mg (44.7%) of the title compound was obtained as a colorless oil. IR (neat): 2946, 1680, 1598, 1
498, 1338, 1302, 1260, 1094, 7
30,560 cm ^-1 . NMR (CDCl ₃ ) δ: 1.52 to 2.16 (6H,
m), 2.34 (2H, t, J = 6.5Hz), 2.5
9-2.90 (2H, m), 2.90-3.40 (1
H, m), 3.23 (2H, t, J = 6.5Hz),
3.88 (3H, s), 4.39 (2H, s), 6.8
7 to 7.35 (4H, m), 7.29 (5H, s),
7.65-8.05 (4H, m).

Example 16 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-methoxy
-N- (2-propenyl) benzenesulfonamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (68 mg, 0.162 mmol) and allyl chloride (2
By repeating the same procedure as in Example 13 using 0 μl, 0.224 mmol), 63 mg (84.4%) of the title compound was obtained as a colorless oil. IR (neat): 2944, 1680, 1596, 1
500, 1302, 1230, 1206, 1156, 1
094, 976, 834, 586, 560 cm ^-1 . NMR (CDCl ₃ ) δ: 1.56 to 2.31 (6H,
m), 2.54 (2H, t, J = 7Hz), 2.75-
3.39 (5H, m), 3.86 (5H, s), 5.1
3 (1H, d, J = 12Hz), 5.15 (1H, d,
J = 16.5 Hz), 5.44-5.94 (1H,
m), 6.70 to 7.30 (4H, m), 7.50 to
8.10 (4H, m).

Example 17 N-Ethoxycarbonylmethyi
Ru-N- {2- [4- (4-fluorobenzoyl) pipet
Lysino] ethyl} -4-methoxybenzenesulfonami
De N- {2- [4- (4- fluorobenzoyl) piperidino] ethyl} -4-methoxy benzenesulfonamide (68 mg, 0.162 mmol) and ethyl bromoacetate (25 [mu] l, 0.224 mmol) performed using Example 1
The same operation as in 3 was carried out to obtain 61 mg (74.3%) of the title compound as a pale yellow oily substance. IR (neat): 2948, 1750, 1680, 1
596, 1500, 1338, 1302, 1260, 1
228, 1206, 1156, 1094 cm ^-1 . NMR (CDCl ₃ ) δ: 1.22 (3H, t, J =
7.5 Hz), 1.44 to 2.27 (6H, m), 2.
57 (2H, t, J = 6Hz), 2.70 to 3.50
(3H, m), 3.37 (2H, t, J = 6Hz),
3.85 (3H, s), 4.10 (2H, q, J = 7.
5 Hz), 4.21 (2H, s), 6.80 to 7.30
(4H, m), 7.65-8.15 (4H, m).

Example 18 N-benzoyl-N- {3-
[4- (4-Fluorophenyl) piperazinyl] propyi
Ru} -4-methoxybenzenesulfonamide N- {3- [4- (4-fluorophenyl) piperazinyl] propyl} -4-methoxybenzenesulfonamide (47 mg, 0.115 mmol) and benzoyl chloride (21 μl, 0. The same procedure as in Example 13 was performed using 18 mmol) to obtain 42.2 mg (71.7%) of the title compound as a colorless oily substance. IR (neat): 2940, 2820, 1684, 1
596, 1512, 1500, 1356, 1262, 1
232, 1162, 1090, 1018, 830, 73
0,700,578,558 cm ^-1 . NMR (CDCl ₃ ) δ: 1.67 to 2.09 (2H,
m), 2.13 to 2.62 (6H, m), 2.70 to
3.22 (4H, m), 3.55 to 4.03 (2H,
m), 3.85 (3H, s), 6.59 to 7.10 (6
H, m), 7.17 to 7.60 (5H, m), 7.81
(2H, d, J = 9 Hz).

Example 19 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-methoxy
Methyl-N- (2-methoxyphenyl) benzamide 4-methoxymethyl-N- (2-methoxyphenyl) benzamide (126 mg, 0.46) under argon atmosphere.
4 mmol), 1- (2-chloroethyl) -4- (4-
Fluorobenzoyl) piperidine hydrochloride (157 mg,
0.511 mmol) and sodium iodide (154 m)
g, 1.02 mmol) in DMF (3 ml),
Sodium hydride (40 mg, 60%, 1.0 mmol) was added at room temperature. After stirring at the same temperature for 10 minutes and at 60 ° C. for 3 hours and 30 minutes, DMF was distilled off and water (10 m
l) was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium carbonate, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 80: 1-ethyl acetate) to give 128 mg of the title compound as a colorless oil ( 54.7%) was obtained. IR (neat): 2940, 1680, 1644, 1
598, 1410, 1378, 1308, 1278, 1
262, 1240, 1158, 1112, 752, 60
4 cm ^-1 . NMR (CDCl ₃ ) δ: 1.55 to 1.95 (4H,
m), 1.98 to 2.36 (2H, m), 2.63 (2
H, t, J = 7.5 Hz), 2.80 to 3.46 (3
H, m), 3.29 (3H, s), 3.48 to 3.92.
(1H, m), 3.67 (3H, s), 3.94-4.
50 (1H, m), 4.33 (2H, s), 6.73
(1H, d, J = 8Hz), 6.83 (1H, d, J =
8 Hz), 6.93 to 7.43 (8H, m), 7.95
(2H, dd, J = 9Hz, 6Hz).

Example 20 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -3-methoxy
-N- (2-pyridyl) benzamide 3-methoxy-N- (2-pyridyl) benzamide (4
By performing the same operation as in Example 19 using 1 mg, 0.18 mmol), 19 mg (25.9%) of the title compound was obtained as a yellow oil. IR (neat): 2928, 1680, 1634, 1
598, 1572, 1544, 1502, 1452, 1
388, 1350, 1286, 1228, 1156, 7
66,730 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 2.06 (4H,
m), 2.06 to 2.47 (2H, m), 2.57 to
3.40 (5H, m), 3.85 (3H, s), 4.4
3 (2H, t, J = 6Hz), 6.35 to 6.62 (1
H, m), 6.70 to 7.70 (7H, m), 7.70
~ 8.07 (3H, m), 8.35 (1H, d, J = 9)
Hz).

Example 21 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-tetrahi
Doropyranyloxymethyl-N- (2-methoxyphenyl
Ru) benzamide 4-tetrahydropyranyloxymethyl-N- (2-methoxyphenyl) benzamide (166 mg, 0.48
The title compound was obtained as a pale yellow oil in an amount of 163 m.
g (58.4%) was obtained. IR (neat): 2944, 1680, 1644, 1
598, 1502, 1390, 1278, 1240, 1
202, 1156, 1118, 1032, 974, 75
2,604 cm ^-1 . NMR (CDCl ₃ ) δ: 1.36 to 2.00 (10
H, m), 2.00 to 2.40 (2H, m), 2.63
(2H, t, J = 7.5 Hz), 2.80 to 3.30
(3H, m), 3.30 to 4.30 (4H, m), 3.
78 (3H, s), 4.36 (1H, d, J = 12.5)
Hz), 4.60 (1H, br-s), 4.66 (1
H, d, J = 12.5 Hz), 6.72 (1 H, d, J
= 8 Hz), 6.82 (1H, d, J = 7.5 Hz),
6.93 to 7.40 (8H, m), 7.93 (2H, d
d, J = 9 Hz, 6 Hz).

Example 22 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -3-tetrahi
Doropyranyloxymethyl-N- (2-methoxyphenyl
) Benzamide 3-tetrahydropyranyloxymethyl-N- (2-methoxyphenyl) benzamide (159 mg, 0.46
The title compound was obtained as a pale yellow oil in an amount of 191 m.
g (71.3%) was obtained. IR (neat): 2944, 1680, 1646, 1
598, 1502, 1386, 1278, 1118, 1
026 cm ^-1 . NMR (CDCl ₃ ) δ: 1.38 to 2.00 (10
H, m), 2.00 to 2.36 (2H, m), 2.63
(2H, t, J = 6.5 Hz), 2.80 to 3.30
(3H, m), 3.35 to 4.30 (4H, m), 3.
68 (3H, s), 4.33 (1H, d, J = 12.5
Hz), 4.54 (1H, br-s), 4.61 (1
H, d, J = 12.5 Hz), 6.72 (1 H, d, J
= 8 Hz), 6.82 (1H, d, J = 8 Hz), 6.
91 to 7.40 (8H, m), 7.95 (2H, dd,
J = 9 Hz, 6 Hz).

Example 23 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-tetrahi
Doropyranyloxymethyl-N- (3-methoxybenzyl
Ru) benzamide 4-tetrahydropyranyloxymethyl-N- (3-methoxybenzyl) benzamide (178 mg, 0.50
Was carried out in the same manner as in Example 19 to obtain 130 mg of the title compound as a colorless oily substance.
(44.2%) was obtained. IR (neat): 2944, 1680, 1636, 1
598, 1422, 1262, 1234, 1156, 1
128, 1034, 974 cm ^-1 . NMR (CDCl ₃ ) δ: 1.38 to 2.32 (14
H, m), 2.36 to 3.68 (6H, m), 3.70.
~ 4.10 (1H, m), 3.80 (3H, s), 4.
37-4.95 (5H, m), 6.60-6.95 (2
H, m), 7.07 to 7.57 (6H, m), 7.14
(2H, dd, J = 9Hz, 9Hz), 7.95 (2
H, dd, J = 9 Hz, 6 Hz).

Example 24 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-Methoxyphenyl) benzamide 4-nitro-N- (2-methoxyphenyl) benzamide (272 mg, 1 mmol) was used to perform the same procedure as in Example 19 to give the title compound as a pale yellow powder. Was obtained in an amount of 348 mg (68.8%). Melting point: 166 to 168 ° C IR (KBr): 2938, 2818, 1680, 16
44, 1596, 1518, 1503, 1380, 13
44, 1302, 1275 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 1.95 (4H,
m), 2.00 to 2.34 (2H, m), 2.45 to
2.76 (2H, m), 2.80 to 3.30 (3H,
m), 3.68 (3H, s), 3.60 to 3.85 (1
H, m), 4.02 to 4.34 (1H, m), 6.62.
~ 6.90 (2H, m), 6.98-7.26 (4H,
m), 7.40 (2H, d, J = 8.0 Hz), 7.8
0-8.03 (4H, m).

Example 25 4-{[N- [2- [4-
(4-Fluorobenzoyl) piperidino] ethyl] -2
Example 1 using -methoxyanilino ] carbonyl} pyridine 4-{(2-methoxyanilino) carbonyl} pyridine (200 mg, 0.87 mmol).
The same operation as in 9 was performed to obtain 215 mg (53.2%) of the title compound as a colorless amorphous substance. IR (KBr): 2944, 2818, 1674, 16
47, 1598, 1503, 1413, 1230, 12
06,747 cm ^-1 . NMR (CDCl ₃ ) δ: 1.65 to 2.35 (6H,
m), 2.50 to 2.76 (2H, m), 2.80 to
3.28 (3H, m), 3.70 (3H, s), 3.5
5 to 3.82 (1H, m), 4.05 to 4.33 (1
H, m), 6.64 to 6.92 (2H, m), 7.00
~ 7.24 (6H, m), 7.80 ~ 8.07 (2H,
m), 8.40 (2H, d, J = 6.0 Hz). Example 26 4- {N- [2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl] -2-methoxyanilino] ca
Lubonyl} pyridine N-oxide 4-[[2-methoxyanilino) carbonyl) pyridine N-oxide (200 mg, 0.82 mmol) was used to carry out the same operation as in Example 19 to obtain a pale yellow powder amorphous substance. 302 mg (7
7.2%) was obtained. IR (KBr): 2944, 1680, 1647, 15
96, 1503, 1443, 1398, 1260, 11
67 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.40 (6H,
m), 2.49 to 2.72 (2H, m), 2.78 to
3.29 (3H, m), 3.69 (3H, s), 3.6
6 to 3.87 (1H, m), 3.97 to 4.25 (1
H, m), 6.70 to 7.34 (8H, m), 7.80
~ 8.06 (4H, m).

Example 27 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxyphenyl) -3-nitrobenzenesulfonamide N- (2-methoxyphenyl) -3-nitrobenzenesulfonamide (190 mg, 0.616 mmol) was used to perform the same operation as in Example 19 to obtain a yellow oily substance. 70 mg (21.0%) of the title compound was obtained. IR (neat): 2950, 1678, 1596, 1
530, 1496, 1350, 1280, 1260, 1
160, 1122, 974, 910, 754, 732
592,576 cm ^-1 . NMR (CDCl ₃ ) δ: 1.54 to 2.32 (6H,
m), 2.53 (2H, t, J = 7.5Hz), 2.7
0-3.30 (3H, m), 3.38 (3H, s),
3.57 to 4.00 (2H, m), 6.67 to 7.77
(7H, m), 7.77 to 8.14 (3H, m), 8.
37 (1H, d, J = 7.5 Hz), 8.57 (1H,
br-s).

Example 28 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-methoxy
-N- (2-thiazolyl) benzenesulfonamide 4-methoxy-N- (2-thiazolyl) benzenesulfonamide (135 mg, 0.50 mmol) was used to carry out the same operation as in Example 19 to obtain a beige color. 53 mg (21.0%) of the title compound was obtained as a powder. IR (KBr): 1680, 1596, 1510, 12
90, 1256, 1232, 1140, 1086, 93
0,564 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.95 (4H,
m), 1.96 to 2.33 (2H, m), 2.44 to
3.37 (5H, m), 3.81 (3H, s), 4.0
2 (2H, t, J = 6 Hz), 6.70 to 7.33 (5
H, m), 7.73-8.20 (4H, m).

Example 29 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-methoxy
-N- (3-methoxyphenyl) benzenesulfonami
By performing the same operation as in Example 19 using de 4-methoxy-N- (3-methoxyphenyl) benzenesulfonamide (174 mg, 0.593 mmol), 87.4 mg of the title compound was obtained as colorless flocculent crystals. (28.0
%)Obtained. Melting point: 129 to 132 ° C IR (KBr): 1674, 1598, 1496, 13
44, 1258, 1238, 1210, 1160, 10
98,1030,690,586,562 cm ^-1 . _{NMR (CDCl 3) δ: 1.44~1.90} (4H,
m), 1.97 to 2.32 (2H, m), 2.49 (2
H, t, J = 7.5 Hz), 2.68 to 3.33 (3
H, m), 3.67 (2H, t, J = 7.5 Hz),
3.74, 3.85 (each 3H, s), 6.47
~ 7.33 (8H, m), 7.54 (2H, d, J = 9
Hz), 7.93 (2H, dd, J = 9Hz, 6H
z).

Example 30 N- (2-cyanophenyl)
-N- {2- [4- (4-fluorobenzoyl) piperi
Dino] ethyl} -4-methoxybenzenesulfonamide N- (2-cyanophenyl) -4-methoxybenzenesulfonamide (234 mg, 0.812 mmol) was used to perform the same procedure as in Example 19 to give 107 mg (25.
3%) was obtained. IR (KBr): 2950, 2228, 1680, 15
96, 1496, 1350, 1262, 1158, 10
92, 834, 688, 576, 552 cm ^-1 . NMR (CDCl ₃ ) δ: 1.35 to 2.22 (6H,
m), 2.54 (2H, t, J = 6.5Hz), 2.6
5 to 3.28 (3H, m), 3.73 (2H, t, J =
6.5 Hz), 3.87 (3H, s), 6.77 to 7.
35 (5H, m), 7.35 to 7.77 (5H, m),
7.91 (2H, dd, J = 9Hz, 6Hz).

Example 31 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-to
Lifluoromethylphenyl) -4-methoxybenzenes
Rufonamide N- (2-trifluoromethylphenyl) -4-methoxybenzenesulfonamide (225 mg, 0.679 mmol) was used to carry out the same operation as in Example 19 to give the title compound as a colorless oil (46. 7 mg
(12.2%) was obtained. IR (neat): 2948, 1680, 1598, 1
498, 1450, 1352, 1316, 1262, 1
228, 1206, 1158, 1112, 1092, 1
036,836,730,664,604,580,5
56 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 2.20 (6H,
m), 2.30 to 3.30 (5H, m), 3.40 to
3.78 (2H, m), 3.88 (3H, s), 6.8
3 to 7.27 (5H, m), 7.35 to 7.55 (2
H, m), 7.56 to 7.80 (3H, m), 7.90
(2H, dd, J = 9Hz, 6Hz).

Example 32 N-Cyclohexyl-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -4-methoxybenzenesulfonamide N-Cyclohexyl-4-methoxybenzenesulfonamide (290 mg, 1.08 mmol) was carried out in the same manner as in Example 19 to give the title compound as a pale yellow candy. Was obtained in an amount of 300 mg (55.3%). IR (neat): 2936, 2856, 1680, 1
596, 1498, 1448, 1334, 1300, 1
258, 1236, 1150, 1092, 972, 66
4,582,556 cm ^-1 . NMR (CDCl ₃ ) δ: 1.00 to 2.40 (16
H, m), 2.48 to 2.80 (2H, m), 2.85
˜3.74 (6H, m), 3.85 (3H, s), 6.
94 (2H, d, J = 9Hz), 7.13 (2H, d
d, J = 9 Hz, 9 Hz), 7.76 (2H, d, J =
9Hz), 7.96 (2H, dd, J = 9Hz, 6H
z).

Example 33 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Tokishifeniru) -3-pyridinesulfonamide N-(2-methoxyphenyl) -3-pyridinesulfonamide (132 mg, by performing the same operation as in Example 19 using 0.50 mmol), the title as a colorless solid 55 mg (22.1%) of the compound was obtained. Melting point: 126.5-128.5 ° C IR (KBr): 2924, 1676, 1594, 15
00, 1364, 1284, 1204, 1164, 11
16,982,744,608,600 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 1.90 (4H,
m), 1.94 to 2.31 (2H, m), 2.52 (2
H, t, J = 7.5 Hz), 2.68 to 3.45 (3
H, m), 3.33 (3H, s), 3.50 to 3.90.
(2H, m), 6.76 (1H, d, J = 8Hz),
6.85-7.60 (6H, m), 7.73-8.20
(2H, m), 8.60 to 9.00 (2H, m).

Example 34 3-{[N- [2- [4-
(4-Fluorobenzoyl) piperidino] ethyl] -2
-Methoxyanilino] sulfonyl} pyridine N-Oki
Sid 3 - [(2-methoxy-anilino) sulfonyl] pyridine N- oxide (120 mg, 0.428 mmol) by the same manner as in Example 19 using, 101 mg (45 the title compound as a yellow oil .9%)
Obtained. IR (neat): 3430, 3110, 2944, 2
805, 1678, 1596, 1498, 1466, 1
430, 1358, 1258, 1160, 1010, 9
76,912,854,786,720,670,58
8 cm ^-1 . NMR (CDCl ₃ ) δ: 1.55 to 1.95 (4H,
m), 1.96 to 2.31 (2H, m), 2.50 (2
H, t, J = 7.5 Hz), 2.70 to 3.24 (3
H, m), 3.51 (3H, s), 3.60 to 3.91.
(2H, m), 6.83 (1H, d, J = 8Hz),
7.00 (1H, d, J = 7.5 Hz), 7.13 (2
H, dd, J = 9 Hz, 9 Hz), 7.20 to 7.58
(4H, m), 7.95 (2H, dd, J = 9Hz, 6
Hz), 8.27 (1H, d, J = 6 Hz), 8.50
(1H, br-s).

Example 35 4-{[N- [2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -2
-Methoxyanilino] sulfonyl} benzoic acid 4-[(2-methoxyanilino) sulfonyl] benzoic acid (261 mg, 0.85 mmol), 1- (2-chloroethyl) -4- (4-fluoro) under an argon atmosphere. Benzoyl) piperidine hydrochloride (286 mg, 0.93
5 mmol) and sodium iodide (281 mg, 1.
87 mmol) was dissolved in DMF (8 ml) and sodium hydride (136 mg, 60%, 3.4 mmol) was added at room temperature. After stirring at 60 ° C. for 8 hours, DMF was distilled off and water (10 ml) was added. After adjusting to pH 6 to 7 with 2N hydrochloric acid, extraction (salting out) was performed with ethyl acetate, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was evaporated and the obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 5).
Purification at 0: 1 to 40: 1 to 30: 1) gave 135 mg (29.4%) of the title compound as a beige amorphous powder. IR (KBr): 1680, 1596, 1504, 13
84, 1344, 1226, 1160 cm ^-1 . NMR (CDCl ₃ ) δ: 1.75 to 2.50 (4H,
m), 2.65 to 4.30 (12H, m), 6.50 to
8.20 (13H, m). MS (FAB, m / z): 321, 357, 467, 4
99,541 (M ⁺ +1).

Example 36 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxyphenyl) -p-toluenesulfonamide under argon atmosphere, N- (2-methoxyphenyl) -p
-Toluenesulfonamide (277 mg, 1.0 mmol) and a catalytic amount of sodium iodide in DMF (3 ml).
, Sodium hydride (44 mg, 60%, 1.
1 mmol) was added at room temperature. 60 minutes at the same temperature for 30 minutes
After stirring at 0 ° C for 10 minutes, 1- (2-chloroethyl)-
4- (4-fluorobenzoyl) piperidine (324m
g, 1.2 mmol) was divided into 3 times, and each was added to DMF.
It was dissolved in (1 ml) and added every hour at 60 ° C. After further stirring at the same temperature for 1 hour and 30 minutes, DMF was distilled off, water (10 ml) was added and extraction with ether was performed, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium carbonate, the solvent was evaporated and the obtained residue was subjected to silica gel column chromatography (ether: hexane = 2:
Purification in 1) gave 467 mg (91.5%) of the title compound as a colorless oil. IR (neat): 2944, 1680, 1598, 1
496, 1342, 1280, 1262, 1158, 1
094,656 cm ^-1 . NMR (CDCl ₃ ) δ: 1.54 to 1.94 (4H,
m), 1.95 to 2.30 (2H, m), 2.40 (3
H, s), 2.51 (2H, t, J = 7.5 Hz),
2.72 to 3.25 (3H, m), 3.37 (3H,
s), 3.71 (2H, t, J = 7.5Hz), 6.7.
6 (1H, d, J = 8.5 Hz), 6.95 (1H,
d, J = 8.5 Hz), 7.06 to 7.42 (4H,
m), 7.12 (2H, dd, J = 9Hz, 9Hz),
7.58 (2H, d, J = 8.5Hz), 7.93 (2
H, dd, J = 9 Hz, 6 Hz).

Example 37 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-tetrahi
Doropyranyloxymethyl-N- (2-methoxyphenyl
) Benzenesulfonamide 4-tetrahydropyranyloxymethyl-N- (2-methoxyphenyl) benzenesulfonamide (377m
(g, 1.0 mmol) was carried out in the same manner as in Example 36 to obtain 524 mg (85.8%) of the title compound as a pale yellow oily substance. IR (neat): 2924, 1680, 1598, 1
498, 1344, 1262, 1160, 1118, 1
034,976,908,732,592 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 2.33 (12
H, m), 2.52 (2H, t, J = 7.5 Hz),
2.70-3.20 (3H, m), 3.36 (3H,
s), 3.50 to 4.06 (4H, m), 4.53 (1
H, d, J = 12.5 Hz), 4.70 (1 H, br-
s), 4.83 (1H, d, J = 12.5 Hz), 6.
60 to 7.35 (6H, m), 7.40 (2H, d, J
= 9 Hz), 7.65 (2H, d, J = 9 Hz), 7.
93 (2H, dd, J = 9Hz, 6Hz).

Example 38 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-tetrahi
Doropyranyloxymethyl-N- (2-methoxyethyl
Ru) benzamide 4-tetrahydropyranyloxymethyl-N- (2-methoxyethyl) benzamide (268 mg, 0.914
(127 mmol) to give 127 mg of the title compound as a pale yellow solid.
(26.4%) was obtained. Melting point: 91 to 95 ° C IR (KBr): 2944, 1664, 1628, 15
96, 1430, 1224, 1114, 1016, 97
8,906,840,596 cm ^-1 . NMR (CDCl ₃ ) δ: 1.36 to 2.30 (12
H, m), 2.36 to 3.37 (5H, m), 3.32
(3H, s), 3.39 to 4.17 (8H, m), 4.
51 (1H, d, J = 12.5Hz), 4.68 (1
H, br-s), 4.78 (1H, d, J = 12.5H
z), 7.12 (2H, dd, J = 9Hz, 9Hz),
7.38 (4H, s), 7.93 (2H, dd, J = 9)
Hz, 6 Hz).

Example 39 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Tokishifeniru) -4-phthalimide-methylbenzamide A method N-(2-methoxyphenyl) -4-phthalimide-methylbenzamide (167 mg, by performing the same operation as in Example 36 using 0.432 mmol), 56 mg of the title compound as a pale yellow amorphous
(20.9%) was obtained. Method B Crude N-formylmethyl-N
By performing the same operation as in Example 14 using-(2-methoxyphenyl) -4-phthalimidomethylbenzamide (300 mg, 0.70 mmol), 186 mg (28.8%) of the title compound was obtained. Method C 4-chloromethyl-N- {2- [4- (4-fluorobenzoyl)
Piperidino] ethyl} -N- (2-methoxyphenyl)
By performing the same operation as in Reference Example 36 using benzamide (310 mg, 0.609 mmol), 330 mg (87.4%) of the title compound was obtained. IR (KBr): 2944, 1716, 1680, 16
42, 1596, 1502, 1392, 1306, 12
78,1238,974,938,752,716cm
^-1 . NMR (CDCl ₃ ) δ: 1.53 to 1.95 (4H,
m), 1.97 to 2.33 (2H, m), 2.60 (2
H, t, J = 7.5 Hz), 2.77 to 3.37 (3
H, m), 3.48 to 3.87 (1H, m), 3.65.
(3H, s), 3.96 to 4.36 (1H, m), 4.
72 (2H, s), 6.72 (1H, d, J = 8H
z), 6.80 (1H, d, J = 7.5 Hz), 6.9.
3 to 7.35 (8H, m), 7.55 to 8.13 (6
H, m).

Example 40 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxiphenyl) -4-morpholinomethylbenzamide N- (2-methoxyphenyl) -4-morpholinomethylbenzamide (128 mg, 0.392 mmol) was used to carry out the same operation as in Example 36 to obtain a colorless oily substance. 48.3 mg (22.0%) of the title compound
Obtained. IR (neat): 2948, 1680, 1640, 1
598, 1502, 1454, 1412, 1390, 1
304, 1280, 1262, 1240, 1116, 8
66,752,732,604 cm ^-1 . NMR (CDCl ₃ ) δ: 1.54 to 1.93 (4H,
m), 2.00 to 2.50 (2H, m), 2.63 (2
H, t, J = 7.5 Hz), 2.76 to 3.26 (3
H, m), 3.36 (2H, s), 3.46-3.96.
(5H, m), 3.67 (3H, s), 3.98-4.
40 (1H, m), 6.72 (1H, d, J = 7.5H
z), 6.81 (1H, d, J = 7.5 Hz), 6.9.
1 to 7.37 (8H, m), 7.94 (2H, dd, J
= 9 Hz, 6 Hz).

Example 41 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxyphenyl) -4-dimethylaminomethylbenzua
Mido N- (2-methoxyphenyl) -4-dimethylaminomethylbenzamide (131 mg, 0.461 mmol)
By performing the same operation as in Example 36 using
106 mg (4%) of the title compound as a pale yellow amorphous substance.
4.4%) was obtained. IR (KBr): 1680, 1640, 1598, 14
12, 1316, 1280, 1222 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.55 to 2.0
6 (4H, m), 2.06 to 2.56 (2H, m),
2.21 (6H, s), 2.73 (2H, t, J = 7.
5Hz), 2.86 to 3.30 (3H, m), 3.43
(2H, s), 3.56 to 4.40 (2H, m), 3.
70 (3H, s), 6.55 to 6.92 (2H, m),
6.94 to 7.43 (8H, m), 7.96 (2H, d
d, J = 9 Hz, 6 Hz).

Example 42 4- (N-tert-butoki)
Cycarbonyl-N-methylamino) methyl-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzamide 4- (N-tert-butoxycarbonyl-N-methylamino) methyl-N- (2-methoxyphenyl) benzamide (493 mg, 1.33 mmol) By performing the same operation as in Example 36, 580 mg (74.0%) of the title compound was obtained as a colorless oil. IR (neat): 2938, 1737, 1692, 1
644, 1596, 1503, 1392, 1239, 1
143 cm ^-1 . NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.
62 to 2.30 (6H, m), 2.52 to 3.26 (5
H, m), 2.72 (3H, s), 3.60 to 3.84.
(1H, m), 3.69 (3H, s), 4.00-4.
20 (1H, m), 4.29 (2H, s), 6.65
7.30 (10H, m), 7.95 (2H, dd, J =
9 Hz, 6 Hz).

Example 43 4-Cyano-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-Methoxyphenyl) benzamide Example 36 using 4-cyano-N- (2-methoxyphenyl) benzamide (252 mg, 1.0 mmol).
The title compound was obtained as colorless flocculent crystals by the same operation as in (250 mg, 51.5%). Melting point: 155 to 158 ° C IR (KBr): 2932, 2228, 1678, 16
42, 1594, 1502, 1406, 1392, 13
06, 1274, 1226, 854 cm ^-1 . NMR (CDCl ₃ ) δ: 1.65 to 1.97 (4H,
m), 1.97 to 2.34 (2H, m), 2.42 to
2.74 (2H, m), 2.75 to 3.37 (3H,
m), 3.40 to 3.90 (1H, m), 3.69 (3
H, s), 4.00 to 4.43 (1H, m), 6.56
~ 6.95 (2H, m), 6.96 ~ 7.70 (8H,
m), 7.95 (2H, dd, J = 9Hz, 6Hz).

Example 44 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-methoxyphenyl) benzamide 4-nitro-N- (3-methoxyphenyl) benzamide (1.09 g, 4.00 mmol) Example 3
The same operation as in 6 was performed to obtain 1.19 g (53.7%) of the title compound as pale yellow flocculent crystals. Melting point: 133-135 ° C IR (KBr): 1678, 1634, 1600, 15
18, 1408, 1380, 1276, 1230, 11
36,1048,978 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.33 (5H,
m), 2.60 (2H, t, J = 6.6Hz), 1.9
7 to 2.34 (2H, m), 2.80 to 3.35 (4
H, m), 3.66 (3H, s), 4.03 (2H,
t, J = 6.6 Hz), 6.53 to 6.80 (3H,
m), 7.00 to 7.15 (1H, m), 7.10 (2
H, dd, each J = 9.0 Hz), 7.42 (2
H, d, J = 9.0 Hz), 7.98 (2H, dd, J
= 9.0, 6.0 Hz).

Example 45 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-Methoxyphenyl) benzamide Example 3 using 4-nitro-N- (4-methoxyphenyl) benzamide (857 mg, 3.14 mmol).
The same operation as in 6 was performed to give 973.5 mg (61.4%) of the title compound as a yellow powder. Melting point: 154-156 ° C IR (KBr): 1677, 1641, 1599, 15
12, 1443, 1377, 1347, 1296, 12
75, 1248, 1221, 1200, 1170, 11
55,1131,1110,1035,972,867
cm ^-1 . NMR (CDCl ₃ ) δ: 1.67 to 2.00 (4H,
m), 2.00 to 2.35 (2H, m), 2.60 (2
H, t, J = 6.5 Hz), 2.80 to 3.40 (3
H, m), 3.74 (3H, s), 4.03 (2H,
t, J = 6.5 Hz), 6.72 (2H, d, J = 9.
0 Hz), 6.83 to 7.50 (6H, m), 7.80
~ 8.10 (4H, m).

Example 46 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2,5-Dimethoxyphenyl) benzamide 4-nitro-N- (2,5-dimethoxyphenyl) benzamide (1.21 g, 4.00 mmol) was carried out in the same manner as in Example 36. , 1.48 g (69.1%) of the title compound was obtained as a yellow amorphous. Melting point: 154-156 ° C IR (KBr): 2950,1682,1644,16
00, 1504, 1346, 1224, 1048, 97
6,714 cm ^-1 . NMR (CDCl ₃ ) δ: 1.77 to 2.31 (6H,
m), 2.61 to 3.19 (5H, m), 3.64 (3
H, s), 3.69 (3H, s), 4.16 (2H,
t, J = 7.0 Hz), 6.71 (2H, dd, J =
2.0, 8.1 Hz), 7.05 to 7.52 (5H,
m), 7.88-8.04 (4H, m).

Example 47 3-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Methoxyphenyl) benzamide 3-Nitro-N- (3-methoxyphenyl) benzamide (816.0 mg, 3.00 mmol) was used to perform the same operation as in Example 36 to obtain a colorless powder. 823.9 mg (54.7%) of the title compound was obtained. Melting point: 123-125 ° C IR (KBr): 2950, 1676, 1640, 15
98, 1532, 1400, 1352, 1304, 12
32, 1208, 1118, 1026 cm ^-1 . NMR (CDCl ₃ ) δ: 1.55 to 2.31 (5H,
m), 2.64 (2H, t, J = 6.6Hz), 2.7
6 to 3.30 (4H, m), 3.71 (3H, s),
4.07 (2H, t, J = 6.6Hz), 6.45-
6.80 (3H, m), 6.90 to 7.38 (1H,
m), 7.13 (2H, dd, eachachJ = 8.8H)
z), 7.40 (1H, d, J = 7.7 Hz), 7.5
0 to 7.72 (1H, m), 7.72 to 8.20 (4
H, m).

Example 48 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2,4-dimethoxyphenyl) benzamide 4-nitro-N- (2,4-dimethoxyphenyl) benzamide (908 mg, 3.00 mmol) was used for the same procedure as in Example 36 to give an orange color. As a powder, 1.46 g (91.0%) of the title compound was obtained. Melting point: 51 to 54 ° C IR (KBr): 1680, 1646, 1598, 15
10, 1410, 1346, 1310, 1280, 12
08,1158,1142,1030,852,836
cm ^-1 . NMR (CDCl ₃ ) δ: 1.25 to 3.73 (13
H, m), 3.70 (3H, s), 3.73 (3H,
s), 4.16 (2H, t, J = 7.0Hz), 6.2
7 to 6.34 (2H, m), 6.98 to 7.23 (3
H, m), 7.41 (2H, d, J = 8.6Hz),
7.88 to 7.94 (2H, m), 7.99 (2H,
d, J = 8.6 Hz).

Example 49 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Methylphenyl) benzamide 4-nitro-N- (3-methylphenyl) benzamide (640 mg, 2.50 mmol) Example 36
The same operation as in (1) was performed to obtain 517 mg (42.1%) of the title compound as a colorless powder. Melting point: 150 to 152 ° C IR (KBr): 2935, 2830, 1677, 16
41, 1599, 1515, 1410, 1344, 12
99,1281,1227,1134 cm ^-1 . NMR (CDCl ₃ ) δ: 1.61 to 2.32 (6H,
m), 2.26 (3H, s), 2.62 (2H, t, J
= 7.0 Hz), 2.81 to 3.41 (3H, m),
4.06 (2H, t, J = 7.0Hz), 6.71
7.71 (8H, m), 7.81 to 8.14 (4H,
m).

Example 50 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (phenyl) benzamide 4-nitro-N- (phenyl) benzamide (970.
The same operation as in Example 36 was carried out using 0 mg (4.01 mmol) to obtain 1.13 g (59.5%) of the title compound as a colorless powder. Melting point: 177 to 181 ° C IR (KBr): 1678, 1640, 1594, 15
16, 1494, 1408, 1380, 1342, 13
18, 1300, 1274, 1224, 1136, 97
6,870,852,718,698 cm ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.32 (6H,
m), 2.60 (2H, dd, J = 6.6, 6.4H
z), 2.93 to 3.30 (3H, m), 4.07 (2
H, dd, J = 6.6, 6.4 Hz), 7.03-7.
18 (7H, m), 7.41 (2H, d, J = 8.7H
z), 7.88-8.04 (4H, m).

Example 51 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Methylthiophenyl) benzamide 4-nitro-N- (3-methylthiophenyl) benzamide (1.15 g, 4.00 mmol) was used to carry out the same operation as in Example 36 to obtain a pale yellow powder. As a result, 1.73 g (81.3%) of the title compound was obtained. Melting point: 153-154 ° C IR (KBr): 1680, 1644, 1602, 15
80, 1522, 1434, 1372, 1344, 13
08, 1298, 1226, 1138 cm ^-1 . NMR (CDCl ₃ ) δ: 1.16 to 2.27 (6H,
m), 2.36 (3H, s), 2.62 (2H, t, J
= 6.4 Hz), 2.95 to 3.22 (3H, m),
4.07 (2H, t, J = 6.4Hz), 6.79-
6.86 (1H, m), 7.00 to 7.23 (5H,
m), 7.43 (2H, d, J = 8.6Hz), 7.9
3 (2H, d, J = 8.8Hz), 8.03 (2H,
d, J = 8.8 Hz).

Example 52 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-trifluoromethylphenyl) benzamide 4-nitro-N- (2-trifluoromethylphenyl)
By performing the same operation as in Example 36 using benzamide (450.0 mg, 1.45 mmol), 299 mg (40.6 mg) of the title compound was obtained as yellow needle crystals.
%)Obtained. Melting point: 156.6 to 157.8 ° C IR (KBr): 2960, 2841, 1678, 16
56, 1600, 1524, 1316, 1126, 86
2,577,614 cm ^-1 . NMR (CDCl ₃ ) δ: 1.68 to 2.25 (6H,
m), 2.61 to 2.86 (3H, m), 3.05
3.43 (2H, m), 4.57 (2H, brs),
7.09 (2H, d, J = 8.6Hz), 7.33-
7.61 (6H, m), 7.89 to 8.08 (4H,
m).

Example 53 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-trifluoromethylphenyl) benzamide 4-nitro-N- (3-trifluoromethylphenyl)
The same operation as in Example 36 was carried out using benzamide (1.55 g, 5.00 mmol) to give 1.14 g (42.0%) of the title compound as a colorless powder. Melting point: 123 to 137.1 ° C IR (KBr): 2948, 1678, 1648, 16
02, 1344, 1136, 859, 722, 601c
m ^-1 . NMR (CDCl ₃ ) δ: 1.79 to 1.95 (4H,
m), 2.05 to 2.20 (2H, m), 2.60 (2
H, t, J = 6.2 Hz), 2.90 to 3.29 (3
H, m), 4.09 (2H, t, J = 9.0 Hz),
7.04 to 7.50 (8H, m), 7.88 to 8.10
(4H, m).

Example 54 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-pyridyl) benzamide 4-nitro-N- (3-pyridyl) benzamide (97
The same operation as in Example 36 was performed using 3 mg, 4.00 mmol) to obtain 178 mg (9.3%) of the title compound as a colorless powder. IR (KBr): 2935, 1677, 1644, 15
99, 1518, 1344, 1299, 1278, 12
24, 1134, 849 cm ^-1 . NMR (CDCl ₃ ) δ: 1.41 to 2.36 (6H,
m), 2.62 (2H, t, J = 6.0Hz), 2.7
6 to 3.41 (3H, m), 4.08 (2H, t, J =
6.0 Hz), 7.21 (2H, t, J = 9.0H
z), 6.67 to 7.70 (4H, m), 7.70 to
8.17 (4H, m), 8.17 to 8.53 (2H,
m).

Example 55 2-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Methoxyphenyl) benzamide 2-nitro-N- (3-methoxyphenyl) benzamide (816 mg, 3.00 mmol) Example 3
The same operation as in 6 was performed to obtain 1.497 g (98.9%) of the title compound as a pale yellow amorphous substance. IR (KBr): 2930, 1678, 1648, 16
00, 1530, 1488, 1408, 1346, 12
08,1156,910 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.35 (6H,
m), 2.67 (2H, t, J = 6.0Hz), 2.9
0 to 3.30 (4H, m), 3.63 (3H, s),
4.05 (2H, t, J = 6.0Hz), 7.10 (2
H, dd, eachchJ = 9.0 Hz), 6.53-6.
80 (3H, m), 6.90 to 7.55 (4H, m),
7.75 to 8.05 (1H, m), 7.95 (2H, d
d, J = 9.0, 6.0).

Example 56 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Nitrophenyl) benzamide 4-nitro-N- (3-nitrophenyl) benzamide (718 mg, 2.50 mmol) Example 36
By the same procedure as in 1.1, 1.11 g (53.4%) of the title compound was obtained as a pale yellow oil. IR (neat): 2950, 1680, 1656, 1
600, 1530, 1408, 1350, 1274, 1
226, 1156, 854 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 2.40 (5H,
m), 2.43 (2H, t, J = 6.0Hz), 2.7
7 to 3.40 (4H, m), 4.09 (2H, t, J =
6.0 Hz), 7.13 (2H, dd, eachJ =
9.0 Hz), 7.76-8.27 (6H, m).

Example 57 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-ethoxycarbonylphenyl) benzamide 4-nitro-N- (2-ethoxycarbonylphenyl)
By performing the same operation as in Example 36 using benzamide (600.0 mg, 2.00 mmol), 523 mg (49.1%) of the title compound was obtained as a colorless powder. Melting point: 187 to 190 ° C IR (KBr): 1678, 1656, 1600, 13
14,846,763,645,610 cm ^-1 . NMR (CDCl ₃ ) δ: 1.71-1.89 (4H,
m), 2.01 to 2.23 (2H, m), 2.26 to
2.83 (2H, m), 2.91 to 3.17 (3H,
m), 3.48 to 3.63 (1H, m), 3.88 (3
H, s), 4.30 to 4.53 (1H, m), 7.03.
~ 7.46 (7H, m), 7.76 ~ 8.02 (5H,
m).

Example 58 4-Cyano-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-Methoxyphenyl) benzamide Example 3 using 4-cyano-N- (4-methoxyphenyl) benzamide (2.02 g, 8.00 mmol).
The same operation as in 6 was performed to obtain 2.32 g (59.8%) of the title compound as a colorless powder. Melting point: 136-149 ° C IR (KBr): 2940, 2227, 1678, 16
40, 1510, 1250, 1035, 972, 83
2,601 cm ^-1 . NMR (CDCl ₃ ) δ: 1.78 to 2.31 (6H,
m), 2.58 (2H, t, J = 6.6Hz), 2.9
4 to 3.30 (3H, m), 3.75 (3H, s),
4.01 (2H, t, J = 6.6Hz), 6.40 (2
H, d, J = 9.0 Hz), 6.94 to 7.42 (8
H, m), 7.88-8.03 (2H, m).

Example 59 3-Methyl-4-nitro-N
-{2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (4-methoxyphenyl) benzua
The title compound was obtained as a colorless powder by performing the same operation as in Example 36 by using amido 3-methyl-4-nitro-N- (4-methoxyphenyl) benzamide (1.14 g, 4.00 mmol). 0.06 g (51.1%) was obtained. Melting point: 125.7-126.4 ° C IR (KBr): 2930, 1678, 1640, 15
10, 1346, 1250, 972, 835, 731
602 cm ^-1 . NMR (CDCl ₃ ) δ: 1.79 to 2.30 (6H,
m), 2.49 (3H, s), 2.59 (2H, t, J
= 6.4 Hz), 2.95 to 3.28 (3H, m),
3.75 (3H, s), 4.01 (2H, t, J = 6.
4Hz), 6.75 (2H, d, J = 9.0Hz),
6.97 to 7.32 (6H, m), 7.11 (1H,
d, J = 8.4 Hz), 7.95 (2H, dd, J =
8.8, 6.5 Hz).

Example 60 3-Methoxy-4-nitro-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (4-methoxyphenyl) benzua
The title compound was obtained as a pale yellow powder by performing the same operation as in Example 36 using amide 3-methoxy-4-nitro-N- (4-methoxyphenyl) benzamide (1.36 g, 4.50 mmol). 1.60 g (66.5%)
Obtained. Melting point: 152-153 ° C IR (KBr): 2950, 1680, 1640, 16
06,1512,1250,975,837,720c
m ^-1 . NMR (CDCl ₃ ) δ: 1.79 to 2.30 (6H,
m), 2.59 (2H, t, J = 6.6Hz), 2.9
5 to 3.36 (3H, m), 3.76 (3H, s),
3.81 (3H, s), 4.02 (2H, t, J = 6.
6 Hz), 6.77 (2H, d, J = 9.0 Hz),
6.90 to 7.26 (6H, m), 7.60 (1H,
d, J = 8.4 Hz), 7.96 (2H, dd, J =
8.6, 5.5 Hz).

Example 61 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-Fluorophenyl) benzamide 4-nitro-N- (4-fluorophenyl) benzamide (1.04 g, 4.00 mmol) Example 3
The same operation as in 6 was performed to obtain 1.41 g (71.6%) of the title compound as a pale yellow powder. Melting point: 194 to 196 ° C IR (KBr): 1680, 1642, 1600, 15
16, 1504, 1376, 1342, 1306, 12
76,1240,1222,1136 cm ^-1 . NMR (CDCl ₃ ) δ: 1.78 to 2.18 (6H,
m), 2.58 (2H, dd, J = 6.4, 6.2H
z), 2.93 to 3.05 (3H, m), 4.03 (2
H, dd, J = 6.4, 6.2 Hz), 6.92 to 7.
23 (6H, m), 7.40 (2H, d, J = 8.6H
z), 7.88 to 8.08 (4H, m).

Example 62 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-Methylphenyl) benzamide Example 36 using 4-nitro-N- (4-methylphenyl) benzamide (1.03 g, 4.01 mmol).
By performing the same operation as above, 1.61 g (59.1%) of the title compound was obtained as a pale yellow powder. Melting point: 175 to 178 ° C IR (KBr): 1678, 1640, 1600, 15
16, 1376, 1342, 1296, 1376, 12
22 cm ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.16 (6H,
m), 2.27 (3H, s), 2.59 (2H, dd,
J = 6.6, 6.4 Hz), 2.95-3.10 (3
H, m), 4.04 (2H, dd, J = 6.6, 6.4)
Hz), 6.89 to 7.25 (6H, m), 7.41
(2H, d, J = 8.6 Hz), 7.88 to 8.05
(4H, m).

Example 63 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (phenyl) benzamide 4-nitro-N- (phenyl) benzamide (969.
By performing the same operation as in Example 36 using 0 mg (4.00 mmol), 1.02 g (53.6%) of the title compound was obtained as a pale yellow powder. Melting point: 178 to 180 ° C IR (KBr): 1680, 1640, 1596, 15
30, 1492, 1394, 1352, 1308, 12
78, 1226, 1208, 1160, 1126, 97
0,724,706 cm ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.32 (6H,
m), 2.63 (2H, t, J = 6.6Hz), 2.9
4 to 3.27 (3H, m), 4.08 (2H, t, J =
6.6 Hz), 7.03 to 7.64 (9 H, m), 7.
87-8.02 (3H, m), 8.09 (1H, s).

Example 64 3-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-Methylphenyl) benzamide 3-nitro-N- (4-methylphenyl) benzamide (1.03 g, 4.00 mmol) Example 36
By carrying out the same operation as above, 1.07 g (57.0%) of the title compound was obtained as a pale yellow powder. Melting point: 131 to 134 ° C IR (KBr): 1680, 1640, 1598, 15
30,1512,1346 cm ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.16 (6H,
m), 2.26 (3H, s), 2.60 (2H, t, J
= 6.4 Hz), 2.95 to 3.20 (3H, m),
4.04 (2H, t, J = 6.4Hz), 6.97-
7.63 (8H, m), 7.86 to 8.02 (3H,
m), 8.10 (1H, s).

Example 65 3-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-Fluorophenyl) benzamide 3-nitro-N- (4-fluorophenyl) benzamide (1.04 g, 4.00 mmol) Example 3
The same operation as in 6 was carried out to obtain 507.0 mg (25.7%) of the title compound as a pale yellow powder. Melting point: 97 to 113 ° C IR (KBr): 1656, 1594, 1530, 15
08, 1350, 1310, 1216, 724 cm ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.31 (6H,
m), 2.60 (2H, t, J = 6.6Hz), 2.9
2-3.19 (3H, m), 4.03 (2H, t, J =
6.6 Hz), 6.82 to 7.22 (6H, m), 7.
34 to 7.62 (2H, m), 7.87 to 8.03 (3
H, m), 8.10 (1H, s).

Example 66 3-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Methylthiophenyl) benzamide 3-nitro-N- (3-methylthiophenyl) benzamide (1.54 g, 4.00 mmol) was used to carry out the same operation as in Example 36 to obtain a pale yellow powder. As a title compound, 1.04 g (49.6%) was obtained. Melting point: 148 to 149 ° C IR (KBr): 1674, 1640, 1594, 15
28, 1388, 1376, 1348, 1302, 12
22,1204,1170,1142,726,692
cm ^-1 . NMR (CDCl ₃ ) δ: 1.69 to 2.26 (6H,
m), 2.36 (3H, s), 2.63 (2H, t, J
= 6.5 Hz), 2.95 to 3.20 (3H, m),
4.07 (2H, t, J = 6.5Hz), 6.83-
7.23 (7H, m), 7.30 (1H, d, J = 7.
8Hz), 7.63 (1H, d, J = 7.8Hz),
7.92 (1H, d, J = 8.6Hz), 7.98 (1
H, d, J = 8.6 Hz), 7.34 to 7.62 (2
H, m), 8.13 (1H, s).

Example 67 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3,4-methylenedioxyphenyl) benzamid
The title compound was obtained as a pale yellow powder by performing the same operation as in Example 36 using de 4-nitro-N- (3,4-methylenedioxyphenyl) benzamide (1.14 g, 4.00 mmol). 1.49g (72.0%)
Obtained. Melting point: 197-198 ° C IR (KBr): 1680, 1644, 1599, 15
18,1503,1485,1446,1410,13
80,1341,1302,1281,1269,12
36, 1215, 1173, 1155, 1128, 11
10,1035,972,870,843,717cm
^-1 . NMR (CDCl ₃ ) δ: 1.65 to 2.00 (4H,
m), 2.00-2.43 (2H, m), 2.60 (2
H, t, J = 6.5 Hz), 2.83 to 3.33 (3
H, m), 4.00 (2H, t, J = 6.5Hz),
5.96 (2H, s), 6.48 to 6.70 (3H,
m), 7.00 to 7.29 (3H, m), 7.45 (2
H, d, J = 8.8 Hz), 7.80-8.20 (4
H, m).

Example 68 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (1-naphthyl) benzamide 4-nitro-N- (1-naphthyl) benzamide (58
By carrying out the same operation as in Example 36 using 4.0 mg, 2.00 mmol), 375.7 mg (35.8%) of the title compound was obtained as a pale yellow powder. Melting point: 174 to 175 ° C IR (KBr): 1680, 1644, 1599, 15
21, 1410, 1380, 1341, 1305, 12
78, 1230, 1206, 1155, 1134, 11
10,975,870,852,832 cm ^-1 . NMR (CDCl ₃ ) δ: 1.67 to 1.97 (4H,
m), 1.97 to 2.32 (2H, m), 2.63 (2
H, t, J = 6.6 Hz), 2.80 to 3.30 (3
H, m), 3.74 (1H, quint., J = 6.6.
Hz), 4.61 (1H, quint., J = 6.6H)
z), 6.93-8.10 (15H, m).

Example 69 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-chlorophenyl) benzamide 4-nitro-N- (4-chlorophenyl) benzamide (1.11 g, 4.00 mmol) Example 36
By performing the same operation as above, 1.21 g (59.2%) of the title compound was obtained as a pale yellow powder. Melting point: 175 to 177 ° C. IR (KBr): 1680, 1644, 1600, 14
90, 1374, 1348, 1306, 1280, 12
70, 1222, 1134, 1094 cm ^-1 . NMR (CDCl ₃ ) δ: 1.79 to 2.20 (6H,
m), 2.59 (2H, t, J = 6.4Hz), 2.9
3 to 3.05 (3H, m), 4.04 (2H, t, J =
6.4 Hz), 7.00 to 7.26 (6H, m), 7.
42 (2H, d, J = 8.6 Hz), 7.89 to 8.1
0 (4H, m).

Example 70 4-Nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3,4-Dimethylphenyl) benzamide 4-nitro-N- (3,4-dimethylphenyl) benzamide (1.08 g, 4.00 mmol) was used in the same manner as in Example 36. As a pale yellow powder, 1.26 g (62.3%) of the title compound was obtained. Melting point: 197-199 ° C IR (KBr): 1678, 1640, 1600, 15
16,1504,1410,1378,1344,13
28, 1302, 1276, 1228, 1136, 87
0,856,842,720 cm ^-1 . NMR (CDCl ₃ ) δ: 2.16 (6H, s), 1.
59 to 2.33 (6H, m), 2.60 (2H, t, J
= 6.6 Hz), 2.95 to 3.28 (3H, m),
4.03 (2H, t, J = 6.6Hz), 6.23 ~
6.71 (5H, m), 7.43 (2H, d, J = 8.
6 Hz), 7.89 to 8.05 (4H, m).

Example 71 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3,5-Dimethylphenyl) benzamide 4-nitro-N- (3,5-dimethylphenyl) benzamide (1.08 g, 4.00 mmol) was used in the same manner as in Example 36. As a pale yellow powder, 686.1 mg (34.1%) of the title compound was obtained. IR (KBr): 1680, 1638, 1598, 14
08, 1382, 1332, 1310, 1296, 12
34,1126,854,716 cm ^-1 . NMR (CDCl ₃ ) δ: 2.19 (6H, s), 1.
69 to 2.32 (6H, m), 2.60 (2H, t, J
= 6.6 Hz), 2.95 to 3.20 (3H, m),
4.03 (2H, t, J = 6.6Hz), 6.70 (2
H, s), 6.79 (1H, s), 7.04 to 7.23.
(2H, m), 7.43 (2H, d, J = 8.6H
z), 7.89-8.07 (4H, m).

Example 72 4-Nitro-N- {3- [4
-(4-Fluorobenzoyl) piperidino] propyl}
-N- (3-Methoxyphenyl) benzamide 4-nitro-N- (3-methoxyphenyl) benzamide (816.0 mg, 3.00 mmol) was used to perform the same operation as in Example 36 to give a pale yellow color. 872.0 mg (56.0 mg) of the title compound as an amorphous substance.
%)Obtained. IR (KBr): 1680, 1644, 1600, 15
24, 1490, 1408, 1392, 1348, 13
14,1282,1234,1200,1156,91
0,862 cm ^-1 . NMR (CDCl ₃ ) δ: 1.55 to 2.23 (7H,
m), 2.43 (2H, t, J = 7.2Hz), 2.7
5 to 3.28 (3H, m), 3.70 (3H, s),
3.98 (2H, t, J = 7.2Hz), 6.41
6.78 (3H, m), 6.90 to 7.28 (1H,
m), 7.13 (2H, dd, J = 9.0Hz), 7.
45 (2H, d, J = 8.8Hz), 7.89 (2H,
d, J = 8.8 Hz), 7.95 (2H, dd, J =
9.0, 6.0 Hz).

Example 73 4-nitro-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Methoxyphenyl) benzamide 4-nitro-N- (3-methoxyphenyl) benzamide (50.0 g, 183.6 mmol) was dissolved in dioxane (900 ml) and potassium hydroxide (30.3) was added.
g, 85%, 459.0 mmol) at room temperature and added 60
After stirring at C for 1 hour, N-1- (2-chloroethyl) -4- (4-fluorobenzoyl) piperidine hydrochloride (67.5 g, 220.0 mmol) was added at room temperature. The reaction mixture was stirred at 50 ° C. for 24 hours, ice water was added to the mixture, extraction with ethyl acetate was performed, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give the title compound (47.2 g, 50.8%) as pale yellow fluffy crystals. Melting point: 133-135 ° C IR (KBr): 1678, 1634, 1600, 15
18, 1408, 1380, 1276, 1230, 11
36,1048,978 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.33 (5H,
m), 2.60 (2H, t, J = 6.6Hz), 1.9
7 to 2.34 (2H, m), 2.80 to 3.35 (4
H, m), 3.66 (3H, s), 4.03 (2H,
t, J = 6.6 Hz), 6.53 to 6.80 (3H,
m), 7.00 to 7.15 (1H, m), 7.10 (2
H, dd, each J = 9.0 Hz), 7.42 (2
H, d, J = 9.0 Hz), 7.98 (2H, dd, J
= 9.0, 6.0 Hz).

Example 74 N- {3- [4- (4-full
Orophenyl) piperazinyl] propyl} -4-methoki
Ci-N- (2-methoxyphenyl) benzenesulfone
Under bromide argon atmosphere, 4-methoxy-N-(2-methoxyphenyl) benzenesulfonamide (200 mg, 0.
682 mmol) was dissolved in DMF (3 ml) and sodium hydride (150 mg, 60%, 3.75 mmol) was added.
Was added at room temperature and stirred for 1 hour, then 1- (3-bromopropyl) -4- (4-fluorophenyl) piperazine 2
DM hydrobromide (347 mg, 0.75 mmol)
It was dissolved in F (3 ml) and added dropwise. After stirring at 50 ° C. for 5 hours, ice water (10 ml) was added, extraction was performed with ethyl acetate, the extract was washed with water and saturated brine, dried over anhydrous sodium carbonate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ether) to give 130 mg (37.1) of the title compound as colorless prism crystals.
%)Obtained. Melting point: 121 to 122.5 ° C. IR (KBr): 2948, 2820, 1596, 15
12, 1496, 1460, 1342, 1300, 12
56, 1178, 1158, 1114, 1096, 10
26,830,804,754,588,562c
m ^-1 . NMR (CDCl ₃ ) δ: 1.45 to 1.90 (2H,
m), 2.13 to 2.70 (6H, m), 2.87 to
3.26 (4H, m), 3.43 (3H, s), 3.6
3 (2H, t, J = 7Hz), 3.83 (3H, s),
6.60 to 7.10 (8H, m), 7.13 to 7.40
(2H, m), 7.60 (2H, d, J = 9Hz).

Example 75 4-Fluoro-N- {3-
[4- (4-Fluorophenyl) piperazinyl] propyi
Ru} -N- (2-methoxyphenyl) benzenesulfone
Amido 4-fluoro-N- (2-methoxyphenyl) benzenesulfonamide (141 mg, 0.50 mmol) was used to perform the same operation as in Example 74 to obtain 103 mg (41.1 mg) of the title compound as a colorless powder. %)Obtained. Melting point: 115 to 118 ° C IR (KBr): 1508, 1492, 1340, 12
88, 1250, 1222, 1162, 816, 78
2,554 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 1.88 (2H,
m), 2.25 to 2.73 (6H, m), 2.85
3.23 (4H, m), 3.40 (3H, s), 3.6
6 (2H, t, J = 7 Hz), 6.63 to 7.46 (1
0H, m), 7.66 (2H, dd, J = 9Hz, 6H
z).

Example 76 N- {3- [4- (4-full
Orophenyl) piperazinyl] propyl} -N- (2-
Methoxyphenyl) -3-nitrobenzenesulfonami
De N-(2-methoxyphenyl) -3-nitrobenzenesulfonamide (190 mg, 0.616 mmol) by the same manner as in Example 74 using the title compound as a yellow powder 196 mg (60.2% )Obtained. Melting point: 95 to 98 ° C IR (KBr): 1528, 1506, 1496, 13
48, 1280, 1268, 1246, 1228, 11
74,1162,828,786,592,576cm
^-1 . NMR (CDCl ₃ ) δ: 1.40 to 1.92 (2H,
m), 2.22 to 2.70 (6H, m), 2.88 to
3.28 (4H, m), 3.37 (3H, s), 3.6
8 (2H, t, J = 7 Hz), 6.68 to 7.10 (6
H, m), 7.18 to 7.45 (2H, m), 7.62
(1H, dd, J = 7.5Hz, 7.5Hz), 7.9
8 (1H, d, J = 7.5 Hz), 8.35 (1H,
d, J = 7.5 Hz), 8.55 (1H, br-s).

Example 77 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-hydroxy
Cimethyl-N- (2-methoxyphenyl) benzenesul
Honamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-tetrahydropyranyloxymethyl-N- (2-methoxyphenyl) benzenesulfonamide (101 mg, 0.165 mmol) in methanol ( 5 ml) and p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) was added at room temperature. After stirring at the same temperature for 2 hours, methanol was distilled off, saturated aqueous sodium hydrogen carbonate (5 ml) was added, extraction was performed with ethyl acetate, and the mixture was washed with water and saturated brine. The aqueous layer was further extracted with ethyl acetate, washed with water and saturated brine, the organic layers were combined, dried over anhydrous sodium carbonate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless oil (8)
Obtained 7 mg (100%). IR (neat): 3520, 2944, 1680, 1
598, 1496, 1342, 1280, 1262, 1
238, 1158, 732 cm ^-1 . NMR (CDCl ₃ ) δ: 1.46 to 1.90 (4H,
m), 1.90 to 2.15 (1H, m), 2.15
2.32 (2H, m), 2.46 (2H, t, J = 7.
5 Hz), 2.69 to 2.99 (2H, m), 3.00
~ 3.26 (1H, m), 3.41 (3H, s), 3.
70 (2H, t, J = 7.5Hz), 4.75 (2H,
s), 6.77 (1H, d, J = 9 Hz), 6.95
(1H, d, J = 9Hz), 7.11 (2H, dd, J
= 9 Hz, 9 Hz), 7.27 (2H, d, J = 9H
z), 7.40 (2H, d, J = 8.5 Hz), 7.6
7 (2H, d, J = 8.5 Hz), 7.92 (2H, d
d, J = 9 Hz, 6 Hz).

Example 78 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-hydroxy
Cimethyl-N- (2-methoxyphenyl) benzamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-tetrahydropyranyloxymethyl-N- (2-methoxyphenyl) benzamide (163
The title compound was obtained as a colorless solid in an amount of 128 mg (91.9%) by the same procedure as in Example 77. Melting point: 87-91 ° C IR (KBr): 3408, 2948, 1680, 16
38, 1598, 1502, 1410, 1298, 12
78, 1264, 1240, 752, 730, 602c
m ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.96 (5H,
m), 2.00 to 2.40 (2H, m), 2.63 (2
H, t, J = 7.5 Hz), 2.76 to 3.40 (3
H, m), 3.50 to 3.93 (1H, m), 3.68
(3H, s), 3.96 to 4.33 (1H, m), 4.
57 (2H, s), 6.73 (1H, d, J = 8H
z), 6.84 (1H, d, J = 7.5 Hz), 6.9.
5 to 7.43 (8H, m), 7.95 (2H, dd, J
= 9 Hz, 6 Hz).

Example 79 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -3-hydroxy
Cimethyl-N- (2-methoxyphenyl) benzamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -3-tetrahydropyranyloxymethyl-N- (2-methoxyphenyl) benzamide (191
The title compound was obtained as a colorless oil in an amount of 148 mg (90.9%) by the same procedure as in Example 77. IR (neat): 3416, 2944, 1680, 1
642, 1598, 1504, 1394, 1278, 1
240,734 cm ^-1 . NMR (CDCl ₃ ) δ: 1.45 to 1.90 (5H,
m), 1.98 to 2.36 (2H, m), 2.63 (2
H, t, J = 7.5 Hz), 2.79 to 3.22 (3
H, m), 3.40 to 3.92 (1H, m), 3.70.
(3H, s), 4.04 to 4.35 (1H, m), 4.
52 (2H, s), 6.73 (1H, d, J = 8H
z), 6.83 (1H, d, J = 8 Hz), 6.94-
7.39 (8H, m), 7.96 (2H, dd, J = 9
Hz, 6 Hz).

Example 80 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-hydroxy
Cimethyl-N- (3-methoxybenzyl) benzamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-tetrahydropyranyloxymethyl-N- (3-methoxybenzyl) benzamide (130
(100 mg (89.7%) of the title compound as a colorless oily substance was obtained by the same procedure as in Example 77. IR (neat): 3416, 2944, 1678, 1
600, 1424, 1262, 1234, 1208, 1
156, 1048, 974, 730 cm ^-1 . NMR (CDCl ₃ ) δ: 1.45 to 2.30 (8H,
m), 2.37 to 3.65 (6H, m), 3.80 (3
H, s), 4.70 (4H, br-s), 6.64-
6.95 (2H, m), 7.10 to 7.60 (6H,
m), 7.13 (2H, dd, J = 9Hz, 9Hz),
7.95 (2H, dd, J = 9Hz, 6Hz).

Example 81 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-hydroxy
Cimethyl-N- (2-methoxyethyl) benzamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-tetrahydropyranyloxymethyl-N- (2-methoxyethyl) benzamide (424m
The title compound was obtained as a colorless solid in an amount of 307 mg (86.2%) by the same procedure as in Example 77. Melting point: 95-99 ° C IR (KBr): 3450, 2940, 2820, 16
64, 1628, 1596, 1464, 1428, 12
90, 1280, 1212, 1170, 1112, 10
48,1014,978 cm ^-1 . NMR (CDCl ₃ ) δ: 1.43 to 2.30 (7H,
m), 2.36 to 3.39 (5H, m), 3.32 (3
H, s), 3.39 to 3.90 (6H, m), 4.71.
(2H, s), 7.12 (2H, dd, J = 9Hz, 9
Hz), 7.38 (4H, s), 7.94 (2H, d
d, J = 9 Hz, 6 Hz).

Example 82 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxyphenyl) -4-dimethylaminomethylbenzene
Sulfonamide and N- (2-methoxyphenyl) -N
-{2- [4- (4-dimethylaminobenzoyl) pipet
Lysino] ethyl} -4-dimethylaminomethylbenzene
Sulfonamide in dry air, N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N
-(2-Methoxyphenyl) benzenesulfonamide (80 mg, 0.152 mmol) was added to methylene chloride (2
ml) and DMF (1 drop) and thionyl chloride (0.1 ml, 1.37 mmol) were added dropwise under ice cooling. After stirring at the same temperature for 2 hours, the solvent was distilled off. The obtained residue was placed in a 25 ml eggplant-shaped flask equipped with a cold finger and dissolved in dioxane (1 ml) to prepare 5
A 0% aqueous dimethylamine solution (1 ml) was added. 80 ° C
After stirring at room temperature for 2 hours and 30 minutes, dioxane was distilled off and diluted with ethyl acetate (15 ml). The residue obtained by drying over anhydrous sodium carbonate and distilling off the solvent was purified by PTLC (methylene chloride: methanol = 35: 1) to give N- {2- [4- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
33.5 mg (39.8 mg) of-(2-methoxyphenyl) -4-dimethylaminomethylbenzenesulfonamide
%), And N- (2-methoxyphenyl) -N- {2- [4- (4-dimethylaminobenzoyl) piperidino] ethyl} -4-dimethylaminomethylbenzenesulfonamide as a highly polar component of a colorless solid. 5 mg (54.
0%) was obtained.

Low polar component: N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-dimethylaminomethylbenzenesulfonamide IR (neat): 2944, 2816, 2776, 1
680, 1598, 1496, 1458, 1342, 1
280, 1262, 1160, 592 cm ^-1 . NMR (CDCl ₃ ) δ: 1.46 to 1.93 (4H,
m), 1.95 to 2.35 (2H, m), 2.23 (6
H, s), 2.51 (2H, t, J = 7.5 Hz),
2.70-3.20 (3H, m), 3.39 (3H,
s), 3.44 (2H, s), 3.72 (2H, t, J
= 7.5 Hz), 6.76 (1H, d, J = 8.5H)
z), 6.95 (1H, d, J = 8.5 Hz), 7.1
1 (2H, dd, J = 9Hz, 9Hz), 7.15 ~
7.49 (4H, m), 7.65 (2H, d, J = 8.
5Hz), 7.93 (2H, dd, J = 9Hz, 6H
z).

Highly polar component: N- (2-methoxyphenyl) -N- {2- [4- (4-dimethylaminobenzoyl) piperidino] ethyl} -4-dimethylaminomethylbenzenesulfonamide Melting point: 152-155 ° C IR (KBr): 3440, 2816, 1656, 15
98, 1496, 1342, 1280, 1264, 11
60, 1116, 730, 592 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.92 (4H,
m), 1.95 to 2.36 (2H, m), 2.23 (6
H, s), 2.52 (2H, t, J = 7.5 Hz),
2.72 to 3.24 (3H, m), 3.02 (6H,
s), 3.40 (3H, s), 3.46 (2H, s),
3.72 (2H, t, J = 7.5Hz), 6.45-
7.05 (4H, m), 7.06 to 7.50 (4H,
m), 7.65 (2H, d, J = 8Hz), 7.83
(2H, d, J = 8.5 Hz).

Example 83 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4-formyl
-N- (2-methoxyphenyl) benzenesulfonami
De activated manganese dioxide (870 mg, 10.0 mmol)
Was suspended in methylene chloride (10 ml) and dissolved in methylene chloride (3 ml) N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N- (2-methoxyphenyl). Benzenesulfonamide (259 mg, 0.492 mmol) was added.
After stirring at room temperature for 30 minutes, the mixture was filtered with silica gel (1 g), and further eluted with ethyl acetate. The filtrate and the eluate were combined and the solvent was distilled off to obtain 211 mg (81.7%) of the title compound as a colorless amorphous substance. IR (KBr): 2940, 1706, 1678, 15
98, 1496, 1348, 1294, 1260, 12
00, 1158, 1116, 974, 754, 716.
604,580 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.95 (4H,
m), 1.95 to 2.32 (2H, m), 2.52 (2
H, t, J = 7.5 Hz), 2.70 to 3.47 (3
H, m), 3.30 (3H, s), 3.55 to 4.00
(2H, m), 6.76 (1H, d, J = 8Hz),
6.90 (1H, d, J = 8Hz), 7.12 (2H,
dd, J = 9 Hz, 9 Hz), 7.16 to 7.50 (2
H, m), 7.70-8.14 (6H, m), 10.1
(1H, s).

Example 84 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -4- (N-hi)
Droxyimino) -N- (2-methoxyphenyl) ben
Zensulfonamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-formyl-N- (2-methoxyphenyl) benzenesulfonamide (63 mg, 0.12 mmol) and hydroxyamine hydrochloride ( 9.5 mg, 0.
132 mmol) was dissolved in ethanol (2 ml) and anhydrous sodium carbonate (14 mg, 0.132 mmol) and water (1 ml) were added. After stirring at room temperature for 1 hour and 30 minutes, ethanol was distilled off, water (10 ml) was added, and crystals were filtered. The crystals were washed with water and hexane, dissolved in methylene chloride (50 ml) and dried over anhydrous sodium carbonate, and the solvent was evaporated to give the title compound as a colorless powder (65 mg, 100%). Melting point: 162 to 168 ° C IR (KBr): 3450, 2950, 2840, 16
76, 1594, 1500, 1344, 1264, 12
04, 1156, 1106, 990, 726, 604,
588 cm ^-1 . NMR (CDCl ₃ ) δ: 1.62-1.96 (4H,
m), 1.96 to 2.40 (2H, m), 2.60 (2
H, t, J = 7.5 Hz), 2.80 to 3.55 (3
H, m), 3.31 (3H, s), 3.83 (2H,
t, J = 7.5 Hz), 6.75 (1H, d, J = 8H)
z), 6.96 (1H, d, J = 8.5 Hz), 7.1
2 (2H, dd, J = 9Hz, 9Hz), 7.16-
7.43 (3H, m), 7.46 to 7.80 (4H,
m), 7.93 (2H, dd, J = 9Hz, 6Hz),
8.11 (1H, s).

Example 85 4-carbamoyl-N- {2
-[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzenesulfone
Under an amido argon atmosphere, 4-{[N- [2- [4- (4-fluorobenzoyl) piperidino] ethyl} -2-methoxyanilino] sulfonyl} benzoic acid (63 mg, 0.1
17 mmol) was dissolved in THF (1 ml), N-methylmorpholine (14 μl, 0.13 mmol) and isobutyl chloroformate (16.8 μl, 0.13 mmol).
Was added dropwise under ice cooling. After stirring at room temperature for 15 minutes, 28
Aqueous ammonia solution (0.5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with methylene chloride, dried over anhydrous sodium carbonate and the solvent was distilled off to obtain a pale yellow oily substance, which was subjected to silica gel column chromatography (ether-ethyl acetate-methylene chloride: methanol = 10: 1).
32 mg (50.9%) of the title compound was obtained as a pale yellow oil. IR (neat): 3368, 2944, 1672, 1
596, 1496, 1406, 1342, 1280, 1
262, 1240, 1116, 912, 732, 66
2,600 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.93 (4H,
m), 1.95 to 2.30 (2H, m), 2.46 (2
H, t, J = 7 Hz), 2.80 to 3.28 (3H,
m), 3.38 (3H, s), 3.56 to 3.93 (2
H, m), 6.10 (1H, br-s), 6.78 (1
H, d, J = 8.5 Hz), 6.97 (1H, d, J =
9Hz), 7.13 (2H, dd, J = 9Hz, 9H
z), 7.17 to 7.50 (2H, m), 7.65
8.40 (7H, m).

Example 86 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxiethyl) -4-phthalimidomethylbenzamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N- (2-methoxyethyl) benzamide (216
mg, 0.488 mmol), phthalimide (86 m
g, 0.585 mmol) and triphenylphosphine (155 mg, 0.585 mmol) in THF (3 m
l) and dissolved in diethyl azodicarboxylate (93 μl,
0.585 mmol) was added dropwise under ice cooling. 1 at the same temperature
After stirring for an hour, water (10 ml) was added, extraction was performed with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous sodium carbonate and the solvent was evaporated to give a pale yellow oil, which was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 20: 1) to give a colorless amorphous product. Compound 2
Obtained 59 mg (92.8%). IR (KBr): 2940, 1716, 1678, 16
30, 1596, 1426, 1392, 1348, 12
28,1112,974,718 cm ^-1 . NMR (CDCl ₃ ) δ: 1.47 to 2.30 (6H,
m), 2.33 to 3.85 (11H, m), 3.30.
(3H, s), 4.85 (2H, s), 7.13 (2
H, dd, J = 9 Hz, 9 Hz), 7.34 (2H,
d, J = 8.5 Hz), 7.46 (2H, d, J = 8.
5 Hz), 7.58 to 8.10 (6H, m).

Example 87 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxyphenyl) -4-phthalimidomethylbenzenesul
Honamide Using N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N- (2-methoxyphenyl) benzenesulfonamide (80 mg, 0.152 mmol) under argon atmosphere. By performing the same procedure as in Example 68, 78 mg (78.3%) of the title compound was obtained as a colorless amorphous substance. IR (KBr): 1716, 1678, 1598, 14
96, 1392, 1346, 1280, 1260, 11
58,1092,716 cm ^-1 . NMR (CDCl ₃ ) δ: 1.52 to 1.92 (4H,
m), 1.93 to 2.30 (2H, m), 2.50 (2
H, t, J = 7.5 Hz), 2.70 to 3.00 (2
H, m), 3.00 to 3.40 (1H, m), 3.24
(3H, s), 3.50 to 3.85 (2H, m), 4.
89 (2H, s), 6.60-8.10 (16H,
m).

Example 88 N- {2- [4- (4-full
Orobenzoyl) piperidino] ethyl} -N- (2-me
Toxyphenyl) -4-succinimidomethylbenzami
Under de argon atmosphere, N- {2- [4- (4- fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N-(2-methoxyphenyl) benzamide (54
mg, 0.11 mmol), succinimide (13 m
g, 0.132 mmol) and triphenylphosphine (34.6 mg, 0.132 mmol) in THF (1 m
l) and dissolved in diethyl azodicarboxylate (21 μl,
0.132 mmol) was added dropwise under ice cooling. 30 at room temperature
After stirring for 1 minute, water (10 ml) was added, extraction was performed with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous sodium carbonate and the solvent was distilled off, and the resulting residue was purified by PTLC (chloroform: methanol = 20: 1) to give 42 mg (66.8%) of the title compound as a pale yellow amorphous substance. Obtained. IR (KBr): 3472, 2944, 2800, 17
04, 1683, 1644, 1401, 1305, 11
64 cm ^-1 . NMR (CDCl ₃ ) δ: 1.70 to 1.95 (4H,
m), 2.03 to 2.40 (2H, m), 2.66 (4
H, s), 2.60 to 2.80 (2H, m), 2.80
˜3.25 (3H, m), 3.79 (3H, s), 3.
40-3.80 (1H, m), 4.00-4.28 (1
H, m), 4.53 (2H, s), 6.74 (1H,
d, J = 8 Hz), 6.82 (1H, d, J = 8H
z), 7.00 to 7.30 (8H, m), 7.93 (2
H, dd, J = 9 Hz, 6 Hz).

Example 89 4-Aminomethyl-N- {2
-[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzenesulfone
Amido N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-phthalimidomethylbenzenesulfonamide (77 mg,
0.117 mmol) in methanol-THF (3: 2)
Dissolve in a mixed solution (2.5 ml), and add hydrazine hydrate (1
ml) was added under ice cooling. After stirring at the same temperature for 15 minutes, the organic solvent was distilled off and methylene chloride extraction was performed. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium carbonate, and the solvent was evaporated to give a residue.
HF-water (3: 1: 1) mixed solution (3 ml) was added.
After stirring at room temperature for 2 hours, the solvent was evaporated, and the residue was diluted with ethyl acetate (15 ml). Saturated aqueous sodium hydrogen carbonate (5 ml) was added, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium carbonate and the solvent was evaporated to give a pale yellow oily substance, which was subjected to silica gel column chromatography (methylene chloride: methanol = 20:
Purification by 1-9: 1) gave 47 mg (76.4%) of the title compound as a colorless oil. IR (neat): 3380, 2944, 1680, 1
598, 1496, 1340, 1280, 1262, 1
158, 1094, 730 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 1.93 (6H,
m), 1.93 to 2.30 (2H, m), 2.50 (2
H, t, J = 7 Hz), 2.70 to 3.28 (3H,
m), 3.40 (3H, s), 3.72 (2H, t, J
= 7.5 Hz), 3.94 (2H, s), 6.77 (1
H, d, J = 8.5 Hz), 6.95 (1H, d, J =
8.5 Hz), 7.12 (2H, dd, J = 9 Hz, 9
Hz), 7.15 to 7.50 (2H, m), 7.35
(2H, d, J = 8.5 Hz), 7.66 (2H, d,
J = 8.5 Hz), 7.93 (2H, dd, J = 9H)
z, 6 Hz).

Example 90 4-Aminomethyl-N- {2
-[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyethyl) benzamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyethyl) -4-phthalimidomethylbenzamide (258 mg, 0 By repeating the same procedure as in Example 89 using .451 mmol), 131 mg (6) of the title compound was obtained as a colorless solid.
5.8%) was obtained. Melting point: 85 to 90 ° C. IR (KBr): 2944, 2820, 1664, 16
28, 1598, 1462, 1428, 1290, 12
80, 1222, 1170, 1112, 1012, 97
8,854,840 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.35 (8H,
m), 2.42 to 3.40 (5H, m), 3.32 (3
H, s), 3.40 to 3.76 (6H, m), 3.89.
(2H, s), 7.12 (2H, dd, J = 9Hz, 9
Hz), 7.26 (4H, s), 7.93 (2H, d
d, J = 9 Hz, 6 Hz).

Example 91 4-Aminomethyl-N- {2
-[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzamide N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-phthalimidomethylbenzamide (56 mg, 0 0.0904
(89 mmol) in the same manner as in Example 89 to give 32 mg (7 mg) of the title compound as a colorless oil.
2.3%) was obtained. IR (neat): 2944, 1678, 1638, 1
598, 1500, 1440, 1410, 1390, 1
310, 1278, 1240, 1158, 1140, 1
024, 976, 754 cm ^-1 . NMR (CDCl ₃ ) δ: 1.35 to 2.00 (6H,
m), 2.00 to 2.36 (2H, m), 2.63 (2
H, t, J = 7.5 Hz), 2.80 to 3.36 (3
H, m), 3.46 to 3.93 (1H, m), 3.68
(3H, s), 3.75 (2H, s), 3.93-4.
35 (1H, m), 6.74 (1H, d, J = 8H
z), 6.83 (1H, d, J = 7.5 Hz), 6.9.
3 to 7.40 (8H, m), 7.95 (2H, dd, J
= 9 Hz, 6 Hz).

Example 92 4-amino-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-methoxyphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (264.0 mg, 0.52 mmol) ) Was dissolved in methanol (5 ml) and concentrated hydrochloric acid (2.0
ml) and tin (powder, 186.0 mg, 1.57 mmol) were added under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was poured into ice water and pour with a 10% aqueous sodium hydroxide solution.
After adjusting to H9 to 10 and adding chloroform, the insoluble matter was filtered through Celite. The residue was washed with chloroform, the filtrate was extracted with chloroform, and the organic layer was washed with water and saturated saline. The solvent was distilled off after drying over anhydrous sodium sulfate, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound as a colorless amorphous substance.
43.0 mg (97.9%) was obtained. IR (KBr): 3336, 2936, 1678, 16
28, 1600, 1438, 1384, 1278c
m ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 1.95 (4H,
m), 2.00 to 2.34 (2H, m), 2.45 to
2.76 (2H, m), 2.80 to 3.30 (3H,
m), 3.70 (3H, s), 3.60 to 3.85 (1
H, m), 4.02 to 4.34 (1H, m), 6.35.
(2H, d, J = 9.0 Hz), 6.83 (2H, t,
J = 6.0 Hz), 6.95 to 7.30 (6H, m),
7.93 (2H, dd, J = 9.0, 6.0Hz).

Example 93 4-amino-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-methoxyphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (505.0 mg, 1.00 mmol) Was performed in the same manner as in Example 92 to obtain 490.7 mg (quantitative) of the title compound as a pale yellow powder. Melting point: 126-127.5 ° C. IR (KBr): 3360, 2944, 1680, 16
34, 1600, 1438, 1380, 1310c
m ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.35 (5H,
m), 2.63 (2H, t, J = 7.0Hz), 2.8
5 to 3.20 (4H, m), 3.69 (3H, s),
3.60-3.86 (2H, m), 4.02 (2H, m
t, J = 7.0 Hz), 6.40 (2H, d, J = 8.
6 Hz), 6.56 to 6.83 (1 H, m), 6.69
(2H, d, J = 8.6 Hz), 6.95 to 7.30
(3H, m), 7.11 (2H, dd, eachJ =
9.0 Hz), 7.95 (2H, dd, J = 9.0,
6.0 Hz).

Example 94 4-amino-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (4-Methoxyphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (968.6 mg, 1.92 mmol) Was performed in the same manner as in Example 92 to give the title compound as a pale yellow amorphous compound in an amount of 905.7.
mg (99.4%) was obtained. IR (KBr): 2944, 1677, 1626, 16
02, 1509, 1440, 1380, 1287, 12
45, 1221, 1170, 1155, 1137, 11
07,1029,972,834,759,603,5
91 cm ^-1 . NMR (CDCl ₃ ) δ: 1.61-1.98 (4H,
m), 1.98 to 2.32 (2H, m), 2.62 (2
H, t, J = 7.1 Hz), 2.80 to 3.35 (3
H, m), 3.76 (3H, s), 3.99 (2H,
t, J = 7.1 Hz), 6.40 (2H, d, J = 8.
6 Hz), 6.74 (2H, d, J = 9.0 Hz),
6.85 to 7.25 (6H, m), 7.80 to 8.03
(2H, m).

Example 95 4-amino-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2,5-dimethoxyphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,5-dimethoxyphenyl) benzamide (535.0 mg, (1.00 mmol) was used to carry out the same operation as in Example 92 to give the title compound as a colorless amorphous product in an amount of 479.
0 mg (94.9%) was obtained. IR (KBr): 3370, 2950, 1678, 16
30,1602,1504,1222,1041,84
0,763 cm ^-1 . NMR (CDCl ₃ ) δ: 1.76 to 2.35 (6H,
m), 2.63 (2H, t, J = 7.0Hz), 2.9
5 to 3.16 (3H, m), 3.61 (3H, s),
3.69 (3H, s), 3.72 to 3.85 (2H,
m), 6.38 (2H, brd, J = 8.6Hz),
6.69 (3H, brs), 7.02 to 7.26 (4
H, m), 7.87-8.03 (2H, m). Example 9
6 3-amino-N- {2- [4- (4-fluoroben
Zoyl) piperidino] ethyl} -N- (3-methoxy group
Example) Using 3-phenyl- benzamide 3-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (730.0 mg, 1.45 mmol). By performing the same operation as in 92, 690.0 mg (quantitative) of the title compound was obtained as a pale yellow powder. Melting point: 141 to 142 ° C IR (KBr): 3372, 2944, 1672, 16
28, 1600, 1488, 1318, 1210, 11
64, 1074, 974 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.33 (5H,
m), 2.69 (2H, t, J = 6.8Hz), 2.8
4 to 3.30 (4H, m), 3.69 (3H, s),
4.02 (2H, t, J = 6.8Hz), 6.40 ~
6.76 (6H, m), 6.86 (1H, d, J = 7.
7Hz), 7.05 (1H, d, J = 7.7Hz),
7.12 (2H, dd, eachachJ = 8.8Hz),
7.93 (2H, dd, J = 8.8, 5.5Hz).

Example 97 4-amino-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2,4-dimethoxyphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,4-dimethoxyphenyl) benzamide (527.0 mg, 0.98 mmol) was used to perform the same operation as in Example 92 to obtain 439.3 mg of the title compound as a pale yellow powder.
(88.3%) was obtained. Melting point: 135 to 138 [deg.] C. IR (KBr): 1680, 1602, 1512, 14
40, 1410, 1389, 1308, 1224, 12
06, 1179, 1158, 1026, 954, 83
7,765,603 cm ^-1 . NMR (CDCl ₃ ) δ: 1.73 to 3.91 (13
H, m), 3.69 (3H, s), 3.76 (3H,
s), 4.19 (2H, dd, J = 6.6, 5.3H)
z), 6.34 to 6.43 (4H, m), 6.92 to
7.17 (5H, m), 7.87 to 7.95 (2H,
m).

Example 98 4-amino-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-Methylphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methylphenyl) benzamide (517.0 mg, 1.00 mmol) Was performed in the same manner as in Example 92 to give the title compound as a colorless amorphous product in an amount of 485.0 m.
g (quantitative) was obtained. IR (KBr): 3300, 2935, 2780, 16
77, 1626, 1599, 1440, 1377, 12
99, 1227, 1155, 834 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 2.38 (6H,
m), 2.26 (3H, s), 2.64 (2H, t, J
= 7.0 Hz), 2.84 to 3.38 (3H, m),
3.51-3.86 (2H, m), 4.20 (2H,
t, J = 7.0 Hz), 6.39 (2H, d, J = 9.
0 Hz), 6.71 to 7.34 (8H, m), 7.94
(2H, dd, J = 9.0, 6.0 Hz).

Example 99 4-Amino-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
Example Using N- (phenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (phenyl) benzamide (713.0 mg, 1.50 mmol) By performing the same operation as in 92, 671.9 mg (quantitative) of the title compound was obtained as pale yellow needle crystals. Melting point: 156-157 ° C IR (KBr): 1680, 1626, 1596, 14
94, 1376, 1296, 1278, 1222, 12
04,1172,1156,1138,974,83
6,758,698,598 cm ^-1 . _{NMR (CDCl 3) δ: 1.71~2.31} (6H,
m), 2.64 (2H, t, J = 6.8Hz), 2.9
4-3.25 (3H, m), 3.72 (2H, br
s), 4.03 (2H, t, J = 6.8Hz), 6.3
9 (2H, d, J = 8.1 Hz), 7.09 to 7.17
(9H, m), 7.92 (1H, d, J = 8.1H
z).

Example 100 4-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methylthiophenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methylthiophenyl) benzamide (793.7 mg, 1 (0.52 mmol) in the same manner as in Example 92 to give 274.4 m of the title compound as a colorless amorphous.
g (36.7%) was obtained. IR (KBr): 1676, 1628, 1600, 14
38, 1374, 1296, 1262, 1224, 12
04,1172,1156,1140,974,83
8,760,698 cm ^-1 . NMR (CDCl ₃ ) δ: 1.77 to 1.86 (4H,
m), 2.04 to 2.22 (2H, m), 2.34 (3
H, s), 2.62 (2H, t, J = 6.8 Hz),
2.94 to 3.17 (3H, m), 3.74 (2H, b
rs), 4.01 (2H, t, J = 6.8Hz), 6.
41 (2H, d, J = 8.4 Hz), 6.82 to 7.2
2 (8H, m), 7.92 (1H, d, J = 8.6H
z), 7.98 (1H, d, J = 8.4 Hz).

Example 101 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-trifluoromethylphenyl) benz
Amido 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-trifluoromethylphenyl) benzamide (275.0 mg, 0.5
(1 mmol) in the same manner as in Example 92 to give the title compound as a colorless amorphous compound.
Obtained 4.0 mg (quantitative). IR (KBr): 3370, 2948, 1632, 16
00, 1314, 1172, 1126, 977, 76
9,608 cm ^-1 . NMR (CDCl ₃ ) δ: 1.63 to 2.22 (6H,
m), 2.45 to 3.54 (6H, m), 3.74 (2
H, brs), 4.32 to 4.63 (1H, m), 6.
43 (2H, brd, J = 8.4 Hz), 7.03 to.
7.46 (8H, m), 7.94 (2H, dd, J =
8.8, 5.5 Hz).

Example 102 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-trifluoromethylphenyl) benz
Amido 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-trifluoromethylphenyl) benzamide (543.0 mg, 1.0
(0 mmol) in the same manner as in Example 92 to give the title compound as a colorless amorphous (50 mg).
Obtained 4.0 mg (98.2%). IR (KBr): 3371, 950, 1680, 16
32, 1600, 1332, 1274, 1172, 11
26,975, 841,702 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 1.89 (4H,
m), 2.04 to 2.30 (2H, m), 2.61 (2
H, t, J = 6.5 Hz), 2.91 to 3.31 (3
H, m), 3.78 (2H, brs), 4.03 (2
H, t, J = 6.5 Hz), 6.42 (2H, d, J =
8.6 Hz), 7.03 to 7.46 (8 H, m), 7.
94 (2H, dd, J = 9.0, 5.5 Hz).

Example 103 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-pyridyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-pyridyl) benzamide (160.0 mg, 0.34 (90 mmol) (quantitative) was obtained as a pale yellow amorphous by performing the same operation as in Example 92. IR (KBr): 3450, 2950, 1680, 16
32, 1602, 1479, 1425, 1374, 12
24, 1155, 837 cm ^-1 . NMR (CDCl ₃ ) δ: 1.38 to 2.34 (6H,
m), 2.64 (2H, t, J = 6.0Hz), 2.8
2 to 3.39 (3H, m), 3.78 (2H, br
s), 4.07 (2H, t, J = 6.0Hz), 6.4
0 (2H, d, J = 9.0 Hz), 6.92 to 7.60
(6H, m), 7.97 (2H, dd, J = 9.0,
6.0 Hz), 8.24-8.44 (2H, m).

Example 104 2-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methoxyphenyl) benzamide 2-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (936.4 mg, 1 (85 .3 mmol) in the same manner as in Example 92 to give 853.3 mg (9%) of the title compound as a colorless oil.
7.1%) was obtained. IR (KBr): 3450, 2950, 1680, 16
20, 1598, 1492, 1316, 1246, 11
58,910 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.33 (5H,
m), 2.60 (2H, t, J = 6.0Hz), 2.7
6 to 3.30 (4H, m), 3.63 (3H, s),
4.03 (2H, t, J = 6.0Hz), 4.60 (2
H, brs), 6.13 to 7.00 (8H, m), 7.
10 (2H, dd, eachachJ = 9.0Hz), 7.9
2 (2H, dd, J = 9.0, 6.0 Hz).

Example 105 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-aminophenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-aminophenyl) benzamide (1.1 g, 2 By performing the same operation as in Example 92 using 0.11 mmol), 557.0 mg (57.0 mg) of the title compound was obtained as a light brown powder.
%)Obtained. Melting point: 107.5 to 110.5 ° C IR (KBr): 3400, 1680, 1626, 15
96, 1494, 1392, 1377, 1305, 12
18,1158,852 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.35 to 2.4
2 (7H, m), 2.63 (2H, t, J = 7.0H
z), 2.83 to 3.40 (3H, m), 3.40 to
3.85 (3H, m), 3.99 (2H, t, J = 7.
0 Hz), 6.23 to 6.60 (4H, m), 6.76
~ 7.33 (6H, m), 7.95 (2H, dd, J =
9.0, 6.0 Hz).

Example 106 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxycarbonylphenyl) benz
Amido 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxycarbonylphenyl) benzamide (506.0 mg, 0.9
(5 mmol) in the same manner as in Example 92 to give the title compound as a colorless amorphous compound (30 mg).
7.0 mg (64.2%) was obtained. IR (KBr): 3368, 1722, 1630, 15
98,1296,976,821,761,600cm
^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.15 (6H,
m), 2.66 to 3.15 (5H, m), 3.70 (2
H, brs), 3.81 (3H, s), 4.06-4.
45 (2H, m), 6.36 (2H, d, J = 8.4H
z), 7.02 to 7.45 (7H, m), 7.72 to
8.03 (3H, m).

Example 107 3-Methyl-4-amino-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (4-methoxyphenyl) benzua
Amido 3-methyl-4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (1.02 g, 1.97)
95 mg of the title compound as a yellow amorphous by performing the same operation as in Example 92.
5.0 mg (99.1%) was obtained. IR (KBr): 3370, 2941, 1678, 16
26, 1598, 1510, 1244, 1034, 97
5,838,605 cm ^-1 . NMR (CDCl ₃ ) δ: 1.67 to 2.31 (6H,
m), 2.02 (3H, s), 2.61 (2H, t, J
= 6.8 Hz), 2.53 to 3.34 (3H, m),
3.75 (3H, s), 3.98 (2H, t, J = 6.
8 Hz), 6.35 (1H, d, J = 8.1 Hz),
6.82-7.26 (8H, m), 7.95 (2H, d
d, J = 8.6, 5.5 Hz).

Example 108 3-Methoxy-4-amino
-N- {2- [4- (4-fluorobenzoyl) piperi
Dino] ethyl} -N- (4-methoxyphenyl) benz
Amido 3-methoxy-4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-
Methoxyphenyl) benzamide (1.57 g, 2.9)
(3 mmol) was used to perform the same operation as in Example 92 to obtain 1.24 g (83.8%) of the title compound as a pale yellow amorphous substance. IR (KBr): 3342, 2930, 1675, 16
20, 1510, 1234, 1028, 830, 601
cm ^-1 . NMR (CDCl ₃ ) δ: 1.70 to 1.86 (4H,
m), 2.04 to 2.31 (2H, m), 2.63 (2
H, t, J = 6.9 Hz), 2.95 to 3.33 (3
H, m), 3.75 (3H, s), 3.99 (2H,
t, J = 6.9 Hz), 6.41 (1H, d, J = 7.
9 Hz), 6.70 to 7.26 (8 H, m), 7.95
(2H, dd, J = 8.8, 5.5Hz).

Example 109 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-fluorophenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-fluorophenyl) benzamide (707.9 mg, 1 (0.43 mmol) in the same manner as in Example 92 to obtain 255.7 m of the title compound as a colorless amorphous.
g (38.6%) was obtained. IR (KBr): 3364, 1628, 1598, 15
06, 1378, 1310, 1276, 1212, 11
70,1156,1138,836 cm ^-1 . NMR (CDCl ₃ ) δ: 1.78 to 2.46 (6H,
m), 2.62 (2H, t, J = 6.8Hz), 2.7
4 to 3.56 (5H, m), 4.00 (2H, t, J =
6.8 Hz), 6.91 to 8.22 (8H, m), 7.
92 (1H, d, J = 8.4 Hz), 7.98 (1H,
d, J = 8.6 Hz).

Example 110 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-methylphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methylphenyl) benzamide (744.5 mg, 1 0.52 mmol) in the same manner as in Example 92 to give 647.4 mg (9%) of the title compound as a colorless powder.
2.7%) was obtained. Melting point: 164-165 ° C IR (KBr): 1680, 1620, 1598, 15
06, 1376, 1298, 1274, 1170, 83
8 cm ^-1 . NMR (CDCl ₃ ) δ: 1.71 to 2.16 (6H,
m), 2.28 (3H, s), 2.62 (2H, dd,
J = 7.3, 6.6 Hz), 2.95-3.17 (3
H, m), 3.66 to 3.71 (2H, brs), 4.
00 (2H, dd, J = 7.3, 6.6 Hz), 6.4
0 (2H, d, J = 8.6 Hz), 6.99 to 7.22
(8H, m), 7.92 (1H, d, J = 8.6H
z), 7.98 (1H, d, J = 8.6 Hz).

Example 111 3-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (phenyl) benzamide 3-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (phenyl) benzamide (715.5 mg, 1.50 mmol) was used. The same procedure as in Example 92 was performed to obtain 156.8 mg (23.5 mg) of the title compound as a colorless amorphous substance.
%)Obtained. Melting point: 228 to 229 ° C IR (KBr): 1668, 1640, 1592, 14
92, 1388, 1372, 1320, 1302, 12
64, 1222, 1204, 1170, 746, 69
8,606 cm ^-1 . NMR (CDCl ₃ ) δ: 2.36 to 2.69 (6H,
m), 2.62 (2H, t, J = 6.6Hz), 2.9
4 to 3.31 (3H, m), 3.43 to 3.69 (2
H, brs), 4.05 (2H, t, J = 6.6H
z), 6.49 to 7.23 (11H, m), 7.99
(1H, d, J = 8.6 Hz).

Example 112 3-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-methylphenyl) benzamide 3-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methylphenyl) benzamide (735.0 mg, 1 By repeating the same procedure as in Example 92 using .50 mmol), 355.6 mg (5%) of the title compound was obtained as a colorless powder.
1.6%) was obtained. Melting point: 173-175 ° C IR (KBr): 1674, 1630, 1598, 15
08, 1384, 1314, 1298, 1216, 74
0 cm ^-1 . NMR (CDCl ₃ ) δ: 1.59 to 2.15 (6H,
m), 2.26 (3H, s), 2.59 (2H, t, J
= 6.8 Hz), 2.93 to 3.27 (3H, m),
3.32 to 3.70 (2H, m), 4.00 (2H, m)
t, J = 6.8 Hz), 6.49 to 6.57 (2H,
m), 6.70 (1H, s), 6.80 to 7.22 (7)
H, m), 7.91 (1H, d, J = 8.6 Hz),
7.97 (1H, d, J = 8.6 Hz).

Example 113 3-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-fluorophenyl) benzamide 3-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-fluorophenyl) benzamide (491.2 mg, 1 By performing the same operation as in Example 92 using 0.000 mmol), 272.6 mg (5) of the title compound was obtained as a colorless powder.
8.8%) was obtained. Melting point: 159 to 162 ° C IR (KBr): 1640, 1594, 1588, 15
06, 1386, 1374, 1274, 1220, 12
00,978,844,746,614 cm ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.21 (6H,
m), 2.58 (2H, t, J = 6.6Hz), 2.9
2 to 3.03 (3H, m), 3.59 (2H, br
s), 3.99 (2H, t, J = 6.6Hz), 6.4
7 to 6.68 (3H, m), 6.82 to 7.22 (7
H, m), 7.93 (1H, d, J = 8.6 Hz),
7.99 (1H, d, J = 8.6 Hz).

Example 114 3-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methylthiophenyl) benzamide 3-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methylthiophenyl) benzamide (785.0 mg, 1 The same procedure as in Example 92 was performed using .50 mmol) to give 439.1 mg (5%) of the title compound as a colorless powder.
9.5%). Melting point: 172-174 ° C IR (KBr): 1672, 1626, 1592, 14
58, 1394, 1318, 1304, 1210, 11
68,972,862,786,754,694c
m ^-1 . NMR (CDCl ₃ ) δ: 2.33 (3H, s), 1.
73-2.40 (6H, m), 2.60 (2H, dd,
J = 6.6, 6.4 Hz), 2.94 to 3.41 (3
H, m), 3.42 to 3.71 (2H, m), 4.03.
(2H, dd, J = 6.6, 6.4 Hz), 6.50-
7.25 (10H, m), 7.93 (1H, d, J =
8.6 Hz), 7.99 (1H, d, J = 8.6H
z).

Example 115 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-chlorophenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-chlorophenyl) benzamide (760.6 mg, 1.49) In the same manner as in Example 92 to give 517.6 m of the title compound as a colorless amorphous.
g (72.4%) was obtained. IR (KBr): 1680, 1628, 1600, 14
90, 1410, 1374, 1310, 1288, 12
66, 1224, 1204, 1172, 1156, 11
38,1090,974,834,762,598cm
^-1 . NMR (CDCl ₃ ) δ: 1.85 to 2.19 (6H,
m), 2.60 (2H, dd, J = 6.8, 6.6H
z), 2.92 to 3.17 (3H, m), 3.77 (2)
H, brs), 3.99 (2H, dd, J = 6.8,
6.6 Hz), 6.42 (2H, d, J = 7.4H)
z), 6.98 to 7.88 (8H, m), 7.95 (2
H, dd, J = 8.6, 5.5 Hz).

Example 116 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3,4-dimethylphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,4-dimethylphenyl) benzamide (751 (8 mg, 1.49 mmol) was carried out in the same manner as in Example 92 to give 567.2 mg of the title compound as a light brown powder.
(80.4%) was obtained. Melting point: 188 to 190 ° C. IR (KBr): 1680, 1620, 1598, 15
62, 1502, 1380, 1298, 1276, 12
64, 1184, 1176, 1160, 1140, 11
30,854,838 cm ^-1 . NMR (CDCl ₃ ) δ: 2.17 (6H, s), 1.
68-2.36 (6H, m), 2.66 (2H, dd,
J = 7.3, 6.8 Hz), 2.97-3.20 (3
H, m), 3.72 (2H, brs), 4.01 (2
H, dd, J = 7.3, 6.8 Hz), 6.40 (2
H, d, J = 8.6 Hz), 6.80 to 7.26 (7
H, m), 7.95 (2H, dd, J = 8.6, 5.5)
Hz).

Example 117 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3,5-dimethylphenyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,5-dimethylphenyl) benzamide (663 0.2 mg, 1.32 mmol) was used to carry out the same operation as in Example 92 to give the title compound as a pale brown amorphous product.
Obtained 7 mg (96.3%). IR (KBr): 1680, 1626, 1596, 13
76, 1314, 1264, 1232, 1180, 11
56,838,760 cm ^-1 . NMR (CDCl ₃ ) δ: 2.20 (6H, s), 1.
57-2.31 (6H, m), 2.62 (2H, dd,
J = 7.0, 6.8 Hz), 2.95-3.01 (3
H, m), 3.71 (2H, brs), 3.98 (2
H, dd, J = 7.0, 6.8 Hz), 6.40 (2
H, d, J = 8.6 Hz), 6.71 to 6.76 (3
H, m), 7.03 to 7.26 (6H, m), 7.95.
(2H, dd, J = 8.6, 5.5Hz).

Example 118 4-amino-N- {3-
[4- (4-Fluorobenzoyl) piperidino] propyi
Ru} -N- (3-methoxyphenyl) benzamide 4-nitro-N- {3- [4- (4-fluorobenzoyl) piperidino] propyl} -N- (3-methoxyphenyl) benzamide (872.0 mg, 1 (80.68 mmol) to give 808.8 m of the title compound as a colorless amorphous by performing the same operation as in Example 92.
g (98.5%) was obtained. IR (KBr): 2948, 1680, 1628, 16
00, 1488, 1452, 1380, 1310, 12
30, 1198, 1180, 1158 cm ^-1 . NMR (CDCl ₃ ) δ: 1.57 to 2.20 (7H,
m), 2.42 (2H, d, J = 7.5 Hz), 2.8
0 to 3.26 (4H, m), 3.69 (3H, s),
3.60 to 3.76 (2H, m), 3.92 (2H, m)
d, J = 7.5 Hz), 6.40 (2H, d, J = 8.
6 Hz), 6.50 to 6.75 (3 H, m), 7.11
(2H, dd, J = 8.6, 5.5Hz), 7.15
(2H, d, J = 8.6 Hz), 7.95 (2H, d
d, J = 8.6, 5.5 Hz).

Example 119 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3,4-methylenedioxyphenyl) ben
Zamido 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,4-methylenedioxyphenyl) benzamide (300.0 mg, 0.
By performing the same operation as in Example 92 using 578 mmol), 245.0 mg (86.7%) of the title compound was obtained as a pale yellow amorphous substance. IR (KBr): 1680, 1602, 1503, 14
85, 1446, 1389, 1338, 1299, 12
33, 1209, 1173, 1153, 1131, 10
35,837,753 cm ^-1 . NMR (CDCl ₃ ) δ: 1.70 to 2.00 (4H,
m), 2.00 to 2.36 (2H, m), 2.62 (2
H, t, J = 6.8 Hz), 2.86 to 3.40 (3
H, m), 3.95 (2H, t, J = 6.8Hz),
6.88 to 7.30 (4H, m), 7.80 to 8.10
(2H, m).

Example 120 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (1-naphthyl) benzamide 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (1-naphthyl) benzamide (360.6 mg, 0.687) (35 mmol) and the same operation as in Example 92 was performed to obtain 352.9 mg (quantitative) of the title compound as a pale yellow amorphous substance. IR (KBr): 3352, 1680, 1626, 15
99, 1506, 1437, 1401, 1374, 13
38, 1299, 1227, 1179, 1155, 11
40, 1104, 972, 837, 774 cm ^-1 . NMR (CDCl ₃ ) δ: 1.70 to 1.90 (4H,
m), 1.97 to 2.34 (2H, m), 2.68 (2
H, t, J = 6.5 Hz), 2.80 to 3.30 (3
H, m), 3.70 (1H, quint., J = 6.5.
Hz), 4.52 (1H, quint., J = 6.5H)
z), 6.25 (2H, d, J = 8.5 Hz), 6.9.
0-8.20 (13H, m).

Example 121 4- (Acetylamino) me
Cyl-N- {2- [4- (4-fluorobenzoyl) pi
Peridino] ethyl} -N- (2-methoxyethyl) ben
Under the atmosphere of zamide argon, 4-aminomethyl-N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-methoxyethyl) benzamide (80 mg,
0.181 mmol) was dissolved in methylene chloride (3 ml), and triethylamine (63 μl, 0.452 mmol) and acetic anhydride (24 μl, 0.217 mmol) were added dropwise under ice cooling. After stirring at the same temperature for 20 minutes, water (10 ml) was added and extraction with ethyl acetate was performed, and the organic layer was washed with saturated brine. After drying over anhydrous sodium carbonate and evaporating the solvent, the residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to give 68.
Obtained 5 mg (78.3%). Melting point: 100 to 103 ° C. IR (KBr): 3276, 2944, 2820, 16
64, 1628, 1596, 1464, 1430, 12
90,1222,1170,1114 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.93 (4H,
m), 1.95 to 2.35 (2H, m), 2.03 (3
H, s), 2.39 to 3.40 (5H, m), 3.32
(3H, s), 3.40 to 3.90 (6H, m), 4.
42 (2H, d, J = 5.7 Hz), 6.24 (1H,
br-s), 7.12 (2H, dd, J = 9Hz, 9H
z), 7.16 to 7.50 (4H, m), 7.94 (2
H, dd, J = 9 Hz, 6 Hz).

Example 122 4- (Acetylamino) me
Cyl-N- {2- [4- (4-fluorobenzoyl) pi
Peridino] ethyl} -N- (2-methoxyphenyl) be
Under Nzuamido argon atmosphere, 4-aminomethyl--N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (2-methoxyphenyl) benzamide (60m
g, 0.123 mmol) was dissolved in methylene chloride (2 ml), pyridine (23 μl, 0.284 mmol) and acetic anhydride (13 μl, 0.138 mmol) were added dropwise under ice cooling, and then a catalytic amount of 4 was added. -Dimethylaminopyridine was added. After stirring at the same temperature for 20 minutes and at room temperature for 12 hours, water (10 ml) was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The residue obtained by distilling off the solvent after drying over anhydrous sodium carbonate was purified by PTLC (chloroform: methanol = 20: 1) to give 58 mg (8 mg) of the title compound as a colorless amorphous substance.
9.0%) was obtained. IR (KBr): 3304, 2944, 1674, 16
41, 1596, 1503, 1413, 1392, 13
80,1278 cm ^-1 . NMR (CDCl ₃ ) δ: 1.43 to 2.33 (6H,
m), 1.98 (3H, s), 2.62 (2H, t, J
= 7.5 Hz), 2.82 to 3.30 (3H, m),
3.52 to 3.92 (1H, m), 3.67 (3H,
s), 4.00 to 4.43 (1H, m), 4.31 (2)
H, d, J = 6 Hz), 5.60 (1H, br-s),
6.73 (1H, d, J = 8Hz), 6.90 (1H,
d, J = 9 Hz), 6.98 to 7.40 (8H, m),
7.93 (2H, dd, J = 9Hz, 6Hz).

Example 123 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (2.65 g, 5 0.58 mmol) and acetic anhydride (0.79 ml, 8.37 mmol) were carried out in the same manner as in Example 122 to give 2.44 g (84.3) of the title compound as colorless amorphous.
%)Obtained. IR (KBr): 3310, 2944, 1680, 16
32, 1596, 1530, 1407, 1374, 13
31, 1270, 1236, 750 cm ^-1 . NMR (CDCl ₃ ) δ: 1.69 to 1.90 (4H,
m), 2.06 (3H, s), 2.00 to 2.35 (2
H, m), 2.63 (2H, t, J = 7.0 Hz),
2.80-3.25 (3H, m), 3.65 (3H,
s), 3.70-3.90 (1H, m), 3.95-
4.35 (1H, m), 6.77 (2H, t, J = 9.
0 Hz), 6.96 to 7.30 (8H, m), 7.50
(1H, brs), 7.95 (2H, dd, J = 9.0)
Hz, 6.0 Hz). Example 124 4-acetylamino-N- {2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
-(3-Methoxyphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (1.00 g, 2.10 mmol) And acetic anhydride (0.24 ml, 2.54 mmol) were used to perform the same operation as in Example 122 to obtain 851.0 mg (78.3%) of the title compound as a colorless powder.
Obtained. Melting point: 145.5 to 151.5 ° C. IR (KBr): 1680, 1632, 1600, 15
30, 1488, 1400, 1314, 1282, 11
58 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.43 (5H,
m), 2.10 (3H, s), 2.68 (2H, t, J
= 7.0 Hz), 2.83 to 3.40 (4H, m),
3.69 (3H, s), 4.05 (2H, t, J = 7.
0 Hz), 6.52 to 6.73 (3H, m), 6.78
(2H, s), 6.52 to 7.50 (5H, m), 7.
13 (2H, dd, J = 8.8, 5.5Hz), 7.9
6 (2H, dd, J = 8.8Hz, 5.5Hz).

Example 125 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-methoxyphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (556.9 mg, 1 0.17 ml) and acetic anhydride (0.13 ml, 1.41 mmol)
Was performed in the same manner as in Example 122 to give 476.8 mg (7%) of the title compound as a colorless powder.
8.7%). Melting point: 171-173 ° C IR (KBr): 3316, 1671, 1632, 15
99, 1527, 1512, 1437, 1404, 13
77, 1314, 1296, 1245, 1203, 11
73, 1153, 1113, 1029, 972, 85
2,837,762 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.67 to 2.0
0 (4H, m), 2.00 to 2.40 (2H, m),
2.12 (3H, s), 2.63 (2H, t, J = 6.
9Hz), 2.85 to 3.40 (3H, m), 3.75
(3H, s), 4.01 (2H, t, J = 6.9H
z), 6.72 (2H, d, J = 9.0 Hz), 6.8
7 to 7.40 (8H, m), 6.78 (2H, s),
7.80-8.06 (2H, m).

Example 126 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2,5-dimethoxyphenyl) benz
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,5-dimethoxyphenyl) benzamide (170.0 mg, 0.34 mmol) and acetic anhydride (0 0.16 ml, 1.70 mmol) was used to perform the same operation as in Example 122 to obtain 132.0 of the title compound as a colorless amorphous substance.
mg (71.5%) was obtained. IR (KBr): 3352, 2973, 1678, 16
00, 1508, 1314, 1262, 1222c
m ^-1 . NMR (CDCl ₃ ) δ: 1.76 to 2.38 (6H,
m), 2.11 (3H, s), 2.62 (2H, br
t, J = 7.3 Hz), 2.85 to 3.40 (3H,
m), 3.68 (3H, s), 3.78 (3H, s),
4.01 to 4.08 (2H, m), 6.58 to 6.78
(2H, m), 7.03 to 7.62 (7H, m), 7.
87-8.03 (2H, m).

Example 127 3-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide 3-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (216.0 mg, 0 .45 mmol) and acetic anhydride (0.051 ml, 0.54 mmol) were carried out in the same manner as in Example 122 to give the title compound as a colorless amorphous product, 197.5.
mg (84.9%) was obtained. IR (KBr): 3300, 2948, 1680, 16
40, 1598, 1434, 1376, 1282, 10
46 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.33 (5H,
m), 2.08 (3H, s), 2.60 (2H, t, J
= 6.6 Hz), 2.83 to 3.30 (4H, m),
3.66 (3H, s), 4.05 (2H, t, J = 6.
6 Hz), 6.53 to 6.75 (2 H, m), 6.75
~ 7.28 (6H, m), 7.40 (1H, brs),
7.46-7.70 (1H, m), 7.93 (2H, d
d, J = 8.8, 5.5 Hz).

Example 128 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2,4-dimethoxyphenyl) benz
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,4-dimethoxyphenyl) benzamide (203.4 mg, 0.40 mmol) and acetic anhydride (0 0.046 ml, 0.49 mmol) and the same operation as in Example 122 was carried out to give the title compound as a colorless amorphous substance, 161.
Obtained 2 mg (73.6%). IR (KBr): 1680, 1630, 1598, 15
30, 1510, 1408, 1312, 1282, 12
60, 1208, 1158, 850 cm ^-1 . NMR (CDCl ₃ ) δ: 1.68 to 4.27 (14
H, m), 3.67 (3H, s), 3.73 (3H,
s), 6.20-6.38 (2H, m), 6.93-
7.20 (7H, m), 7.87 to 7.95 (2H,
m).

Example 129 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methylphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methylphenyl) benzamide (285.0 mg, 0 0.62 mmol) and acetic anhydride (0.071 ml, 0.74 mmol) were carried out in the same manner as in Example 122 to give 311.8 as the title compound as a colorless amorphous substance.
mg (99.9%) was obtained. IR (KBr): 3310, 2940, 2790, 16
80, 1629, 1602, 1527, 1446, 13
74, 1227, 1155, 849 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.42-2.3
5 (6H, m), 2.09 (3H, s), 2.24 (3
H, s), 2.62 (2H, t, J = 7.0Hz),
2.78 to 3.38 (3H, m), 4.02 (2H,
t, J = 7.0 Hz), 6.60 to 7.46 (11H,
m), 7.95 (2H, dd, J = 9.0, 6.0H
z).

Example 130 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (phenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (phenyl) benzamide (503.8 mg, 1.13 mmol) and anhydrous. By performing the same operation as in Example 122 using acetic acid (0.128 ml, 1.36 mmol), 309.9 mg (71.0 mg) of the title compound was obtained as a light brown amorphous substance.
%)Obtained. IR (KBr): 1680, 1632, 1599, 15
30, 1407, 1374, 1314, 1260c
m ^-1 . NMR (CDCl ₃ ) δ: 1.77 to 1.99 (5H,
m), 2.11 (3H, s), 2.26 to 2.31 (2
H, m), 2.63 (2H, t, J = 6.8 Hz),
2.93-3.17 (3H, m), 4.04 (2H,
t, J = 6.8 Hz), 6.99 to 7.40 (11H,
m), 7.92 (2H, d, J = 7.9Hz), 7.9
8 (1H, d, J = 7.9 Hz).

Example 131 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-thiomethylphenyl) benzami
Do 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-thiomethylphenyl) benzamide (220.6 mg, 0.45 mmol) and acetic anhydride (0. (051 ml, 0.54 mmol) in the same manner as in Example 122 to give 231.2 of the title compound as a colorless amorphous.
mg (91.8%) was obtained. IR (KBr): 1680, 1630, 1598, 15
30, 1476, 1438, 1406, 1372, 13
12, 1260, 1226, 1204, 1156, 85
0,760 cm ^-1 . NMR (CDCl ₃ ) δ: 1.77 to 1.96 (4H,
m), 2.04 to 2.19 (2H, m), 2.12 (3
H, s), 2.45 (4H, s), 2.61 (2H,
t, J = 6.6 Hz), 2.94 to 3.18 (3H,
m), 4.03 (2H, t, J = 6.6Hz), 6.8
0 to 7.38 (10H, m), 7.92 (2H, d, J
= 8.6 Hz), 7.98 (1H, d, J = 8.6H)
z).

Example 132 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-trifluoromethylphenyl) be
Insamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-trifluoromethylphenyl) benzamide (243.0 mg, 0.4
74 mmol) and acetic anhydride (0.13 ml, 1.40)
Was performed in the same manner as in Example 122 to give the title compound (26) as a colorless amorphous.
5.0 mg (quantitative) was obtained. IR (KBr): 3348, 2942, 1680, 16
36, 1600, 1316, 1262, 1172, 84
2,760,608 cm ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 1.83 (4H,
m), 2.04 to 2.19 (2H, m), 2.09 (3
H, s), 2.52 to 3.52 (6H, m), 4.45.
(1H, brs), 7.03 to 7.87 (10H,
m), 7.92 (2H, dd, J = 8.8, 5.5H)
z).

Example 133 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-trifluoromethylphenyl) be
Insamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-trifluoromethylphenyl) benzamide (256.0 mg, 0.4
74 mmol) and acetic anhydride (0.13 ml, 1.40)
Was performed in the same manner as in Example 122 to give the title compound (26) as a colorless amorphous.
7.0 mg (96.2%) was obtained. IR (KBr): 3335.2949, 1680, 15
98, 1408, 1330, 1262, 1128, 84
3,697 cm ^-1 . NMR (CDCl ₃ ) δ: 1.69 to 1.87 (4H,
m), 2.04 to 2.32 (2H, m), 2.12 (3
H, s), 2.61 (2H, t, J = 6.2 Hz),
2.89-3.20 (3H, m), 4.05 (2H,
t, J = 6.2 Hz), 7.03 to 7.44 (10H,
m), 7.95 (2H, dd, J = 8.8, 5.5H
z).

Example 134 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-pyridyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-pyridyl) benzamide (150.0 mg, 0.335 151.0 mg (9 mg) of the title compound as a colorless amorphous by performing the same operation as in Example 122 using acetic anhydride (0.038 ml, 0.40 mmol).
5.6%) was obtained. IR (KBr): 3290, 2920, 1680, 16
41, 1599, 1530, 1428, 1407, 13
74, 1227, 1158, 849 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.35 (6H,
m), 2.12 (3H, s), 2.64 (2H, t, J
= 7.0 Hz), 2.79 to 3.32 (3H, m),
4.50 (2H, t, J = 7.0Hz), 6.92-
7.62 (9H, m), 7.94 (2H, dd, J =
9.0, 6.0 Hz).

Example 135 2-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide 2-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (238.0 mg, 0 .50 mmol) and acetic anhydride (0.057 ml, 0.60 mmol) were carried out in the same manner as in Example 122 to give 170.4 of the title compound as a colorless amorphous.
mg (65.9%) was obtained. IR (KBr): 3459, 2940, 1680, 16
35, 1595, 1505, 1440, 1370, 12
90, 1160, 1035, 960 cm ^-1 . NMR (CDCl ₃ ) δ: 1.43 to 2.35 (5H,
m), 2.20 (3H, s), 2.60 (2H, t, J
= 6.0 Hz), 2.80 to 3.30 (4H, m),
3.63 (3H, s), 4.05 (2H, t, J = 6.
0 Hz), 6.45 to 7.00 (5 H, m), 7.08
(2H, t, J = 8.8Hz), 7.10 (2H, d
d, eachJ = 9.0 Hz), 7.93 (2H, d
d, J = 9.0, 6.0 Hz), 8.20 (1H, d,
J = 9.0 Hz), 9.15 to 9.33 (1H, m).

Example 136 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-acetylaminophenyl) benz
Amido 2-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-acetylaminophenyl) benzamide (230.0 mg, 0.50 mmol) and acetic anhydride (0. (113 ml, 0.60 mmol) was used to carry out the same operation as in Example 122 to give 24 the title compound as a pale yellow amorphous substance.
Obtained 8.0 mg (91.2%). IR (KBr): 3290, 2930, 1677, 16
02, 1533, 1488, 1443, 1374, 12
30,849 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.36 (6H,
m), 2.06 (6H, s), 2.64 (2H, t, J
= 7.0 Hz), 2.80 to 3.34 (3H, m),
4.01 (2H, t, J = 7.0Hz), 6.65
7.63 (10H, m), 7.74-8.31 (4H,
m).

Example 137 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxycarbonylphenyl) be
Insamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxycarbonylphenyl) benzamide (291.0 mg, 0.5
(8 mmol) and acetic anhydride (0.11 ml, 1.16 mmol) were used to carry out the same operation as in Example 122 to give the title compound as a colorless amorphous compound (30 mg).
3.0 mg (96.0%) was obtained. IR (KBr): 3351, 948, 1724, 16
78, 1598, 1312, 1260, 972, 84
8,758,602 cm ^-1 . _{NMR (CDCl 3) δ: 1.71~2.23} (6H,
m), 2.09 (6H, s), 2.66 to 3.22 (5
H, m), 3.60 to 3.75 (1H, m), 3.82.
(3H, s), 4.16 to 4.45 (1H, m) ,,
7.02 to 7.72 (10H, m), 7.93 (2H,
dd, J = 8.8, 5.5 Hz).

Example 138 3-Methyl-4-acetyl
Amino-N- {2- [4- (4-fluorobenzoyl)
Piperidino] ethyl} -N- (3-methoxyphenyl)
Benzamide 4-amino-3-methyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (489.0 mg, 1.
00 mmol) and acetic anhydride (0.19 ml, 2.00)
The title compound was obtained as a colorless amorphous compound in the same manner as in Example 122 by performing the same operation as in Example 122.
Obtained 4.0 mg (89.3%). IR (KBr): 3298, 2949, 1678, 15
12,1246,972,835,601 cm ^-1 . _{NMR (CDCl 3) δ: 1.71~2.32} (6H,
m), 2.13 (6H, s), 2.60 (2H, t, J
= 6.8 Hz), 3.32 (2H, t, J = 6.8H)
z), 2.95 to 3.32 (3H, m), 3.75 (3
H, s), 3.99 (2H, t, J = 6.8Hz),
6.74 (2H, d, J = 8.8Hz), 6.96-
7.25 (6H, m), 7.74 (1H, brs),
7.95 (2H, dd, J = 8.6, 5.5Hz).

Example 139 3-Methoxy-4-acetyl
Lumino-N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (3-methoxypheny
Ru) benzamido 4-amino-3-methoxy-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-
Methoxyphenyl) benzamide (253.0 mg,
0.50 mmol) and acetic anhydride (0.095 ml,
By performing the same operation as in Example 122 using 1.00 mmol), 213.0 mg (77.9%) of the title compound was obtained as a yellow amorphous substance. IR (KBr): 3435, 2945, 1680, 16
36, 1596, 1510, 1246, 1031, 82
9,600 cm ^-1 .

Example 140 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-fluorophenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-fluorophenyl) benzamide (227.3 mg, 0 .49 mmol) and acetic anhydride (0.083 ml, 0.88 mmol) were used to carry out the same operation as in Example 122 to obtain 202.
Obtained 1 mg (81.6%). IR (KBr): 1680, 1628, 1598, 15
32, 1506, 1406, 1372, 1312, 12
62,1214,850 cm ^-1 . NMR (CDCl ₃ ) δ: 1.85 to 2.32 (6H,
m), 2.11 (3H, s), 2.60 (2H, t, J
= 6.6 Hz), 2.82 to 3.19 (4H, m),
4.01 (2H, t, J = 6.6Hz), 6.90 ~
7.62 (9H, m), 7.88 to 8.04 (3H,
m).

Example 141 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-methylphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methylphenyl) benzamide (452.7 mg, 0 .99 mmol) and acetic anhydride (0.122 ml, 1.19 mmol) were carried out in the same manner as in Example 122 to give the title compound as a pale brown amorphous product in an amount of 473.
Obtained 6 mg (95.4%). IR (KBr): 1680, 1628, 1598, 15
32, 1512, 1444, 1406, 1374, 13
14, 1278, 1260, 1226, 1206, 11
56, 1140, 974, 850, 602 cm ^-1 . NMR (CDCl ₃ ) δ: 1.68 to 2.04 (7H,
m), 2.11 (3H, s), 2.27 (3H, s),
2.61 (2H, dd, J = 7.0, 6.4Hz),
2.94 to 3.10 (3H, m), 4.01 (2H, d
d, J = 7.0, 6.4 Hz), 6.98 to 7.26
(10H, m), 7.92 (1H, d, J = 8.2H
z), 7.98 (1H, d, J = 8.2 Hz).

Example 142 3-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (phenyl) benzamide 3-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (phenyl) benzamide (126.4 mg, 0.28 mmol) and anhydrous The same operation as in Example 122 was performed using acetic acid (0.03 ml, 0.32 mmol) to give 101.1 mg (73.1%) of the title compound as a colorless powder. Melting point: 198 to 201 ° C IR (KBr): 1676, 1666, 1648, 15
94, 1428, 1382, 1304, 1292, 12
66, 1228, 1208, 746 cm ^-1 . NMR (CDCl ₃ ) δ: 1.69 to 2.19 (7H,
m), 2.13 (3H, s), 2.60 (2H, t, J
= 6.6 Hz), 2.94 to 3.09 (3H, m),
4.05 (2H, t, J = 6.6Hz), 6.92 ~
7.53 (11H, m), 7.92 (1H, d, J =
8.6 Hz), 7.99 (1H, d, J = 8.6H
z).

Example 143 3-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-methylphenyl) benzamide 3-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methylphenyl) benzamide (230.1 mg, 0 .50 mmol) and acetic anhydride (0.057 ml, 0.60 mmol) were carried out in the same manner as in Example 122 to give the title compound as a pale yellow amorphous substance.
2 mg (97.8%) was obtained. IR (KBr): 1680, 1630, 1512, 75
0 cm ^-1 . _{NMR (CDCl 3) δ: 1.71~2.66} (7H,
m), 2.13 (3H, s), 2.25 (3H, s),
2.58 (2H, dd, J = 6.8, 6.6Hz),
2.94 to 3.19 (3H, m), 4.01 (2H, d
d, J = 6.8, 6.6 Hz), 6.82 to 7.69
(10H, m), 7.93 (1H, d, J = 8.8H
z), 7.99 (1H, d, J = 8.8Hz).

Example 144 3-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-fluorophenyl) benzamide 3-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-fluorophenyl) benzamide (223.2 mg, 0 .48 mmol) and acetic anhydride (0.055 ml, 0.58 mmol) were used to carry out the same operation as in Example 122 to obtain 238.
Obtained 6 mg (98.3%). IR (KBr): 1680, 1642, 1598, 15
52, 1508, 1428, 1374, 1310, 12
14,748 cm ^-1 . NMR (CDCl ₃ ) δ: 1.67 to 2.31 (7H,
m), 2.14 (3H, s), 2.58 (2H, t, J
= 6.4 Hz), 2.93 to 3.25 (3H, m),
4.01 (2H, t, J = 6.4Hz), 6.80 ~
7.56 (10H, m), 7.93 (1H, d, J =
8.6 Hz), 7.99 (1H, d, J = 8.6H
z).

Example 145 3-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methylthiophenyl) benzami
De 3-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methylthiophenyl) benzamide (196.7 mg, 0.40 mmol) and acetic anhydride (0.046 ml). , 0.48 mmol) in the same manner as in Example 122 to give 172.
2 mg (80.7%) were obtained. IR (KBr): 1678, 1636, 1586, 15
52, 1434, 1372, 1310, 1224, 74
8 cm ^-1 . NMR (CDCl ₃ ) δ: 1.73 to 2.40 (7H,
m), 2.13 (3H, s), 2.33 (3H, s),
2.59 (2H, dd, J = 6.6, 6.4Hz),
2.94 to 3.21 (3H, m), 4.03 (2H, d
d, J = 6.6, 6.4 Hz), 6.85 to 7.63
(10H, m), 7.93 (1H, d, J = 8.6H
z), 7.99 (1H, d, J = 8.6 Hz).

Example 146 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-chlorophenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-chlorophenyl) benzamide (328.6 mg, 0.68 And the acetic anhydride (0.078 ml, 0.83 mmol) in the same manner as in Example 122 to give the title compound as a pale yellow amorphous substance.
Obtained 4 mg (97.3%). IR (KBr): 1680, 1630, 1598, 15
30, 1492, 1408, 1372, 1312, 12
60, 1224, 850, 758 cm ^-1 . NMR (CDCl ₃ ) δ: 1.69 to 2.19 (7H,
m), 2.13 (3H, s), 2.59 (2H, t, J
= 6.6 Hz), 2.92 to 3.09 (3 H, m),
4.00 (2H, t, J = 6.6Hz), 6.97-
7.39 (10H, m), 7.95 (2H, dd, J =
8.6, 5.5 Hz).

Example 147 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3,4-dimethylphenyl) benza
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,4-dimethylphenyl) benzamide (333.1 mg, 0.70 mmol) and acetic anhydride (0 0.080 ml, 0.85 mmol) was carried out in the same manner as in Example 122 to obtain 359.
Obtained 9 mg (99.7%). IR (KBr): 2944, 1680, 1628, 15
98, 1530, 1504, 1446, 1408, 13
72, 1312, 1260, 1228, 1206, 11
78, 1156, 1140, 850, 760 cm ^-1 . NMR (CDCl ₃ ) δ: 1.68 to 1.86 (4H,
m), 2.16 (3H, s), 2.16 (6H, s),
2.05 to 2.31 (3H, m), 2.61 (2H,
t, J = 6.8 Hz), 2.94 to 3.18 (3H,
m), 4.00 (2H, t, J = 6.8Hz), 6.7.
9 to 7.27 (9H, m), 7.95 (2H, dd, J
= 8.6, 5.5 Hz).

Example 148 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3,5-dimethylphenyl) benza
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,5-dimethylphenyl) benzamide (382.8 mg, 0.81 mmol) and acetic anhydride (0 0.092 ml, 0.99 mmol) and the same operation as in Example 122 was carried out to give the title compound as a pale brown amorphous product.
Obtained 9 mg (86.4%). IR (KBr): 3252, 2948, 1686, 16
16, 1598, 1518, 1506, 1474, 14
36, 1408, 1396, 1374, 1334, 13
12, 1296, 1236, 1210, 1138, 11
28,974, cm ^-1 . NMR (CDCl ₃ ) δ: 1.67 to 1.86 (4H,
m), 2.12 (3H, s), 2.19 (6H, s),
2.04 to 2.32 (3H, m), 2.61 (2H,
t, J = 6.8 Hz), 2.94 to 3.11 (3H,
m), 4.00 (2H, t, J = 6.8Hz), 6.7.
0 to 6.76 (3H, m), 7.03 to 7.33 (6
H, m), 7.95 (2H, dd, J = 8.6, 5.5)
Hz).

Example 149 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3,4-methylenedioxyphenyl)
Benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,4-methylenedioxyphenyl) benzamide (245.0 mg, 0.
501 mmol) and acetic anhydride (0.057 ml, 0.
By performing the same operation as in Example 122 using 60 mmol), 210.3 mg (79.0%) of the title compound was obtained as a colorless amorphous. IR (KBr): 1671, 1638, 1623, 15
99, 1533, 1506, 1485, 1433, 14
07, 1377, 1314, 1299, 1260, 12
36, 1215, 1173, 1155, 1134, 10
35 cm ^-1 . _{NMR (CDCl 3) δ: 1.62~1.97} (4H,
m), 2.12 (3H, s), 2.00 to 2.40 (2
H, m), 2.64 (2H, t, J = 6.9 Hz),
2.90 to 3.47 (3H, m), 3.99 (2H,
t, J = 6.9 Hz), 5.95 (2H, s), 6.4
0 to 6.70 (3H, m), 6.93 to 7.43 (6
H, m), 7.80 to 8.03 (2H, m).

Example 150 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (1-naphthyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (1-naphthyl) benzamide (352.5 mg, 0.712) (32 mmol) and acetic anhydride (0.081 ml, 0.86 mmol) were carried out in the same manner as in Example 122 to obtain 334.2 mg (8 mg) of the title compound as a pale yellow amorphous substance.
7.4%). IR (KBr): 2944, 1680, 1623, 15
96, 1530, 1443, 1407, 1374, 13
38, 1311, 1260, 1227, 1206, 11
82, 1155, 1140, 1107, 975, 84
9,774 cm ^-1 . NMR (CDCl ₃ ) δ: 1.63 to 1.88 (4H,
m), 2.05 (3H, s), 1.93 to 2.31 (2
H, m), 2.64 (2H, t, J = 6.8 Hz),
2.78 to 3.33 (3H, m), 3.45 to 3.87
(1H, m), 4.35 to 4.72 (1H, m), 6.
90-8.10 (15H, m).

Example 151 4-Acetylamino-N-
{3- [4- (4-fluorobenzoyl) piperidino]
Propyl} -N- (3-methoxyphenyl) benzamid
Do 4-amino-N- {3- [4- (4-fluorobenzoyl) piperidino] propyl} -N- (3-methoxyphenyl) benzamide (300.0 mg, 0.61 mmol) and acetic anhydride (0.069 ml). , 0.73 mmol) in the same manner as in Example 122 to obtain 312.
Obtained 6 mg (96.5%). IR (KBr): 1680, 1628, 1600, 15
30, 1490, 1408, 1374, 1314, 12
82, 1262, 1234, 1156, 910, 760
cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.25 (7H,
m), 2.10 (3H, s), 2.44 (2H, t, J
= 6.8 Hz), 2.75 to 3.30 (4H, m),
3.69 (3H, s), 3.92 (2H, t, J = 6.
8 Hz), 6.46 to 6.75 (3 H, m), 7.12
(2H, dd, J = 8.4 Hz), 7.15 to 7.40
(4H, m), 7.40 to 7.56 (1H, m), 7.
95 (2H, dd, J = 8.4, 4.3 Hz).

Example 152 4-Isobutyrylamino-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (2-methoxyphenyl) benzua
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (200.0 mg, 0.42 mmol) and isobutyryl chloride (0 0.053 ml, 0.
By performing the same operation as in Example 122 using 51 mmol), 222.7 mg (97.0%) of the title compound was obtained as a colorless amorphous. IR (KBr): 1680, 1630, 1598, 15
28,1502,1408,1306,1278,12
42,848,752 cm ^-1 . NMR (CDCl ₃ ) δ: 1.20 (6H, d, J =
6.8 Hz), 1.58 to 2.78 (9H, m), 2.
80-3.30 (3H, m), 3.55-3.90 (1
H, m), 3.69 (3H, s), 3.90 to 4.30.
(1H, m), 6.60 to 7.40 (10H, m),
7.78-8.07 (2H, m).

Example 153 4-butyrylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (200.0 mg, 0 .42 mmol) and butyryl chloride (0.053 ml, 0.51)
(1 mmol) to give the title compound as a colorless amorphous compound (19).
Obtained 6.3 mg (85.5%). IR (KBr): 2956, 1680, 1632, 15
99, 1527, 1503, 1443, 1410, 13
08,1278,1239,1179,1158,11
40, 1116, 1023, 975, 849 cm ^-1 . NMR (CDCl ₃ ) δ: 0.93 (3H, t, J =
7.0 Hz), 1.50 to 2.00 (6 H, m), 2.
00-2.40 (4H, m), 2.47-2.75 (2
H, m), 2.80 to 3.30 (3H, m), 3.60
~ 3.93 (1H, m), 3.68 (3H, s), 3.
97 to 4.30 (1H, m), 6.63 to 7.30 (1
0H, m), 7.80 to 8.03 (2H, m).

Example 154 4-Butyrylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (238.0 mg, 0 .50 mmol) and butyryl chloride (0.10 ml, 0.10 mmol) were used to carry out the same operation as in Example 122 to give the title compound as a colorless amorphous compound (14).
5.0 mg (53.2%) was obtained. IR (KBr): 2980, 1680, 1600, 12
00,970,848,699 cm ^-1 . NMR (CDCl ₃ ) δ: 0.87 (3H, t, J =
7.2 Hz), 1.47 to 2.16 (8H, m), 2.
41 (2H, t, J = 7.2 Hz), 2.63 (2H,
t, J = 6.7 Hz), 2.95 to 3.26 (3H,
m), 3.69 (3H, s), 4.06 (2H, t, J
= 6.7 Hz), 6.64 to 6.72 (3H, m),
6.87-7.44 (7H, m), 7.91 (2H, d
d, J = 8.8, 5.4 Hz).

Example 155 4-propionylamino-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (3-methoxyphenyl) benzua
Mido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (238.0 mg, 0.50 mmol) and propionyl chloride (0.077 ml). , 0.
The same operation as in Example 122 was performed using 60 mmol) to obtain 240.0 mg (90.4%) of the title compound as a yellow amorphous substance. IR (KBr): 3320, 2940, 1680, 16
00, 1306, 971, 850, 699 cm ^-1 . NMR (CDCl ₃ ) δ: 1.20 (3H, t, J =
7.5 Hz), 1.78 to 2.34 (8H, m), 2.
38 (2H, t, J = 7.5 Hz), 2.63 (2H,
t, J = 6.8 Hz), 2.95 to 3.26 (3H,
m), 3.69 (3H, s), 4.03 (2H, t, J
= 6.8 Hz), 6.63 to 6.71 (3H, m),
7.02 to 7.29 (7H, m), 7.95 (2H, d
d, J = 8.8, 5.4 Hz).

Example 156 4-valerylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (238.0 mg, 0 .50 mmol) and valeryl chloride (0.071 ml, 0.60)
Was carried out in the same manner as in Example 122 to give the title compound as a yellow amorphous compound in an amount of 23.
2.0 mg (83.0%) was obtained. IR (KBr): 3305, 2596, 1680, 16
00,1308,972,850,799 cm ^-1 . NMR (CDCl ₃ ) δ: 0.92 (3H, t, J =
6.4 Hz), 1.32 to 2.49 (10 H, m),
2.63 (2H, t, J = 6.8Hz), 2.96-
3.28 (3H, m), 3.70 (3H, s), 4.0
4 (2H, t, J = 6.8 Hz), 6.63 to 6.71
(3H, m), 7.02 to 7.29 (7H, m), 7.
96 (2H, dd, J = 8.8, 5.4Hz).

Example 157 4-pivaloylamino-N
-{2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (2-methoxyphenyl) benzua
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (200.0 mg, 0.42 mmol) and pivaloyl chloride (0 0.062 ml, 0.5
(1 mmol) in the same manner as in Example 122 to give the title compound (2) as a colorless amorphous.
Obtained 14.6 mg (91.2%). IR (KBr): 2956, 1680, 1630, 15
99, 1503, 1461, 1443, 1404, 13
14,1278,1242,1176,1158,11
40, 1116, 1044, 1026, 975, 91
5,852 cm ^-1 . NMR (CDCl ₃ ) δ: 1.26 (9H, s), 1.
50 to 1.93 (4H, m), 2.00 to 2.37 (2
H, m), 2.65 (2H, t, J = 7.0 Hz),
2.80 to 3.38 (3H, m), 3.53 to 3.93
(1H, m), 3.69 (3H, s), 3.93-4.
30 (1H, m), 6.67 to 6.92 (2H, m),
6.97 to 7.33 (6H, m), 7.80 to 8.07
(2H, m).

Example 158 4- (trifluoroacetyl)
Luamino) methyl-N- {2- [4- (4-fluorobe
Nzoyl) piperidino] ethyl} -N- (2-methoxy
Phenyl) benzamide 4-aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (60 mg, 0.123 mmol) and trifluoroacetic anhydride ( 19 μl, 0.135
Was performed in the same manner as in Example 122 to give the title compound as a colorless amorphous.
mg (67.0%) was obtained. IR (KBr): 3406, 3064, 2944, 17
19, 1680, 1641, 1599, 1503, 12
21,1179,1158 cm ^-1 . NMR (CDCl ₃ ) δ: 1.46 to 1.98 (4H,
m), 1.98 to 2.35 (2H, m), 2.62 (2
H, t, J = 7.5 Hz), 2.79 to 3.36 (3
H, m), 3.50 to 3.95 (1H, m), 3.69
(3H, s), 4.00 to 4.54 (1H, m), 4.
40 (2H, d, J = 6Hz), 6.61 to 6.83
(2H, m), 6.90 (1H, d, J = 7.5H
z), 6.96 to 7.40 (8H, m), 7.93 (2)
H, dd, J = 9 Hz, 6 Hz).

Example 159 4-Trifluoroacetyl
Amino-N- {2- [4- (4-fluorobenzoyl)
Piperidino] ethyl} -N- (2-methoxyphenyl)
Benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (200.0 mg, 0.42 mmol) and trifluoroacetic anhydride (0 .18 ml, 1.2
(6 mmol) in the same manner as in Example 122 to give the title compound (2) as a colorless amorphous substance.
53.3 mg (quantitative) was obtained. IR (KBr): 2948, 1720, 1678, 16
28, 1544, 1500, 1440, 1284, 12
00, 1158, 1026, 976 cm ^-1 . NMR (CDCl ₃ ) δ: 1.53 to 2.30 (5H,
m), 2.57 (2H, t, J = 6.0Hz), 3.4
6 to 3.85 (2H, m), 3.65 (3H, s),
3.90-4.30 (2H, m), 6.50-6.89
(1H, m), 6.76 (2H, t, J = 9.0H
z), 6.90 to 7.40 (7H, m), 7.92 (2
H, dd, J = 9.0, 6.0 Hz), 8.43-8.
85 (1H, m).

Example 160 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4- (meta
N-sulfonylamino) methyl-N- (2-methoxyphen)
Nyl) benzamide 4-aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (60 mg, 0.123 mmol) and methanesulfonyl chloride (11 μl). , 0.142
(40 mmol) to carry out the same operation as in Example 122 to obtain 40% of the title compound as a colorless amorphous substance.
mg (57.5%) was obtained. IR (KBr): 2926, 1677, 1638, 15
96,1503,1410,1323,1278,11
46 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.00 (4H,
m), 2.00 to 2.37 (2H, m), 2.46 to
2.78 (2H, m), 2.70 (3H, s), 2.8
1-3.29 (3H, m), 3.40-3.88 (1
H, m), 3.70 (3H, s), 4.00 to 4.41
(1H, m), 4.18 (2H, d, J = 6Hz),
4.69 (1H, br-s), 6.71 (1H, d, J
= 8 Hz), 6.80 (1H, d, J = 8 Hz), 6.
90 to 7.35 (8H, m), 7.93 (2H, dd,
J = 9 Hz, 6 Hz).

Example 161 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-methane
Sulfonylamino-N- (2-methoxyphenyl) ben
Zamido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (50.0 mg, 0.11 mmol)
And methanesulfonyl chloride (0.025 ml, 0.31
(6 mmol) in the same manner as in Example 122 to give the title compound (2) as a colorless amorphous substance.
Obtained 9.5 mg (50.7%). IR (KBr): 3310, 2944, 1680, 16
29, 1599, 1503, 1464, 1395, 13
35, 1278, 1236, 1155, 1116, 97
2 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 1.93 (4H,
m), 2.00 to 2.40 (2H, m), 2.64 (2
H, t, J = 7.0 Hz), 2.90 (3H, s),
2.78 to 3.20 (3H, m), 3.50 to 3.90
(1H, m), 3.70 (3H, s), 3.95-4.
37 (1H, m), 6.77 (2H, t, J = 9.0H
z), 6.93 to 7.40 (8H, m), 7.94 (2
H, dd, J = 9.0, 6.0 Hz).

Example 162 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-methane
Sulfonylamino-N- (3-methoxyphenyl) ben
Zamido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (475.0 mg, 1.00 mmol) and methanesulfonyl chloride (0. 12 ml, 1.5
(0 mmol) in the same manner as in Example 122 to give the title compound (5) as a colorless amorphous.
Obtained 27.8 mg (95.4%). IR (KBr): 1678, 1640, 1598, 15
08,1490,1454,1390,1332,12
84, 1218, 1154, 970 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.73 (7H,
m), 2.93 (3H, s), 2.73 to 3.55 (4
H, m), 3.69 (3H, s), 4.20 to 4.50
(2H, m), 6.66 (3H, brd, J = 7.5H
z), 6.85 to 7.40 (5H, m), 7.94 (2
H, dd, J = 9.0, 6.0 Hz).

Example 163 4- (ethoxycarbonyl)
Amino) methyl-N- {2- [4- (4-fluoroben
Zoyl) piperidino] ethyl} -N- (2-methoxyphenyl)
Phenyl) benzamide 4-aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (60 mg, 0.123 mmol) and ethyl chloroformate ( (13 μl, 0.136 mmol) was carried out in the same manner as in Example 122 to give 50 mg of the title compound as a colorless amorphous substance.
(72.7%) was obtained. IR (KBr): 3340, 2938, 2806, 17
16, 1680, 1641, 1599, 1503, 14
13, 1239, 1137 cm ^-1 . NMR (CDCl ₃ ) δ: 1.22 (3H, t, J =
7.5 Hz), 1.69 to 1.90 (4H, m), 2.
10-2.34 (2H, m), 2.60 (2H, t, J
= 7 Hz), 2.80 to 3.27 (3H, m), 3.6
5 to 3.85 (1H, m), 3.67 (3H, s),
4.00 to 4.30 (1H, m), 4.11 (2H,
q, J = 7.5 Hz), 4.24 (2H, d, J = 6H)
z), 4.88 (1H, br-s), 6.73 (1H,
d, J = 8 Hz), 6.80 to 7.30 (9H, m),
7.93 (2H, dd, J = 9Hz, 6Hz).

Example 164 4-ethoxycarbonyl
Mino-N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (2-methoxyphenyl) be
Insamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (185.0 mg, 0.39 mmol) and ethyl chloroformate (0 (0.11 ml, 1.17 mmol) in the same manner as in Example 122 to give 80.0 mg of the title compound as a colorless oil.
(37.5%) was obtained. IR (neat): 3288, 2948, 1720, 1
680, 1630, 1528, 1440, 1316, 1
120, 1026, 976 cm ^-1 . NMR (CDCl ₃ ) δ: 1.36 (3H, t, J =
7.2 Hz), 1.46 to 2.35 (5 H, m), 2.
63 (2H, t, J = 6.0 Hz), 2.76 to 3.3
0 (4H, m), 3.66 (3H, s), 4.10 (2
H, t, J = 6.0 Hz), 4.15 (2H, q, J =
7.2 Hz), 6.53 to 6.73 (1 H, m), 6.
85 (2H, t, J = 8.4 Hz), 6.90 to 7.3.
3 (8H, m), 7.95 (2H, dd, J = 9.0,
6.0 Hz).

Example 165 4-[(S) -2- (te
rt-Butoxycarbonylamino) propionyl] ami
Nomethyl-N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (2-methoxyethyl)
B) Benzamide 4-aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyethyl) benzamide (120 mg, 0.245 mmol) in methylene chloride (5 ml). Dissolved in Boc-L-
Alanine (46.4 mg, 0.245 mmol) and E
DC hydrochloride (52 mg, 0.270 mmol) was added under ice cooling and the mixture was stirred at the same temperature for 4 hours. After adding water (10 ml), the mixture was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate, extracted with methylene chloride, the organic layer was dried over anhydrous sodium carbonate, and the solvent was distilled off. Purification with ethyl) gave 109 mg (68.9) of the title compound as a colorless amorphous.
%)Obtained. IR (KBr): 3328, 2938, 1713, 16
77, 1641, 1599, 1503, 1392, 12
42,1161 cm ^-1 . NMR (CDCl ₃ ) δ: 1.33 (3H, d, J = 7
Hz), 1.40 (9H, s), 1.66 to 1.90.
(4H, m), 2.00 to 2.32 (2H, m), 2.
62 (2H, t, J = 8Hz), 2.80 to 3.26
(3H, m), 3.60 to 3.80 (1H, m), 3.
69 (3H, s), 4.00 to 4.25 (2H, m),
4.33 (2H, d, J = 6Hz), 4.88 (1H,
br-s), 6.40 (1H, br-s), 6.73
(1H, d, J = 8Hz), 6.89 (1H, d, J =
8 Hz), 6.96 to 7.30 (8H, m), 7.94
(2H, dd, J = 9Hz, 6Hz).

Example 166 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -4- (methylamino) methylben
Zamido 4- (N-tert-butoxycarbonyl-N-methylamino) methyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (144 mg, 0 .239 mmol) was dissolved in methylene chloride (4 ml), trifluoroacetic acid (0.4 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The solvent was evaporated, diluted with methylene chloride (10 ml), washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium carbonate and evaporated to remove the solvent.
119 mg (9
8.9%). IR (KBr): 2944, 2794, 1680, 16
41, 1596, 1503, 1278, 1236, 75
0 cm ^-1 . NMR (CDCl ₃ ) δ: 1.62-1.97 (5H,
m), 2.00 to 2.30 (2H, m), 2.36 (3
H, s), 2.63 (2H, t, J = 7.5 Hz),
2.80-3.26 (3H, m), 3.64 (2H,
s), 3.68 (3H, s), 3.60 to 3.85 (1
H, m), 4.00 to 4.26 (1H, m), 6.73
(1H, d, J = 8Hz), 6.82 (1H, d, J =
8 Hz), 7.00 to 7.31 (8H, m), 7.94
(2H, dd, J = 9Hz, 6Hz).

Example 167 4-[(S) -2-amino
Propionyl] aminomethyl-N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -N- (2
-Methoxyethyl) benzamide 4-[(S) -2- (tert-butoxycarbonylamino) propionyl] aminomethyl-N- {2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
-(2-Methoxyethyl) benzamide (100 mg,
By repeating the same procedure as in Example 166 using 0.156 mmol, 84.7 mg (100%) of the title compound was obtained as a colorless amorphous. IR (KBr): 3370, 2926, 1677, 16
41, 1599, 1503, 1413, 1278, 12
39, 1158, 1122 cm ^-1 . NMR (CDCl ₃ ) δ: 1.10 to 1.45 (3H,
m), 1.70 to 2.58 (8H, m), 2.76 (2
H, t, J = 7 Hz), 2.92 to 3.35 (4H,
m), 3.68 (3H, s), 3.65 to 3.92 (1
H, m), 4.05 to 4.40 (3H, m), 6.51
-6.70 (1H, m), 6.73 (1H, d, J = 8)
Hz), 6.82 to 7.30 (9H, m), 7.93
(2H, dd, J = 9Hz, 6Hz).

Example 168 4-amidino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru-N- (2-methoxyphenyl) benzamide in dry air, 4-cyano-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (100 mg , 0.20
6 mmol) was dissolved in ethanol (2 ml), and hydrogen chloride gas was gradually introduced at -10 ° C for 15 minutes. After stirring at the same temperature for 5 hours and 30 minutes and at room temperature for 1 hour, 10% ammonia-methanol solution (1 ml) was added at room temperature to the residue obtained by distilling off ethanol. After stirring at the same temperature for 16 hours, the solvent was distilled off and the obtained residue was subjected to silica gel column chromatography (ether: methanol = 10:
1 to methylene chloride: methanol = 6: 1), and a methylene chloride-methanol (10: 1) mixed solution (5 ml) was added to remove insolubles, and then the solvent was distilled off to give a colorless solution. 92 mg (88.9%) of the title compound was obtained as an amorphous substance. IR (KBr): 3250, 3064, 1678, 16
42, 1598, 1502, 1440, 1410, 12
80, 1224, 1158, 854 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.4
0 (4H, m), 2.40 to 4.10 (8H, m),
3.74 (3H, s), 4.13 to 4.59 (1H,
m), 6.60-6.93 (2H, m), 6.98-
7.37 (2H, m), 7.16 (2H, dd, J = 9
Hz, 9 Hz), 7.43 (2H, d, J = 8 Hz),
7.58 (2H, d, J = 8Hz), 7.99 (2H,
dd, J = 9 Hz, 6 Hz). MS (FAB, m / z): 120,157,220,2
34,296,357,503 (M ⁺⁺ H).

Example 169 4-amidino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-methoxyphenyl) benzamide 4-cyano-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (728.0 mg, 1 By repeating the same procedure as in Example 168 using .50 mmol), 635.0 mg (8) of the title compound was obtained as a colorless powder.
4.3%) was obtained. IR (KBr): 3270, 3075, 1678, 16
26, 1598, 1510, 1246, 971, 85
3,730,600 cm ^-1 . NMR (CDCl ₃ ) δ: 1.82 to 1.91 (4H,
m), 2.12 to 2.36 (2H, m), 2.62 (2
H, t, J = 6.4 Hz), 2.97 to 3.41 (6
H, m), 3.72 (3H, s), 4.03 (2H,
t, J = 6.4 Hz), 6.74 (2H, d, J = 8.
8Hz), 7.08 (2H, d, J = 8.8Hz),
7.05 to 7.32 (2H, m), 7.40 (2H,
d, J = 8.4 Hz), 7.57 (2H, d, J = 8.
4 Hz), 7.96 (2H, dd, J = 8.8, 5.5
Hz).

Example 170 4- (N-acetylamidide)
No) -N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (2-methoxyphenyl) be
Insamide 4-amidino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (100 mg, 0.20 mmol)
Was performed in the same manner as in Example 122 to obtain 81 mg of the title compound as a pale yellow amorphous substance.
(74.4%) was obtained. IR (KBr): 3264, 2944, 1730, 16
80, 1642, 1596, 1502, 1408, 12
98,1262 cm ^-1 . NMR (CDCl ₃ ) δ: 1.56 to 1.98 (4H,
m), 1.98 to 2.45 (2H, m), 2.16 (3
H, s), 2.46 to 2.80 (2H, m), 2.80
Up to 3.36 (3H, m), 3.54 to 3.93 (1H,
m), 3.70 (3H, s), 4.00 to 4.40 (1
H, m), 6.62 to 6.97 (3H, m), 7.00
~ 7.75 (9H, m), 8.01 (2H, dd, J =
9 Hz, 6 Hz).

Example 171 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4- (N-
Methanesulfonylamidino) -N- (2-methoxyphen
Nil) benzamide 4-amidino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (120 mg, 0.239 mmol) was used as in Example 122. By performing the same operation, 81 mg of the title compound was obtained as a colorless amorphous substance.
(73.6%) was obtained. IR (KBr): 3406, 2944, 1680, 16
41, 1596, 1533, 1503, 1410, 12
78, 1155, 1113, 1020, 972, 85
2,750,603,528 cm ^-1 . NMR (CDCl ₃ ) δ: 1.46 to 2.00 (4H,
m), 2.02 to 2.38 (2H, m), 2.46 to
2.76 (2H, m), 2.80 to 3.37 (3H,
m), 3.04 (3H, s), 3.50 to 3.90 (1
H, m), 3.70 (3H, s), 4.00 to 4.43.
(1H, m), 6.50 to 6.91 (3H, m), 6.
96 to 7.38 (7H, m), 7.55 (2H, d, J
= 8Hz), 7.95 (2H, dd, J = 9Hz, 6H
z).

Example 172 4- (N-ethoxycarbo)
Nilamidino) -N- {2- [4- (4-fluoroben
Zoyl) piperidino] ethyl} -N- (2-methoxyphenyl)
Phenyl) benzamide 4-amidino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (120 mg, 0.239 mmol) was used as in Example 122. By performing the same operation, 108 mg of the title compound was obtained as a colorless amorphous substance.
(78.7%) was obtained. IR (KBr): 3376, 2944, 1680, 16
20,1596,1503,1299,1263,11
34 cm ^-1 . NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7
Hz), 1.50 to 1.97 (4H, m), 2.02
2.38 (2H, m), 2.47 to 2.66 (2H,
m), 2.80 to 3.38 (3H, m), 3.50
3.90 (1H, m), 3.67 (3H, s), 4.0
0 to 4.40 (1H, m), 4.18 (2H, q, J =
7 Hz), 6.50 to 6.90 (3 H, m), 6.93
~ 7.42 (7H, m), 7.63 (2H, d, J = 8)
Hz), 7.94 (2H, dd, J = 9Hz, 6H
z).

Example 173 4- (ethylthiourei)
De) -N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (2-methoxyphenyl) be
Insamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (80.0 mg, 0.168 mmol) in ethanol (2.0 ml). , Ethylthioisocyanate (0.035 ml, 0.404 mmol) was added at room temperature, and the mixture was heated under reflux for 14 hours. After cooling, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 20:
Purification in 1) yielded 95.5 mg (quantitative) of the title compound as a colorless oil. IR (neat): 2944, 1680, 1629, 1
599, 1536, 1503, 1443, 1410, 1
314, 1278, 1260, 1239, 1158, 1
140, 1116, 975, 912, 854, 729,
645 cm ^-1 . NMR (CDCl ₃ ) δ: 1.14 (3H, t, J =
7.3 Hz), 1.50 to 1.88 (4 H, m), 1.
96-2.30 (2H, m), 2.40-2.70 (2
H, m), 2.73 to 3.27 (3H, m), 3.40.
˜3.90 (3H, m), 3.72 (3H, s), 3.
90 to 4.40 (1H, m), 6.60 to 7.38 (1
0H, m), 7.70 to 8.03 (2H, m).

Example 174 4- (tert-butylene)
Raid) -N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (2-methoxypheny
) Benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (77.7 mg, 0.164 mmol) and tert-butyl isocyanate. (0.022m
The title compound was obtained as a colorless oil in an amount of 72.9 mg (77.6%) by performing the same operation as in Example 173 using 1, 0.196 mmol). IR (neat): 3370, 2956, 1680, 1
617, 1599, 1536, 1503, 1452, 1
410, 1392, 1314, 1278, 1251, 1
206, 1179, 1158, 909, 729, 64
5,603 cm ^-1 . NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.
58 to 1.94 (4H, m), 1.98 to 2.32 (2
H, m), 2.49 to 2.75 (2H, m), 2.80.
Up to 3.30 (3H, m), 3.50 to 3.92 (1H,
m), 3.68 (3H, s), 3.92 to 4.30 (1
H, m), 6.60 to 7.30 (10H, m), 7.8
0-8.07 (2H, m).

Example 175 4-ureido-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methoxyphenyl) benzamide 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (237.2 mg, 0 (50 ml) was dissolved in acetic acid-water (1: 2, 1.8 ml), an aqueous solution (0.5 ml) of potassium cyanate (81.1 mg, 0.90 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. did.
Saturated aqueous sodium hydrogen carbonate was added to the reaction solution to make it alkaline with a 10% aqueous sodium hydroxide solution. It was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) and recrystallized from ethyl acetate-ether to give 125.6 mg (48.4%) of the title compound as a colorless powder. It was Melting point: 123 to 128 ° C IR (KBr): 3476, 3352, 1680, 15
98, 1526, 1490, 1438, 1410, 13
96, 1310, 1264, 1238, 1214, 11
82, 1158, 1140, 852, 840 cm ^-1 . NMR (CDCl ₃ ) δ: 1.77 to 2.22 (6H,
m), 2.60 (2H, t, J = 6.4Hz), 2.9
2-3.18 (3H, m), 3.69 (3H, s),
4.02 (2H, t, J = 6.4Hz), 4.80 (2
H, brs), 6.64 to 6.71 (3H, m), 6.
98 to 7.25 (8H, m), 7.95 (2H, dd,
J = 8.6, 5.5 Hz).

Example 176 4- (N-methylacetyl)
Amino) -N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (4-methoxypheny
Ru) benzamide 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (155.0 mg, 0.30
Mmol) in THF (3.0 ml), 60% sodium hydride (28.0 mg, 0.70 mmol) and methyl iodide (0.060 ml, 1.00 mmol) were added at room temperature and stirred for 2 hours. did. A saturated aqueous ammonium chloride solution was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. By recrystallizing the obtained residue from methanol-ether, 128.0 mg (80.4%) of the title compound was obtained as a colorless powder. IR (KBr): 2931, 1680, 1666, 16
36, 1598, 1510, 1242, 1029, 96
0,601 cm ^-1 . NMR (CDCl ₃ ) δ: 1.78 (3H, s), 1.
78 to 1.95 (4H, m), 2.04 to 2.31 (2
H, m), 2.61 (2H, t, J = 6.6 Hz),
2.95 to 3.30 (3H, m), 3.18 (3H,
s), 3.74 (3H, s), 4.02 (2H, t, J
= 6.6 Hz), 6.74 (2H, d, J = 8.8H)
z), 6.93 to 7.36 (8H, m), 7.96 (2
H, dd, J = 8.8, 5.3 Hz).

Example 177 4- (N-methylacetyl)
Amino) -N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (3-methoxypheny
Ru) benzamide 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (310.0 mg, 0.60
(8 mmol) to give the title compound as a colorless amorphous compound in the same manner as in Example 176.
Obtained 9.2 mg (28.0%). IR (neat): 2940, 1654, 1600, 1
376, 1138, 970, 749, 699 cm ^-1 . NMR (CDCl ₃ ) δ: 1.71-1.87 (4H,
m), 1.78 (3H, s), 2.06 to 2.43 (2
H, m), 2.63 (2H, t, J = 6.6 Hz),
2.96 to 3.25 (3H, m), 3.69 (3H,
s), 4.06 (2H, t, J = 6.6Hz), 6.6
4 to 6.72 (4H, m), 6.63 to 6.78 (4
H, m), 6.94 to 7.40 (6H, m), 7.97.
(2H, dd, J = 8.7, 5.6 Hz).

Example 178 4- (pyrrolo-1-yl)
-N- {2- [4- (4-fluorobenzoyl) piperi
Dino] ethyl} -N- (4-methoxyphenyl) benz
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (237.0 mg, 0.50 mmol) in acetic acid (5.0 ml). , 2,5-dimethoxytetrahydrofuran (0.065 ml, 0.50 mmol) was added, and the mixture was heated under reflux for 1 hr. After cooling, acetic acid was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purification in 4) yielded 217.0 mg (82.7%) of the title compound as colorless amorphous. IR (KBr): 2943, 1678, 1638, 15
10, 1330, 1246, 815, 724, 602c
m ^-1 . NMR (CDCl ₃ ) δ: 1.80 to 2.33 (6H,
m), 2.62 (2H, t, J = 6.8Hz), 2.9
6 to 3.33 (3H, m), 3.75 (3H, s),
4.02 (2H, t, J = 6.8Hz), 6.30 (2
H, t, J = 9.0 Hz), 6.72 (2H, dd, J
= 6.8, 2.2 Hz), 6.99 to 7.40 (10
H, m), 7.96 (2H, dd, J = 8.8, 5.6)
Hz).

Example 179 4- (pyrrolo-1-yl)
-N- {2- [4- (4-fluorobenzoyl) piperi
Dino] ethyl} -N- (3-methoxyphenyl) benz
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (238.1 mg, 0.50 mmol) and 2,5-dimethoxytetrahydrofuran (0.0
The same operation as in Example 178 was performed using 66 ml (0.50 mmol) to obtain 205.0 mg (78.0%) of the title compound as a light brown amorphous substance. IR (KBr): 1674, 1638, 1600, 14
88, 1400, 1392, 1326, 1310, 12
80, 1266, 1228, 1140, 842, 728
cm ^-1 . NMR (CDCl ₃ ) δ: 1.69 to 2.25 (6H,
m), 2.64 (2H, t, J = 6.6Hz), 2.9
7 to 3.19 (3H, m), 3.70 (3H, s),
4.06 (2H, t, J = 6.6Hz), 6.31 (2
H, s), 6.66 (2H, s), 6.73 (1H,
s), 7.03 to 7.43 (9H, m), 7.96 (2)
H, dd, J = 8.4, 5.5 Hz).

Example 180 4-N-dimethylamino-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (4-methoxyphenyl) benzua
Mido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (143.0 mg, 0.30 mmol) in methanol (5.0 ml). Dissolved in 37% formaldehyde aqueous solution (1.0 ml) and sodium cyanoborohydride (38.0 mg, 0.60 mmol).
Was added, and the mixture was stirred at room temperature for 24 hours while adjusting the pH of the reaction solution to 5-6 with trifluoroacetic acid. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless amorphous substance (87.0 mg, 61.1%). IR (KBr): 2944, 1678, 1600, 15
10, 1444, 1246, 974, 836, 602c
m ^-1 . NMR (CDCl ₃ ) δ: 1.66 to 2.38 (6H,
m), 2.66 (2H, t, J = 6.8Hz), 2.9
1 (6H, s), 2.97 to 3.36 (3H, m),
3.77 (3H, s), 4.00 (2H, t, J = 6.
8 Hz), 6.42 (2H, d, J = 9.0 Hz),
6.76 (2H, d, J = 9.0Hz), 7.00
7.22 (6H, m), 7.96 (2H, dd, J =
8.8, 5.5 Hz).

Example 181 4-N-dimethylamino-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (3-methoxyphenyl) benzua
Amido 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (238.9 mg, 0.50 mmol) was used as in Example 180. By performing the same operation, the title compound was obtained as a pale yellow amorphous substance 92.3.
mg (36.7%) was obtained. IR (KBr): 1680, 1634, 1600, 15
24, 1486, 1448, 1364, 1310, 12
80, 1230, 1198, 1158, 1136, 10
40,974,824,760,700 cm ^-1 . NMR (CDCl ₃ ) δ: 1.78 to 2.17 (6H,
m), 2.65 (2H, t, J = 6.8Hz), 2.8
9 (6H, s), 2.89 to 3.08 (3H, m),
3.70 (3H, s), 4.02 (2H, t, J = 6.
8Hz), 6.40 (2H, d, J = 8.8Hz),
6.71 (3H, brs), 7.11 to 7.30 (5
H, m), 7.96 (2H, dd, J = 8.6, 5.7)
Hz).

Example 182 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-hydroxyphenyl) benzami
Do 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (50.0 mg, 0.10 mmol) was added to methylene chloride (3. 0 ml) and dissolve at 0 ° C
At room temperature, a solution of boron tribromide (0.018 ml, 0.19 mmol) in methylene chloride (1 ml) was added, and the mixture was stirred at 0 ° C to room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate-chloroform: methanol =
The compound was purified by 10: 1) to obtain 37.3 mg (76.7%) of the title compound as a pale yellow amorphous substance. IR (KBr): 3310, 3124, 2944, 16
80, 1602, 1533, 1488, 1446, 14
10, 1377, 1314, 1263, 1236, 12
09, 1158, 909, 852, 729, 699, 6
48 cm ^-1 . NMR (CDCl ₃ ) δ: 1.60 to 2.00 (4H,
m), 2.00 to 2.40 (2H, m), 2.07 (3
H, s), 2.63 (2H, t, J = 6.0 Hz),
2.83-3.40 (3H, m), 4.01 (2H,
t, J = 6.0 Hz), 6.40 to 6.70 (3H,
m), 6.85 to 7.40 (7H, m), 7.80 to
8.03 (2H, m).

Example 183 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-hydroxyphenyl) benzamid
De 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (280.7 mg, 0.54
Was performed in the same manner as in Example 182 to give 215.0 m of the title compound as a colorless powder.
g (78.7%) was obtained. Melting point: 133-137 ° C IR (KBr): 3328, 3010, 1689, 16
17,1593,1515,1479,1452,14
13,1371, 1314, 1278, 1248, 12
36, 1206, 1185, 1161, 1101, 96
9,852,840,828,759,669,600
cm ^-1 . NMR (CDCl ₃ ) δ: 1,56 to 1.93 (4H,
m), 1.97 to 2.40 (2H, m), 2.10 (3
H, s), 2.63 (2H, t, J = 7.0 Hz),
2.75 to 3.40 (3H, m), 3.99 (2H, m)
t, J = 7.0 Hz), 6.65 (2H, d, J = 8.
8Hz), 6.90 (2H, d, J = 8.8Hz),
6.97 to 7.40 (4H, m), 7.80 to 8.03
(2H, m).

Example 184 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4- (N-
Hydroxyimino) -N- (2-methoxyphenyl) be
Benzene sulfonamide hydrochloride N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4- (N-hydroxyimino) -N-
(2-Methoxyphenyl) benzenesulfonamide (6
5 mg, 0.12 mmol) in methylene chloride (2 ml)
Was added to the solution, saturated hydrogen chloride / ether solution (1 ml) was added, and the mixture was stirred for 5 minutes. Ether (5 ml) was added to the residue obtained by distilling off the solvent to solidify it, and then the precipitate was filtered to give 69 m of the title compound as a colorless amorphous powder.
g (99.8%) was obtained. IR (KBr): 3200, 2950, 1678, 15
98, 1496, 1348, 1282, 1220, 11
58,974,760,728,602 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.85 to 2.4
0 (4H, m), 3.00 to 3.90 (7H, m),
3.36 (3H, s), 3.96 to 4.35 (2H,
m), 6.80 (1H, d, J = 8.5 Hz), 6.9
0 to 7.45 (5H, m), 7.60 (4H, s),
7.96 (2H, dd, J = 9Hz, 6Hz), 8.1
1 (1H, s).

Example 185 4-Methanesulfonylami
No-N- {2- [4- (4-fluorobenzoyl) pipet
Lysino] ethyl} -N- (3-methoxyphenyl) ben
Zuamide hydrochloride 4-methanesulfonylamino-N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -N- (3
-Methoxyphenyl) benzamide (164.0 mg,
(0.30 mmol) was used to perform the same operation as in Example 184 to obtain 15% of the title compound as a colorless powder.
7.1 mg (88.9%) was obtained. Melting point: 125-127 ° C IR (KBr): 1680, 1640, 1598, 14
90, 1456, 1440, 1392, 1332, 12
84, 1218, 1152, 970 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.90 to 2.7
0 (7H, m), 2.93 (3H, s), 3.00
3.90 (4H, m), 3.71 (3H, s), 4.2
3 to 4.53 (2H, m), 6.53 to 6.80 (3
H, m), 6.90 to 7.40 (7H, m), 7.96
(2H, dd, J = 9.0, 6.0 Hz).

Example 186 4- (Pyrrole-1-a)
) -N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (3-methoxyphenyl) be
Insamide hydrochloride 4- (pyrrol-1-yl) -N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -N- (3
-Methoxyphenyl) benzamide (170.2 mg,
The title compound was obtained as a brown powder in the same manner as in Example 184 by using 0.32 mmol).
0.4 mg (94.7%) was obtained. Melting point: 131-134 ° C IR (KBr): 3416, 1678, 1634, 15
98, 1520, 1488, 1476, 1438, 14
12, 1390, 1330, 1282, 1234, 12
14,1158,1068,844,698 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.54 to 2.7
1 (3H, m), 3.73 (3H, s), 3.17-
3.81 (9H, m), 4.45 (4H, t, J = 6.
6 Hz), 6.73 (1 H, s), 6.68 to 6.77
(3H, m), 7.09 to 7.48 (10H, m),
7.97 (2H, dd, J = 8.6, 5.3Hz).

Example 187 4-ureido-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methoxyphenyl) benzamide hydrochloric acid
The salt 4-ureido-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (107.2 mg, 0.21 mmol) was used as Example 184. By performing the same operation, 119.5 mg of the title compound was obtained as a light brown powder.
(Quantitative) obtained. Melting point: 146-149 ° C IR (KBr): 3348, 1680, 1598, 15
32, 1488, 1438, 1412, 1318, 12
56, 1216, 1180, 1156, 948, 84
0,760,698 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.04 to 2.4
1 (6H, m), 3.82 (3H, s), 3.11-
3.88 (5H, m), 4.31 to 4.37 (2H,
m), 6.64 to 6.72 (4H, m), 7.08 to
7.30 (9H, m), 7.95 (2H, dd, J =
8.4, 5.3 Hz).

Example 188 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Hydrochloride 4-Acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (360.0 mg, 0.70
(34 mmol) of the title compound as a colorless powder by performing the same operation as in Example 184 using
g (88.5%) was obtained. Melting point: 138 to 145 ° C IR (KBr): 3445, 1676, 1640, 16
00, 1316, 1218, 851, 762 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.15 (3H,
s), 2.04 to 3.79 (11H, m), 3.70.
(3H, s), 4.22 (2H, t, J = 6.8H
z), 6.65 to 6.74 (3H, m), 7.03 to
7.49 (7H, m), 7.94 (2H, dd, J =
8.8, 5.5 Hz).

Example 189 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methoxyphenyl) benzamide hydrochloric acid
The salt 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (142.0 mg, 0.30 mmol) was used as in Example 184. By performing the same operation, 100.0 mg (6%) of the title compound was obtained as a colorless powder.
0.8%) was obtained. Melting point: 145 to 155 ° C IR (KBr): 3440, 1678, 1600, 14
90, 1210, 1158, 844 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.08 to 3.8
2 (11H, m), 3.71 (3H, s), 4.31-
4.39 (2H, m), 6.70 to 6.82 (3H,
m), 7.08 to 7.44 (7H, m), 7.95 to
8.02 (2H, m).

Example 190 4-Dimethylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Example Using Hydrochloride 4-Dimethylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (83.5 mg, 0.17 mmol) By performing the same operation as for 184, 87.5 mg of the title compound was obtained as an orange powder.
(95.3%) was obtained. Melting point: 119 to 121 ° C. IR (KBr): 3428, 2632, 2552, 24
48, 1678, 1642, 1598, 1506, 14
90, 1452, 1410, 1320, 1284, 12
16, 1180, 1158, 1130, 952, 85
2,700 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.51 to 2.6
8 (2H, m), 3.11 (6H, s), 3.19-
3.42 (6H, m), 3.74 (3H, s), 3.4
9 to 3.93 (3H, m), 4.39 (2H, t, J =
6.6 Hz), 6.73 to 6.87 (3 H, m), 7.
14 (2H, d, J = 8.2Hz), 7.27 to 7.3.
2 (2H, m), 7.54 to 7.56 (3H, m),
7.99 (2H, dd, J = 8.6, 5.5Hz).

Example 191 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -3-methoki
Ci-N- (2-methoxyphenyl) benzamide oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -3-methoxy-N- (2-methoxyphenyl) benzamide (107 mg, 0. 218 mmol) was dissolved in methanol (10 ml) and oxalic acid (19.
7 mg, 0.218 mmol) was added. After stirring at room temperature for 5 minutes, methanol was distilled off and ether (5 ml) was added.
Was added to solidify and then the precipitate was filtered to obtain 100 mg (79.2%) of the title compound as a colorless powder. Melting point: 170.5 to 174 ° C IR (KBr): 3450, 1680, 1644, 15
98, 1504, 1452, 1388, 1226c
m ^-1 . NMR (CDCl ₃ ) δ: 1.86 to 2.50 (4H,
m), 3.10 to 3.83 (7H, m), 3.62,
3.71 (each 3H, s), 3.85 to 4.40
(2H, m), 6.60 to 7.35 (10H, m),
7.67-8.15 (2H, m).

Example 192 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-methoxy
Ci-N- (2-methoxyphenyl) benzenesulfone
Mido-oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxy-N- (2-methoxyphenyl) benzenesulfonamide (56.7 mg, 0.1
(8 mmol) was used to perform the same operation as in Example 191, to obtain 59.8 mg (89.8%) of the title compound as a colorless amorphous powder. IR (KBr): 3440, 1680, 1596, 14
98, 1344, 1260, 1222, 1156, 58
8,562 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.90 to 2.5
0 (4H, m), 3.10 to 3.77 (2H, m),
3.40 (3H, s), 3.77 to 4.10 (2H,
m), 3.86 (3H, s), 6.68 to 7.38 (8)
H, m), 7.53 (2H, d, J = 9 Hz), 7.9
5 (2H, dd, J = 9Hz, 6Hz).

Example 193 4-fluoro-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzenesulfone
Amido oxalate 4-fluoro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzenesulfonamide (81 mg, 0.157
Was carried out in the same manner as in Example 191 to give the title compound as a beige powder in 82.
Obtained 3 mg (86.7%). Melting point: 155 to 165 ° C IR (KBr): 3450, 1682, 1598, 14
96, 1460, 1344, 1292, 1224, 11
68, 1156, 1118, 836, 586, 556c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.90 to 2.3
7 (4H, m), 2.80 to 3.70 (7H, m),
3.35 (3H, s), 3.75 to 4.20 (2H,
m), 6.66 to 7.45 (8H, m), 7.60,
7.93 (each2H, dd, J = 9Hz, 6H
z).

Example 194 N-benzoyl-N- {2
-[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -4-methoxybenzenesulfonamide oxalate N-benzoyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (23.7 mg, 0.0452 mmol) Was performed in the same manner as in Example 191 to give the title compound as a colorless amorphous powder (2)
Obtained 6.2 mg (94.3%). IR (KBr): 3450,1682,1596,14
98, 1364, 1264, 1232, 1162, 70
0,588,554 cm ^-1 . NMR (DMSO _d6- CDCl ₃ ) δ: 1.50-2.
00 (4H, m), 2.30 to 2.70 (2H, m),
2.73 to 3.55 (5H, m), 3.70 to 4.30
(2H, m), 3.90 (3H, s), 6.87-7.
60 (9H, m), 7.65-8.20 (4H, m).

Example 195 N-acetyl-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -4-methoxybenzenesulfonamide oxalate N-acetyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (27.6 mg, 0.0597 mmol)
Was performed in the same manner as in Example 191 to give 30.9 mg (98.
4%) was obtained. Melting point: 169 to 171 ° C IR (KBr): 3450, 1682, 1598, 15
00, 1358, 1310, 1264, 1160, 10
88,558 cm ^-1 . NMR (DMSO _d6- CDCl ₃ ) δ: 1.70-2.
20 (4H, m), 2.35 (3H, s), 2.67-
3.73 (7H, m), 3.75 to 4.24 (2H,
m), 3.90 (3H, s), 6.85 to 7.33 (4
H, m), 7.56 to 8.13 (4H, m).

Example 196 N-benzyl-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -4-methoxybenzenesulfonamide oxalate N-benzyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (22.8 mg, 0.0447 mmol)
Was performed in the same manner as in Example 191 to give 25.9 m of the title compound as a colorless amorphous powder.
g (96.5%) was obtained. IR (KBr): 1682, 1598, 1498, 13
42, 1304, 1260, 1212, 1156, 70
0,560 cm ^-1 . NMR (DMSO _d6- CDCl ₃ ) δ: 1.70-2.
30 (4H, m), 2.45 to 3.65 (7H, m),
3.90 (3H, s), 4.25 (2H, s), 6.8
3 to 7.52 (9H, m), 7.59 to 8.08 (4
H, m).

Example 197 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-methoxy
Ci-N- (2-propenyl) benzenesulfonamide
Acid salt N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxy-N- (2-propenyl)
68 mg (90.1 mg) of the title compound was obtained as a colorless powder by performing the same operation as in Example 191 using benzenesulfonamide (63 mg, 0.137 mmol).
%)Obtained. Melting point: 182 to 185.5 ° C IR (KBr): 1684, 1598, 1498, 14
12, 1344, 1304, 1260, 1214, 11
54,1094,952,836,806,700,6
68,584,560 cm ^-1 . _{NMR (CDCl 3 -DMSO d6) δ} : 1.60~2.
20 (4H, m), 2.69 to 3.22 (4H, m),
3.22 to 3.64 (5H, m), 3.80 (2H, m)
d, J = 6 Hz), 3.88 (3H, s), 5.16
(1H, d, J = 10.5Hz), 5.22 (1H,
d, J = 15 Hz), 5.40-5.90 (1H,
m), 6.90 to 7.36 (4H, m), 7.75 (2
H, d, J = 9 Hz), 8.02 (2H, dd, J = 9)
Hz, 6 Hz).

Example 198 N-ethoxycarbonylmeth
Cyl-N- {2- [4- (4-fluorobenzoyl) pi
Peridino] ethyl} -4-methoxybenzenesulfone
Amidooxalate N-Ethoxycarbonyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (61 mg, 0.120 mmol) as in Example 191. By performing the operation, 65 mg (90.8%) of the title compound was obtained as a cream-colored amorphous powder. IR (KBr): 1748, 1680, 1598, 15
00, 1342, 1304, 1262, 1214, 11
84, 1156, 560 cm ^-1 . NMR (CDCl ₃ ) δ: 1.21 (3H, t, J =
7.5 Hz), 1.80 to 2.43 (4H, m), 3.
00-3.75 (9H, m), 3.86 (3H, s),
4.00 (2H, s), 4.10 (2H, q, J = 7.
5 Hz), 6.79 to 7.32 (4 H, m), 7.56
~ 8.30 (6H, m).

Example 199 N-benzoyl-N- {3
-[4- (4-Fluorophenyl) piperazinyl] pro
Pyr} -4-methoxybenzenesulfonamide oxalate N-benzoyl-N- {3- [4- (4-fluorophenyl) piperazinyl] propyl} -4-methoxybenzenesulfonamide (42.2 mg, 0.0825 mmol) The title compound was obtained as a colorless powder in the same manner as in Example 191, using 45.6 mg (9
1.9%) was obtained. Melting point: 176 to 180 ° C IR (KBr): 1682, 1596, 1512, 13
60, 1266, 1162, 1018, 700, 578
cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.97 to 2.4
3 (2H, m), 2.90 to 3.50 (2H, m),
3.33 (8H, s), 3.73 to 4.05 (2H,
m), 3.89 (3H, s), 6.70 to 7.10 (6
H, m), 7.40 (5H, s), 7.68 (2H,
d, J = 9 Hz).

Example 200 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-methoxy
Cimethyl-N- (2-methoxyphenyl) benzamide
The oxalate salt N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxymethyl-N- (2-methoxyphenyl) benzamide (128 mg, 0.254 mmol) was used as in Example 191. By performing the same operation, 128 mg (8 mg) of the title compound was obtained as a colorless powder.
4.7%) was obtained. Melting point: 151 to 155 ° C IR (KBr): 1680, 1640, 1598, 15
02, 1412, 1388, 1306, 1224, 11
58,752 cm ^-1 . NMR (CDCl ₃ ) δ: 1.90 to 2.56 (4H,
m), 3.06 to 3.83 (7H, m), 3.30 (3
H, s), 3.70 (3H, s), 3.97-4.45.
(2H, m), 4.35 (2H, s), 4.85 (2
H, br-s), 6.77 (1H, d, J = 8.5H
z), 6.86 (1H, d, J = 6.5 Hz), 6.9.
1 to 7.40 (8H, m), 7.95 (2H, dd, J
= 9 Hz, 6 Hz).

Example 201 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -3-methoki
Ci-N- (2-pyridyl) benzamide oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -3-methoxy-N- (2-pyridyl) benzamide (19 mg, 0.0412 mmol Was carried out in the same manner as in Example 191 to give the title compound (22.2) as a beige amorphous powder.
mg (97.7%) was obtained. IR (KBr): 3450,1682,1634,15
96, 1546, 1504, 1454, 1226c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.75 to 2.3
2 (4H, m), 2.95-4.00 (7H, m),
3.83 (3H, s), 4.60 to 5.00 (2H,
m), 6.56 to 7.45 (6H, m), 7.53 to
8.30 (6H, m).

Example 202 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -3-nitrobenzenesulfonami
Example 191 using the oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -3-nitrobenzenesulfonamide (70 mg, 0.129 mmol). The same operation as in (1) was performed to obtain 73.6 mg (90.3%) of the title compound as a colorless amorphous powder. IR (KBr): 3450, 1680, 1598, 15
32, 1496, 1354, 1220, 1172c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.85 to 2.6
0 (4H, m), 2.80 to 3.75 (7H, m),
3.35 (3H, s), 3.82 to 4.35 (2H,
m), 6.67 to 7.50 (6H, m), 7.54 to
8.13 (4H, m), 8.27-8.60 (2H,
m).

Example 203 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-methoxy
Ci-N- (2-thiazolyl) benzenesulfonamide oxalic
Acid salt N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxy-N- (2-thiazolyl)
By performing the same operation as in Example 191, using benzenesulfonamide (52 mg, 0.103 mmol), 50 mg (81.8) of the title compound was obtained as a colorless powder.
%)Obtained. Melting point: 152-158 ° C IR (KBr): 1682, 1598, 1506, 14
44, 1310, 1290, 1256, 1144, 10
88, 932, 704, 574, 562 cm ^-1 . _{NMR (CDCl 3 -DMSO d6) δ} : 1.40~2.
05 (4H, m), 2.27 to 2.75 (2H, m),
2.77 to 3.60 (5H, m), 3.80 (3H,
s), 3.99 to 4.40 (2H, m), 6.72 (1
H, d, J = 3 Hz), 6.96 (2H, d, J = 9H)
z), 7.07 to 7.40 (3H, m), 7.60 to
8.30 (4H, m).

Example 204 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-methoxy
Ci-N- (3-methoxyphenyl) benzenesulfone
Midooxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxy-N- (3-methoxyphenyl) benzenesulfonamide (87 mg, 0.165
(9 mmol) to perform the same operation as in Example 191 to obtain 98.3 mg of the title compound as a colorless powder.
(96.6%) was obtained. Melting point: 163.5 to 167 ° C IR (KBr): 1676, 1598, 1496, 13
46, 1308, 1262, 1214, 1158, 10
94,694 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.3
5 (4H, m), 2.95 to 3.50 (5H, m),
3.50 to 4.17 (4H, m), 3.74, 3.88
(Each 3H, s), 6.52 to 6.73 (2H,
m), 6.83 to 7.40 (6H, m), 7.52 (2
H, d, J = 9 Hz), 8.04 (2H, dd, J = 9)
Hz, 6 Hz).

Example 205 N- (2-cyanophenyi
) -N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -4-methoxybenzenesulfone
Midooxalate N- (2-cyanophenyl) -N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide (107 mg, 0.205
96 mg (7 mg) of the title compound as a colorless powder by performing the same operation as in Example 191 using (mmol).
6.6%). Melting point: 167 to 173 [deg.] C. IR (KBr): 1678, 1638, 1596, 14
96, 1356, 1262, 1218, 1158, 70
4,578,552 cm ^-1 . NMR (CD ₃ OD-CDCl ₃ ) δ: 1.85 to 2.3
0 (4H, m), 2.95 to 3.75 (8H, m),
3.76-4.14 (1H, m), 3.90 (3H,
s), 6.90 to 7.30 (5H, m), 7.37 to
7.96 (5H, m), 8.00 (2H, dd, J = 9
Hz, 6 Hz).

Example 206 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Trifluoromethylphenyl) -4-methoxybenzene
Sulfonamide oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-trifluoromethylphenyl) -4-methoxybenzenesulfonamide (46.7
The title compound was obtained as a colorless powder (49 mg, 90.5%) by performing the same operation as in Example 191 using (mg, 0.0827 mmol). Melting point: 174 to 180 ° C IR (KBr): 1680, 1596, 1498, 13
56, 1316, 1264, 1224, 1160, 10
36,722,576,558 cm ^-1 . _{NMR (CD 3 OD-CDCl 3} ) δ: 1.91~2.3
0 (4H, m), 2.90 to 3.80 (8H, m),
3.80-4.32 (1H, m), 3.90 (3H,
s), 6.79 to 7.30 (5H, m), 7.40 to
8.07 (7H, m).

Example 207 N-cyclohexyl-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -4-methoxybenzenesulfonamide oxalate N-cyclohexyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-methoxybenzenesulfonamide imide (300 mg, 0.597 mmol) Using the same procedure as in Example 191, the title compound was obtained as colorless powder (322 mg, 9
1.0%) was obtained. Melting point: 217 to 222 ° C. (decomposition) IR (KBr): 2925, 1716, 1686, 15
98, 1500, 1322, 1260, 1214, 11
48, 1128, 1102, 1026, 1010, 98
0,954,856,700,666,556 cm ^-1 . _{NMR (CDCl 3 -DMSO d6) δ} : 0.94~2.
30 (14H, m), 2.80 to 4.10 (10H,
m), 3.87 (3H, s), 6.85 to 7.47 (4
H, m), 7.60-8.30 (4H, m).

Example 208 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -3-pyridinesulfonamide oxalic acid
As in Example 191, using the salt N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -3-pyridinesulfonamide (55 mg, 0.1105 mmol). By performing the operation of 53.6 mg of the title compound as a cream powder.
(82.5%) was obtained. Melting point: 178 to 182 ° C IR (KBr): 1684, 1598, 1498, 14
66, 1416, 1338, 1224, 1168, 11
18,956,782,698,594 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.90 to 2.4
0 (4H, m), 3.10 to 3.75 (7H, m),
3.30 (3H, s), 3.83 to 4.20 (2H,
m), 6.65 to 7.56 (7H, m), 7.78 to
8.10 (2H, m), 8.60-8.86 (2H,
m).

Example 209 3-{[N- [2- [4-
(4-Fluorobenzoyl) piperidino] ethyl] -2
-Methoxyanilino] sulfonyl} pyridine N-Oki
Cid oxalate 3-{[N- [2- [4- (4-fluorobenzoyl))
Piperidino] ethyl] -2-methoxyanilino] sulfonyl} pyridine N-oxide (101 mg, 0.19
The title compound was obtained as a pale orange amorphous powder in 114 mg (95.9%) by the same procedures as in Example 191 using 7 mmol). IR (KBr): 3450, 2940, 2820, 16
64, 1628, 1596, 1464, 1428, 12
90, 1280, 1212, 1170, 1112, 10
48,1014,978 cm ^-1 . NMR (CDCl ₃ ) δ: 1.43 to 2.30 (7H,
m), 2.36 to 3.39 (5H, m), 3.32 (3
H, s), 3.39 to 3.90 (6H, m), 4.71.
(2H, s), 7.12 (2H, dd, J = 9Hz, 9
Hz), 7.38 (4H, s), 7.94 (2H, d
d, J = 9 Hz, 6 Hz).

Example 210 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -p-toluenesulfonamide oxalic acid
As in Example 191, using the salt N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -p-toluenesulfonamide (41 mg, 0.0803 mmol). By carrying out the operation described in the above, 40.5 mg (8
4.0%) was obtained. Melting point: 160 to 163 ° C IR (KBr): 1682, 1598, 1496, 13
36, 1224, 1158, 1118, 954, 65
8,558 cm ^-1 . NMR (CDCl ₃ ) δ: 2.00 to 2.55 (4H,
m), 2.40 (3H, s), 3.00 to 3.73 (7
H, m), 3.32 (3H, s), 3.80 to 4.20.
(2H, m), 6.76 (1H, d, J = 8.5H
z), 6.88 to 7.56 (7H, m), 7.47 (2
H, d, J = 8 Hz), 7.93 (2H, dd, J = 9)
Hz, 6 Hz).

Example 211 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -4-morpholinomethylbenzami
Oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-morpholinomethylbenzamide (48.3 mg, 0.08
By performing the same operation as in Example 191, using 63 mmol, 52 mg (92.7%) of the title compound was obtained as a beige-colored amorphous powder. IR (KBr): 1678, 1638, 1598, 15
02, 1454, 1390, 1280, 1224, 11
58, 1116, 864, 756 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.86 to 2.3
5 (4H, m), 2.74 to 4.35 (17H, m),
3.52 (2H, s), 3.70 (3H, s), 6.5
3 to 7.40 (10H, m), 7.95 (2H, dd,
J = 9 Hz, 6 Hz).

Example 212 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -4-dimethylaminomethylbenz
Amido oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-dimethylaminomethylbenzamide (105 mg, 0.2
The same operation as in Example 191 was carried out using (03 mmol) to obtain 117 mg (94.8%) of the title compound as a light beige amorphous powder. IR (KBr): 1680, 1640, 1598, 15
00, 1412, 1316, 1280, 1222c
m ^-1 . _{NMR (CDCl 3 -DMSO d6) δ} : 1.60~2.
16 (4H, m), 2.20 to 3.11 (6H, m),
2.55 (6H, s), 3.15 to 4.60 (5H,
m), 3.72 (3H, s), 6.55 to 6.94 (2
H, m), 7.00 to 7.46 (8H, m), 8.00
(2H, dd, J = 9Hz, 6Hz).

Example 213 N- {3- [4- (4-
Luorophenyl) piperazinyl] propyl} -4-meth
Xy-N- (2-methoxyphenyl) benzene sulfone
Amido oxalate N- {3- [4- (4-fluorophenyl) piperazinyl] propyl} -4-methoxy-N- (2-methoxyphenyl) benzenesulfonamide (130 mg, 0.2
(53 mmol) was used to perform the same operation as in Example 191 to obtain 142 m of the title compound as a colorless powder.
g (93.0%) was obtained. Melting point: 157-160 ° C IR (KBr): 1596, 1510, 1496, 14
62,1342,1256,1162,704,58
8,562 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.65 to 2.1
0 (2H, m), 3.13 to 3.53 (2H, m),
3.33 (8H, s), 3.56 (3H, s), 3.6
7 (2H, t, J = 7Hz), 3.87 (3H, s),
6.65-7.43 (10H, m), 7.55 (2H,
d, J = 9 Hz).

Example 214 4-Fluoro-N- {3-
[4- (4-Fluorophenyl) piperazinyl] propyi
Ru} -N- (2-methoxyphenyl) benzenesulfone
Amido oxalate 4-fluoro-N- {3- [4- (4-fluorophenyl) piperazinyl] propyl} -N- (2-methoxyphenyl) benzenesulfonamide (103 mg, 0.2
The title compound was obtained as a colorless amorphous powder in an amount of 114 mg (93.8%) by performing the same operation as in Example 191 using (05 mmol). IR (KBr): 3450, 1628, 1592, 15
10, 1494, 1460, 1342, 1230, 11
66,836,556 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.60 to 2.1
7 (2H, m), 3.04 to 3.83 (4H, m),
3.33 (8H, s), 3.39 (3H, s), 6.6
5 to 7.42 (10H, m), 7.62 (2H, dd,
J = 9 Hz, 6 Hz).

Example 215 N- {3- [4- (4-
Luorophenyl) piperazinyl] propyl} -N- (2
-Methoxyphenyl) -3-nitrobenzenesulfon
Midooxalate N- {3- [4- (4-fluorophenyl) piperazinyl] propyl} -N- (2-methoxyphenyl) -3-
Nitrobenzenesulfonamide (195mg, 0.36
(9 mmol) was used to perform the same operation as in Example 191 to give the title compound as a yellow prism.
Obtained 9 mg (100%). Melting point: 162.5 to 164 ° C IR (KBr): 1628, 1532, 1512, 14
98, 1460, 1352, 1258, 1228, 11
68,1120 cm ^-1 . NMR (CDCl ₃ ) δ: 1.74 to 2.15 (2H,
m), 3.00 to 3.50 (10H, m), 3.34
(3H, s), 3.55 to 3.85 (2H, m), 6.
67 to 7.11 (6H, m), 7.12 to 7.30 (2
H, m), 7.69 (1H, d, J = 7.5 Hz),
7.98 (1H, d, J = 7.5 Hz), 8.25-
8.52 (2H, m), 9.44 (2H, br-s).

Example 216 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-hydro
Xymethyl-N- (2-methoxyphenyl) benzenes
Rufonamide oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N- (2-methoxyphenyl) benzenesulfonamide (87 mg,
By performing the same operation as in Example 191, using 0.165 mmol), 90.5 mg (88.9%) of the title compound was obtained as a beige amorphous powder. IR (KBr): 3350, 2920, 1680, 16
38, 1596, 1496, 1344, 1220, 11
50 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.85 to 2.4
0 (4H, m), 2.90 to 3.70 (7H, m),
3.37 (3H, s), 3.76 to 4.14 (2H,
m), 4.71 (2H, s), 6.80 (1H, d, J
= 8.5 Hz), 6.99 (1H, d, J = 8.5H)
z), 7.17 (2H, dd, J = 9Hz, 9Hz),
7.29 (2H, d, J = 6Hz), 7.42 (2H,
d, J = 8.5 Hz), 7.60 (2H, d, J = 8.
5Hz), 7.95 (2H, dd, J = 9Hz, 6H
z).

Example 217 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-hydro
Xymethyl-N- (2-methoxyphenyl) benzami
Oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N- (2-methoxyphenyl) benzamide (128 mg, 0.261
(145 mmol) to give 145 mg (95.7%) of the title compound as a pale beige amorphous powder. IR (KBr): 3400, 1680, 1640, 15
98, 1502, 1440, 1412, 1280, 12
22, 1158, 1020, 954 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.95 to 2.3
5 (4H, m), 3.08 to 3.83 (7H, m),
3.70 (3H, s), 3.95 to 4.33 (2H,
m), 4.56 (2H, s), 6.77 (1H, d, J
= 8 Hz), 6.85 (1H, d, J = 7 Hz), 6.
93 to 7.40 (8H, m), 7.95 (2H, dd,
J = 9 Hz, 6 Hz).

Example 218 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -3-hydro
Xymethyl-N- (2-methoxyphenyl) benzami
Oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -3-hydroxymethyl-N- (2-methoxyphenyl) benzamide (148 mg, 0.302
(164 mmol) to give 164 mg (93.5%) of the title compound as a pale beige amorphous powder. IR (KBr): 3390, 2948, 1680, 16
38, 1598, 1502, 1440, 1392, 12
80, 1220, 1158, 1022 cm ^-1 . NMR (CDCl ₃ ) δ: 1.90 to 2.40 (4H,
m), 3.00 to 3.85 (7H, m), 3.70 (3
H, s), 3.95 to 4.30 (2H, m), 4.50.
(2H, s), 6.26 (3H, br-s), 6.75
(1H, d, J = 8Hz), 6.83 (1H, d, J =
6.5 Hz), 6.90 to 7.56 (8H, m), 7.
93 (2H, dd, J = 9Hz, 6Hz).

Example 219 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-hydro
Xymethyl-N- (3-methoxybenzyl) benzami
Oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N- (3-methoxybenzyl) benzamide (100 mg, 0.198
The title compound (110 mg, 93.4%) was obtained as a beige-colored amorphous powder by the same procedure as in Example 191. IR (KB
r): 3400, 1680, 1598, 1490, 14
20, 1216, 1156, 852 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.85 to 2.3
5 (4H, m), 2.95-4.00 (9H, m),
3.80 (3H, s), 4.62 (2H, d, J = 6H
z), 4.77 (2H, s), 6.60 to 6.96 (2
H, m), 7.10 to 7.70 (6H, m), 7.16
(2H, dd, J = 9Hz, 9Hz), 7.94 (2
H, dd, J = 9 Hz, 6 Hz).

Example 220 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4-hydro
Xymethyl-N- (2-methoxyethyl) benzamide
Oxalate N- {2- [4- (4-Fluorobenzoyl) piperidino] ethyl} -4-hydroxymethyl-N- (2-methoxyethyl) benzamide (90 mg, 0.203 mmol) was used as Example 191. By performing the same operation, 105 mg (97.1%) of the title compound was obtained as a pale beige amorphous powder. IR (KBr): 3392, 1678, 1626, 15
98, 1412, 1278, 1216, 1158, 11
12,1078,1014,952,854,718c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.85 to 2.4
3 (4H, m), 2.90 to 4.30 (14H, m),
3.30 (3H, s), 4.67 (2H, s), 7.1
7 (2H, dd, J = 9Hz, 9Hz), 7.20 ~
7.60 (4H, m), 7.95 (2H, dd, J = 9
Hz, 6 Hz).

Example 221 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -4-dimethylaminomethylbenze
Sulfonamide oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-dimethylaminomethylbenzenesulfonamide (33.5
mg, 0.0605 mmol) and the same operation as in Example 191 was performed to obtain 35 mg (89.9%) of the title compound as a colorless amorphous powder. IR (KBr): 1680, 1599, 1497, 13
41, 1220, 1158, 759, 591 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.63 to 2.3
5 (4H, m), 2.20 (6H, s), 2.40 ~
3.59 (8H, m), 3.43 (3H, s), 3.6
5 to 4.15 (3H, m), 6.70 to 7.43 (7
H, m), 7.45 to 7.80 (3H, m), 7.95.
(2H, dd, J = 9Hz, 6Hz).

Example 222 N- (2-methoxyphenyl)
) -N- {2- [4- (4-dimethylaminobenzoyl)
Ru) piperidino] ethyl} -4-dimethylaminomethyl
Benzenesulfonamide oxalate N- (2-methoxyphenyl) -N- {2- [4- (4
-Dimethylaminobenzoyl) piperidino] ethyl}-
4-Dimethylaminomethylbenzenesulfonamide (4
Example 1 using 7.5 mg, 0.0821 mmol)
By performing the same operation as in 91, 51 mg (92.9) of the title compound was obtained as a cream-colored amorphous powder.
%)Obtained. IR (KBr): 1596, 1494, 1342, 11
58,944,754,588 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 2.1
5 (4H, m), 2.27 (6H, m), 2.52 (4
H, s), 2.70 to 3.57 (4H, m), 3.05
(6H, s), 3.42 (3H, s), 3.70-4.
10 (3H, m), 6.65 (2H, d, J = 9H
z), 6.80 (1H, d, J = 8 Hz), 6.96
(1H, d, J = 8Hz), 7.10 to 7.36 (2
H, m), 7.36 to 8.00 (4H, m), 7.81
(2H, d, J = 9 Hz).

Example 223 4-carbamoyl-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyphenyl) benzenesul
Honamide oxalate 4-carbamoyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzenesulfonamide (32 mg, 0.0
The same operation as in Example 191 was carried out using 593 mmol) to obtain 33 mg (88.4%) of the title compound as a beige amorphous powder. IR (KBr): 3460, 1678, 1598, 14
96, 1408, 1348, 1282, 1220, 11
66, 1118, 708, 600 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.90 to 2.4
0 (4H, m), 2.90 to 3.75 (10H, m),
3.80-4.20 (2H, m), 6.84 (2H, m)
d, J = 9 Hz), 6.99 to 7.48 (4H, m),
7.55 to 7.77 (2H, m), 7.79 to 8.20
(4H, m).

Example 224 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -4-succinimide methylbenza
Mido oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-succinimidomethylbenzamide (42 mg, 0.073
The same operation as in Example 191 was carried out using 5 mmol) to obtain 33 mg (67.9%) of the title compound as a beige amorphous powder. IR (KBr): 3472, 2944, 1704, 16
44, 1599, 1503, 1401, 1227, 11
64 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.00 to 2.4
6 (6H, m), 2.66 (4H, s), 3.20-
3.60 (5H, m), 3.68 (3H, s), 4.0
0-4.23 (2H, m), 4.52 (2H, s),
6.76 (1H, d, J = 8Hz), 6.88 (1H,
d, J = 7 Hz), 7.00 to 7.31 (8H, m),
7.92 (2H, dd, J = 9Hz, 6Hz).

Example 225 4-Aminomethyl-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyphenyl) benzenesul
Honamide oxalate 4-aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzenesulfonamide (47 mg, 0.0
By performing the same operation as in Example 191, using 894 mmol), 52 mg (94.5%) of the title compound was obtained as a colorless amorphous powder. IR (KBr): 2940, 1678, 1598, 14
96, 1342, 1282, 1218, 1158, 76
0,586 cm ^-1 . NMR (CDCl ₃ ) δ: 1.40 to 2.25 (4H,
m), 2.25 to 2.89 (4H, m), 2.90 to
3.55 (2H, m), 3.29 (3H, s), 3.5
6 to 5.40 (9H, m), 6.53 to 6.92 (2
H, m), 6.92 to 7.34 (4H, m), 7.36
~ 7.71 (4H, m), 7.73-8.10 (2H,
m).

Example 226 4-Aminomethyl-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyethyl) benzamide oxalic
The acid salt 4-aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyethyl) benzamide (51 mg, 0.1155 mmol) was used as in Example 191. By performing the same operation, 57.6 mg (93.8%) of the title compound was obtained as a pale beige amorphous powder. IR (KBr): 3430, 2948, 1678, 16
26, 1598, 1412, 1296, 1216, 11
58, 1112, 1012, 952, 852, 762c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 2.3
0 (4H, m), 2.30 to 4.40 (13H, m),
3.35 (3H, s), 4.13 (2H, br-s),
6.93 to 7.70 (6H, m), 7.73 to 8.10
(2H, m).

Example 227 4-aminomethyl-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyphenyl) benzamide
The oxalate salt of 4-aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (32 mg, 0.0654 mmol) was used as in Example 191. By performing the same operation, 33 mg (87.1%) of the title compound was obtained as a beige-colored amorphous powder. IR (KBr): 3420, 2948, 1598, 15
02, 1412, 1310, 1224, 1158, 75
8 cm ^-1 . NMR (CDCl ₃ ) δ: 1.50 to 2.13 (4H,
m), 2.13 to 4.50 (11H, m), 3.56
(3H, s), 6.40 to 6.82 (2H, m), 6.
82 to 7.70 (8H, m), 7.72 to 8.20 (2
H, m).

Example 228 4- (acetylamino) me
Cyl-N- {2- [4- (4-fluorobenzoyl) pi
Peridino] ethyl} -N- (2-methoxyethyl) ben
Zamido oxalate 4- (acetylamino) methyl-N- {2- [4- (4
-Fluorobenzoyl) piperidino] ethyl} -N-
(2-Methoxyethyl) benzamide (68 mg, 0.
By performing the same operation as in Example 191, using 141 mmol), 71 mg (84.7%) of the title compound was obtained as a pink amorphous powder. IR (KB
r): 3320, 2940, 1678, 1626, 16
00, 1508, 1412, 1280, 1216, 11
58,1114,1014,952,852,706c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.3
6 (4H, m), 2.03 (3H, s), 2.80 ~
4.10 (16H, m), 3.31 (3H, s), 4.
42 (2H, s), 7.15 (2H, dd, J = 9H
z, 9 Hz), 7.20 to 7.52 (4H, m), 7.
95 (2H, dd, J = 9Hz, 6Hz).

Example 229 4- (acetylamino) me
Cyl-N- {2- [4- (4-fluorobenzoyl) pi
Peridino] ethyl} -N- (2-methoxyphenyl) be
Insamide oxalate 4- (acetylamino) methyl-N- {2- [4- (4
-Fluorobenzoyl) piperidino] ethyl} -N-
(2-methoxyphenyl) benzamide (58 mg,
0.109 mmol) was used to carry out the same operation as in Example 191, to give the title compound as a colorless powder.
Obtained 0 mg (59.0%). Melting point: 159-161 ° C IR (KBr): 3400, 1728, 1680, 16
26, 1599, 1563, 1503, 1413, 12
78,1224 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.83 to 2.4
6 (4H, m), 1.99 (3H, s), 2.52
2.75 (1H, m), 3.15 to 4.80 (6H,
m), 3.71 (3H, s), 3.90 to 4.40 (2
H, m), 4.30 (2H, s), 6.62 to 7.38.
(10H, m), 7.83 to 8.05 (2H, m).

Example 230 4- (trifluoroacetyl)
Luamino) methyl-N- {2- [4- (4-fluorobe
Nzoyl) piperidino] ethyl} -N- (2-methoxy
Phenyl) benzamide oxalate 4- (trifluoroacetylamino) methyl-N- {2
-[4- (4-Fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (4
8 mg, 0.0820 mmol) in Example 191
By the same operation as in (3), 37 mg (66.8%) of the title compound was obtained as a colorless powder. Melting point: 107-109 ° C IR (KBr): 3406, 3064, 2944, 17
19, 1680, 1641, 1599, 1503, 12
21,1179,1158 cm ^-1 . NMR (CDCl ₃ ) δ: 1.90 to 2.40 (4H,
m), 3.10 to 3.80 (7H, m), 3.70 (3
H, s), 3.95 to 4.28 (2H, m), 4.42.
(2H, d, J = 6 Hz), 6.45 to 7.60 (13
H, m), 7.91 (2H, dd, J = 9Hz, 6H
z).

Example 231 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4- (meta
N-sulfonylamino) methyl-N- (2-methoxyphen)
Nyl) benzamide oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4- (methanesulfonylamino) methyl-N- (2-methoxyphenyl) benzamide (40 m
The title compound was obtained as a colorless powder in an amount of 40 mg (86.3%) by performing the same operation as in Example 191 using g, 0.0705 mmol). Melting point: 89 to 92 ° C IR (KBr): 2926, 1722, 1677, 16
41, 1599, 1503, 1440, 1410, 13
20,1278,1221 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.5
5 (5H, m), 2.75 (3H, s), 3.10
3.85 (6H, m), 3.72 (3H, s), 3.9
7 to 4.40 (2H, m), 4.18 (2H, s),
6.76 (1H, d, J = 8Hz), 6.92 (1H,
d, J = 8 Hz), 7.00 to 7.42 (8H, m),
7.94 (2H, dd, J = 9Hz, 6Hz).

Example 232 4- (ethoxycarbonyl)
Amino) methyl-N- {2- [4- (4-fluoroben
Zoyl) piperidino] ethyl} -N- (2-methoxyphenyl)
Phenyl) benzamide oxalate 4- (ethoxycarbonylamino) methyl-N- {2-
[4- (4-Fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (5
0 mg, 0.0890 mmol) in Example 191
The same operation as in (1) was performed to obtain 47 mg (81.0%) of the title compound as a colorless powder. Melting point: 118 to 120 ° C IR (KBr): 2940, 1710, 1682, 16
40, 1598, 1502, 1414, 1278, 12
26 cm ^-1 . NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 8
Hz), 1.70-2.50 (8H, m), 3.20-
3.75 (4H, m), 3.70 (3H, s), 4.1
1 (2H, q, J = 8Hz), 4.00 to 4.30 (1
H, m), 4.25 (2H, d, J = 6 Hz), 6.7
0-7.31 (10H, m), 7.91 (2H, dd,
J = 9 Hz, 6 Hz).

Example 233 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -N- (2-
Methoxyphenyl) -4- (methylamino) methylben
Zamido oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) -4-
(Methylamino) methylbenzamide (119 mg,
(0.236 mmol) was used to perform the same operation as in Example 191 to obtain 1 of the title compound as a colorless powder.
Obtained 08 mg (77.0%). Melting point: 174 to 176 ° C IR (KBr): 3454, 3010, 2944, 28
06, 1674, 1644, 1596, 1503, 12
99,1278 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 1.9
5 (4H, m), 2.16 to 2.80 (4H, m),
2.40 (3H, s), 2.85 to 3.42 (3H,
m), 3.70 (3H, s), 3.83 (2H, s),
3.80-4.38 (2H, m), 6.65-6.89
(2H, m), 6.94 to 7.36 (8H, m), 7.
93 (2H, dd, J = 9Hz, 6Hz).

Example 234 4-amidino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzamide oxalic acid
Salt 4-amidino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (89 mg, 0.177 mmol)
Was performed in the same manner as in Example 191 to give 91 m of the title compound as a colorless amorphous powder.
g (86.8%) was obtained. IR (KBr): 3360, 3064, 1678, 16
42, 1598, 1502, 1440, 1410, 12
80, 1224, 1158, 720 cm ^-1 . _{NMR (CDCl 3 -DMSO d6) δ} : 1.90~2.
70 (4H, m), 3.00 to 5.00 (9H, m),
3.76 (3H, s), 6.58 to 7.00 (2H,
m), 7.00 to 7.84 (9H, m), 7.85
8.25 (2H, m), 9.11 (2H, br-s),
9.53 (2H, br-s). MS (FAB, m / z): 120,157,220,2
34,296,357,503 (M ⁺⁺ H).

Example 235 4- (N-acetylamidy)
No) -N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (2-methoxyphenyl) be
Insamide oxalate 4- (N-acetylamidino) -N- {2- [4- (4
-Fluorobenzoyl) piperidino] ethyl} -N-
(2-Methoxyphenyl) benzamide (80 mg,
By performing the same operation as in Example 191, using 0.147 mmol), 84 mg (90.0%) of the title compound was obtained as a pale yellow amorphous powder. IR (KBr): 3262, 2938, 1644, 15
99,1503,1443,1410,1278,12
24, 1158, 1119, 1086, 1044, 10
20,954,852,756,720 cm ^-1 . NMR (CDCl ₃ ) δ: 2.08 to 2.38 (4H,
m), 2.54 (3H, s), 3.05 to 3.60 (7
H, m), 3.70 (3H, s), 4.00 to 4.33.
(2H, m), 6.55 to 6.93 (2H, m), 6.
94 to 7.29 (5H, m), 7.37 (2H, d, J
= 7.5 Hz), 7.64 (2H, d, J = 7.5H)
z), 7.93 (2H, dd, J = 9Hz, 6Hz),
8.73 (1H, br-s).

Example 236 N- {2- [4- (4-
Luorobenzoyl) piperidino] ethyl} -4- (N-
Methanesulfonylamidino) -N- (2-methoxyphen
Nyl) benzamide oxalate N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -4- (N-methanesulfonylamidino)
-N- (2-methoxyphenyl) benzamide (101
(100 mg (85.7%) of the title compound was obtained as a pale yellow amorphous powder by the same procedure as in Example 191. IR (KBr): 3406, 1641, 1596, 15
33, 1503, 1410, 1278, 1224, 11
55,1116,957,852,756,528cm
^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.8
0 (4H, m), 3.03 (3H, s), 3.14-
3.90 (7H, m), 3.69 (3H, s), 3.9
5 to 4.38 (2H, m), 6.74 (1H, d, J =
8 Hz), 6.84 (1H, d, J = 7.5 Hz),
6.95 to 7.45 (6H, m), 7.62 (2H,
d, J = 8.5 Hz), 7.94 (2H, dd, J = 9)
Hz, 6 Hz).

Example 237 4- (N-ethoxycarbo)
Nilamidino) -N- {2- [4- (4-fluoroben
Zoyl) piperidino] ethyl} -N- (2-methoxyphenyl)
Phenyl) benzamide oxalate 4- (N-ethoxycarbonylamidino) -N- {2-
[4- (4-Fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (1
07 mg, 0.186 mmol) in Example 191
By performing the same operation as above, 113 mg (91.4%) of the title compound was obtained as a pale yellow amorphous powder. IR (KBr): 3388, 1623, 1599, 15
03,1461,1407,1368,1299,12
63, 1224, 1158, 1140, 1119, 10
20,954,855,756,720 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.31 (3H,
t, J = 7 Hz), 1.85 to 2.34 (4H, m),
2.95 to 3.90 (7H, m), 3.70 (3H,
s), 3.93 to 4.33 (2H, m), 4.17 (2
H, q, J = 7 Hz), 6.75 (1H, d, J = 8H)
z), 6.84 (1H, d, J = 7.5 Hz), 6.9.
6 to 7.45 (6H, m), 7.66 (2H, d, J =
8Hz), 7.96 (2H, dd, J = 9Hz, 6H
z).

Example 238 4-nitro-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzamide oxalic acid
Similar to example 191, using the salt 4-nitro-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (120 mg, 0.24 mmol). By performing the operation
106 mg (75.0 mg) of the title compound as a pale yellow powder.
%)Obtained. Melting point: 201 to 203 ° C IR (KBr): 2944, 2608, 1686, 16
56, 1599, 1524, 1503, 1410, 13
47,1278,1227,1155 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.90 to 2.2
4 (4H, m), 3.10 to 3.65 (7H, m),
3.73 (3H, s), 4.04 (2H, m), 6.7
0 to 6.96 (2H, m), 7.00 to 7.33 (4
H, m), 7.45 (2H, d, J = 9.0 Hz),
7.84 to 8.06 (4H, m).

Example 239 4-{[N- [2- [4-
(4-Fluorobenzoyl) piperidino] ethyl] -2
-Methoxyanilino] carbonyl} pyridine oxalate 4-{[N- [2- [4- (4-fluorobenzoyl)
Piperidino] ethyl] -2-methoxyanilino] carbonyl} pyridine (200 mg, 0.43 mmol) was used to perform the same operation as in Example 191, to give 221 mg (92.5%) of the title compound as a colorless powder. Obtained. Melting point: 98 to 100 ° C IR (KBr): 1678, 1654, 1620, 15
98,1502,1434,1412,1396,12
24 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.85 to 2.5
4 (6H, m), 2.86 to 3.64 (6H, m),
3.70 (3H, s), 3.90 to 4.22 (1H,
m), 6.66 to 6.94 (2H, m), 7.01 to
7.22 (6H, m), 7.81 to 8.04 (2H,
m), 8.37 (2H, d, J = 6.0 Hz).

Example 240 4-{[N- [2- [4-
(4-Fluorobenzoyl) piperidino] ethyl] -2
-Methoxyanilino] carbonyl} pyridine N-oxy
Deoxalate 4-{[N- [2- [4- (4-fluorobenzoyl))
Piperidino] ethyl] -2-methoxyanilino] carbonyl} pyridine N-oxide (269 mg, 0.56 mmol) was used to carry out the same operation as in Example 191, to give 259 mg of the title compound as a pale yellow powder.
(81.2%) was obtained. Melting point: 121 to 124 ° C. IR (KBr): 2920, 2848, 1680, 16
47, 1614, 1596, 1503, 1272, 12
24, 1158, 843 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.00 to 2.3
1 (4H, m), 3.13 to 3.69 (8H, m),
3.72 (3H, s), 4.00 to 4.23 (1H,
m), 6.74 to 7.31 (8H, m), 7.82 to
8.03 (4H, m).

Example 241 4-[(S) -2-amino
Propionyl] aminomethyl-N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -N- (2
-Methoxyphenyl) benzamide dioxalate 4-[(S) -2-aminopropionyl] aminomethyl-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) Benzamide (84.7 mg, 0.155 mmol) was dissolved in methanol (5 ml) to give oxalic acid (28 mg, 0.311).
Mmol) was added. After stirring at room temperature for 5 minutes, the amorphous substance obtained by distilling off methanol was removed with acetone (5 m
It was washed with l). By filtering the precipitate, 84 mg (85.
1%) was obtained. IR (KBr): 3076, 1718, 1682, 16
36, 1598, 1502, 1440, 1412, 12
78,1224 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.25 to 1.5
5 (3H, m), 2.03 to 2.30 (4H, m),
3.25 to 3.90 (9H, m), 3.74 (3H,
s), 4.00 to 4.42 (4H, m), 6.78 to
7.41 (10H, m), 7.92 to 8.15 (2H,
m). MS (FAB, m / z): 220, 354, 561 (M
⁺ +1).

Example 242 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyphenyl) benzamide
Oxalate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (135.0 mg, 0.26
(10 mmol) of the title compound as a colorless powder by performing the same operation as in Example 191.
g (68.2%) was obtained. Melting point: 190-192 ° C IR (KBr): 3364, 2926, 2854, 17
31, 1680, 1644, 1598, 1530, 14
07, 1377, 1311, 1278, 1227, 11
82,1020 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.07 (3H,
s), 2.10 to 2.30 (4H, m), 3.10
3.64 (8H, m), 3.70 (3H, s), 4.0
0 to 4.26 (2H, m), 6.70 to 6.93 (2
H, m), 6.96 to 7.45 (8H, m), 7.98.
(2H, dd, J = 9.0, 6.0 Hz).

Example 243 4-Methanesulfonylami
No-N- {2- [4- (4-fluorobenzoyl) pipet
Lysino] ethyl} -N- (2-methoxyphenyl) ben
Zamido oxalate 4-methanesulfonylamino-N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -N- (2
-Methoxyphenyl) benzamide (29.5 mg,
(0.05 mmol) in the same manner as in Example 191 to give the title compound (2) as a colorless powder.
0.7 mg (60.3%) was obtained. Melting point: 75-76 ° C IR (KBr): 3364, 2930, 1680, 16
41, 1599, 1503, 1443, 1395, 13
32,1302,1281,1152 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.90 to 2.3
3 (4H, m), 2.90 (3H, s), 3.10
3.80 (8H, m), 3.72 (3H, s), 3.9
0 to 4.30 (2H, m), 6.60 to 7.40 (10
H, m), 7.96 (2H, dd, J = 9.0, 6.0)
Hz).

Example 244 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (282.4 mg, 0.55
Mmol) in methanol (1.5 ml),
At, a methanol solution (3.0 ml) of fumaric acid (63.8 mg, 0.55 mmol) was added. The precipitated crystals were collected by filtration and washed with ether to give the title compound (278.3 mg, 80.0%) as a colorless powder. Melting point: 215 to 222 ° C (decomposition) IR (KBr): 3450, 1680, 1644, 16
00, 1528, 1408, 1316, 1218, 11
60,852 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.60 to 2.4
3 (5H, m), 2.10 (3H, s), 2.68 (2
H, t, J = 7.0 Hz), 2.83 to 3.40 (4
H, m), 3.69 (3H, s), 4.05 (2H,
t, J = 7.0 Hz), 6.52 to 6.73 (3H,
m), 6.78 (2H, s), 6.52 to 7.50 (5
H, m), 7.13 (2H, dd, J = 8.8Hz),
7.98 (2H, dd, J = 8.8, 5.5 Hz).

Example 245 4-ethoxycarbonyl
Mino-N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (2-methoxyphenyl) be
Benzamide fumarate 4-ethoxycarbonylamino-N- {2- [4- (4
-Fluorobenzoyl) piperidino] ethyl} -N-
(2-Methoxyphenyl) benzamide (80.0m
g, 0.15 mmol) and the same operation as in Example 244 was performed to obtain 74.6 mg (77.0%) of the title compound as a light brown powder. Melting point: 142-146 ° C IR (KBr): 2950, 1724, 1578, 16
38, 1598, 1500, 1410, 1314, 12
26,1190 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.27 (3H,
t, J = 7.3 Hz), 1.80 to 2.20 (5H,
m), 2.40 to 3.43 (4H, m), 3.68 (3
H, s), 3.93 to 4.30 (2H, m), 4.17.
(2H, q, J = 7.3 Hz), 6.73 (2H,
s), 6.85 (2H, t, J = 7.5Hz), 6.9.
0-7.33 (9H, m), 7.94 (2H, dd, J
= 8.8, 5.5 Hz).

Example 246 4-trifluoroacetyl
Amino-N- {2- [4- (4-fluorobenzoyl)
Piperidino] ethyl} -N- (2-methoxyphenyl)
Benzamide fumarate 4-trifluoroacetylamino-N- {2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
-(2-Methoxyphenyl) benzamide (253.3
The title compound was obtained as a colorless powder in an amount of 167.7 mg (61.0%) by the same procedure as in Example 244. Melting point: 213-215 ° C (decomposition) IR (KBr): 2950, 1720, 1680, 16
40, 1598, 1500, 1410, 1385, 12
40, 1200, 1150, 950 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 2.0
6 (5H, m), 2.20 to 3.46 (6H, m),
3.70 (3H, s), 3.76 to 4.26 (2H,
m), 6.73 (2H, s), 6.81 (2H, t, J
= 6.8 Hz), 6.93 to 7.51 (9H, m),
7.95 (2H, dd, J = 8.8, 5.5 Hz).

Example 247 4- (3-ethylthiouree)
Id) -N- {2- [4- (4-fluorobenzoyl)
Piperidino] ethyl} -N- (2-methoxyphenyl)
Benzamide fumarate 4- (3-ethylthioureido) -N- {2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
-(2-Methoxyphenyl) benzamide (95.5m
(g, 0.17 mmol) was carried out in the same manner as in Example 244 to obtain 87.9 mg (76.3%) of the title compound as a colorless powder. Melting point: 154-156 ° C IR (KBr): 1678, 1640, 15982, 1
544, 1502, 1420, 1382, 1314, 1
278, 1226 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.16 (3H,
t, J = 7.1 Hz), 1.70 to 2.12 (4H,
m), 2.20 to 3.46 (11H, m), 3.72.
(3H, s), 6.78 (2H, s), 6.60 to 7.
40 (10H, m), 7.80 to 8.10 (2H,
m).

Example 248 4- (tert-butylene)
Raid) -N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (2-methoxypheny
Ru) benzamide fumarate 4- (tert-butylureido) -N- {2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
-(2-Methoxyphenyl) benzamide (72.9 m
g, 0.13 mmol) and the same operation as in Example 244 was performed to obtain 84.2 mg (96.1%) of the title compound as a pale yellow powder. Melting point: 110-114 ° C IR (KBr): 2968, 1683, 1638, 15
99, 1536, 1503, 1452, 1410, 13
92, 1312, 1278, 1251, 1209, 11
79, 1158, 1119, 975, 954, 846
753 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.32 (9H,
s), 1.77 to 2.20 (4H, m), 2.20 to
3.55 (8H, m), 3.69 (3H, s), 3.8
3 to 4.20 (1H, m), 6.66 to 7.32 (10
H, m), 6.78 (2H, s), 7.80 to 8.03.
(2H, m).

Example 249 4-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-methoxyphenyl) benzamide fumar
Example Using the Phosphate 4-Amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (150.0 mg, 0.32 mmol) By performing the same operation as in 244, 151.6 mg of the title compound was obtained as a pale yellow powder.
(81.2%) was obtained. Melting point: 152-158 ° C IR (KBr): 1678, 1632, 1600, 15
00, 1388, 1224, 1182, 1160, 75
6 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.76 to 2.0
3 (4H, m), 2.30 to 2.60 (2H, m),
2.70 to 3.00 (2H, m), 3.00 to 3.47
(3H, m), 3.69 (3H, s), 3.80-4.
22 (2H, m), 6.37 (2H, d, J = 8.0H
z), 6.70-6.90 (4H, m), 6.98-
7.30 (6H, m), 7.80 to 8.07 (2H,
m).

Example 250 4-Isobutyrylamino-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (2-methoxyphenyl) benzua
Midofumarate 4-isobutyrylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (222.7 mg, 0.
(41 mmol) in the same manner as in Example 244 to give the title compound as a pale pink powder.
Obtained 8.0 mg (99.2%). Melting point: 154-157 ° C IR (KBr): 2968,1683,1641,15
99, 1530, 1503, 1455, 1410, 13
86, 1305, 1278, 1251, 1224, 11
79, 1155, 1116, 1020, 975, 95
7,849,753 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.18 (6H,
d, J = 5.3 Hz), 1.75 to 2.00 (4H,
m), 2.20 to 3.50 (8H, m), 3.69 (3
H, s), 3.80 to 4.20 (2H, m), 6.67.
~ 6.93 (4H, m), 7.00 ~ 7.40 (8H,
m), 7.83 to 8.03 (2H, m).

Example 251 4-butyrylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxyphenyl) benzamide
Fumarate 4-butyrylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (196.3 mg, 0.36)
Was carried out in the same manner as in Example 244 to give 227.8 of the title compound as a pale orange powder.
mg (95.7%) was obtained. Melting point: 155 to 160 ° C IR (KBr): 1683, 1638, 1599, 15
30, 1503, 1455, 1407, 1386, 13
08,1251,1224,1203,1179,11
55,957,852,750 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 0.98 (3H,
t, J = 8.0 Hz), 1.47 to 2.07 (6H,
m), 2.10 to 3.48 (9H, m), 3.69 (3
H, s), 3.85 to 4.30 (2H, m), 6.67.
~ 6.93 (4H, m), 7.00 ~ 7.40 (8H,
m), 7.80-8.10 (2H, m).

Example 252 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-methoxyphenyl) benzamide fuma
Example using the phosphate 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (132.9 mg, 0.28 mmol) By performing the same operation as in 244, the title compound was obtained as a pale yellow amorphous.
Obtained 3 mg (82.4%). IR (KBr): 1680, 1600, 1510, 14
40, 1386, 1292, 1248, 1226, 11
82,1158,838 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.72 to 2.1
0 (4H, m), 2.30 to 2.70 (2H, m),
2.70 to 3.23 (2H, m), 3.23 to 3.58
(3H, m), 3.77 (3H, s), 4.08 (2
H, t, J = 7.0 Hz), 6.42 (2H, d, J =
9.0 Hz), 6.60 to 7.33 (8H, m), 6.
77 (2H, s), 7.80-8.10 (2H, m).

Example 253 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-methoxyphenyl) benzamide
Fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (476.8 mg, 0.92)
In the same manner as in Example 244 to give 515.6 m of the title compound as a colorless powder.
g (88.3%) was obtained. Melting point: 202-208 ° C IR (KBr): 1683, 1641, 1596, 15
12, 1443, 1410, 1386, 1317, 12
93, 1257, 1227, 1179, 1158c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 2.0
3 (4H, m), 2.13 (3H, s), 2.20-
2.92 (4H, m), 2.92 to 3.30 (3H,
m), 3.78 (3H, s), 4.08 (2H, t, J
= 8.0 Hz), 6.60 to 7.47 (10 H, m),
6.82 (2H, s), 7.80-8.10 (2H,
m).

Example 254 4-pivaloylamino-N
-{2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (2-methoxyphenyl) benzua
Midofumarate 4-pivaloylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxyphenyl) benzamide (214.6 mg, 0.3
By performing the same operation as in Example 244 using 8 mmol), 263.9 mg (quantitative) of the title compound was obtained as a pale yellow amorphous substance. IR (KBr): 1680, 1641, 1599, 15
03, 1443, 1404, 1314, 1278, 12
45, 1224, 1158, 975, 849, 753c
m ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.26 (9H,
s), 1.70 to 2.03 (4H, m), 2.40 to
3.40 (7H, m), 3.69 (3H, s), 3.8
0 to 4.20 (2H, m), 6.60 to 6.90 (2
H, m), 6.75 (2H, s), 6.90 to 7.40.
(8H, m), 7.80 to 8.04 (2H, m).

Example 255 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2,5-dimethoxyphenyl) benzamid
Dofumarate Using 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,5-dimethoxyphenyl) benzamide (152.0 mg, 0.30 mmol) By performing the same operation as in Example 244, 175.0 mg of the title compound as a yellow powder is obtained.
(80.4%) was obtained. Melting point: 199.5 to 200.8 ° C IR (KBr): 3470, 3380, 2951, 16
83, 1641, 1617, 1514, 1223, 85
0,652 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.95 to 2.1
6 (5H, m), 2.18 to 3.80 (6H, m),
3.61 (3H, s), 3.69 (3H, s), 3.8
0 to 4.20 (2H, m), 6.35 (2H, d, J =
7.8 Hz), 6.72 (5 H, s), 7.08-7.
26 (4H, m), 7.91 to 8.06 (2H, m).

Example 256 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2,5-dimethoxyphenyl) benz
Amido fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,5-dimethoxyphenyl) benzamide (109.0 mg,
(0.20 mmol) was used to perform the same operation as in Example 244 to give the title compound (11) as a colorless powder.
Obtained 1.0 mg (84.3%). Melting point: 207 to 208 ° C IR (KBr): 3460, 1945, 1679, 16
40, 1598, 1506, 1316, 1223, 85
5 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.94 to 2.1
5 (4H, m), 2.09 (3H, s), 2.61
3.53 (7H, m), 3.61 (3H, s), 3.6
9 (3H, s), 4.01 (2H, brs), 6.71
(2H, d, J = 4.8 Hz), 7.05 to 7.41
(7H, m), 7.89-8.04 (2H, m).

Example 257 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methoxyphenyl) benzamide fumara
Example using the phosphate 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (185.1 mg, 0.39 mmol) By performing the same operation as for 244, 215.8 mg (9
3.8%) was obtained. Melting point: 155 to 157 ° C IR (KBr): 3444, 3360, 1680, 16
28, 1600, 1516, 1440, 1384, 13
14,1214,1180,1042 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.2
3 (5H, m), 2.56 to 3.60 (8H, m),
3.70 (3H, s), 4.18 (2H, t, J = 7.
5Hz), 6.42 (2H, d, J = 8.6Hz),
6.53 to 6.72 (2H, m), 6.75 (2H,
s), 7.00 to 7.30 (6H, m), 6.75 (2
H, s), 7.95 (2H, dd, J = 8.8, 5.5)
Hz).

Example 258 3-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methoxyphenyl) benzamide fumara
Example Using the Phosphate 3-Amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (153.7 mg, 0.32 mmol) By performing the same operation as for 244, the title compound was obtained as a pale yellow amorphous substance.
Obtained 9 mg (93.5%). IR (KBr): 3460, 3364, 1680, 16
38,1598,1456,1318,1234,11
58, 1080, 980 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.1
6 (5H, m), 2.56 to 3.50 (8H, m),
3.68 (3H, s), 4.11 (2H, t, J = 5.
7 Hz), 6.40 to 7.33 (10 H, m), 6.7
5 (2H, s), 7.96 (2H, dd, J = 8.8,
5.5 Hz).

Example 259 3- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Fumarate 3-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (197.5 mg, 0.38
(16 mmol) to give the title compound as a pale red powder in an amount of 176.6.
mg (73.6%) was obtained. Melting point: 122 to 125 ° C IR (KBr): 3300, 2930, 1676, 16
40, 1598, 1456, 1318, 1234, 11
58, 1080, 980 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.73 to 2.2
0 (5H, m), 2.12 (3H, s), 2.33 ~
2.75 (2H, m), 2.83 (2H, t, J = 7.
5 Hz), 2.95 to 3.46 (2H, m), 3.68
(3H, s), 4.12 (2H, t, J = 7.5H
z), 6.53 to 6.90 (3H, m), 6.76 (2
H, s), 6.93 to 7.43 (6H, m), 7.73
(1H, d, J = 7.5 Hz), 7.96 (2H, d
d, J = 9.0, 6.0 Hz).

Example 260 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2,5-dimethoxyphenyl) benzamid
Dofumarate salt 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,5-dimethoxyphenyl) benzamide (102.3 mg, 0.20 mmol) was used. By performing the same operation as in Example 244, the title compound was obtained as a colorless amorphous compound in 92.
Obtained 4 mg (74.3%). Melting point: 105 to 106 ° C. IR (KBr): 1710, 1680, 1600, 15
10, 1438, 1410, 1308, 1278, 12
24, 1208, 1182, 1158 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.17 to 2.2
0 (4H, m), 2.25 to 3.91 (15H, m),
3.69 (3H, s), 3.77 (3H, s), 6.3
8 to 6.51 (3H, m), 6.81 (2H, s),
7.00 to 7.34 (5H, m), 7.00 to 7.34
(5H, m), 7.99 to 8.09 (2H, m).

Example 261 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2,5-dimethoxyphenyl) benz
Amido fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2,5-dimethoxyphenyl) benzamide (102.1 mg,
By performing the same operation as in Example 244 using 0.19 mmol), 80.0 mg (64.7%) of the title compound was obtained as a colorless amorphous. Melting point: 109-110 ° C IR (KBr): 1681, 1636, 1597, 15
29, 1510, 1439, 1406, 1312, 12
58, 1223, 1208, 1181, 1158, 10
27,851 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.93 to 2.0
6 (4H, m), 2.27 (3H, s), 2.35
3.25 (2H, m), 3.27 to 4.84 (8H,
m), 3.69 (3H, s), 3.77 (3H, s),
6.38 to 6.51 (3H, m), 6.81 (2H,
s), 7.00 to 7.34 (5H, m), 7.00
7.34 (5H, m), 7.99 to 8.09 (2H,
m).

Example 262 4-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methylphenyl) benzamide fumar
Example 244 Using the acid salt 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methylphenyl) benzamide (184.5 mg, 0.40 mmol). By performing the same operation as in 7.
mg (31.2%) was obtained. IR (KBr): 3330, 2935, 2450, 16
80, 1629, 1599, 1440, 1380, 13
02, 1230, 1155, 843 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.15 to 2.1
0 (6H, m), 2.26 (3H, s), 2.34 ~
3.50 (7H, m), 4.10 (2H, t, J = 7.
0Hz), 6.40 (2H, d, J = 9.0Hz),
6.77 (2H, s), 6.61 to 7.31 (8H,
m), 7.94 (2H, dd, J = 9.0, 6.0H
z).

Example 263 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methylphenyl) benzamido
Mar salt of 4-acetylamino--N- {2- [4- (4- fluorobenzoyl) piperidino] ethyl}-N-(3- methylphenyl) benzamide (236.0mg, 0.47 mmol) performed using By performing the same operation as in Example 244, 246.0 mg of the title compound was obtained as a colorless powder.
(84.8%) was obtained. Melting point: 196 to 202 ° C IR (KBr): 3250, 2400, 1683, 16
44, 1599, 1530, 1407, 1380, 12
30,1161,849 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.11 (3H,
s), 2.26 (3H, s), 1.50 to 2.60 (6
H, m), 2.76 (2H, t, J = 7.0 Hz),
2.93 to 3.53 (3H, m), 4.09 (2H,
t, J = 7.0 Hz), 6.80 (2H, s), 6.7
0-7.43 (11H, m), 7.95 (2H, dd,
J = 9.0, 6.0 Hz).

Example 264 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (phenyl) benzamide fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (phenyl)
By carrying out the same procedure as in Example 244 using benzamide (314.3 mg, 0.64 mmol),
349.8 mg (90.5 mg) of the title compound was obtained as a colorless powder.
%)Obtained. Melting point: 210 to 214 ° C. IR (KBr): 1686, 1641, 1599, 15
27, 1497, 1452, 1410, 1389, 13
14, 1260, 1227, 1185, 1158, 85
2,759 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.86 to 1.9
7 (6H, m), 2.09 (3H, s), 2.28-
2.55 (4H, m), 2.66 to 2.94 (4H,
m), 3.04 to 3.08 (2H, m), 4.11 (2
H, dd, J = 7.0, 6.6 Hz), 6.78 (2
H, s), 7.06 to 7.42 (9H, m), 7.93.
(2H, dd, J = 9.0, 6.0 Hz).

Example 265 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methylthiophenyl) benzamide
Mar salt of 4-amino -N- {2- [4- (4- fluorobenzoyl) piperidino] ethyl}-N-(3- methylthiophenyl) benzamide (148.2mg, 0.30 mmol) using Example By performing the same operation as for H.244, 488.0 mg (8
0.3%) was obtained. Melting point: 224-227 ° C. IR (KBr): 1710, 1680, 1600, 15
12, 1312, 1204, 1192, 836 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.17 to 2.2
0 (4H, m), 2.43 (3H, s), 3.29-
4.09 (15H, m), 6.38 to 6.98 (5H,
m), 7.00 to 7.33 (5H, m), 7.98 to
8.01 (2H, m).

Example 266 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (2-trifluoromethylphenyl) benz
Amido fumarate 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-trifluoromethylphenyl) benzamide (102.6 mg, 0.2
(0 mmol) in the same manner as in Example 244 to give 112.0 of the title compound as a colorless powder.
Obtained mg (89.0%). Melting point: 175 to 176 ° C IR (KBr): 3480, 3380, 1676, 16
40, 1602, 1314, 1226, 1174, 11
28,646 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.81 to 1.9
1 (4H, m), 2.19 to 2.44 (2H, m),
2.66 to 4.51 (7H, m), 6.46 (2H, b
rd, J = 8.6 Hz), 6.79 (2H, s), 7.
05-7.61 (8H, m), 7.88-8.04 (2
H, m).

Example 267 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-trifluoromethylphenyl) be
Benzamide fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-trifluoromethylphenyl) benzamide (139.0 m
The title compound was obtained as a colorless powder in an amount of 143.0 mg (85.1%) by the same procedure as in Example 244. Melting point: 188 to 190 ° C. IR (KBr): 3380, 1680, 1600, 15
32, 1318, 1262, 1166, 1076, 70
5,646 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.88 to 1.9
9 (4H, m), 2.09 (3H, s), 2.36-
2.65 (2H, m), 2.82 (2H, t, J = 6.
9 Hz), 3.06 to 3.23 (3H, m), 4.15
(2H, t, J = 6.9 Hz), 6.77 (2H,
s), 7.06 to 7.46 (10H, m), 7.96
(2H, dd, J = 8.8, 5.5Hz).

Example 268 4-Amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-trifluoromethylphenyl) benz
Amido fumarate 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-trifluoromethylphenyl) benzamide (140.0 mg, 0.2
(7 mmol) was used to carry out the same operation as in Example 244 to obtain 110.
1 mg (64.1%) was obtained. Melting point: 149 to 150 ° C IR (KBr): 3476, 2952, 1680, 16
00, 1336, 1130, 840, 701 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.75 to 1.9
4 (4H, m), 2.20 to 2.40 (4H, m),
2.65-3.41 (5H, m), 4.08 (2H,
t, J = 6.8 Hz), 6.43 (2H, t, J = 8.
4 Hz), 6.78 (2H, s), 7.03 to 7.42
(8H, m), 7.95 (2H, dd, J = 8.6,
5.5 Hz).

Example 269 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-trifluoromethylphenyl) be
Benzamide fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-trifluoromethylphenyl) benzamide (139.0 m
The title compound was obtained as a colorless powder in an amount of 157.0 mg (94.0%) by the same procedure as in Example 244. Melting point: 205-206 ° C IR (KBr): 3343, 1680, 1600, 13
14, 1264, 1174, 1130, 850, 76
3,609 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.82 to 1.9
8 (4H, m), 2.09 (3H, s), 2.33 ~
2.60 (2H, m), 2.80 (2H, t, J = 6.
6Hz), 3.05 to 3.30 (3H, m), 4.13
(2H, t, J = 6.6 Hz), 6.78 (2H,
s), 7.05 to 7.46 (10H, m), 7.96
(2H, dd, J = 8.8, 5.5Hz).

Example 270 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-pyridyl) benzamide fumaric acid
The salt 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-pyridyl) benzamide (151.0 mg, 0.31 mmol) was used as in Example 244. By performing the same operation, 145.0 mg (7%) of the title compound was obtained as a colorless powder.
7.6%). Melting point: 200 to 208 ° C. IR (KBr): 3245, 1683, 1644, 15
99, 1527, 1428, 1410, 1314, 12
30,1182,849 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.12 (3H,
s), 1.60 to 2.44 (6H, m), 2.68 (2
H, t, J = 7.0 Hz), 2.97 to 3.72 (3
H, m), 4.09 (2H, t, J = 7.0 Hz),
6.80 (2H, s), 6.97 to 7.60 (8H,
m), 7.95 (2H, dd, J = 9.0, 6.0H
z) 8.24-8.70 (3H, m).

Example 271 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methylthiophenyl) benzami
Dofumarate 4- Acetylamino -N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methylthiophenyl) benzamide (167.2 mg, 0.3
(1 mmol) was used to perform the same operation as in Example 244 to obtain 177.7 of the title compound as a colorless powder.
mg (88.2%) was obtained. Melting point: 128 to 133 ° C IR (KBr): 1680, 1640, 1598, 15
32, 1476, 1440, 1408, 1372, 13
14, 1260, 1226, 1180, 1158, 97
2,954,852,760 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.11 (3H,
s), 1.89 to 2.52 (10H, m), 2.50
(3H, s), 2.74 to 2.77 (2H, m), 3.
04-3.45 (4H, m), 4.09 (2H, dd,
J = 6.6, 6.4 Hz), 6.77 to 7.40 (10
H, m), 7.95 (2H, dd, J = 8.6, 6.0)
Hz).

Example 272 2- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Fumarate 2-Acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (170.4 mg, 0.33
(14 mmol) of the title compound as a colorless powder by performing the same operation as in Example 244 using
g (70.0%) was obtained. Melting point: 105 to 107 ° C IR (KBr): 3450, 1678, 1598, 14
92, 1386, 1284, 1158 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.23 (3H,
s), 1.63 to 2.50 (5H, m), 2.68 (2
H, t, J = 6.6 Hz), 2.85 to 3.46 (2
H, m), 3.67 (3H, s), 4.10 (2H,
t, J = 6.6 Hz), 6.40 to 6.92 (4H,
m), 6.80 (2H, s), 6.92 to 7.35 (5
H, m), 7.95 (2H, dd, J = 9.0, 6.0)
Hz), 8.17 (1H, d, J = 8.4 Hz), 9.
30 (1H, brs).

Example 273 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-aminophenyl) benzamide fumar
Example 244 Using the acid salt 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-aminophenyl) benzamide (123.0 mg, 0.27 mmol). The title compound was obtained as a pale yellow amorphous by the same operation as in 107.
Obtained 8 mg (70.1%). IR (KBr): 3350, 1680, 1599, 14
94, 1440, 1218, 1158, 840 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.3
0 (4H, m), 2.70 to 3.77 (11H, m),
4.17 (2H, t, J = 7.0Hz), 6.18-
6.57 (5H, m), 6.73 (2H, s), 6.8
0 to 7.32 (5H, m), 7.95 (2H, dd, J
= 9.0, 6.0 Hz).

Example 274 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-acetylaminophenyl) benz
Amido fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-acetylaminophenyl) benzamide (231.0 mg,
(0.424 mmol) was used to perform the same operation as in Example 244 to give the title compound (2) as a colorless powder.
01.0 mg (75.6%) was obtained. Melting point: 214.5 to 222.5 ° C IR (KBr): 3260, 3060, 1689, 13
26, 1596, 1530, 1446, 1389, 12
48,1155,855 cm ^-1 . NMR (CDCl ₃ -DMSO-d ₆ ) δ: 1.52
3.29 (11H, m), 2.10 (6H, s), 2.
51-3.36 (6H, m), 4.13 (2H, t, J
= 7.0 Hz), 6.80 (2H, s), 6.92-
7.55 (10H, m), 7.97 (2H, dd, J =
9.0, 6.0 Hz), 8.49-8.78 (2H,
m).

Example 275 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (2-methoxycarbonylphenyl) be
Insamide fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (2-methoxycarbonylphenyl) benzamide (164.0 m
The title compound was obtained as a colorless powder in an amount of 150.4 mg (75.6%) by the same procedure as in Example 244. Melting point: 176 to 186 ° C IR (KBr): 3342, 1714, 1680, 15
98, 1314, 1264, 843, 759, 675
600 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.83 to 2.0
1 (4H, m), 2.08 (3H, s), 2.51
3.36 (6H, m), 3.80 (3H, s), 4.1
7-4.41 (1H, m), 6.73 (2H, s),
7.06 to 7.70 (10H, m), 7.96 (2H,
dd, J = 8.6, 5.5 Hz).

Example 276 4-amidino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (4-methoxyphenyl) benzamide fuma
Example Using the Phosphate 4-Amidino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methoxyphenyl) benzamide (150.0 mg, 0.30 mmol) By performing a similar operation to that of 244, the title compound was obtained as a colorless amorphous product with a yield of 185.0.
mg (quantitative) was obtained. Melting point: 137 to 164 ° C IR (KBr): 3370, 3045, 1678, 16
38,1510,848,652,603 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.05 to 2.2
7 (4H, m), 2.73 to 3.43 (7H, m),
3.72 (3H, s), 4.09 to 4.29 (2H,
m), 6.74 (2H, s), 6.75 (2H, d, J
= 8.8 Hz), 7.07 to 7.63 (8H, m),
7.94 (2H, dd, J = 8.6, 5.3Hz).

Example 277 4-Acetylamino-3-
Methyl-N- {2- [4- (4-fluorobenzoyl)
Piperidino] ethyl} -N- (4-methoxyphenyl)
Benzamide fumarate 4-acetylamino-3-methyl-N- {2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
-(4-Methoxyphenyl) benzamide (159.0
The title compound was obtained as a colorless powder in an amount of 176.4 mg (90.7%) by the same procedure as in Example 244. Melting point: 171-172 ° C IR (KBr): 3440, 2951, 1682, 16
44, 1598, 1512, 1304, 1032, 84
7,637 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.71 to 2.0
4 (4H, m), 2.14 (6H, s), 2.42 ~
2.66 (2H, m), 2.85 (2H, t, J = 7.
5 Hz), 3.11 to 3.39 (3H, m), 3.75
(3H, s), 4.09 (2H, t, J = 7.5H
z), 6.69 to 6.79 (4H, m), 6.95 to
7.32 (6H, m), 7.53 to 7.62 (1H,
m), 7.96 (2H, dd, J = 8.8, 5.5H)
z).

Example 278 4-Acetylamino-3-
Methoxy-N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (4-methoxypheny
Le) Benzamide fumarate 4-acetylamino-3-methoxy-N- {2- [4-
(4-Fluorobenzoyl) piperidino] ethyl} -N
-(4-Methoxyphenyl) benzamide (137.0
160.0 mg (96.4%) of the title compound was obtained as colorless needle crystals by performing the same operation as in Example 244 by using (mg, 0.25 mmol). Melting point: 189 to 193 ° C IR (KBr): 3440, 2945, 1680, 16
38, 1598, 1510, 1301, 759, 643
cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.89 to 2.0
4 (4H, m), 2.16 (3H, s), 2.35
3.31 (7H, m), 3.73 (3H, s), 3.7
6 (3H, s), 4.08 (2H, t, J = 7.3H
z), 6.78 (2H, s), 6.70 to 7.32 (8)
H, m), 7.88-8.14 (3H, m).

Example 279 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-methylphenyl) benzamide
Mar salt of 4-acetylamino--N- {2- [4- (4- fluorobenzoyl) piperidino] ethyl}-N-(4-methylphenyl) benzamide (307.9mg, 0.61 mmol) performed using By performing the same operation as in Example 244, 335.3 mg of the title compound was obtained as a colorless powder.
(89.0%) was obtained. Melting point: 217 to 221 ° C (decomposition) IR (KBr): 1682, 1638, 1594, 15
30, 1510, 1452, 1414, 1390, 13
16,1262,1228,1184,1158,11
36,1110,974,852,764,636cm
^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.79 to 1.8
4 (4H, m), 2.08 (3H, s), 2.27 (3
H, s), 2.56 to 2.70 (4H, m), 2.95.
Up to 3.23 (3H, m), 3.94 to 4.08 (3H,
m), 6.74 to 7.56 (10H, m), 7.95
(2H, dd, J = 8.8, 5.5Hz).

Example 280 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-fluorophenyl) benzamide
Fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-fluorophenyl) benzamide (158.8 mg, 0.31
The title compound was obtained as a colorless amorphous compound in the same manner as in Example 244 by performing the same operation as in Example 244.
Obtained 1.9 mg (68.4%). Melting point: 210 to 214 ° C. (decomposition) IR (KBr): 1684, 1632, 1594, 15
30, 1510, 1410, 1386, 1332, 13
16,1264,1224 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.77 to 1.8
3 (4H, m), 2.08 (3H, s), 2.09-
2.29 (2H, m), 2.59 to 2.67 (4H,
m), 2.88 to 3.04 (4H, m), 3.14 to
3.78 (2H, m), 4.00 (2H, dd, J =
6.4, 6.2 Hz), 6.96 (2H, d, J = 8.
6 Hz), 7.03 to 7.22 (5 H, m), 7.44
(2H, d, J = 8.6Hz), 7.58 (1H, br
s), 7.89-8.04 (2H, m).

Example 281 4- (Pyrrole-1-a)
) -N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (4-methoxyphenyl) be
4- ( Pyrrol -1-yl) -N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -N- (4
-Methoxyphenyl) benzamide (131.0 mg,
By performing the same operation as in Example 244 using (0.25 mmol), 144.0 mg (90.0%) of the title compound was obtained as colorless needle crystals. Melting point: 167-169 ° C IR (KBr): 3446, 2951, 1680, 16
10, 1512, 1330, 836, 710 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.94 to 2.0
4 (4H, m), 2.07 to 2.88 (4H, m),
3.12-3.34 (3H, m), 3.75 (3H,
s), 4.13 (2H, d, J = 6.3Hz), 6.3
1 (2H, t, J = 2.2Hz), 6.76 (2H,
s), 6.77 (2H, d, J = 8.8Hz), 6.9.
6 to 7.40 (10H, m) 7.96 (2H, dd, J
= 8.8, 5.3 Hz).

Example 282 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-hydroxyphenyl) benzami
Dofumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-hydroxyphenyl) benzamide (154.3 mg, 0.3
By repeating the same procedure as in Example 244 using 1 mmol), 167.6 mg (88.3%) of the title compound was obtained as a pale yellow amorphous substance. IR (KBr): 2974, 1683, 1641, 15
99, 1530, 1485, 1443, 1410, 13
80, 1314, 1257, 1182, 1152, 97
2,954,849,759 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.0
5 (4H, m), 2.10 (3H, s), 2.37-
3.67 (7H, m), 4.13 (2H, t, J = 7.
0 Hz), 6.77 (2H, s), 6.30 to 7.40
(10H, m), 7.80 to 8.05 (2H, m).

Example 283 4- (N-methyl-acetyl)
Luamino) -N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (4-methoxypheny
Le) Benzamide fumarate 4- (N-methyl-acetylamino) -N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-methoxyphenyl) benzamide (115.
By performing the same operation as in Example 244 using 0 mg (0.22 mmol), 141.0 mg (quantitative) of the title compound was obtained as colorless needle crystals. Melting point: 143-145 ° C IR (KBr): 3450, 1680, 1652, 16
00, 1512, 1250, 857, 651 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.78 (3H,
s), 1.78 to 2.03 (4H, m), 2.29 to
2.60 (2H, m), 2.81 (2H, t, J = 7.
0 Hz), 3.08 to 3.40 (3H, m), 3.17
(3H, s), 3.75 (3H, s), 4.10 (2
H, t, J = 7.0 Hz), 6.74 (2H, d, J =
8.8 Hz), 6.78 (2H, s), 6.96-7.
37 (8H, m), 7.96 (2H, dd, J = 8.
8, 5.5 Hz).

Example 284 4- (N-dimethylamido)
No) -N- {2- [4- (4-fluorobenzoyl) pi]
Peridino] ethyl} -N- (4-methoxyphenyl) be
Benzamide fumarate 4- (N-dimethylamino) -N- {2- [4- (4-
Fluorobenzoyl) piperidino] ethyl} -N- (4
-Methoxyphenyl) benzamide (110.0 mg,
(0.22 mmol) was used to perform the same operation as in Example 244 to obtain 114.0 mg (61.1%) of the title compound as colorless needle crystals. Melting point: 226 to 228 ° C. (decomposition) IR (KBr): 3440, 2940, 1600, 15
10, 1370, 1032, 832, 644 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.95 to 2.0
6 (4H, m), 2.62 to 3.45 (7H, m),
2.92 (6H, s), 3.77 (3H, s), 4.1
1 (2H, t, J = 7.0Hz), 6.43 (2H,
d, J = 9.0 Hz), 6.77 (2H, s), 6.7
8 (2H, d, J = 9.0 Hz), 6.97 to 7.30
(6H, m), 7.97 (2H, dd, J = 8.8,
5.5 Hz).

Example 285 3-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (phenyl) benzamide fumarate 3-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (phenyl)
By performing the same operation as in Example 244 using benzamide (91.1 mg, 0.19 mmol), 74.3 mg (65.9) of the title compound was obtained as a pale yellow powder.
%)Obtained. Melting point: 137 to 138 ° C IR (KBr): 1676, 1648, 1596, 15
60, 1494, 1430, 1382, 1306, 12
90, 1264, 1228, 1158, 976, 74
8,698 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.77 to 1.9
3 (4H, m), 2.13 (3H, s), 2.27-
2.43 (2H, m), 2.67 (2H, t, J = 6.
6 Hz), 2.97 to 3.84 (8H, m), 4.07
(2H, t, J = 6.6 Hz), 6.79 to 6.84
(2H, m), 7.14 to 7.34 (9H, m), 7.
93 (1H, d, J = 8.6Hz), 7.99 (1H,
d, J = 8.6 Hz).

Example 286 3- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-methylthiophenyl) benzami
Dofumarate 3-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-methylthiophenyl) benzamide (127.2 mg, 0.2
(8 mmol) to carry out the same operation as in Example 244 to obtain 88.1 of the title compound as a pale yellow powder.
mg (56.9%) was obtained. Melting point: 95-97 ° C IR (KBr): 1680, 1640, 1588, 15
52, 1374, 1314, 1226 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.80 to 2.1
2 (4H, m), 2.13 (3H, s), 2.35 (3
H, s), 2.31 to 2.54 (4H, m), 2.77.
(2H, t, J = 6.6 Hz), 3.06 to 3.31
(6H, m), 4.12 (2H, t, J = 6.6H
z), 6.81 to 7.39 (10H, m), 7.93.
(1H, d, J = 8.4 Hz), 7.99 (1H, d,
J = 8.4 Hz).

Example 287 3- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-methylphenyl) benzamide
Mar salt of 3-acetylamino--N- {2- [4- (4- fluorobenzoyl) piperidino] ethyl}-N-(4-methylphenyl) benzamide (199.4mg, 0.40 mmol) performed using By performing the same operation as in Example 244, the title compound as a pale brown amorphous compound
Obtained 0.2 mg (93.2%). Melting point: 93 to 95 [deg.] C. IR (KBr): 1680, 1598 cm < ^-1 >. NMR (CDCl ₃ -CD ₃ OD) δ: 1.87 to 2.4
3 (6H, m), 2.13 (3H, s), 2.28 (3
H, s), 2.70 (2H, t, J = 6.6 Hz),
2.98 to 3.62 (4H, m), 4.07 (2H,
t, J = 6.6 Hz), 6.82 to 7.28 (9H,
m), 7.69 to 7.72 (1H, m), 7.93 (1
H, d, J = 8.8 Hz), 7.99 (1H, d, J =
8.8 Hz).

Example 288 3-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-fluorophenyl) benzamide
Fumarate 3-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-fluorophenyl) benzamide (182.5 mg, 0.36
The title compound was obtained as a pale brown amorphous compound in the same manner as in Example 244 by performing the same operation as in Example 244.
Obtained 84.2 mg (82.3%). Melting point: 93 to 95 ° C IR (KBr): 1682, 1640, 1598, 15
54, 1508, 1378, 1320, 1220, 11
56 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.84 to 1.9
6 (4H, m), 2.12 (3H, s), 2.20-
2.45 (3H, m), 2.61 to 3.42 (9H,
m), 4.04 (2H, t, J = 6.4Hz), 6.6
9 to 7.70 (10H, m), 7.93 (1H, d, J
= 8.6 Hz), 7.99 (1H, d, J = 8.8H
z).

Example 289 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-hydroxyphenyl) benzamid
Dofumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (4-hydroxyphenyl) benzamide (215.0 mg, 0.4
(3 mmol) in the same manner as in Example 244 to give the title compound as a pale yellow powder.
0 mg (96.0%) was obtained. Melting point: 72 to 74 ° C IR (KBr): 3044, 1680, 1598, 15
12, 1448, 1408, 1378, 1316, 12
64, 1228, 1182, 1158, 976, 95
2,842,760 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 2.1
3 (6H, m), 2.08 (3H, s), 2.30 ~
2.73 (5H, m), 3.88-4.20 (2H,
m), 6.53 to 6.99 (4H, m), 6.75 (2
H, s), 7.00 to 7.40 (6H, m), 7.80
~ 8.05 (2H, m).

Example 290 4-propionylamino-
N- {2- [4- (4-fluorobenzoyl) piperidi
No] ethyl} -N- (3-methoxyphenyl) benzua
Midofumarate 4-propionylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (106.0 mg, 0.
20 mmol) was used to perform the same operation as in Example 244 to obtain 110.
0 mg (85.3%) was obtained. Melting point: 214 to 218 ° C IR (KBr): 3445, 1680, 1600, 12
96,1216,853,638 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 (3H,
t, J = 7.4 Hz), 1.83 to 2.00 (4H,
m), 2.22 to 3.86 (9H, m), 3.70 (3
H, s), 3.88 to 4.20 (2H, m), 6.61.
~ 6.77 (5H, m), 7.05 ~ 7.45 (7H,
m), 7.89-8.04 (2H, m).

Example 291 4-valerylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Fumarate 4-valerylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (142.0 mg, 0.25
152.0 m of the title compound as a colorless powder by performing the same operation as in Example 244 using
g (85.9%) was obtained. Melting point: 229 to 230 ° C (decomposition) IR (KBr): 3450, 2951, 1678, 16
00, 1296, 1180, 857, 646 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 0.92 (3H,
t, J = 6.4 Hz), 1.00 to 4.37 (22H,
m), 3.71 (3H, s), 6.64 to 6.77 (5
H, m), 7.06 to 7.45 (7H, m), 7.96
(2H, dd, J = 8.6, 5.5Hz).

Example 292 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3,4-methylenedioxyphenyl)
Benzamide fumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,4-methylenedioxyphenyl) benzamide (210.3 m
The title compound was obtained as a colorless powder (195.9 mg, 76.5%) by the same procedure as in Example 244. Melting point: 223-224 ° C IR (KBr): 1710, 1680, 1644, 15
96, 1530, 1506, 1485, 1452, 14
10, 1389, 1317, 1257, 1218, 11
82,1161,1041,849 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 2.0
0 (4H, m), 2.11 (3H, s), 2.20 ~
2.57 (2H, m), 2.74 (2H, t, J = 6.
9Hz), 2.87 to 3.47 (3H, m), 4.03
(2H, t, J = 6.9 Hz), 5.95 (2H,
s), 6.37 to 6.70 (3H, m), 6.79 (2)
H, s), 6.90 to 7.50 (6H, m), 7.80
~ 8.05 (2H, m).

Example 293 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3,4-dimethylphenyl) benza
Midofumarate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3,4-dimethylphenyl) benzamide (218.2 mg, 0.
(42 mmol) in the same manner as in Example 244 to give the title compound as a colorless powder.
Obtained 6 mg (84.3%). Melting point: 210 to 212 ° C. (decomposition) IR (KBr): 1710, 1682, 1656, 16
42, 1534, 1504, 1408, 1382, 13
16,1262,1234,1218,1182,11
60,848,762,636 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.09 (3H,
s), 2.19 (6H, brs), 1.96 to 2.92.
(10H, m), 3.01 (2H, t, J = 7.0H
z), 3.20 to 3.54 (3H, m), 4.16 (2
H, t, J = 6.8 Hz), 6.73 (2H, s),
6.87-7.47 (7H, m), 8.05 (2H, d
d, J = 8.6, 5.5 Hz).

Example 294 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (4-chlorophenyl) benzamide
Mar salt of 4-acetylamino--N- {2- [4- (4- fluorobenzoyl) piperidino] ethyl}-N-(4-chlorophenyl) benzamide (159.0mg, 0.30 mmol) using Example By performing the same operation as in 244, 140.8 mg of the title compound was obtained as a colorless powder.
(73.6%) was obtained. Melting point: 218 to 220 ° C. (decomposition) IR (KBr): 1682, 1636, 1596, 15
30, 1492, 1414, 1384, 1318, 12
62, 1228, 1186 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.78 to 1.8
4 (4H, m), 2.10 (3H, s), 2.10
2.31 (2H, m), 2.61 to 2.68 (3H,
m), 2.93 to 3.83 (7H, m), 4.01 (2
H, t, J = 6.8 Hz), 6.75 (2H, s),
7.00 to 7.23 (4H, m), 7.40 to 7.53
(4H, m), 7.96 (2H, dd, J = 8.6,
5.5).

Example 295 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (1-naphthyl) benzamide fumaric acid
Example 244 using the salt 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (1-naphthyl) benzamide (334.2 mg, 0.622 mmol). By performing the same operation, 360.7 mg of the title compound was obtained as a pale yellow powder.
(88.8%) was obtained. Melting point: 217 to 221 ° C (decomposition) IR (KBr): 3050, 1680, 1644, 15
99, 1530, 1350, 1407, 1383, 13
14, 1260, 1230, 1182, 1158, 84
9,771 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.50 to 1.9
7 (4H, m), 2.02 (3H, s), 2.20 ~
2.60 (2H, m), 2.60 to 3.43 (5H,
m), 3.55 to 3.92 (1H, m), 4.40 to
4.75 (1H, m), 6.73 (2H, s), 6.9
0-8.08 (15H, m).

Example 296 4- Acetylamino -N-
{3- [4- (4-fluorobenzoyl) piperidino]
Propyl} -N- (3-methoxyphenyl) benzamid
Dofumarate 4-acetylamino-N- {3- [4- (4-fluorobenzoyl) piperidino] propyl} -N- (3-methoxyphenyl) benzamide (312.6 mg, 0.5
(9 mmol) was used to perform the same operation as in Example 244 to obtain the title compound as a colorless powder, 308.7.
mg (80.9%) was obtained. Melting point: 190 to 193 ° C IR (KBr): 1682, 1634, 1600, 15
28, 1490, 1408, 1314, 1258, 11
82,1050,844 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.76 to 2.2
5 (6H, m), 2.09 (3H, s), 2.56 ~
3.00 (4H, m), 3.69 (3H, s), 3.9
4 (2H, dd, J = 7.0, 6.5Hz), 6.50
.About.6.80 (3H, m), 6.74 (2H, s), 6.
95 to 7.50 (7H, m), 7.96 (2H, dd,
J = 8.5, 5.3 Hz).

Example 297 4-amino-N- {3-
[4- (4-Fluorobenzoyl) piperidino] propyi
Ru} -N- (3-methoxyphenyl) benzamide fumara
Example Using Phosphate 4-Amino-N- {3- [4- (4-fluorobenzoyl) piperidino] propyl} -N- (3-methoxyphenyl) benzamide (300.0 mg, 0.61 mmol) By performing the same operation as in 244, 321.3 mg (8
1.1%) was obtained. Melting point: 170 to 172 ° C IR (KBr): 1680, 1598, 1562, 14
88, 1452, 1394, 1306, 1282, 12
30,1180,1158 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.70 to 2.2
3 (6H, m), 2.50 to 2.95 (4H, m),
3.00 to 3.53 (5H, m), 3.70 (3H,
s), 3.92 (2H, t, J = 7.0Hz), 6.4
1 (2H, d, J = 8.4 Hz), 6.50 to 6.85
(2H, m), 6.74 (2H, s), 6.95 to 7.
36 (6H, m), 7.95 (2H, dd, J = 8.
6, 5.5 Hz).

Example 298 4- (N-methyl-acetyl)
Luamino) -N- {2- [4- (4-fluorobenzoi
Ru) piperidino] ethyl} -N- (3-methoxypheny
Le) Benzamide fumarate 4- (N-methyl-acetylamino) -N- {2- [4
-(4-Fluorobenzoyl) piperidino] ethyl}-
N- (3-methoxyphenyl) benzamide (81.8
The title compound was obtained as a colorless powder in an amount of 69.7 mg (69.8%) by the same procedure as in Example 244. Melting point: 161-167 ° C IR (KBr): 3440, 1648, 1600, 13
82, 1304, 1158, 854, 700 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 1.78 (3H,
s), 1.84 to 2.01 (4H, m), 2.22 to
2.64 (2H, m), 2.82 (2H, t, J = 6.
7 Hz), 3.18 (3H, s), 3.09 to 3.40.
(3H, m), 3.70 (3H, s), 4.14 (2
H, t, J = 6.7 Hz), 6.63 to 6.78 (4
H, m), 6.96 to 7.41 (6H, m), 7.95.
(2H, dd, J = 8.6, 5.5Hz).

Example 299 4-Acetylamino-N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Tartrate 4-acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (155.0 mg, 0.30
143.0 mg (7 mg) of the title compound as a colorless powder by performing the same operation as in Example 244 using (3 mmol) and tartaric acid (35.0 mg, 0.30 mmol).
5.3%) was obtained. Melting point: 152-175 ° C IR (KBr): 3440, 3325, 1686, 16
00, 1312, 1216, 851 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.10 (3H,
s), 1.99 to 4.44 (12H, m), 3.70.
(3H, s), 6.62 to 6.77 (3H, m), 7.
07-7.45 (7H, m), 7.91-8.06 (2
H, m).

Example 300 4- Acetylamino -N-
{2- [4- (4-fluorobenzoyl) piperidino]
Ethyl} -N- (3-methoxyphenyl) benzamide
Maleate 4-Acetylamino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (155.0 mg, 0.30
164.0 mg of the title compound as a colorless powder by performing the same operation as in Example 244 using maleic acid (45.0 mg, 0.30 mmol) and maleic acid.
(82.0%) was obtained. Melting point: 212.0 to 213 ° C IR (KBr): 3447, 1686, 1640, 15
98, 1320, 1214, 856 cm ^-1 . NMR (CDCl ₃ -CD ₃ OD) δ: 2.11 (3H,
s), 2.16 to 3.75 (11H, m), 3.70.
(3H, s), 4.27 (2H, t, J = 7.0H
z), 6.23 (2H, s), 6.58 to 6.77 (3
H, m), 7.08 to 7.45 (7H, m), 7.98.
(2H, dd, J = 8.7, 5.4 Hz).

Example 301 4-amino-N- {2-
[4- (4-Fluorobenzoyl) piperidino] eth
Ru} -N- (3-methoxyphenyl) benzamide hemi
Fumarate 4-amino-N- {2- [4- (4-fluorobenzoyl) piperidino] ethyl} -N- (3-methoxyphenyl) benzamide (475.0 mg, 1.00 mmol) in methanol (4. It was dissolved in 0 ml), and a solution of fumaric acid (58.0 mg, 0.50 mmol) in methanol (3.0 ml) was added at 0 ° C. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of ethanol-water to give 481.0 mg of the title compound as a colorless powder.
(90.0%) was obtained. Melting point: 176 to 179 ° C IR (KBr): 3450, 3340, 1672, 16
32, 1602, 1510, 1490, 1362, 13
18,1284,1202,1122,960,840
cm ^-1 . _{NMR (CDCl 3 -DMSO-d 6} ) δ: 1.50~
2.00 (5H, m), 2.13 to 2.49 (2H,
m), 2.72 (2H, t, J = 7.5Hz), 2.9
0 to 3.25 (4H, m), 3.69 (3H, s),
4.05 (2H, t, J = 7.5Hz), 6.40 (2
H, d, J = 8.5 Hz), 6.50 to 6.80 (2
H, m), 6.75 (1H, s), 6.93 to 7.26.
(6H, m), 7.95 (2H, dd, J = 8.8,
5.5 Hz).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 233/66 7106-4H 233/69 7106-4H 235/46 7106-4H 235/48 7106-4H 237/30 7106-4H 237/32 7106-4H 237/42 7106-4H 251/48 8829-4H 255/57 257/18 8318-4H 271/20 9451-4H 309/65 309/66 311/13 311 / 15 323/42 C07D 211/18 211/22 211/26 213/71 213/81 295/12 A 401/06 211 241 401/12 211 241 405/12 213 // C07C 69/612 9279-4H (72) Inventor Gen Kago 1 Tanaka, Yuno, Iisaka-cho, Fukushima-shi, Fukushima Prefecture (72) Inuki Inoue Toki, Nishino, Fukushima-shi, Yuno-ji, Isaka-cho, Fukushima-ken (72) Inventor, Shoko Ishigami Tanaka, Inosaka, Fukushima-shi, Fukushima-shi Tanaka 1 (72) Inventor Shinichi Yamada 51-2 Nakayamaki, Miyama, Fukushima City, Fukushima Prefecture (72) Inventor Takahiro Yamaguchi Fukushima 1 Tanaka, Yuno, Iisaka-cho, Fukushima 1 (72) Yoichi Mame, 1 Tanaka, Yuno, Iisaka-cho, Fukushima-shi, Fukushima (72) Inventor, Isamu Sato 18-9, Yuno, Isaka, Fukushima-shi, Fukushima Inventor Kentaro Furushiro 9-6 Kuroyama, Koriyama, Shiroishi City, Miyagi Prefecture (72) Inventor Senichi Narita 1-8-2-902 Iriya, Taito-ku, Tokyo

Claims (8)

[Claims] 1. A general formula: (In the formula, A is a group represented by a member of the group consisting of —CONR ⁴ — or —SO ₂ NR ⁴ —, and B is a single bond or —CHO.
H- or a carbonyl group, D represents a methine, a nitrogen atom or = N (→ O)-, Q represents a methine group or a nitrogen atom, R ¹ and R ² may be the same or different, and a hydrogen atom, Halogen atom, linear or branched lower alkyl group, lower alkenyl group, lower alkoxy group, lower hydroxyalkyl group, lower alkoxy substituted alkyl group, lower alkyl substituted or unsubstituted amino group, lower acylamino group, substituted sulfonylamino group A lower alkoxycarbonylamino group, a lower alkyl substituted or unsubstituted aminoalkyl group, a lower acylaminoalkyl group, a substituted sulfonylaminoalkyl group, a lower alkoxycarbonylaminoalkyl group, a substituted or unsubstituted amidino group,
It represents a substituted or unsubstituted ureido group, a substituted or unsubstituted thioureido group, an azole group, a carboxyl group, a lower alkoxycarbonyl group, a formyl group, a lower alkyl substituted or unsubstituted carbamoyl group, a cyano group, an oxime group or a nitro group. , R ³ represents a hydrogen atom, a halogen atom or a mono- or di-substituted alkylamino group of a lower alkyl group, R ⁴ represents a lower alkyl group, a lower alkenyl group, a lower alkoxy substituted alkyl group, a lower alkoxycarbonyl substituted alkyl group, a substituted or Unsubstituted aralkyl group, lower acyl group, substituted or unsubstituted aryloyl group, halogen atom as a substituent, lower alkyl group, halogenated lower alkyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, lower acylamino group, cyano Group, lower Represents a phenyl group which may contain 1 or 2 rukylthio groups, a naphthyl group or a 5- or 6-membered aromatic heterocycle, and n represents an integer of 2 to 6)
A substituted cyclic amine compound represented by or a salt thereof. 2. A compound represented by the general formula: which is a synthetic intermediate of compound (1). (In the formula, A represents a group represented by a member of the group consisting of —CONR ⁴ — or —SO ₂ NR ⁴ —, D represents methine, a nitrogen atom or ═N (→ O) —, and R ¹ , R ² May be the same or different, and may be a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower hydroxyalkyl group, a lower alkoxy-substituted alkyl group, a lower alkyl-substituted or unsubstituted. An amino group, a lower acylamino group, a substituted sulfonylamino group,
Lower alkoxycarbonylamino group, lower alkyl substituted or unsubstituted aminoalkyl group, lower acylaminoalkyl group, substituted sulfonylaminoalkyl group, lower alkoxycarbonylaminoalkyl group, substituted or unsubstituted amidino group, substituted or unsubstituted ureido Base,
A substituted or unsubstituted thioureido group, an azole group, a carboxyl group, a lower alkoxycarbonyl group, a formyl group, a lower alkyl-substituted or unsubstituted carbamoyl group, a cyano group, an oxime group or a nitro group, R ⁴
Is a lower alkyl group, a lower alkenyl group, a lower alkoxy substituted alkyl group, a lower alkoxycarbonyl substituted alkyl group, a substituted or unsubstituted aralkyl group, a lower acyl group, a substituted or unsubstituted aryloyl group, a halogen atom as a substituent, a lower alkyl Group, halogenated lower alkyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, lower acylamino group, cyano group, phenyl group which may contain 1 or 2 lower alkylthio groups, naphthyl group or 5- or 6-membered aromatic ring Represents a group heterocycle,
R ⁵ represents a halogen atom, a hydroxyl group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a P-toluenesulfonyloxy group, a tetrahydropyranyloxy group, a lower alkoxy group, a lower acyloxy group or a trimethylsilyloxy group, and n is 2 to And represents an integer of 6.). 3. A compound represented by the general formula: which is a synthetic intermediate of compound (1). (In the formula, A represents a group represented by a member of the group consisting of —CONR ⁴ — or —SO ₂ NR ⁴ —, D represents methine, a nitrogen atom or ═N (→ O) —, and R ¹ , R ² May be the same or different, and may be a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower hydroxyalkyl group, a lower alkoxy-substituted alkyl group, a lower alkyl-substituted or unsubstituted. An amino group, a lower acylamino group, a substituted sulfonylamino group,
Lower alkoxycarbonylamino group, lower alkyl substituted or unsubstituted aminoalkyl group, lower acylaminoalkyl group, substituted sulfonylaminoalkyl group, lower alkoxycarbonylaminoalkyl group, substituted or unsubstituted amidino group, substituted or unsubstituted ureido Base,
A substituted or unsubstituted thioureido group, an azole group, a carboxyl group, a lower alkoxycarbonyl group, a formyl group, a lower alkyl-substituted or unsubstituted carbamoyl group, a cyano group, an oxime group or a nitro group, R ⁴
Is a lower alkyl group, a lower alkenyl group, a lower alkoxy substituted alkyl group, a lower alkoxycarbonyl substituted alkyl group, a substituted or unsubstituted aralkyl group, a lower acyl group, a substituted or unsubstituted aryloyl group, a halogen atom as a substituent, a lower alkyl Group, halogenated lower alkyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, lower acylamino group, cyano group, phenyl group which may contain 1 or 2 lower alkylthio groups, naphthyl group or 5- or 6-membered aromatic ring Represents a group heterocycle,
n represents an integer of 2 to 6). 4. A general formula: (In the formula, A represents a group represented by a member of the group consisting of —CONR ⁴ — or —SO ₂ NR ⁴ —, D represents methine, a nitrogen atom or ═N (→ O) —, and R ¹ , R ² May be the same or different, and may be a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower hydroxyalkyl group, a lower alkoxy-substituted alkyl group, a lower alkyl-substituted or unsubstituted. An amino group, a lower acylamino group, a substituted sulfonylamino group,
Lower alkoxycarbonylamino group, lower alkyl substituted or unsubstituted aminoalkyl group, lower acylaminoalkyl group, substituted sulfonylaminoalkyl group, lower alkoxycarbonylaminoalkyl group, substituted or unsubstituted amidino group, substituted or unsubstituted ureido Base,
A substituted or unsubstituted thioureido group, an azole group, a carboxyl group, a lower alkoxycarbonyl group, a formyl group, a lower alkyl-substituted or unsubstituted carbamoyl group, a cyano group, an oxime group or a nitro group, R ⁴
Is a lower alkyl group, a lower alkenyl group, a lower alkoxy substituted alkyl group, a lower alkoxycarbonyl substituted alkyl group, a substituted or unsubstituted aralkyl group, a lower acyl group, a substituted or unsubstituted aryloyl group, a halogen atom as a substituent, a lower alkyl Group, halogenated lower alkyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, lower acylamino group, cyano group, phenyl group which may contain 1 or 2 lower alkylthio groups, naphthyl group or 5- or 6-membered aromatic ring Represents a group heterocycle,
X represents a halogen atom, a hydroxyl group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a P-toluenesulfonyloxy group, and n represents an integer of 2 to 6) and a compound represented by the general formula: (In the formula, B represents a single bond or -CHOH- or a carbonyl group, Q represents a methine group or a nitrogen atom, and R ³ represents a hydrogen atom, a halogen atom or a mono- or di-substituted alkylamino group of a lower alkyl group.) A compound represented by the general formula: (Wherein A, B, D, Q, R ¹ , R ² , R ³ and n have the same meanings as defined above), and a method for producing a substituted cyclic amine compound or a salt thereof. 5. A general formula: (In the formula, A represents a group represented by a member of the group consisting of —CONR ⁴ — or —SO ₂ NR ⁴ —, D represents methine, a nitrogen atom or ═N (→ O) —, and R ¹ , R ² May be the same or different, and may be a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower hydroxyalkyl group, a lower alkoxy-substituted alkyl group, a lower alkyl-substituted or unsubstituted. An amino group, a lower acylamino group, a substituted sulfonylamino group,
Lower alkoxycarbonylamino group, lower alkyl substituted or unsubstituted aminoalkyl group, lower acylaminoalkyl group, substituted sulfonylaminoalkyl group, lower alkoxycarbonylaminoalkyl group, substituted or unsubstituted amidino group, substituted or unsubstituted ureido Base,
A substituted or unsubstituted thioureido group, an azole group, a carboxyl group, a lower alkoxycarbonyl group, a formyl group, a lower alkyl-substituted or unsubstituted carbamoyl group, a cyano group, an oxime group or a nitro group, R ⁴
Is a lower alkyl group, a lower alkenyl group, a lower alkoxy substituted alkyl group, a lower alkoxycarbonyl substituted alkyl group, a substituted or unsubstituted aralkyl group, a lower acyl group, a substituted or unsubstituted aryloyl group, a halogen atom as a substituent, a lower alkyl Group, halogenated lower alkyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, lower acylamino group, cyano group, phenyl group which may contain 1 or 2 lower alkylthio groups, naphthyl group or 5- or 6-membered aromatic ring Represents a group heterocycle,
5. The substituted cyclic group according to claim 4, wherein the compound represented by the formula (n is an integer of 2 to 6) is reacted with the compound (4) according to claim 4 to condense and then reduced. A process for producing an amine compound (1) or a salt thereof. 6. A general formula: (In the formula, A represents a group represented by a member of the group consisting of —CONR ⁴ — or —SO ₂ NR ⁴ —, D represents methine, a nitrogen atom or ═N (→ O) —, and R ¹ , R ² May be the same or different, and may be a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower hydroxyalkyl group, a lower alkoxy-substituted alkyl group, a lower alkyl-substituted or unsubstituted. An amino group, a lower acylamino group, a substituted sulfonylamino group,
Lower alkoxycarbonylamino group, lower alkyl substituted or unsubstituted aminoalkyl group, lower acylaminoalkyl group, substituted sulfonylaminoalkyl group, lower alkoxycarbonylaminoalkyl group, substituted or unsubstituted amidino group, substituted or unsubstituted ureido Base,
A substituted or unsubstituted thioureido group, an azole group, a carboxyl group, a lower alkoxycarbonyl group, a formyl group, a lower alkyl-substituted or unsubstituted carbamoyl group, a cyano group, an oxime group or a nitro group, R ⁴
Is a lower alkyl group, a lower alkenyl group, a lower alkoxy substituted alkyl group, a lower alkoxycarbonyl substituted alkyl group, a substituted or unsubstituted aralkyl group, a lower acyl group, a substituted or unsubstituted aryloyl group, a halogen atom as a substituent, a lower alkyl Group, halogenated lower alkyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, lower acylamino group, cyano group, phenyl group which may contain 1 or 2 lower alkylthio groups, naphthyl group or 5- or 6-membered aromatic ring Group heterocycle)
And a compound represented by the general formula: (In the formula, B represents a single bond or -CHOH- or a carbonyl group, Q represents a methine group or a nitrogen atom, R ³ represents a hydrogen atom, a halogen atom or a mono- or di-substituted alkylamino group of a lower alkyl group, Y is a halogen atom, p-
A toluenesulfonyloxy group, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group,
Is an integer of 2 to 6), and the compound represented by the formula (1) or a salt thereof is used for the production of the substituted cyclic amine compound (1) according to claim 4. 7. A general formula: (In the formula, A ′ represents a group represented by —CO— or —SO ₂ —, D represents methine, a nitrogen atom or ═N (→ O) —, R represents
¹ and R ² may be the same or different and each is a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower hydroxyalkyl group, a lower alkoxy-substituted alkyl group, a lower alkyl group. Substituted or unsubstituted amino group, lower acylamino group, substituted sulfonylamino group, lower alkoxycarbonylamino group, lower alkyl substituted or unsubstituted aminoalkyl group, lower acylaminoalkyl group, substituted sulfonylaminoalkyl group, lower alkoxycarbonylamino Alkyl group, substituted or unsubstituted amidino group, substituted or unsubstituted ureido group, substituted or unsubstituted thioureido group, azole group, carboxyl group, lower alkoxycarbonyl group, formyl group, lower alkyl substituted or unsubstituted carbyl group And a compound represented by the following general formula: embedded image which represents a vamoyl group, a cyano group, an oxime group or a nitro group, and X represents a hydroxyl group or a halogen atom. (In the formula, B is a single bond, -CHOH-, a carbonyl group,
Q represents a methine group or a nitrogen atom, R ³ represents a hydrogen atom,
Represents a halogen atom or a mono- or di-substituted alkylamino group of a lower alkyl group, R ⁴ represents a lower alkyl group, a lower alkenyl group, a lower alkoxy-substituted alkyl group, a lower alkoxycarbonyl-substituted alkyl group, a substituted or unsubstituted aralkyl group, a lower An acyl group, a substituted or unsubstituted aryloyl group, a halogen atom as a substituent, a lower alkyl group, a halogenated lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower acylamino group, a cyano group, a lower alkylthio group Or 2
A phenyl group, a naphthyl group, or a 5- or 6-membered aromatic heterocycle which may be included, and n is an integer of 2 to 6) is reacted. The method for producing the substituted cyclic amine compound (1) or a salt thereof according to 1. 8. An agent for circulatory organ containing the substituted cyclic amine compound (1) according to claim 1 or a salt thereof.