JPH11349572A - New amide derivative and salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having pharmacological activities such as a hydroxytryptamine antagonistic activity, etc. SOLUTION: This pyrazole is a compound of formula I [R<1> is a (substituted) heterocyclic ring; R is H, a lower alkyl; a lower alkoxy or the like], e.g. N-(2,2- dimethoxyethyl)-3-nitroaniline. The compound of formula I is obtained by reacting a compound of formula II or its reactive derivative at its amino group (e.g.; a Schiff base type imino or its enamine-type tautomer or the like formed by a reaction of the compound of formula II with a carbonyl compound) with a compound of the formula: R<3> -COOH or its reactive derivative at its carboxy group (acid chloride, acid azide or the like). The above compound has a 5- hydroxytryptamine antagonistic activity, and useful for the prevention and treatment of anxiety, depression, obsessive-compulsive neurosis, migraine, etc. In order to administer the above compound as an active ingredient, it is preferable to use the compound by approximately 0.01-500 mg daily.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel amide derivative and a salt thereof. In particular, the present invention relates to a novel amide derivative having pharmacological activity such as 5-hydroxytryptoamine (5-HT) antagonism and a salt thereof. The amide derivative or a salt thereof is useful in humans and animals such as anxiety, depression, obsessive-compulsive disorder, migraine, anorexia, Alzheimer's disease, sleep disorder, bulimia, panic attack, etc.
Abuse disorders such as cocaine, ethanol, nicotine and benzodiazepines, disorders related to schizophrenia or trauma to the spinal cord, and / or head disorders such as hydrocephalus, or to prevent or prevent such disorders. Useful as 5-HT antagonism.

[0002]

With regard to the prior art in this field, compounds of the following general formula are known.

[0003]

DISCLOSURE OF THE INVENTION As a result of extensive research, the inventors of the present invention have been able to obtain amide derivatives having potent pharmacological activity. The amide derivative of the present invention is novel and can be represented by the following general formula (I). General formula: (Wherein, R ¹ is a heterocyclic group which may have a suitable substituent, R ² is hydrogen, a lower alkyl group, a lower alkoxy group or an acyl group, and R ³ is a group which has a suitable substituent. A condensed or non-condensed phenyl group or a pyridyl group optionally having a suitable substituent.).

The target compound (I) of the present invention can be produced by the following method.

Wherein R ¹ , R ² and R ³ are the same as above.

The target compound (I) can be produced by the method shown in the following examples. Furthermore, the target compound (I) obtained by the above-mentioned production method can have its side chain converted within the scope of the compound of the present invention, as shown in Examples below.

Compounds (I), (II) and (III)
Suitable salts of are the conventional non-toxic pharmaceutically acceptable salts and include salts with bases or acid addition salts, such as salts with inorganic bases, such as alkali metal salts (e.g.,
Sodium salts, potassium salts, cesium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts; salts with organic bases, such as organic amine salts (eg, triethylamine salt, pyridine salt, Picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N′N-dibenzylethylenediamine salts and the like); inorganic acid addition salts (eg, hydrochloride, hydrobromide, hydroiodide, Sulfates,
Phosphoric acid and the like; organic carboxylic acid addition salts and organic sulfonic acid addition salts (for example, formate, acetate trifluoroacetate, oxalate, maleate, tartrate, methanesulfonate, benzenesulfonate, p -Toluenesulfonate, etc.); salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.), and preferred examples thereof are acid addition salts.

In the above and following description of the present specification, preferred examples and explanations of various definitions included within the scope of the present invention are described in detail below.

"Lower" means 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Preferred "lower alkyl groups" include straight or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like. Among them, preferred are those having 1 to 4 carbon atoms, and particularly preferred is methyl.

Preferable "heterocyclic group" of "heterocyclic group optionally having substituent (s)" include those described below as examples of "heterocyclic group". Suitable "substituent" of "heterocyclic group optionally having substituent (s)"
As is a conventional substituent used in the field of pharmacy,
Ar (lower) alkyl (eg benzyl, phenethyl,
Phenylpropyl, benzhydryl, trityl, etc.), methylthio, ethylthio, etc., amino, the lower alkyls described above, and the following aryls. These substituents are 1
Or you may have two or more.

"Fused or non-fused phenyl" is phenyl which may be condensed with a carbocyclic or heterocyclic ring. Examples of the carbocyclic ring include benzene, naphthalene, indene, biphenylene and fluorene. ,
A 3- to 8-membered (more preferably 5- to 6-membered) unsaturated heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrol, pyrroline, imidazole, pyrazole, pyridine, dihydropyridine, pyrimidine, pyrazine, pyridazine etc;

A 3- to 8-membered (more preferably 5- to 6-membered) unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazole, isoxazole and the like;

A 3- to 8-membered (more preferably 5- to 6-membered) unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazole and isothiazole; A 3- to 8-membered (more preferably 5- to 6-membered) unsaturated heterocyclic group containing 2, for example, thiophene, dihydroditin and the like;

A 3- to 8-membered (more preferably 5- to 6-membered) unsaturated heterocyclic group containing an oxygen atom, such as furan;

An unsaturated heterocyclic group containing one or two oxygen atoms and one or two sulfur atoms, for example, dihydrooxatin;

Unsaturated fused heterocyclic group containing 1 to 4 nitrogen atoms, for example, indole, isoindole, indoline, indolizine, benzimidazole, tetrahydrobenzimidazole, quinoline, isoquinoline, tetrahydroisoquinoline , Indazole, benzotriazo-
Quinazoline, quinoxaline, phthalazine, 3H-pyrrolo [1,2-c] [1,4] oxazine and the like;

Oxygen atoms 1-2 and nitrogen atoms 1-3
Unsaturated heterocyclic monocyclic groups, such as benzothiazole,
Benzothiadiazole and the like;

An unsaturated heterocyclic group containing 1 or 2 sulfur atoms, such as benzothiophene and benzoditin;

An unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, indeno [3,2-d] thiazole;

Unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atoms, for example, indeno [3,2-d] pyridine, carbazole, indole, cyclopentenoindole and the like;

An unsaturated heterocyclic group containing 1 or 2 oxygen atoms,
For example, benzoxatin and the like;

An unsaturated fused heterocyclic group containing an oxygen atom, such as benzofuran and dihydrobenzofuran;

Suitable "fused and unfused phenyl" include phenyl, naphthyl (eg, 1-naphthyl, 2
-Naphthyl), fluorenyl (eg, 1-fluorenyl, 4-fluorenyl, etc.), indolyl (eg, 4-
Indolyl), dibenzothienyl (eg, 1-dibenzothienyl), dibenzofuryl (eg, 1-dibenzofuryl), pyrrolo [1,2-a] indolinyl (eg, pyrrolo [1,2-a] indoline- 6-yl or the like) 4H-pyrrolo [2,1-c] [1,4] benzoxazinyl [for example, 4H-pyrrolo [2,1-c] [1,
4] benzoxazin-6-yl and the like.

Preferred substituents for "fused and non-fused phenyl" and "pyridyl" are those used in the field of pharmacy, and include the lower alkyls described above, the di-lower alkylamines described below, the lower alkoxys shown below, Halogen, cyano, hydroxy, (optionally substituted with the following halogen, the above lower alkyl, and the following lower alkoxy)
The following aryl, the following aryl (lower) alkoxy,
The following halogenated aryl, ar (lower) alkyl, the following aryloxy, the following aroyl, the following aryl (lower) alkanoyl, the following heterocyclic group, the following oxo, nitro, amino, cyclohexyl, Cyclohexenyl, trifluoromethylbenzenesulfonylamino and the like.

Preferred "lower alkoxy groups" include 1
Linear or branched alkoxy having from 6 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
Pentyloxy, hexyloxy and the like can be mentioned, and among them, preferred are those having 1 to 4 carbon atoms, and particularly preferred is methoxy.

Suitable "di (lower) alkylamines" include dimethylamine and diethylamine.

Preferred "halogens" include fluorine, chlorine, bromine and iodine.

Suitable "acyl groups" include carboxyl, carbamoyl, aliphatic acyl and acyl groups containing an aromatic or heterocyclic ring.

The acyl groups are derived, for example, from organic carboxylic acids, organic carbonic acids, organic sulfuric acids, organic sulfonic acids, and carboxylic acids.

Suitable acyls can be exemplified as follows.
Carbamoyl; lower or higher alkanol groups (eg formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, anddecanoyl, dodecanoyl, tridacanoyl, tetra Decanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.),
Lower or higher cycloalkylcarbonyl groups (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), lower or higher alkanesphonyl groups (eg, methanesulfonyl, ethanesulfonyl, etc.), lower or higher alkoxysulfonyl groups (eg, methoxysulfonyl) ,
An aliphatic acyl group such as ethoxysulfonyl); an aroyl group (eg, benzoyl, toluoyl, naphthoyl, etc.);
Al (lower) alkanoyl group (for example, phenyl (lower)
Alkanoyl).

For the acyl moiety mentioned above, 1
To 5 identical or different suitable substituents, for example halogen groups (eg fluorine, chlorine, bromine or iodine),
Lower alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), lower alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyl) Oxy, etc.), hydroxy, carboxy, protected hydroxy, protected carboxy, mono (or di or tri) halo (lower) alkyl, N, N-di (lower) alkylamino (e.g. N , N-dimethiamino,
N, N-diethylamino, N, N-dipropylamino,
N, N-dibutylamino, N, N-dipentylamino,
N, N-dihexylamino, N-methyl-N-butylamino and the like).

Suitable "lower alkoxycarbonyl" includes methoxycarbonyl, ethoxycarbonyl and the like.

Suitable "ar (lower) alkylaminocarbonyl" includes benzylaminocarbonyl and the like.

Suitable "heterocyclic carbonyl" includes morpholinocarbonyl and the like.

Suitable "arylaminocarbonyl" includes phenylaminocarbonyl and the like.

Suitable "di (lower) alkylaminocarbonyl" include dimethylaminocarbonyl, diethylaminocarbonyl and the like.

The preferred "aryl" of "aryloxy", "aroyl" and "aryl (lower) alkanoyl"
And the aryl portion include phenyl, naphthyl and the like. The "aryl" and aryl moieties listed above can be substituted by a suitable substituent such as trihalo (lower) alkyl (eg, trifluoromethyl, etc.).

Preferred "aryl (lower) alkanoyl"
Examples include phenylacetyl, phenylpropionyl and the like. As the above “heterocyclic group”, an oxygen atom,
At least one heteroatom such as sulfur or nitrogen
And a saturated or unsaturated monocyclic or polycyclic heterocyclic group. Preferred heterocyclic groups include pyrrolyl, pyridyl, thiazolyl, thienyl, triazolyl,
Oxazolyl and the like.

The above "heterocyclic group" can be substituted by a suitable substituent such as lower alkyl and aryl described above. The production method of the target compound (I) will be described in detail below. The target compound (I) or a salt thereof is a compound (I)
It can be produced by reacting I) or a reactive derivative thereof at an amino group or a salt thereof with compound (III) or a reactive derivative thereof at a carboxy group or a salt thereof.

Suitable reactive derivatives at the amino group of compound (II) include compound (II) and an aldehyde,
Schiff base imino or an enamine tautomer thereof formed by reaction with a carbonyl compound such as a ketone; silyl such as compound (II) and bis (trimethylsilyl) acedamide, mono (trimethylsilyl) acedamide, bis (trimethylsilyl) urea A silyl derivative produced by a reaction with a compound; a derivative produced by reacting a compound (II) with phosphorus trichloride or phosgene;

Suitable salts of the compound (II) and its reactive derivative include those exemplified for the compound (I).

Suitable reactive derivatives of the carboxy group of compound (III) include acid halides, acid anhydrides, active amides, active esters and the like. Preferred examples of reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid,
Dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphoric acid,
Sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, (lower) alkanesulfonic acid [eg methanesulfonic acid etc.], aliphatic carboxylic acid [eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2 A mixed acid anhydride with an acid such as -ethylbutyric acid, trichloroacetic acid or the like] or an aromatic carboxylic acid [for example, benzoic acid or the like]; symmetrical acid anhydride, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole An active amide with an active ester such as cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pen Chlorophenyl ester, pentafluorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p- nitrophenyl thioester, p- cresyl shea thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,
8-quinolylthioester, etc.]; or an N-hydroxy compound [eg, N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H -Benzotriazole and the like]. These reactive derivatives can be appropriately selected from these depending on the type of compound (III) used.

Suitable salts of the compound (III) and its reactive derivative include alkali metal salts [eg, sodium salts, potassium salts, etc.], alkaline earth metal salts [eg, calcium salts, magnesium salts, etc.], ammonium salts, Organic base salts [eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt), etc.
And the acid addition salts exemplified for compound (I).

The reaction is usually carried out with water, alcohol (eg, methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, It can be carried out in a conventional solvent such as pyridine or any other organic solvent that does not adversely affect the reaction. Among these solvents, the hydrophilic solvent can be used as a mixture with water.

When the compound (III) is used in the form of a free acid or a salt thereof in this reaction, the reaction is preferably carried out in the presence of a conventional condensing agent. Examples of the condensing agent include carbodiimides Or a salt thereof [eg, N, N′-
Dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-di-ethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide; N- Ethyl-N '-(3-di-methylaminopropyl) carbodiimide or its hydrochloride), N, N'-carbonylbis- (2-methylimidazole); diphenylphosphoric acid azide, diethylphosphoric acid cyanidate, bis ( 2-oxo-3
-Oxazolidinyl) phosphine chloride; N, N'-carbonyldiimidazole, N, N'-carbonylbis-
(2-methylimidazole); ketene imine compound [for example, pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine, etc.]; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite Polyethyl isopropyl; polyisopropyl isopropyl; phosphorous oxychloride (phosphoryl chloride); phosphorus trichloride; diphenylphosphate azide; thionyl chloride; oxalyl chloride; lower alkyl haloformate {eg, ethyl chloroformate, isopropyl chloroformate, etc.); 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide internal salt; benzotriazol-1-yl-oxy-tris-
(Dimethylamino) phosphonium hexafluorophosphate; 1-hydroxybenzotriazole, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-
Benzotriazole; a so-called Vilsmeier reagent prepared by the reaction of N, N'-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, and the like.

The reaction may also include an alkali metal bicarbonate,
Tri (lower) alkylamine, pyridine, N- (lower)
It can be carried out in the presence of an inorganic or organic base such as alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like.

The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling, at room temperature, or under heating.

The target compound (I) of the present invention can be isolated and purified by conventional methods such as extraction, precipitation, fractional crystallization, recrystallization, column chromatography and the like.

The target compound (I) thus obtained
Can be converted to its salt in a conventional manner.

The target compound (I) and its pharmaceutically acceptable salts include solvates [eg clathrates (eg hydrates)].

The compound (I) of the present invention exhibits pharmacological activity such as 5-HT antagonism, especially 5HT _2C antagonism, and therefore, anxiety, depression, obsessive-compulsive disorder, migraine, anorexia Central nervous system (CNS) disorders such as Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal symptoms due to substance abuse such as cocaine, ethanol, nicotine, benzazepine, schizophrenia, or spinal cord It is useful as a 5-HT antagonist for the treatment or prevention of disorders related to trauma and / or head diseases such as hydrocephalus.

For the purpose of therapeutic or prophylactic administration, the desired compound (I) of the present invention and its pharmaceutically acceptable salts may be any of the organic or inorganic solid forms suitable for oral, parenteral and topical administration. Alternatively, the compound can be used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient by mixing with a pharmaceutically acceptable carrier such as a liquid excipient. Pharmaceutical preparations include solid forms such as tablets, dragees, granules and capsules or liquid forms such as solutions, suspensions, syrups, emulsions and lemonades.

If desired, the above preparations may contain auxiliary ingredients, stabilizers, lubricants or other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, stearic acid. Magnesium, clay, sucrose,
Cornstarch, talc, gelatin, agar, pectin,
Peanut oil, olive oil, cocoa butter, ethylene glycol and the like may be contained.

The dose of Compound (I) varies depending on the age and condition of the patient, the type of disease or condition, and the type of Compound (I) applied. Generally, from about 0.01 mg to about 500 mg per day is administered to a patient. For the treatment of diseases, the compound of interest (I) of the present invention is administered at an average dose of about 0.05 mg, 0.1 mg, 0.25 m
g, 0.5 mg, 1 mg, 20 mg, 50 mg, 100
Used as mg.

Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples.

Production Example 1 Dimethoxyacetaldehyde (crude, 7.54 g), acetic acid (2.07 ml) and sodium tris (acetoxy) borohydride were added to a solution of 3-nitroaniline (5.0 g) in 1,2-dichloromethane (50 ml). (15.
34g) is added. The mixture is stirred at room temperature for 1 hour and cooled with aqueous sodium hydrogen carbonate solution (150 ml). The organic layer was separated, dried over sodium sulfate, subjected to chromatography using a silica gel column, and eluted with hexane-chloroform (1: 1 v / v) to give N- (2,2-
Dimethoxyethyl) -3-nitroaniline (3.30
g). IR (KBr, cm ^-1 ): 1623, 1531 NMR (DMSO-d ₆ , δ): 3.22 (2H, t,
J = 6 Hz), 3.32 (6H, s), 4.49 (1
H, t, J = 6 Hz), 6.38 (1H, br.t, J
= 6 Hz), 7.00-7.20 (1H, m), 7.3
0-7.40 (2H, m), 7.40-7.45 (1
H, m)

Production Example 2 To a solution of N- (2,2-dimethoxyethyl) -3-nitroaniline (1.0 g) in methylene chloride (20 ml) was added triethylamine (1.84 ml) and acetyl chloride (0.70 ml). And stirred at room temperature for 2 hours. The mixture was washed with water, dried over sodium sulfate, and the solvent was distilled off to obtain crude N-acetyl-N- (2,2-dimethoxyethyl) -3-nitroaniline (1.41 g), which was further purified. Used in the next step without. IR (KBr, cm ^-1 ): 1664 NMR (DMSO-d ₆ , δ) 2.00 (3H, s),
3.25 (6H, s), 3.76 (2H, d, J = 6H
z), 4.45-4.60 (1H, m), 7.60-
7.80 (2H, m), 8.10-8.30 (2H,
m)

Production Example 3 N-acetyl-N- (2,2-dimethoxyethyl) -3
-To a solution of nitroaniline (1.00 g) in acetic acid (30 ml), add ammonium acetate (0.86 g) and reflux for 2 hours. After cooling, acetic acid is distilled off and the resulting mass is dissolved in chloroform. The solution was washed with 1N sodium hydroxide solution, dried over sodium sulfate, subjected to column chromatography using silica gel, eluted with chloroform, and extracted with 2-methyl-1- (3-nitrophenyl) imidazole (0. .10 g). IR (KBr, cm ^-1 ): 1525 NMR (DMSO-d ₆ , δ): 2.34 (3H,
s), 6.97 (1H, d, J = 1 Hz), 7.45.
(1H, d, J = 1 Hz), 7.83 (1H, t, J =
8 Hz), 7.97 (1H, dt, J = 8 Hz, J = 1)
Hz), 8.25-8.35 (2H, m)

Production Example 4 N- [3- (2,2-dimethoxyethylamino) phenyl] fluorene-1-carboxamide IR (KBr, cm ^-1 ): 1655, 1614, 154
7 NMR (DMSO-d ₆ , δ): 3.14 (2H, t,
J = 6 Hz), 3.32 (6H, s), 4.18 (2
H, s), 4.52 (1H, t, J = 6 Hz), 5.6.
4 (1H, br.t, J = 6 Hz), 6.35-6.4
5 (1H, m), 6.95-7.10 (2H, m),
7.17 (1H, s), 7.30-7.75 (5H,
m), 7.96 (1H, d, J = 6 Hz), 8.09
(1H, d, J = 7 Hz), 10.08 (1H, s)

Production Example 5 N, N′-bis (t) was added to a solution of N- [3-(,, 2-dimethoxyethylamino) phenyl] fluorene-1-carboxamide (100 mg) in methylene chloride (10 ml).
-Butoxycarbonyl) thiourea (75 mg), triethylamine (90 μl) and 2-chloro-1-methylpyridinium iodide (79 mg) are added. The mixture is stirred at room temperature for one week. The mixture is washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, evaporated and chromatographed on silica gel, eluting with chloroform-methanol (0-3%, v / v). , 1,2-bis (t-butoxycarbonyl) -3
-(2,2-Dimethoxyethylamino) -3- [fluorene-1-carboxamido) phenyl] guanidine (0.18 g) is obtained. IR (KBr, cm ^-1 ): NMR (DMSO-d ₆ , δ): 1.24 (9H,
s), 1.37 (9H, s), 3.25 (6H, s),
3.74 (2H, d, J = 5 Hz), 4.18 (2H,
s), 4.61 (1H, t, J = 5 Hz), 6.78.
(1H, td, J = 7 Hz, J = 2 Hz), 6.97
(1H, t, J = 7 Hz), 7.30-7.80 (6
H, m), 7.97 (1H, d, J = 7 Hz), 8.0
5-8.20 (2H, m), 9.29 (1H, s), 1
0.43 (1H, s)

Production Example 6 A solution of 3-nitroaniline (13.81 g) in water (100 m
1) To the suspension in 1) is added phosphoric acid (9.8 g), glyoxal (11.5 ml in 40% water) and formaldehyde (8.6 ml in 35% water). 90 ° C the mixture
And heated to an aqueous ammonium chloride solution (10.7 g 4
0 ml water) is added dropwise over 1 hour. 95
After stirring at C for a further 10 minutes, the mixture is cooled, solid potassium hydroxide (22.4 g) is added and the mixture is extracted three times with chloroform-methanol (9: 1 v / v). Combine the extracts and extract with 4N hydrochloric acid. The acidic solution is cooled in an ice bath and made alkaline to pH 12 with 8N aqueous sodium hydroxide. Collect the formed precipitate, wash with water,
After drying, 1- (3-nitrophenyl) imidazole (1
3.55 g) are identified in a known sample (AL Johnsonet. Al., J. Med.
Chem. 12, 1024 (1969)). IR (KBr, cm ^-1 ): NMR (DMSO-d ₆ , δ):

Production Example 7 N-benzyl-5- (imidazole-1-yl) -3-
Nitrobenzamide IR (KBr, cm ^-1 ): 165
3,1539 NMR (DMSO-d ₆ , δ): 4.56 (1H, d,
J = 6 Hz), 7.19 (1H, s), 7.20-7.
40 (5H, m), 8.02 (1H, t, J = 1H
z), 8.53 (1H, s), 8.58 (1H, t, J
= 2 Hz), 8.60-8.70 (2H, m), 9.4
8 (1H, t, J = 6Hz)

Production Example 8 1- (2-methoxy-5-nitrophenyl) imidazo-
IR: (KBr, cm ^-1 ): 1595 NMR (DMSO-d ₆ , δ): 3.99 (3H,
s), 7.10 (1H, s), 7.48 (1H, d, J
= 7 Hz), 7.57 (1H, t, J = 1 Hz), 8.
04 (1H, s), 8.25-8.40 (2H, m)

Production Example 9 1- (3-nitrophenyl) -4,5,6,7-tetrahydrobenzimidazole mp: red oil IR (KBr, cm ^-1 ): MASS: 244 (M + 1) NMR ( _{DMSO-d 6, δ):} 1.77 (4H, b
r, s), 2.60 (4H, br.s), 7.81 (1
H, t, J = 8 Hz), 7.90-8.00 (2H,
m), 8.20-8.30 (2H, m)

Production Example 10 1- (3-ethoxycarbonyl-5-nitrophenyl)
Imidazole IR (KBr, cm ^-1 ): 1733, 1535 NMR (DMSO-d ₆ , δ): 1.39 (3H, t,
J = 7 Hz), 4.43 (2H, q, J = 7 Hz),
7.18 (1H, s), 8.07 (1H, t, J = 1H
z), 8.50-8.60 (3H, m), 8.77 (1
(H, t, J = 2 Hz)

Production Example 11 1- (3-Nitrophenyl) imidazole (13.85)
To a suspension of g) in ethanol (70 ml) and water (70 ml) was added ammonium chloride (1.57 g),
Gently reflux in an oil bath. Except oil bath, iron (14.3
g) is added in three portions. The exothermic reaction is completed and the mixture is refluxed for 1 hour in an oil bath. The cooled mixture is filtered through celite and the solvent is distilled off. The resulting mass is partitioned between 1N aqueous sodium hydroxide solution and methylene chloride. The separated organic layer was dried over potassium carbonate, the solvent was distilled off, and the residue was crystallized from diisopropyl ether to obtain 1- (3-aminophenyl) imidazole (9.23 g). IR (KBr, cm ^-1 ): 1650, 1608, 159
3,1510 NMR (DMSO-d ₆ , δ): 5.46 (2H,
s), 6.53 (1H, dt, J = 7 Hz, J = 1H
z), 6.60-6.75 (2H, m), 7.07 (1
H, t, J = 1 Hz), 7.12 (1 H, t, J = 8 H)
z), 7.56 (1H, t, J = 1 Hz), 8.67
(1H, t, J = 1Hz)

Production Example 12 1- (3-Aminophenyl) -2-methylthioimidazole IR (KBr, cm ^-1 ): 1604 MASS: 206 (M + 1) NMR (DMSO-d ₆ , δ): 2.50 (3H,
s), 5.46 (2H, br.s), 6.40-6.6.
5 (3H, m), 7.04 (1H, d, J = 1 Hz),
7.13 (1H, t, J = 8 Hz), 7.35 (1H,
d, J = 1Hz)

Production Example 13 1- (2-methoxy-5-nitrophenyl) imidazo-
To a suspension of toluene (2.00 g) in methanol (50 ml) was added palladium-activated carbon (10%, 0.2 g) and the mixture was stirred under a hydrogen atmosphere for 5 hours. After completion of the reaction, the catalyst is removed by filtration. The solvent of the filtrate was distilled off, and the residue was triturated with diisopropyl ether to obtain 1- (5-amino-2-methoxyphenyl) imidazole (1.53 g). IR (KBr, cm ^-1 ): 1633 NMR (DMSO-d ₆ , δ): 3.66 (3H,
s), 6.50-6.65 (2H, m), 6.95 (1
H, d, J = 9 Hz), 7.01 (1H, t, J = 1H)
z), 7.33 (1H, t, J = 1 Hz), 7.80
(1H, t, J = 1Hz)

Production Example 14 1- (3-Aminophenyl) -4,5,6,7-tetrohydrobenzimidazole is obtained and used without purification.

Production Example 15 1- (3-amino-5-ethoxycarbonylphenyl)
Imidazole IR (KBr, cm ^-1 ): 1711 NMR (DMSO-d ₆ , δ): 1.33 (3H, t,
J = 7 Hz), 4.31 (2H, q, J = 7 Hz),
5.75 (2H, br.s), 6.96 (1H, t, J
= 2 Hz), 7.14 (1H, d, J = 1 Hz), 7.
20-7.25 (2H, m), 7.67 (1H, t, J
= 1 Hz), 8.23 (1H, s)

Production Example 16 N-benzyl-5- (imidazole-1-yl) -3-
Nitrobenzamide (0.17 g) in ethanol (10
ferric chloride (43 mg) and activated carbon (0.
3 g) and hydrazine monohydrate (0.10 ml) are added. The mixture is stirred at 70 ° C. for 2 hours. After cooling, the mixture is filtered through celite and the solvent is distilled off. The resulting mass is partitioned between aqueous sodium bicarbonate and chloroform. The separated organic layer was dried over sodium sulfate, and the solvent was distilled off to obtain 3-amino-N-benzyl-5- (imidazole-1-yl) benzamide (0.10 g). IR (KBr, cm ^-1 ): 1648, 1590 NMR (DMSO-d ₆ , δ): 4.47 (1H, d,
J = 6 Hz), 5.61 (2H, br.s), 6.85
(1H, t, J = 2 Hz), 7.00-7.10 (2
H, m), 7.15-7.40 (6H, m), 7.61
(1H, t, J = 1 Hz), 8.11 (1H, d, J =
1Hz), 8.92 (1H, br.t, J = 6Hz)

Production Example 17 2,2-Dimethoxypropyl-1-amine (3.22
In g) of ethanol (60 ml) at room temperature is added 3-nitrophenylisocyanonate (3.94 g). The mixture is stirred at room temperature for 2 hours and the insoluble material is filtered off. The solvent of the filtrate was distilled off, subjected to column chromatography using silica gel, and eluted with methylene chloride-methanol.
N- (3-Nitrophenyl) -N '-(2,2-dimethoxypropyl) urea is obtained as yellow crystals. mp: 110-111 ° C IR (KBr, cm ^-1 ): 3408, 3352, 166
8,1558 MASS: 252 (M-MeOH + 1) NMR (DMSO-d 6, δ): 1.20 (3H,
s), 3.14 (6H, s), 3.26 (2H, d, J
-5.9), 6.29 (1H, t, J = 6.0), 7.
46-7.61 (2H, m), 7.76 (1H, dd)
d, J = 7.7, 1.4, 1.4), 8.53 (1H,
dd, J = 2.0, 2.0), 9.09 (1H, s).

Production Example 18 N- (3-nitrophenyl) -N '-(2,2-dimethoxypropyl) urea (4.70 g), methanol-water (9: 1 0.2 M, 83 ml) and 4 Reflux for 90 minutes to dissolve all toluenesulfonic acid monohydrate (0.47 g). After cooling, the mixture was iced / water (40
0 ml). After 1 hour, filter, wash with water,
Dry at 0 ° C. under reduced pressure to obtain 5-methyl-1- (3-nitrophenyl) imidazolone (2.93 g) as yellow crystals. mp: 213-214 ° C IR (KBr, cm ^-1 ): 1678 MASS: 220 (M + 1) NMR (DMSO-d ₆ , δ): 1.95 (3H, d,
J = 1.3), 6.35 (1H, q, J = 1.3),
7.72-7.85 (2H, m), 8.18-8.23
(2H, m), 10.13 (1H, br s).

Production Example 19 5-methyl-1- (3-nitrophenyl) imidazolone (0.60 g), triethylamine hydrochloride (0.90 g)
g), toluene (10 ml) and phosphorus oxychloride (5
ml) is refluxed for 17 hours. After cooling to room temperature,
The solvent is distilled off. Toluene (10 ml) is added and the solvent is again distilled off. Methylene chloride (30 ml) and saturated aqueous sodium carbonate solution (30 ml) are added, and the mixture is vigorously stirred for 2 hours. The organic layer was separated and methylene chloride (twice, 20 times each)
ml) and extract the aqueous layer. The organic layers are combined, dried over potassium carbonate, filtered, and the solvent is distilled off. The resulting precipitate was applied to column chromatography using silica gel, eluted with methylene chloride / methanol, and 2-chloro-
5-Methyl-1- (3-nitrophenyl) imidazole (0.24 g) is obtained as a light brown powder. MASS: 238, 240 (M + 1, Cl isoto
_{pes) NMR (DMSO-d 6} , δ): 2.03 (3H, d,
J = 0.9), 6.86 (1H, q, J = 0.9),
7.85-7.99 (2H, m), 8.35-8.44
(2H, m).

Production Example 20 2-chloro-5-methyl-1- (3-nitrophenyl)
Imidazole (0.24 g), methanol (10 ml)
And a mixture of 10% palladium on carbon (20 mg) is stirred vigorously under a hydrogen atmosphere for 6 hours. Filter through celite and evaporate the solvent. Dissolve the residue in methylene chloride and add 1
Wash with N sodium hydroxide (10 ml), dry over magnesium sulfate, filter and evaporate the solvent. The residue was subjected to column chromatography using silica gel and eluted with a mixed solution of methylene chloride-methanol to give 3- (5-methylimidazole-1-yl) aniline (82 mg) as a yellow oil. MASS: 174 (M + 1) NMR (DMSO-d 6, δ): 2.12 (3H, d,
J = 0.9), 5.41 (2H, brs), 6.45 −
6.64 (3H, m), 6.77 (1H, dq, J =
1.0, 0.9), 7.14 (1H, dd, J = 7.
9, 7.9), 7.63 (1H, d, J = 1.0).

Production Example 21 A mixture of 3'-nitro-2-aminoacetophenone hydrochloride (2.17 g) in methylene chloride (50 ml) was cooled to -40 ° C. under a nitrogen atmosphere, and propionic anhydride (1.41 ml) was obtained. And triethylamine (2.93)
ml) is added dropwise over 5 minutes. Warm slowly to room temperature over 2 hours. Water (100 ml) and methylene chloride (50 ml) were added, the organic layer was separated, washed with sodium chloride,
Dry over magnesium sulfate, filter and evaporate the solvent.
The residue was subjected to column chromatography using silica gel, eluted with a methylene chloride / methanol mixture solution, recrystallized from ethyl acetate, and 3′-nitro-2- (N-propionyl) aminoacetophenone (1.84 g) was obtained. Obtained as white crystals. mp: 122-123 ° C IR (KBr, cm ^-1 ): 3386, 1699, 166
0 MASS: 237 (M + 1) NMR (DMSO, δ): 1.01 (3H, t, J =
7.5), 2.19 (2H, q, J = 7.5), 4.6
6 (2H, d, J = 5.6), 7.85 (1H, dd,
J = 8.0, 8.0), 8.27 (1H, t, J = 5.
6), 8.41 (1H, ddd, J = 8.0, 1.9,
1.9), 8.49 (1H, ddd, J = 8.0, 1.
9, 1.9), 8.65 (1H, dd, J = 1.9,
1.9).

Production Example 22 A mixture of 3'-nitro-2- (N-propionyl) aminoacetophenone (1.0 g), toluene (10 ml), acetic acid (2 ml) and 40% methylamine (2 ml) in methanol was mixed with 16%. Reflux for hours. The solvent is distilled off, and methylene chloride, water and then an aqueous sodium hydroxide solution are added until the mixture becomes strongly alkaline. The organic layer is separated, dried over magnesium sulfate, filtered, and the solvent is distilled off. Chromatography using silica gel, methylene chloride /
Elution with a mixed solvent of methanol gives 2-ethyl-1-methyl-5- (3-nitrophenyl) imidazole as a brown liquid. MASS: 232 (M + 1) NMR (DMSO, δ): 1.26 (3H, t, J =
7.5), 2.72 (2H, q, J = 7.5), 3.5
9 (3H, s), 7.10 (1H, s), 7.7
4 (1H, ddd, J = 7.6, 7.6, 1.
1), 7.91 (1H, ddd, J = 7.8,
1.4, 1.4), 8.16-8.21 (1H,
m), 8.22 (1H, s).

Production Example 23 2-ethyl-1-methyl-5- (3-nitrophenyl)
A mixture of imidazole (0.68 g), iron (1.0 g), ammonium chloride (0.1 g), ethanol (10 ml) and water (5 ml) is refluxed for 1 hour. After cooling, the mixture was filtered through celite, brine (50 ml) and methylene chloride (50 ml) were added, the organic layer was separated, and the aqueous layer was extracted again with methylene chloride (twice or more, 25 m each).
l). The organic layers are combined, dried over magnesium sulfate, filtered, and the solvent is distilled off. The residue was subjected to column chromatography using silica gel, extracted with a mixed solvent of methylene chloride / methanol and recrystallized from ethyl acetate to give 3- (2
-Ethyl-1-methylimidazole-5-yl) aniline (0.45 g) is obtained as white crystals. mp: 119-120 ° C (EtOAc) IR (KBr, cm ^-1 ): 3408, 3332,
3213, 1602 MASS: 202 (M + 1) NMR (DMSO-d ₆ , δ): 1.23 (3H,
t, J = 7.5), 2.68 (2H, q, J =
7.5), 3.49 (3H, s), 5.16 (2
H, brs), 6.49-6.59 (3H,
m), 6.76 (1H, s), 7.07 (1H,
dd, J = 7.8, 7.8).

Production Example 24 3′-Nitro-2- (N, N-diformylamino) acetophenone mp: 126-127 ° C. IR (KBr, cm ⁻¹ ): 1705, 1670 NMR (CDCl ₃ , δ): 5 .14 (2H,
s), 7.76 (1H, dd, J = 8.0, 8.
0), 8.31 (1H, ddd, J = 7.8,
1.2, 1.2), 8.51 (1H, ddd,
J = 8.2, 2.2, 1.1), 8.81 (1
H, dd, J = 1.9, 1.9), 9.06
(2H, s).

Production Example 25 3′-Nitro-2- (N-formylamino) acetophen mp: 126-128 ° C. IR (KBr, cm ⁻¹ ): 3375, 1699,
1668 NMR (CDCl ₃ , δ): 4.89 (1H, d
d, J = 4.6, 0.8), 6.67 (1H,
brs), 7.76 (1H, dd, J = 8.
0, 8.0), 8.31 (1H, ddd, J =
7.8, 1.3, 1.3), 8.37 (1H,
s), 8.50 (1H, ddd, J = 8.2,
2.2, 1.0), 8.83 (1H, dd, J
= 1.9, 1.9).

Production Example 26 1-methyl-5- (3-nitrophenyl) imidazole mp: 151-153 ° C. IR (KBr, cm ⁻¹ ): 1560, 1523,
1489 NMR (DMSO-d ₆ , δ): 3.75 (3H,
s), 7.27 (1H, d, J = 1.1),
7.75 (1H, dd, J = 8.0, 8.0),
7.79 (1H, d, J = 1.1), 7.99
(1H, ddd, J = 7.8, 1.1, 1.
1), 8.21 (1H, ddd, J = 8.2,
2.3, 1.0), 8.29 (1H, dd, J
= 1.9, 1.9).

Production Example 27 3- (1-Methylimidazole-5-yl) aniline mp: 88-89 ° C. IR (KBr, cm ⁻¹ ): 3419, 3300,
3192, 1635, 1603, 1495 NMR (DMSO-d ₆ , δ): 3.63 (3H,
s), 5.17 (2H, brs), 6.52-
6.60 (2H, m), 6.65 (1H, dd,
J = 1.8, 1.8), 6.92 (1H, d,
J = 1.1), 7.08 (1H, dd, J = 7.
7, 7.7), 7.63 (1H, d, J = 1.
1).

Production Example 28 Benzylamine (0.21 ml) was added to a suspension of 2-formylamino-3'-nitroacetophenone (0.35 g) in toluene (10 ml). Heat for hours. After cooling to room temperature, the solvent of the reaction mixture is distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel, and ethyl acetate and n
Elution in turn with a 1: 1 mixture of hexane, ethyl acetate and 3% ethanol in ethyl acetate. The fractions containing the desired compound are collected, concentrated under reduced pressure, triturated with diisopropyl ether, and treated with 3- (1-benzylimidazole-5-yl).
Yl) Nitrobenzene (0.235 g) is obtained. LD-mass; 280.2 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , δ); 5.40 (2H,
s), 6.90-7.05 (2H, m), 7.0
5-7.40 (4H, m), 7.66 (1H,
t, J = 7.9 Hz), 7.85 (1H, d,
J = 7.9 Hz), 7.98 (1H, s), 8.0
5-8.24 (2H, m)

Production Example 29 Ethanol (5 ml) of 3- (1-benzylimidazole-5-yl) nitrobenzene (0.22 g) and water (1)
ammonium chloride (17 mg) was added to the mixed solution with iron powder (0.154 g).
Heat at 0 ° C. for 1 hour. After cooling to room temperature, the precipitate was removed by filtration through Celite, and washed successively with ethanol and methylene chloride. The filtrates are combined, washed and concentrated under reduced pressure, and the residue is taken up in water. The aqueous solution is adjusted to around pH 12, and the target compound is extracted several times with methylene chloride. The extracts are combined, washed with brine and dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is triturated with diisopropyl ether to obtain 3- (1-benzylimidazol-5-yl) aniline (0.172 g). LD-mass; 250.2 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , δ); 5.14 (2H,
s), 5.28 (2H, s), 6.40-6.6.
5 (3H, m), 6.83-7.10 (4H,
m), 7.10-7.40 (3H, m), 7.7
7 (1H, s)

Production Example 30 3-Nitrobenzoic acid hydrazide (1.81 g) and methyl isothiocyanate (731 mg) in 1-butanol (7
0 ml) to the suspension in 1,8-diazabicyclo [5.
4.0] Undec-7-ene (0.4 ml) was added.
Reflux for hours. Cool the mixture and pour into water. The precipitate is filtered off, washed with water, dried and 3- (2,3-dihydro-
4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl) nitrobenzene (1.16 g) is obtained. APCl-mass; m / z 237 (M + H ⁺ ) NMR (DMSO-d6): δ; 3.57 (3H,
s), 7.87 (1H, t, J = 8.0 Hz),
8.20 (1H, d, J = 8.0 Hz), 8.4
3 (1H, d, J = 8.0 Hz), 8.54 (1
H, s), 14.09 (1H, broad s)

Production Example 31 3- (2,3-Dihydro-4-methyl-3-thiooxo-4H-1,2,4-triazol-5-yl) nitrobenzene (0.5 g) in acetic acid (20 ml) A solution of sodium nitrite (584 mg) in water (3 ml) is added dropwise to the medium suspension, and the mixture is stirred at 100 ° C. for 1 hour. The mixture is evaporated, diluted with ethyl acetate and washed with brine. The separated organic layer is dried over sodium sulfate, and the solvent is distilled off. The residue is triturated with isopropyl ether, filtered, dried and dried with 1-methyl-5- (3-nitrophenyl) -1,1.
3,4-triazole (393 mg) is obtained. APCl-mass; m / z 205 (M + H ⁺ ) NMR (CDCl ₃ ): δ; 3.87 (3H,
s), 7.75 (1H, t, J = 8.0 Hz),
8.14 (1H, dt, J = 8.0 Hz, 1.4
Hz), 8.27 (1H, s), 8.39 (1
H, dt, J = 8.0 Hz, 1.4 Hz),
8.55 (1H, t, J = 1.4 Hz)

Production Example 32 1-methyl-5- (3-nitrophenyl) -1,3,4
-Triazole (163 mg) in ethanol (3 ml)
And a suspension in tetrahydrofuran (3 ml) were mixed with palladium-carbon (10% w / w, 50% wet, 80m).
In g), hydrogenation is performed for 4 hours under a hydrogen atmosphere. The catalyst was removed by filtration, the solvent of the filtrate was distilled off, and the residue was crystallized from methylene chloride-isopropyl ether to give 1-methyl-5- (3-aminophenyl) -1,3,4-triazole (139 m
g). APCl-mass; m / z 175 (M + H ⁺ ) NMR (DMSOd-6): δ; 3.69 (3H,
s), 5.2-5.4 (2H, broad s),
6.69 (1H, dd, J = 8.0 Hz, 2.2
Hz), 6.80 (1H, d, J = 8.0H)
z), 6.91 (1H, t, J = 2.2H
z), 7.18 (1H, dt, J = 8.0 Hz,
2.2HZ), 8.51 (1H, s)

Production Example 33 A solution of 3-amino-9-fluorenone (0.52 g) in hydrochloric acid (28%, 1 m) was added to an aqueous sodium nitrate solution (18%).
4 mg, 1 ml in water) is added dropwise, and the mixture is added at 0-5 ° C for 3 hours.
Stir for 0 minutes. After adjusting the pH to 6 with potassium carbonate, the mixture was added dropwise to a solution of potassium cyanide (0.45 g), cuprous cyanide (0.31 g) in water (3 ml) and benzene (3 ml) under cooling in an ice bath. Add. The precipitate formed is filtered off and washed with benzene. Combine the filtrate and washings, wash with aqueous sodium bicarbonate and brine,
Dry over sodium sulfate, evaporate the solvent and triturate with diisopropyl ether to give 3-cyano-9-fluorenone (0.22 g). IR (KBr, cm ^-1 ): 2225, 1711 MASS: NMR (DMSO-d ₆ , δ): 7.48
(1H, t, J = 7 Hz), 7.60-7.80
(3H, m), 7.85-8. 00 (2H,
m), 8.38 (1H, s)

Preparation 34 A suspension of 3-cyano-9-fluorenone (0.21 g) in sulfuric acid (50%, 20 ml) is refluxed for 5 hours. After cooling, the mixture is poured into water (100 ml) and extracted with chloroform-methanol (9: 1, v / v). The organic layer is extracted with aqueous sodium hydrogen carbonate. The aqueous solution is adjusted to pH 1 with concentrated hydrochloric acid, and the resulting precipitate is collected and washed with water to give 9-fluorenone-3-carboxylic acid (66 mg). IR (KBr, cm ⁻¹ ): 1714, 1685 MASS: 223 (M−1 ⁻ ) NMR (DMSO-d ₆ , δ): 7.43 (1H,
t, J = 7 Hz), 7.60-7.80 (3H,
m), 7.90-8.00 (2H, m), 8.31
(1H, s), 13.5 (1H, br.s)

Production Example 35 A solution of 9-fluorenone-3-carboxylic acid (55 mg) in methanol (10 ml) was charged with palladium-activated carbon (10 mg).
%, 30 mg) and stirred under a hydrogen atmosphere for 8 hours. The catalyst was removed by filtration, and the solvent was distilled off.
Triturate with 3-fluorenecarboxylic acid (45 m
g). IR (KBr, cm ⁻¹ ): 1682 MASS: 209 (M−1 ⁻ ) NMR (DMSO-d ₆ , δ): 4.01 (2H,
s), 7.30-7.50 (4H, m), 7.6
2 (1H, d, J = 6 Hz), 7.69 (1H,
d, J = 8 Hz), 7.92 (1H, dd,
J = 8 Hz, J = 2 Hz), 8.02 (1H, d
d, J = 8 Hz, J = 2 Hz), 8.45 (1
H, d, J = 1Hz)

Production Example 36 1-Fluorenecarboxylic acid (500 mg), N-chlorosuccinimide (350 mg), acetonitrile (2 m
l) and concentrated hydrochloric acid (0.4 ml) at 50 ° C. for 1 hour.
Heat for 7 hours. Cool to room temperature, filter the resulting precipitate and wash with acetonitrile (3 times, 1 ml each).
The crystals were recrystallized from methanol and then three times from acetic acid to give 7-chloro-1-fluorenecarboxylic acid (0.17%).
g) is obtained as a brown powder. mp: 281-283 ° C IR (KBr, cm ^-1 ): 2500-3000 (CO
OH), 1682 MASS: 259, 261 (3: 1 ratio,
Cl isotopes, MH ₂ O + MeOH +
1) NMR (DMSO-d ₆ , δ): 4.24 (2H,
s), 7.46 (1H, dd, J = 8.2,
2.0), 7.55 (1H, dd, J = 7.6,
7.6), 7.72 (1H, d, J = 2.
0), 7.92 (1H, dd, J = 7.7,
1.0), 7.98 (1H, d, J = 8.2),
8.18, (1H, dd, J = 7.6, 1.
0).

Production Example 37 4-carbomethoxy-1-indanone (0.95 g)
A mixture of pyridinium tribromide (1.68 g) and acetic acid (10 ml) was added at room temperature to 30% hydrobromic acid (2 m
Add l) in acetic acid (all dissolved). After 20 minutes, pour into ice / water (300 ml). After 30 minutes, the crystals are collected by filtration and washed with water to give 2-bromo-4-carbomethoxy-1-indanone (1.30 g) as white crystals. mp: 114-115 ° C IR (KBr, cm ^-1 ): 1736, 1710 MASS: 291, 293 (M + 23, Bris
topes) NMR (CDCl ₃ , δ): 3.79 (1H, d
d, J = 19.7, 3.0), 3.97 (3H,
s), 4.20 (1H, dd, J = 19.7,
7.4), 4.67 (1H, dd, J = 7.
4, 3.0), 7.56 (1H, dd, J =
7.6, 7.6), 8.05 (1H, dd, J
= 7.6, 1.2), 8.36 (1H, dd,
7.6, 1.2).

Production Example 38 A mixture of phosphorus sulfide (2.22 g), dioxane (25 ml) and formaldehyde (9.9 ml) is refluxed for 1 hour. Cool to 50 ° C. and pour into a reaction flask containing 2-bromo-4-carbomethoxy-1-indanone (1.00 g). Reflux for 1 hour, and after cooling, ice / water (200 m
1), made basic by adding sodium carbonate sufficiently, left to stand for 30 minutes, and the resulting precipitate was collected by filtration and washed with water. Dissolve in methylene chloride and saline (50 ml each), separate the organic layer, and separate the aqueous layer with methylene chloride (twice or more,
25 ml each), the organic layers are combined, dried over magnesium sulfate, filtered and the solvent is distilled off. The residue was subjected to column chromatography using silica gel, eluted with a mixed solution of methylene chloride / methanol, recrystallized from methanol, and methyl indeno [3,2-d] thiazol-7-carboxylate (0%). .51 g) as brown crystals. mp: 136-137 ° C. IR (KBr, cm ⁻¹ ): 1716 MASS: 232 (M + 1) NMR (DMSO-d ₆ , δ): 3.92 (3H,
s), 4.26 (2H, s), 7.56 (1H,
dd, J = 7.7, 7.7), 7.87 (1
H, dd, J = 7.7, 1.1), 7.96
(1H, dd, J = 7.7, 1.1), 9.2
2 (1H, s).

Preparation 39 To a mixture of methyl indeno [3,2-d] thiazol-7-carboxylate (0.28 g) in methanol (5 ml) was added 1N sodium hydroxide (5 ml). 24 at room temperature
Stir for hours. The solvent is distilled off. Water (10 ml) is added, followed by 1N hydrochloric acid (6 ml). After 1 hour, the resulting precipitate is collected by filtration, washed with water, dried under reduced pressure at 40 ° C., and dried with indeno [3,2-d] thiazol-7-carboxylic acid (0.
24 g) as a red powder. mp: 270-273 ° C IR (KBr, cm ^-1 ): 1709 MASS: 218 (M + 1) NMR (DMSO-d ₆ , δ): 4.25 (2H,
s), 7.54 (1H, dd, J = 7.6,
7.6), 7.85 (1H, dd, J = 7.8,
1.1), 7.93 (1H, dd, J = 7.
5, 1.1), 9.21 (1H, s), 13.
16 (1H, brs).

Production Example 40 3- (bromoacetyl) benzonitrile mp: 59-61 ° C. IR (KBr, cm ⁻¹ ): 2229, 1707 MASS: 224, 226 (1: 1 ratio,
(Brisotopes, M + 1) NMR (CDCl ₃ , δ): 4.42 (2H,
s), 7.66 (1H, dd, J = 7.9, 7.
9), 7.90 (1H, ddd, J = 7.7,
1.4, 1.4), 8.22 (1H, ddd,
J = 7.9, 1.3, 1.3), 8.28 (1
H, dd, J = 1.3, 1.3)

Production Example 41 3- (bromoacetyl) benzonitrile (8.05 g)
To a mixture of the above in dimethylformamide (36 ml) at room temperature was added diformylimide sodium salt (3.41 g). Dissolve all substances slowly. 1 hour later, TL
C indicates that all the 3- (bromoacetyl) benzonitrile has been consumed. The mixture was mixed with ethyl acetate / water (180 m
1/180 ml), and the separated organic layer was washed with water (2
(180 ml each), washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography using silica gel, eluted with a mixture of methylene chloride / methanol, and recrystallized from ethyl acetate to give 3- (N, N-diformylaminoacetyl) benzonitrile (3.74 g). Obtained as white crystals. mp: 120-121 ° C IR (KBr, cm ⁻¹ ): 2231, 1707,
1668 MASS: 189 (M-CO + 1) NMR (CDCl 3, δ): 5.08 (2H,
s), 7.68 (1H, dd, J = 7.9, 7.
9), 7.92 (1H, ddd, J = 7.8,
1.4, 1.4), 8.20 (1H, ddd,
J = 7.9, 1.2, 1.2), 8.26 (1
H, dd, J = 1.5, 1.5), 9.05
(2H, s).

Production Example 42 To a mixture of 3- (N, N-diformylaminoacetyl) benzonitrile (3.74 g), methanol (25 ml) and methylene chloride (25 ml) was added triethylamine (10 μl) at room temperature. Stir at room temperature for 90 minutes.
The solvent is distilled off. The residue was subjected to column chromatography using silica gel, eluted with a mixture of methylene chloride / methanol, and recrystallized from ethyl acetate to give 3- (N-formylaminoacetyl) benzonitrile (2.51 g) as white crystals. obtain. mp: 124-125 ° C IR (KBr, cm ^-1 ): 3386, 2231,
1705, 1664 MASS: 189 (M + 1) NMR (CDCl ₃ , δ): 4.83 (1H, dd,
J = 4.5, 0.8), 6.62 (1H, br)
s), 7.68 (1H, dd, J = 7.8,
7.8), 7.92 (1H, ddd, J = 7.
7, 1.4, 1.4), 8.19 (1H, dd)
d, J = 7.9, 1.3, 1.3), 8.28
(1H, dd, J = 1.4, 1.4), 8.3
6 (1H, brs).

Production Example 43 A mixture of 3- (N-formylaminoacetyl) benzonitrile (0.80 g) and phosphorus oxychloride (5 ml) was refluxed for 1 hour. After cooling, the solvent is distilled off. Methylene chloride (50 ml) and water are added, then 1N sodium hydroxide is added until it becomes strongly alkaline. Separate the organic layer,
The aqueous layer was extracted with methylene chloride (twice, 25 ml each)
Combine the organic layers, dry over magnesium sulfate, filter,
The solvent is distilled off. The residue was subjected to column chromatography using silica gel, eluted with a methylene chloride / methanol mixture, recrystallized from methanol, and treated with 3- (oxazole-
5-yl) benzonitrile (0.50 g) is obtained as a light brown powder. mp: 136-137 ° C. IR (KBr, cm ⁻¹ ): 2229 MASS: 171 (M + 1) NMR (DMSO-d ₆ , δ): 7.70 (1
H, dd, J = 7.8, 7.8), 7.85 (1
H, ddd, J = 8, 1.1), 7.89 (1
H, s), 8.05 (1H, ddd, J = 8,
1, 1), 8.25 (1H, dd, J = 1,
1), 8.54 (1H, s).

Production Example 44 3- (Oxazol-5-yl) benzonitrile (0.
A mixture of 47 g) and concentrated hydrochloric acid (5 ml) is refluxed for 1 hour. After cooling, pour into ice / water (100 ml). After 30 minutes, the resulting precipitate is collected by filtration, washed with water, and dried under reduced pressure at 40 ° C. to give 3- (oxozol-5-yl) benzoic acid (0.38 g) as a brown powder. mp: 250-252 ° C IR (KBr, cm ^-1 ): 1691 MASS: 190 (M + 1) NMR (DMSO-d ₆ , δ): 7.62 (1H,
dd, J = 7.8, 7.8), 7.84 (1H,
7.s), 7.91-8.01 (2H, m),
25 (1H, dd, J = 1, 1), 8.50 (1
H, s), 13.22 (1H, br s).

Production Example 45 A mixture of 3- (N-formylaminoacetyl) benzonitrile (0.80 g), toluene (10 ml) and phosphorus sulfide (0.80 g) was refluxed for 5 hours, and then phosphorus sulfide (0. An additional 80 g) is added and refluxed for 2 hours. After cooling, decant from the solid residue and wash the solid residue with methylene chloride (10 ml) and 1N sodium hydroxide.
All liquid layers are combined, the organic layer is separated, dried over magnesium sulfate, filtered and the solvent is distilled off. The residue was subjected to column chromatography using silica gel, eluted with a methylene chloride / methanol mixture, and recrystallized from methanol.
3- (thiazol-5-yl) benzonitrile (0.2
6 g) are obtained as yellow crystals. mp: 83-84 ° C. IR (KBr, cm ⁻¹ ): 2227 MASS: 187 (M + 1) NMR (DMSO-d ₆ , δ): 7.66 (1H,
dd, J = 7.9, 7.9), 7.83 (1H,
ddd, J = 7.7, 1.3, 1.3),
8.02 (1H, ddd, J = 7.9, 1.2,
1.2), 8.26 (1H, dd, J = 1.
5, 1.5), 8.48 (1H, d, J = 0.5).
5), 9.17 (1H, d, J = 0.6).

Production Example 46 3- (Thiazol-5-yl) benzoic acid mp: 244-245 ° C. IR (KBr, cm ⁻¹ ): 1699 MASS: 206 (M + 1) NMR (DMSO-d ₆ , δ) : 7.60 (1H,
dd, J = 7.7, 7.7), 7.91-8.0.
0 (2H, m), 8.15 (1H, dd, J =
1.5, 1.5), 8.42 (1H, s),
9.14 (1H, s).

Production Example 47 A mixture of 4-carbomethoxy-1-indanone (1.14 g) and N, N-dimethylformamide dimethyl acetal (6.0 ml) is refluxed for 24 hours. After cooling,
Ethyl acetate (300 ml) was added and water (3 times, 1 each)
00 ml), brine (100 ml), dried over magnesium sulfate, filtered and evaporated. Grind with diisopropyl ether (10 ml), air dry overnight,
4-Carbomethoxy-2-[(dimethylamino) methylene] -1-indanone (1.22 g) is obtained as brown crystals. mp: 192-193 ° C. IR (KBr, cm ⁻¹ ): 1722, 1672 MASS: 246 (M + 1) NMR (DMSO-d ₆ , δ): 3.21 (6H,
s), 3.89 (3H, s), 4.18 (2
H, s), 7.46 (1H, br s), 7.5
4. (1H, dd, J = 7.6, 7.6);
86 (1H, d, J = 6.4), 8.09 (1
H, dd, J = 7.6, 1.2).

Production Example 48 4-Carbomethoxy-2-[(dimethylamino) methylene] -1-indanone (1.0 g), formamidine acetate (2.0 g), toluene (5 ml) and acetic acid (1 m
The mixture of 1) is refluxed for 2 hours. After cooling, the solvent is distilled off. The residue was treated with water / methylene chloride (1: 1, 100 ml)
, Neutralized with an aqueous solution of sodium hydroxide, separated the organic layer, and washed the aqueous layer with methylene chloride (twice or more, 25 m each).
Extract in 1). The organic layers are combined, dried over magnesium sulfate, filtered, and the solvent is distilled off. The residue was subjected to column chromatography using silica gel, eluted with a methylene chloride / methanol mixture, recrystallized from ethanol, and methyl indeno [3,2-d] pyrimidine-6-carboxylate (0.26 g). As a yellow powder. mp: 174-175 ° C. IR (KBr, cm ⁻¹ ): 1720 MASS: 227 (M + 1) NMR (DMSO-d ₆ , δ): 3.95 (3H,
s), 4.35 (2H, s), 7.73 (1
H, dd, J = 7.7, 7.7), 8.20
(1H, dd, 7.7.1.1), 8.34
(1H, d, 7.6), 9.06 (1H,
s), 9.21 (1H, s).

Production Example 49 Methyl indeno [3,2-d] pyrimidine-6-carboxylate (0.25 g), methanol (10 ml) and 1
A solution of N sodium hydroxide (5 ml) is stirred at room temperature for 4 hours. The solvent is distilled off, water (10 ml) is added, and 1N hydrochloric acid (6 ml) is added dropwise. After stirring at room temperature for 60 minutes, the resulting precipitate is collected by filtration, washed with water, and dried under reduced pressure at 40 ° C. to give indeno [3,2-d] pyrimidine-6-carboxylic acid (206 mg) as a yellow powder. obtain. mp: 282-284 ° C. IR (KBr, cm ⁻¹ ): 1707, 1695 MASS: 213 (M + 1) NMR (DMSO-d ₆ , δ): 4.35 (2H,
s), 7.71 (1H, dd, J = 7.6,
7.6), 8.18 (1H, d, J = 7.7),
8.32 (1H, d, J = 6.6), 9.04
(1H, s), 9.20 (1H, s), 13.3
(1H, brs).

Production Example 50 Methyl 3-bromobenzoate (1.08 g), cyclohexene (5.06 ml), palladium acetate (56 mg) and tris (2-methylphenyl) phosphine (152)
mg) in triethylamine (10 ml).
Heat at 0 ° C with a steel autoclave for 24 hours.
The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and the solvent is distilled off. The residue was subjected to column chromatography on silica gel, eluting with 30% methylene chloride in n-hexane to give 3- (3-methoxycarbonylphenyl) cyclohexene (0.17 g). ESI-mass; m / z 239 (M + Na ⁺ ) NMR (CDCl ₃ ): δ 1.6-2.4 (6H,
m), 2.8-3.0 (1H, m), 3.92
(3H, s), 5.7-5.9 (2H, m),
7.3-7.6 (2H, m), 7.8-8.0 (2
H, m)

Production Example 51 A suspension of 3- (3-methoxycarbonylphenyl) cyclohexene (0.25 g) in methanol (2.5 ml) and tetrahydrofuran (2.5 ml) was treated with a 1N aqueous sodium hydroxide solution (1. 62 ml) and stir for 3 hours. 1N hydrochloric acid (1.6 ml) is added to the mixture. The resulting precipitate is collected by filtration and dried to give 3- (3-carboxyphenyl) cyclohexene (224 mg). ESI-mass; m / z 201 (M-H +) NMR (DMSO-d 6): δ1.6-2.4 (6H,
m), 2.8-3.0 (1H, m) 5.6-6.
0 (2H, m), 7.3-7.6 (2H, m)
7-8.0 (2H, m)

Production Example 52 A suspension of 2-hydrazine benzoic acid / hydrochloride (3.77 g) and cyclopentanone (1.77 ml) in acetic acid (5 ml) was stirred at 80 ° C. for 1.5 hours. 6N hydrochloric acid (5 ml) is added to the mixture, and the mixture is refluxed for 4 hours. Cool the mixture,
The precipitate formed is filtered off, washed with methanol, dried and
This gives 2,3-cyclopentenoindole-7-carboxylic acid (178 mg). APCI-mass; m / z 202 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ; 2.4-2.6
(2H, m) 2.7-3.0 (4H, m), 6.
98 (1H, t, J = 8.0 Hz), 7.62
(1H, d, J = 8.0 Hz), 7.74 (1
H, d, J = 8.0 Hz), 10.82 (1H,
s), 12.89 (1H, broad s)

Production Example 53 A suspension of 2-hydrazinobenzoic acid / hydrochloride (2.0 g) in acetic acid (8 ml) was added with butan-2-one (0.9 m).
l) Acetic acid solution is added dropwise at 80 ° C. 1 at 80 ° C
After stirring for 6 hours, 6N hydrochloric acid (8 ml) is added to the mixture and the mixture is stirred at 100 ° C. for another 5 hours. Add water (20
ml) and the mixture is cooled to 5 ° C. The resulting precipitate is collected by filtration, washed successively with cold water and diisopropyl ether to give 2,3-dimethylindole-7-carboxylic acid (0.78 g). APCI-mass; 190 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , δ); 2.17 (3H,
s), 2.37 (3H, s), 7.03 (1H,
t, J = 7.6 Hz), 7.63 (2H, d, J
= 7.6 Hz), 10.55 (1H, s), 1
2.08 (1H, brs)

Production Example 54 To a suspension of 2-hydrazinobenzoic acid / hydrochloride (2.0 g) in acetic acid (8 ml) was added pentan-2-one (0.9 m).
l) Acetic acid solution is added dropwise at 80 ° C. 1 at 80 ° C
After stirring for 6 hours, 6N hydrochloric acid (8 ml) is added to the mixture, and the mixture is stirred at 100 ° C. for 5 hours. After cooling to room temperature, the reaction mixture is taken up in a mixture of ethyl acetate and water. Separate the organic layer, wash with brine and dry over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was diluted with diisopropyl ether.
Triturate with 3-ethyl-2-methylindole-
7-carboxylic acid (0.39 g) is obtained. APCI-mass; 204 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , δ); 1.14 (3H,
t, J = 7.5 Hz), 2.37 (3H, s),
2.66 (2H, q, J = 7.5 Hz), 7.0
2 (1H, t, J = 7.5 Hz), 7.58-
7.78 (2H, m) 10.55 (1H, s),
12.85 (1H, brs)

Production Example 55 Sodium hydride (suspended in mineral oil, 60%, 0.113
To a suspension of g) in N, N-dimethylformamide (3 ml) is added carbazole-1-carboxylic acid (0.30 g) portionwise at room temperature. After stirring for 30 minutes, methyl iodide (0.88 ml) is added to the mixture and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into a mixture of ethyl acetate and water, the organic layer is separated, washed with brine and dried over magnesium sulfate. The solvent was dried under reduced pressure and the residue was subjected to column chromatography using silica gel, 1%
Eluted with a mixture of ~ 3% ethyl acetate and n-hexane.
Methyl carbazole-1-carboxylate (0.17
g). LD-mass; 262.2 (m / z, [M + Na]
⁺ ) NMR (DMSO-d ₆ , δ); 3.84 (3H,
s), 3.96 (3H, s), 7.20-7.38
(2H, m), 7.54 (1H, dt, J = 1.
2, 7.1 Hz), 7.67 (1H, d, J =
8.3 Hz), 7.79 (1H, dd, J = 1.
2, 7.6 Hz), 8.23 (1H, d, J =
7.8 Hz), 8.41 (1H, dd = 1.2,
7.8Hz)

Production Example 56 Methyl 9-methylcarbazole-1-carboxylate (0.
To a suspension of 167 g) in methanol (5 ml) and tetrahydrofuran (5 ml) is added a 4N aqueous sodium hydroxide solution (0.88 ml) and the mixture is heated at 90 ° C. for 4 hours. The solvent of the reaction mixture is distilled off under reduced pressure. The residue is poured into a mixture of ethyl acetate and water and adjusted to around pH 1 with 6N hydrochloric acid. Separate the organic layer, wash with brine and dry over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is triturated with diisopropyl ether to obtain 9-methylcarbazole-1-carboxylic acid (153 mg). LD-mass; 226.1 (m / z, [M +
Z] ⁺ ) NMR (DMSO-d ₆ , δ); 3.90 (3H,
s), 7.20-7.35 (2H, m), 7.3
5-7.60 (1H, m), 7.65 (1H, d =
8.2 Hz), 7.79 (1H, dd, J = 1.
2, 7.6 Hz), 8.21 (1H, d, J =
7.8 Hz), 8.37 (1 H, dd, J = 1.
2, 7.8 Hz)

Example 1 3- (imidazole-1-yl) alinine (100 m
g) in dichloromethane (10 ml) solution and benzoyl chloride (0.073 ml) and triethylamine (0.088).
ml). The mixture is stirred for 2 hours at room temperature, the dichloromethane solution is washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, evaporated and evaporated with a mixture of ethyl acetate and diisopropyl ether (1: 1 v / v). Trituration gives N- [3- (imidazole-1-yl) phenyl] benzamide (0.07 g). mp: 155-158 ° C IR (KBr): 1666, 1606 cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.38 (1H, d, J = 8 Hz), 7.40
−7.70 (5H, m), 7.78 (1H, d, J = 8)
Hz), 7.95-8.05 (2H, m), 8.07
(1H, s), 8.19 (1H, s), 10.46 (1
H, s) MASS: 264 (M + 1 ⁺ )

Example 2 To a suspension of 3-benzoylbenzoic acid (70 mg) in dichloromethane (5 ml) was added dropwise a drop of oxalyl chloride (30 μl) and N, N-dimethylformamide at 0 ° C. with stirring. After stirring at 0 ° C for 30 minutes, the mixture was stirred at 0 ° C with 3- (imidazol-1-yl) aniline (49m
g) and triethylamine (108 μl) are added dropwise to a dichloromethane solution (3 ml). After stirring for 1 hour at room temperature, the reaction mixture is poured into water (20 ml) and extracted with dichloromethane: methanol = 10: 1 (30 ml).
The organic layer is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The resulting precipitate is washed with diisopropyl ether and washed with 1N- [3- (imidazol-1-yl) phenyl].
Obtain -3-benzoylbenzamide (50 ml). mp: 166-167 ° C IR (KBr): 3398, 3367, 3296,
3249, 3207, 3141, 3078, 297
6,1660,1606 cm ^-1 NMR (DMSO-d ₆ , δ): 7.13 (1H,
s), 7.36-7.41 (1H, m), 7.52
(1H, t, J = 8.0 Hz), 7.56-7.82
(8H, m), 7.96 (1H, d, J = 7.7H)
z), 8.04 (1H, s), 8.18 (1H,
s), 8.26-8.33 (2H, m), 10.64
(1H, s)

Example 3 The following compounds were obtained in the same manner as in Example 2. (1) N- [3- (imidazole-1-yl) phenyl] -2-methyl-5- (pyrrol-1-yl) benzamide mp: 80-83 ° C IR (KBr): 3246,3199 , 3126,
3072, 3030, 2970, 2925, 167
0.1608 cm ^-1 NMR (DMSO-d ₆ , δ): 2.53 (3H,
s), 6.35 (2H, t, J = 2.1 Hz), 7.
09 (2H, t, J = 2.1 Hz), 2.18-7.5
3 (9H, m), 8.03-8.06 (2H, m)

(2) (1) N- [3- (imidazole-
1-yl) phenyl] -3-biphenylcarboxamide mp: 155-156 ° C IR (KBr): 3741, 3612, 3554,
3435, 3406, 3367, 3300, 173
8,1660 cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1
H, s), 7.37-7.57 (5H, m), 7.62.
−7.69 (2H, m), 7.77−7.81, (3
H, m), 7.90-7.99 (2H, m), 8.06
-8.08 (1H, m), 8.20 (1H, s), 8.
25 (1H, s), 10.65 (1H, s)

Example 4 3- (Imidazol-1-yl) aniline (74 mg) and 4-dimethylaminopyridine (12 mg) were added to a solution of 3-phenikibenzoic acid (100 mg) in dichloromethane (5 ml).
2 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (161 mg) were stirred at room temperature. After stirring overnight at room temperature, the mixture is poured into water and extracted with dichloromethane. The extract is washed with 5% aqueous potassium hydrogen sulfate solution and water. The organic layer is separated, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography,
The mixture was eluted with a mixture of chloroform and methanol (100: 1), recrystallized from a mixture of isopropyl ether and ethyl acetate (1: 1) to give N- [3- (imidazole-1).
-Yl) phenyl] -3-phenoxybenzamide (1
07 mg). mp: 140-141 ° C IR (KBr): 3248, 3140, 3111,
3070, 3032, 1662, 1608 cm ^-1 NMR (DMSO-d ₆ , δ): 7.02 (1H,
s), 7.05-7.06 (1H, m), 7.15-
7.22 (4H, m), 7.33-7.63 (8H,
m), 7.86 (1H, s), 7.94-7.99 (1
H, m), 8.23 (1H, s)

Example 5 The following compounds were obtained in the same manner as in Example 4. (1) N- [3- (imidazole-1-yl) phenyl] -4H-pyrrolo [2,1-c] [1,4] benzoxazine-6-carboxamide hydrochloride mp: 168-172 ° C IR (KBr): 3327, 3103, 3066
2970, 2927, 2852, 1674, 1603
cm ^-1 NMR (D ₂ O, δ): 5.26-5.35 (2
H, m), 6.19-6.24 (1H, m), 6.40.
−6.47 (1H, m), 7.06 to 7.95 (10
H, m), 9.14 (1H, s)

(2) N- [3- (Imidazol-1-yl) phenyl] -3 (pyrrol-1-yl) benzamide hydrochloride mp: 129-133 ° C IR (KBr): 3402, 3107, 3060,
1676, 1606 cm ^-1 NMR (D ₂ O, δ):. 6.37-6.41 (2
H, m), 7.25-7.30 (2H, m), 7.43.
−7.50 (1H, m), 7.60-7.75 (6H,
m), 7.81-7.88 (2H, m), 7.95 (1
H, s), 9.14 (1H, s)

(3) N- [3- (imidazole-1-yl) phenyl] -1-methyl-4-indolecarboxamide mp: 206-208 ° C. IR (KBr): 3244,3134,3109,
3068, 3030, 2978, 2912, 165
7,1608 cm ^-1 NMR (DMSO-d ₆ , δ): 3.86 (3H,
s), 6.85 (1H, d, J = 3.0 Hz), 7.
13 (1H, s), 7.29 (1H, t, J = 7.8H)
z), 7.29-7.37 (1H, m), 7.46-
7.54 (2H, m), 7.61-7.72 (3H,
m), 7.80 (1H, d, J = 8.7 Hz), 8.
10 (1H, t, J = 1.9 Hz), 8.18 (1H,
s), 10.39 (1H, s)

(4) N- [3- (imidazole-1-yl) phenyl] -4-indolecarboxamide mp: 172-176 ° C IR (KBr): 3329,3207,3114,16
58, 1604 cm ^-1 NMR (DMSO-d ₆ , δ): 6.86 (1H,
s), 7.13 (1H, s), 7.23 (1H, t,
J = 7.7 Hz), 7.33-7.40 (1H, m),
7.46-7.67 (5H, m), 7.78-7.8
3 (1H, m), 8.10 (1H, s), 8.18
(1H, s), 10.37 (1H, s), 11.39
(1H, br)

(5) N- [3- (Imidazol-1-yl) phenyl] -3- (pyridin-3-yl) benzamide mp: 177-179 ° C IR (KBr): 3425, 3303, 3269,
3213,3147,3101,3035,166
_{^{2,1608cm -1 NMR (CDC1 3, δ}} ): 7.18-7.21
(2H, m), 7.34-7.59 (4H, m), 7.
65 (1H, d, J = 7.7 Hz), 7.78-7.8
2 (1H, m), 7.92-7.95 (3H, m),
8.02 (1H, d, J = 1, 9 Hz), 8.13 (1
H, d, J = 1.7 Hz), 8.33 (1H, s),
8.65 (1H, s), 8.90 (1H, s)

(6) N- [3- (imidazole-1-yl) phenyl] -1-fluorenecarboxamide mp: 228-230 ° C IR (KBr): 3435, 3282, 3248,
3130, 3070, 3030, 1662, 1606
cm ^-1 NMR (DMSO-d ₆ , δ): 4.22 (2H,
s), 7.14 (1H, s), 7.36-7.44
(3H, m), 7.47-7.67 (5H, m),
7.77 (1H, d, J = 7.8 Hz), 7.99 (1
H, d, J = 6.5 Hz), 8.09-8.19 (3
H, m), 10.55 (1H, s)

(7) N- [3- (imidazole-1-yl) phenyl] -2,6-dimethoxy-3- (pyrrol-1-yl) benzamide mp: 94-97 ° C IR (KBr ): 3286, 3253, 3199,
3126, 2968, 2846, 1678, 1606
cm ^-1 NMR (CDCl ₃ , δ): 3.43 (3H,
s), 3.89 (3H, s), 6.32 (2H, t,
J = 2.1 Hz), 6.78 (1H, d, J = 8.9)
Hz), 6.93 (2H, t, J = 2.0 Hz), 7.
16-7.37 (4H, m), 7.45 (2H, d, J
= 4.9 Hz), 7.87 (1H, s), 7.94
(1H, s), 8.04 (1H, s)

(8) N- [3- (imidazole-1-yl) phenyl] -2,5-dimethoxybenzamide mp: 163-166 ° C IR (KBr): 3425,3404,3369,
3317, 3097, 2835, 1666, 1608
cm ^-1 NMR (DMSO-d ₆ , δ): 3.77 (3H,
s), 3.87 (3H, s), 7.12-7.15.
(2H, m), 7.23 (1H, d, J = 2.6H
z), 7.51 (1H, dd, J = 6.8 Hz, 2.
1Hz), 7.62 (1H, t, J = 8.0Hz),
7.81-7.85 (1H, m), 7.92 (1H,
t, J = 1.6 Hz), 8.25 (2H, dd, J =
3.4 Hz, 1.7 Hz), 9.69 (1 H, t, J
= 1.3Hz), 10.50 (1H, s)

Example 6 3- (1-Methylimidazole-5-yl) aniline (87 mg) and 1-fluorenecarboxylic acid (105 m
To a mixture of g) in methylene chloride (2.5 ml) is added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153 mg). Two hours later, the mixture was subjected to thin layer chromatography, eluting with a mixed solution of methylene chloride-methanol (10: 1). The eluate was diluted with a mixture of methylene chloride-methanol (10: 1) (40 ml), washed with brine (twice, 25 ml each), filtered,
The solvent is distilled off. Column chromatography using silica gel gave methylene chloride-methanol (5.
0: 1) to a mixture of methylene chloride-methanol (10: 1) and eluted with N- [3- (1-methylimidazole-
5-yl) phenyl] -1-fluorenecarboxamide (0.15 g) is obtained. mp: 118-121 ° C IR (KBr): 3240, 1653 cm ^-1 NMR (DMSO-d ₆ , δ): 3.72 (3H,
s), 4.21 (2H, s), 7.07 (1H,
s), 7.25 (1H, d, J = 7.7 Hz), 7.3
0-7.80 (7H, m), 7.84 (1H, d, J =
8.1), 7.90-8.00 (2H, m), 8.12
(1H, d, J = 7.4 Hz), 10.44 (1H, d, J = 7.4 Hz)
brs) MASS: 366 (M + 1 ⁺ ).

Example 7 The following compounds were obtained in the same manner as in Example 6. (1) N- [3- (1-Methylimidazole-5-yl) phenyl] -3-biphenylcarboxamide mp: 78-80 ° C IR (KBr): 1658 cm ^-1 NMR (DMSO-d ₆ , δ) ): 3.72 (3
H, s), 7.07 (1H, br s), 7.25 (1
H, d, J = 7.7 Hz), 7.38-8.00 (12
H, m), 8.23 (1H, br s), 10.44
(1H, brs) MASS: 354 (M + 1 ⁺ )

(2) N- [3- (imidazole-1-yl) phenyl] -9-oxo-1-fluorenecarboxamide mp: 197-198 ° C IR (KBr): 1685 cm-1 NMR (DMSO- d ₆ , δ): 7.14 (1H,
s), 7.37-7.77 (9H, m) 7.89 (1
H, d, J = 7.4 Hz), 7.96-8.00 (2
H, m), 8.17 (1H, s), 10.78 (1H,
brs) MASS: 366 (M + 1 ⁺ ).

(3) N- [3- (imidazole-1-yl) phenyl] -2-naphthalenecarboxamide mp: 213-215 ° C IR (KBr): 1668 cm ^-1 NMR (DMSO-d ₆ , δ): 7.15 (1H,
s), 7.39 (1H, d, J = 9.1 Hz), 7.
54 (1H, dd, J = 8.0 Hz, 8.0 Hz),
7.63-7.69 (3H, m), 7.83 (1H,
d, J = 8.0 Hz), 8.01-8.11 (5H,
m), 8.21 (1H, s), 8.62 (1H,
s), 8.62 (1H, s), 10.65 (1H, br)
s) MASS: 314 (M + 1 ⁺ )

(4) N- [3- (imidazole-1-yl) phenyl] -1-naphthalenecarboxamide mp: 75-79 ° C IR (KBr): 167,1658 cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.39 (1H, d, J = 8.8 Hz), 7.
53 (1H, dd, J = 8.0 Hz, 8.0 Hz),
7.57-7.81 (6H, m), 8.00-8.25
(5H, m), 10.80 (1H, brs) MASS: 314 (M + 1 ⁺ )

(5) N- [3- (imidazole-1-yl) phenyl] -3- (4-trifluoromethylphenyl) benzamide mp: 209-211 ° C. IR (KBr): 1675 cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
m), 7.40 (1H, d, J = 7.6 Hz), 7.
53 (1H, dd, J = 8.0 Hz, 8.0 Hz),
7.62-7.81 (3H, m), 7.86-7.90
(2H, m), 7.96-8.11 (5H, m),
8.20 (1H, s), 8.32 (1H, s), 1
0.58 (1H, brs) MASS: 408 (M + 1 ⁺ )

(6) N- [3- (Imidazol-1-yl) phenyl] -3-thiazol-4-yl) benzamide mp: 160-161 ° C IR (KBr): 1656 cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.39 (1H, d, J = 9.0 Hz), 7.
53 (1H, dd, J = 7.9 Hz, 7.9 Hz),
7.65 (1H, dd, J = 7.7 Hz, 7.7H
z), 7.68 (1H, s), 7.80 (1H, d,
J = 8.1 Hz), 7.95 (1H, d, J = 7.7H)
z), 8.07 (1H, s), 8.19-8.24
(2H, m), 8.32 (1H, d, J = 1.8H
z), 8.58 (1H, s), 9.27 (1H, d,
J = 1.8 Hz), 10.59 (1H, brs) MASS: 347 (M + 1 ⁺ )

(7) N- [3- (imidazol-1-yl) phenyl] -3- (2 = methylthiazol-4-yl) benzamide mp: 57-59 ° C. IR (KBr): 1660 cm − ^-1 NMR (DMSO-d ₆ , δ): 2.75 (3H,
s), 7.14 (1H, s), 7.38 (1H, dd)
d, J = 7.0 Hz, 1.1 Hz, 1.1 Hz), 7.
52 (1H, dd, J = 8.0 Hz, 8.0 Hz),
7.61 (1H, dd, J = 7.8Hz, 7.8H
z), 7.68 (1H, dd, J = 1.3 Hz, 1.
6.3 Hz), 7.79 (1H, d, J = 〜7 Hz), 7.
92 (1H, d, J = 〜7 Hz), 8.05-8.09
(2H, m), 8.14-8.19 (2H, m),
8.51 (1H, dd, J = 1.6 Hz, 1.6H
z), 10.56 (1H, s) MASS: 361 (M + 1 ⁺ )

(8) N- [3- (imidazol-1-yl) phenyl] -3- (2-phenylthiazol-4-
Yl) benzamide mp: 74-76 ° C IR (KBr): 1662 cm ^- NMR (DMSO-d ₆ , δ): 7.15 (1H,
s), 7.40 (1H, d, J = 7.0 Hz), 7.
49-7.57 (4H, m), 7.60-7.69 (2
H, m), 7.80 (1H, d, J = 8.2 Hz),
7.98 (1H, d, J = 7.3 Hz), 8.04-
7.11 (3H, m), 8.21 (1H, s),
27-8.34 (2H, m), 8.62 (1H, s),
10.62 (1H, brs) MASS: 423 (M + 1 ⁺ )

Example 8 3- (imidazole-1-yl) aniline (100 m
g) in dichloromethane (10 ml) solution and 3-cyanobenzoic acid (92 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g).
g) is added. The mixture was stirred at room temperature for 5 hours, washed with aqueous sodium bicarbonate, dried over sodium sulfate,
The solvent was distilled off, and the residue was triturated with diisopropyl ether.
Obtain cyano-N- [3- (imidazol-1-yl) phenyl] benzamide (0.17 g). mp: 183-186 ° C IR (KBr): 2229,1672,1612
cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.41 (1H, dd, J = 8 Hz, 2H
z), 7.54 (1H, t, J = 8 Hz), 7.68
(1H, t, J = 2 Hz), 7.78 (2H, t, J)
= 8 Hz), 8.04 (1H, d, J = 2 Hz),
8.10 (1H, dd, J = 7 Hz, 2 Hz), 8.2
0 (1H, s), 8.28 (1H, dt, J = 7H
z, 2 Hz), 8.43 (1H, d, J = 2 Hz),
10.64 (1H, s) MASS: 289 (M + 1 ⁺ )

Example 9 The following compounds were obtained in the same manner as in Example 8. (1) N- [3- (imidazole-1-yl) phenyl] -3-methoxybenzamide mp: 171-174 ° C IR (KBr): 1668,1604 cm ^-1 NMR (DMSO-d ₆ , δ) : 3.85 (3H,
s), 7.13 (1H, d, J = 1 Hz), 7.18
(1H, ddd, J = 8 Hz, 2 Hz, 1 Hz), 7.
35-7.60 (5H, m), 7.67 (1H, t,
J = 2 Hz), 7.77 (1H, d, J = 8 Hz),
8.06 (1H, t, J = 2 Hz), 7.77 (1H,
d, J = 8 Hz), 8.06 (1H, t, J = 2H)
z), 8.19 (1H, s), 10.43 (1H,
s) MASS: 294 (M + 1 ⁺ )

(2) N- [3- (imidazole-1-yl) phenyl] -4-fluorenecarboxamide mp: 170-172 ° C IR (Nujol): 1640 cm ^-1 NMR (DMSO-d ₆ , δ): 4.01 (2H,
s), 7.14 (1H, s), 7.30-7.90
(11H, m), 8.11 (1H, s), 8.19 (1
H, s), 10.86 (1H, s) MASS: 352 (M + 1 ⁺ )

(3) N- [3- (imidazol-1-yl) phenyl] -4- (1-pyrrolyl) pyridine-2-
Carboxamide mp: 157-159 ° C IR (KBr): 1690 cm ^-1 NMR (DMSO-d ₆ , δ): 6.41 (2H,
s), 7.14 (1H, s), 7.42 (1H, d,
J = 8 Hz), 7.52 (1 H, t, J = 8 Hz),
7.65-7.80 (3H, m), 7.90-8.10.
(2H, m), 8.32 (1H, d, J = 2 Hz),
8.73 (1H, d, J = 7.5 Hz), 10.88
(1H, s) MASS: 330 (M + 1 ⁺ )

(4) N- [3- (imidazol-1-yl) phenyl] -9-oxo-9H [1,2-a] pyrroloindoline-6-carboxamide

Mp: 255-259 ° C. IR (KBr): 1690, 1615, 1560
cm ^-1 NMR (DMSO-d ₆ , δ): 6.42-6.4
6 (1H, m), 6.92 (1H, d, J = 4H
z), 7.14 (1H, s), 7.40 (1H, d,
J = 8 Hz), 7.53 (1 H, t, J = 8 Hz),
7.60-7.85 (5H, m), 8.05 (1H,
s), 8.11 (1H, s), 8.19 (1H, s),
10.70 (1H, brs) MASS: 355 (M + 1 ⁺ )

(5) N- [3- (imidazole-1-yl) phenyl] -7-nitrofluorene-1-carboxamide mp: 213-217 ° C IR (KBr): 1673, 1610 cm ^-1 NMR ( _{DMSO-d 6, δ):} 4.39 (2H,
s), 7.14 (1H, s), 7.35-8.40
(11H, m), 8.52 (1H, s), 10.66
(1H, s) MASS: 397 (M + 1 ⁺ )

(6) N- [3- (imidazole-1-yl) phenyl] -1-dibenzothiophene-carboxamide mp: 239-241 ° C IR (KBr): 1657, 1606 cm ^-1 NMR (DMSO- d ₆ , δ): 7.16 (1H,
s), 7.43 (1H, d, J = 9 Hz), 7.50
−7.65 (3H, m), 7.70-7.90 (3H,
m), 8.00-8.15 (2H, m), 8.23
(1H, s), 8.35-8.50 (2H, m), 8.
66 (1H, d, J = 7 Hz), 10.73 (1H,
s) MASS: 370 (M + 1 ⁺ )

(7) N- [3- (imidazol-1-yl) phenyl] -3- (3-thienyl) benzamide mp: 155-160 ° C IR (KBr): 1666,1606 cm ^--1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.39 (1H, d, J = 9 Hz), 7.45
−8.10 (10H, m), 8.20 (1H, s),
8.28 (1H, s), 10.53 (1H, s) MASS: 346 (M + 1 ⁺ )

(8) 6-chloro-N- [3- (imidazol-1-yl) phenyl] -1-dibenzofurancarboxamide mp: 157-160 ° C IR (KBr): 1680, 1606 cm ^- NMR (DMSO −d ₆ , δ): 7.15 (1H,
s), 7.42 (1H, d, J = 9 Hz), 7.50
−8.00 (7H, m), 8.09 (1H, s),
8.22 (1H, s), 8.40-8.45 (2H,
m), 10.70 (1H, brs) MASS: 388 (M + 1 ⁺ ).

(9) N- [3- (imidazol-1-yl) phenyl] -7-nitro-9-oxofluorene-
1-carboxamide mp: 243-247 ° C IR (KBr): 1697, 1666, 1604
cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.41 (1H, d, J = 8 Hz), 7.54.
(1H, t, J = 8 Hz), 7.60-7.75 (3
H, m), 7.85 (1H, t, J = 8 Hz),
7.99 (1H, s); 15-8.25 (3
H, m), 8.27 (1H, d, J = 2 Hz), 8.
9. 59 (1H, dd, J = 6 Hz, 2 Hz);
77 (1H, s) MASS: 411 (M + 1 ⁺ )

(10) N- [3- (imidazole-1-
Yl) phenyl] -4- (1-pyrrolyl) benzamide mp: 187-191 ° C IR (KBr): 1666, 1608 cm ^-1 NMR (DMSO-d ₆ , δ): 6.33 (2H,
t, J = 2 Hz), 7.14 (1H, s), 7.38
(1H, d, J = 9 Hz), 7.40-7.60 (3
H, m), 7.68 (1H, s), 7.75-7.85.
(3H, m), 8.07 (2H, s), 8.12 (1
H, s), 8.19 (1H, s), 10.46 (1H,
s) MASS: 329 (M + 1 ⁺ ).

(11) N- [3- (imidazole-1-
Yl) phenyl] -3- (1,2,4-triazole-
4-yl) benzamide mp: 145-155 ° C IR (KBr): 1672, 1612 cm ^-1 NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.41 (1H, d, J = 9 Hz), 7.54.
(1H, t, J = 8 Hz), 7.68 (1H, s),
7.76 (2H, t, J = 8 Hz), 7.90-8.1
0 (3H, m), 8.20 (1H, s), 8.30
(1H, s), 9.25 (2H, s), 10.66 (1
H, brs) MASS: 331 (M + 1 ⁺ )

(12) N- [3- (imidazole-1-
Yl) -2-methylphenyl] -1-fluorenecarboxamide mp: 127-131 ° C. IR (KBr): 1645, 1601 cm ⁻¹ NMR (DMSO-d ₆ , δ): 2.06 (3H,
s), 4.22 (2H, s), 7.13 (1H,
s), 7.20-7.50 (5H, m), 7.55-
7.65 (3H, m), 7.75-7.90 (2H,
m), 7.98 (1H, d, J = 6 Hz), 8.13
(1H, d, J = 7 Hz), 10.15 (1H, br
s) MASS: 366 (M + 1 ⁺ ).

(13) N- [3- (imidazole-1-
Yl) -4-methylphenyl] -1-fluorenecarboxamide mp: 205-209 ° C IR (KBr): 1664, 1604 cm ^-1 NMR (DMSO-d ₆ , δ): 2.13 (3H,
s), 4.19 (2H, s), 7.12 (1H,
s), 7.30-7.90 (10H, m), 7.98
(1H, d, J = 7 Hz), 8.12 (1H, d, J
= 8 Hz), 10.50 (1H, s) MASS: 366 (M + 1 ⁺ )

(14) N- [3- (3-Methylimidazole-4-yl) phenyl-1-dibenzothiophenecarboxamide] mp: 170-175 ° C. IR (KBr): 1655,1614 cm ^-1 NMR ( _{DMSO-d 6, δ):} 3.75 (3H,
s), 7.10 (1H, d, J = 1 Hz), 7.29
(1H, d, J = 8 Hz), 7.45-7.65 (3
H, m), 7.70-7.80 (2H, m), 7.8
8 (1H, d, J = 8 Hz), 7.96 (1H, d, J = 8 Hz)
s), 8.04-8.10 (1H, m), 8.37 (1
H, d, J = 8 Hz), 8.40-8.50 (1H,
m), 8.65 (1H, d, J = 8 Hz), 10.6
3 (1H, s) MASS: 384 (M + 1 ⁺ )

Example 10 3- (Imidazol-1-yl) aniline (100 m
g) in dimethyl sulfoxide (2 ml) solution, 60% sodium hydride (30 mg suspension in mineral oil), methyl 2-methoxy-5- (pyrrol-1-yl) benzoate (1)
(70 mg) at room temperature under stirring. Stir the resulting mixture overnight. The mixture is poured into ice water (20 ml) and extracted with ethyl acetate (30 ml). The organic layer is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel and eluted with chloroform. The fractions containing the target compound are combined, the solvent is distilled off under reduced pressure, and the obtained precipitate is washed with diisopropyl ether, and N- [3- (imidazole-1-yl) phenyl] -2 -Methoxy-5- (pyrrol-1-yl)
Obtain benzamide (143 mg). mp: 162-163 ° C. IR (Nujol): 1660, 1600 cm ⁻¹ NMR (DMSO-d ₆ , δ): 3.93 (3H,
s), 6.26 (2H, t, J = 2.1 Hz), 7.
13 (1H, s), 7.25-7.39 (4H, m),
7.50 (1H, t, J = 8.0 Hz), 7.67 −
7.79 (4H, m), 8.02 (1H, s), 8.
18 (1H, s), 10.43 (1H, s)

Example 11 Ethanol (10 m) of benzalphthalide (0.21 g)
l) To the solution is added 3- (imidazol-1-yl) aniline (0.15 g). The mixture is refluxed for 20 hours, purified by chromatography on silica gel and eluted with chloroform-methanol (0-2%). The resulting oil was pulverized with diisopropyl ether to give N-
[3- (Imidazol-1-yl) phenyl] -2-
(Phenylacetyl) benzamide (0.17 g) is obtained. mp: 158-161 ° C. IR (Nujol): 1695, 1680 cm ⁻¹ NMR (DMSO-d ₆ , δ): 3.29 (1H,
d, J = 14 Hz), 3.49 (1H, d, J = 14)
Hz), 6.60-6.70 (2H, m), 7.00-
7.15 (3H, m), 7.16 (1H, s), 7.3
8 (1H, s), 7.40-7.80 (8H, m),
7.91 (1H, s), 8.19 (1H, s) MASS: 382 (M + 1 ⁺ )

Example 12 6-chloro-N- [3- (imidazol-1-yl) phenyl] -1-dibenzofurancarboxamide (52 m
To a solution of g) in acetic acid (5 ml) are added 10% palladium-carbon (30 mg) and ammonium formate (150 mg). The mixture is stirred at 110 ° C. for 8 hours. After cooling, the catalyst is filtered off. The solvent of the filtrate is distilled off, the residue is dissolved in chloroform, and washed successively with an aqueous solution of sodium hydrogen carbonate, water and brine. The solution was dried over sodium sulfate, evaporated and triturated with diisopropyl ether to give N-
[3- (Imidazol-1-yl) phenyl] -1-dibenzofurancarboxamide (22 mg) is obtained. mp: 161-163 ° C. IR (KBr): 1678, 1604 cm ⁻¹ NMR (DMSO-d ₆ , δ): 7.15 (1H,
s), 7.40-7.65 (5H, m), 7.71
(1H, s), 7.75-7.90 (3H, m),
8.11 (1H, s), 8.20-8.30 (2H,
m), 8.39 (1H, d, J = 6 Hz), 10.6
7 (1H, s) MASS: 354 (M + 1 ⁺ )

Example 13 N- [3- (imidazole-1-yl) phenyl] -7
-Nitrofluorene-1-carboxamide (0.10
To a solution of g) in methanol (20 ml) is added 10% palladium on activated carbon (20 mg). The mixture was treated with hydrogen (1a
tm) Stir for 8 hours at room temperature in an atmosphere. The catalyst is removed by filtration. The solvent of the filtrate was distilled off, triturated with diisopropyl ether, and treated with 7-amino-N- [3- (imidazole-1-).
Yl) phenyl] -1-fluorenecarboxamide (0.07 g) is obtained. mp: 160-165 ° C IR (KBr): 1657, 1608 cm ^-1 NMR (DMSO-d ₆ , δ): 4.03 (2H,
s), 5.29 (2H, br s), 6.62 (1H,
d, J = 8 Hz), 6.79 (1H, s), 7.14
(1H, s), 7.30-7.90 (8H, m), 8.
10 (1H, s), 8.18 (1H, s), 10.4
9 (1H, brs) MASS: 367 (M + 1 ⁺ )

Example 14 1- (3-Aminophenyl) imidazole (0.10
g) in dichloromethane (10 ml)
Dimethoxybenzoyl chloride (0.15 g) is added. After stirring at room temperature for 2 hours, the mixture is poured into aqueous sodium hydrogen carbonate solution, and the organic layer is separated. The obtained solution was dried over sodium sulfate, and the solvent was distilled off.
Recrystallized from diisopropyl ether (1: 2 v / v), N- [3- (imidazole-1-yl) phenyl]
-3,4-Dimethoxybenzamide (0.06 g) is obtained. mp: 176-181 ℃ IR (KBr, cm -1): 1662, 1604 MASS: 324 (M + 1) NMR (DMSO-d 6, δ): 3.85 (6H,
s), 7.05-7.15 (2H, m), 7.3.
6 (1H, d, J = 8 Hz), 7.48 (1H, d, J = 8 Hz)
d, J = 8 Hz), 7.55 (1H, d, J)
= 2 Hz), 7.60-7.70 (2H, m),
7.74 (1H, d, J = 8 Hz), 8.05 (1
H, dd, J = 2 Hz, J = 1 Hz), 8.1
9 (1H, s), 10.28 (1H, s)

Example 15 1- (3-Aminophenyl) imidazole (71.5 m
g) in dichloromethane (10 ml)
(3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (140 mg) and 2-biphenylenecarboxylic acid (58 mg) are added. After stirring at room temperature for 48 hours, the mixture is added to an aqueous sodium hydrogen carbonate solution, and the organic layer is separated. Drying the resulting solution over sodium sulfate,
The solvent was distilled off and recrystallized from ethyl acetate-diisopropyl ether (1: 4 v / v) to give N- [3- (imidazole-1-yl) phenyl] biphenylene-2-carboxamide (65 mg). Get. mp: 200-203 ° C IR (KBr, cm ⁻¹ ): 1676, 1612 MASS: 338 (M + 1) NMR (DMSO-d ₆ , δ): 6.80-7.0
0 (5H, m), 7.13 (1H, s), 7.
27 (1H, s), 7.36 (1H, dt, J
= 9 Hz, J = 2 Hz), 7.40-7.55 (2
H, m), 7.66 (1H, t, J = 2H
z), 7.73 (1H, d, J = 9 Hz),
8.03 (1H, t, J = 2 Hz), 8.17
(1H, s), 10.30 (1H, s)

Example 16 The following compounds were obtained in the same manner as in Example 15. N- [3- (imidazole-1-yl) phenyl]-
2,3-dimethoxy-benzamide mp: 93-96 ℃ IR (KBr, cm -1): 1673, 1599 MASS: 324 (M + 1) NMR (DMSO-d 6, δ): 3.82 (3H,
s), 3.87 (3H, s), 7.10-7.2
5 (4H, m), 7.35 (1H, d, J = 8H
z), 7.49 (1H, t, J = 8 Hz),
7.60-7.75 (2H, m), 8.01 (1
H, br. s), 8.17 (1H, s), 1
0.47 (1H, s)

Example 17 The following compounds were obtained in the same manner as in Example 15. N- [3- (imidazole-1-yl) phenyl] -3
- dimethyl-aminobenzamide mp: 166-169 ℃ IR (KBr, cm -1): 1664, 1604 MASS: 307 (M + 1) NMR (DMSO-d 6, δ): 2.98 (6H,
s), 6.95 (1H, d, J = 8 Hz),
7.14 (1H, s), 7.20-7.40 (4
H, m), 7.50 (1H, t, J = 8H
z), 7.67 (1H, s), 7.76 (1H,
d, J = 8 Hz), 8.06 (1H, s),
8.19 (1H, s), 10.34 (1H, s)

Example 18 The following compounds were obtained in the same manner as in Example 15. N- [3- (imidazole-1-yl) phenyl] -3
- methylbenzamide mp: 124-126 ℃ IR (KBr, cm -1): 1662, 1606 MASS: 278 (M + 1) NMR (DMSO-d 6, δ): 2.41 (3H,
s), 7.13 (1H, s), 7.30-7.6
0 (4H, m), 7.67 (1H, s),
7.70-7.85 (3H, m), 8.05 (1
H, s), 8.18 (1H, s), 10.42
(1H, s)

Example 19 The following compounds were obtained in the same manner as in Example 15. 3-Chloro-N- [3- (imidazole-1-yl) phenyl] benzamide mp: 179-182 ° C IR (KBr, cm ^-1 ): 1668, 1606 MASS: 298 (M + 1) NMR (DMSO-d) ₆ , δ): 7.14 (1H,
s), 7.40 (1H, d, J = 9 Hz),
7.45-7.80 (5H, m), 7.94 (1
H, dt, J = 8 Hz, J = 2 Hz), 8.0
0-8.10 (2H, m), 8.19 (1H,
s), 10.56 (1H, s)

Example 20 The following compounds were obtained in the same manner as in Example 15. 3,5-dimethoxy-N- [3- (imidazole-1-
Yl) phenyl] benzamide mp: 133-137 ° C. IR (KBr, cm ⁻¹ ): 1685, 1604 MASS: 324 (M + 1) NMR (DMSO-d ₆ , δ): 3.84 (3H,
s), 6.75 (1H, t, J = 2 Hz),
7.10-7.15 (3H, m), 7.38 (1
H, d, J = 8 Hz), 7.51 (1H, t,
J = 8 Hz), 7.67 (1H, s), 7.
76 (1H, d, J = 8 Hz), 8.05 (1
H, t, J = 2 Hz), 8.19 (1H,
s), 10.38 (1H, s)

Example 21 The following compounds were obtained in the same manner as in Example 15. 3,5-dimethoxy-N- [3- (imidazole-1-
Yl) phenyl] benzamide mp: 85-87 ℃ IR (KBr, cm -1): 1673, 1606 MASS: 308 (M + 1) NMR (DMSO-d 6, δ): 2.20 (3H,
s), 3.84 (3H, s), 7.00-7.1.
5 (3H, m), 7.20-7.40 (2H,
m), 7.48 (1H, t, J = 8 Hz),
7.20-7.60 (2H, m), 8.02 (1
H, s), 8.15 (1H, S), 10.5
1 (1H, s)

Example 22 The following compounds were obtained in the same manner as in Example 15. N- [3- (imidazol-1-yl) phenyl] -fluorene-2-carboxamide mp: 230-232 ° C IR (KBr, cm ^-1 ): 1668, 1606 MASS: 352 (M + 1) NMR (DMSO- d ₆ , δ): 4.06 (3H,
s), 7.14 (1H, s), 7.30-7.6
0 (4H, m), 7.60-7.70 (2H,
m), 7.82 (1H, d, J = 8 Hz),
8.00-8.10 (4H, m), 8.21 (2
H, d, J = 7 Hz), 10.50 (1H,
s)

Example 23 The following compounds were obtained in the same manner as in Example 15. N- [3- (imidazole-1-yl) phenyl] -6
- methoxynaphthalene-2-carboxamide mp: 199-201 ℃ IR (KBr, cm -1): 1666, 1612 MASS: 344 (M + 1) NMR (DMSO-d 6, δ): 3.93 (3H,
s), 7.15 (1H, s), 7.28 (1H,
dd, J = 9 Hz, J = 2 Hz), 7.35−
7.45 (2H, m), 7.53 (1H, t,
J = 8 Hz), 7.69 (1H, s), 7.82
(1H, d, J = 9 Hz), 7.90-8.05
(3H, m), 8.10 (1H, t, J = 2H
z), 8.20 (1H, s), 8.54 (1H,
s), 10.55 (1H, s)

Example 24 The following compounds were obtained in the same manner as in Example 15. 6-Hydroxy-N- [3- (imidazole-1-yl) phenyl] naphthalene-2-carboxamide mp: 265-275 ° C IR (KBr, cm ^-1 ): 1648, 1606 MASS: 330 (M + 1) NMR _{(DMSO-d 6, δ)} : 7.10-7.25
(3H, m), 7.37 (1H, d, J = 9H
z), 7.52 (1H, t, J = 8 Hz),
7.68 (1H, t, J = 1 Hz), 7.75-
8.00 (3H, m), 8.05-8.15 (2H,
m), 8.19 (1H, s), 8.49 (1
H, s), 10.11 (1H, s), 10.5
0 (1H, s)

Example 25 The following compounds were obtained in the same manner as in Example 15. N- [3- (Imidazol-1-yl) -4-methoxyphenyl] fluorene-1-carboxamide mp: 235-241 ° C IR (KBr, cm ^-1 ): 1674, 1608 MASS: 382 (M + 1) NMR _{(DMSO-d 6, δ)} : 3.83 (3H,
s), 4.20 (2H, s), 7.08 (1H,
s), 7.20-7.50 (4H, m), 7.5
0-7.85 (4H, m), 7.90 (2H,
s), 7.98 (1H, d, J = 7 Hz),
8.12 (1H, d, J = 7 Hz), 10.41
(1H, s)

Example 26 The following compounds were obtained in the same manner as in Example 15. N- [3- (4,5,6,7-tetrahydrobenzimidazol-1-yl) phenyl] fluorene-1-carboxamide mp: 251-220 ° C IR (KBr, cm ^-1 ): 1672, 1604 MASS 406 (M + 1) NMR ( DMSO-d 6, δ): 1.78 (4H,
br. s), 2.40-2.60 (4H, m),
4.21 (2H, s), 7.19 (1H, d,
J = 9 Hz), 7.30-7.65 (5H, m),
7.70-7.80 (2H, m), 7.84 (1
H, d, J = 8 Hz), 7.93 (1H,
s), 7.98 (1H, d, J = 6 Hz),
8.13 (1H, d, J = 7 Hz), 10.56 (1
H, s)

Example 27 The following compounds were obtained in the same manner as in Example 15. N- [3- (ethoxycarbonyl) -5- (imidazo-
Ru-1-yl) phenyl] fluorene-1-carboxamide mp: 170-173 ° C. IR (KBr, cm ⁻¹ ): 1722, 1676, 16
10 MASS: 424 (M + 1 ) NMR (DMSO-d 6, δ): 1.37 (3H,
3. t, J = 7 Hz), 4.24 (2H, s),
39 (2H, q, J = 7 Hz), 7.17 (1
H, s), 7.30-7.50 (2H, m),
7.55-7.70 (2H, m), 7.75-7.
90 (3H, m), 7.99 (1H, d, J = 6
Hz), 8.15 (1H, d, J = 7Hz),
8.28 (1H, s), 8.35 (1H, t, J
= 2 Hz), 8.46 (1H, d, J = 2 Hz), 1
0.76 (1H, s)

Example 28 The following compounds were obtained in the same manner as in Example 15. N- [3- (2-methylthioimidazole-1-yl)
Phenyl] fluorene-1-carboxamide mp: 180-183 ° C IR (KBr, cm ⁻¹ ): 1676, 1604 MASS: 398 (M + 1) NMR (DMSO-d ₆ , δ): 2.54 (3H,
s), 4.20 (2H, s), 7.12 (1H,
d, J = 1 Hz), 7.18 (1H, d, J)
= 9Hz), 7.30-7.70 (6H, m),
7.75 (1H, d, J = 7 Hz), 7.85 (1
H, d, J = 8 Hz), 7.90-8.05
(2H, m), 8.13 (1H, d, J = 7H
z), 10.16 (1H, s)

Example 29 A suspension of 3-fluorenecarboxylic acid (41 mg) in dichloromethane (5 ml) was added to N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (75 m
g) and 1- (3-aminophenyl) imidazole (62
mg). After stirring at room temperature for 14 hours, the mixture is added to an aqueous sodium hydrogen carbonate solution, and the organic layer is separated.
The obtained solution was dried over sodium sulfate, the solvent was distilled off, and the residue was purified by chromatography on silica gel, and chlorofilm-methanol (0-1% v / v) was used.
To give N- [3- (imidazole-1-yl) phenyl] fluorene-3-carboxamide (22 mg). mp: 149-151 ° C. IR (KBr, cm ⁻¹ ): 1653, 1606 MASS: 352 (M + 1) NMR (DMSO-d ₆ , δ): 4.04 (2H,
s), 7.14 (1H, s), 7.30-7.55
(4H, m), 7.60-7.80 (4H, m),
7.90-8.05 (2H, m), 8.10 (1H,
t, J = 2 Hz), 8.20 (1H, s), 8.
50 (1H, d, J = 1 Hz), 10.53 (1H,
s)

Example 30 3-amino-N-benzyl-5- (imidazole-1-
Yl) benzamide (80 mg) in dichloromethane (1
0 ml) and N, N'-dimethylformamide (5 ml)
N- (3-dimethylaminopropyl) -N ′
-Ethylcarbodiimide / hydrochloric acid (105 mg), fluorene-1-carboxylic acid (58 mg) and 4- (dimethylamino) pyridine (7 mg) are added. After stirring at room temperature for 7 hours, the mixture is added to an aqueous sodium hydrogen carbonate solution, and the organic layer is separated. The obtained solution was dried over sodium sulfate, the solvent was distilled off, the residue was purified by chromatography on silica gel, and chloroform-methanol (0-2) was used.
%, V / v) to give N- [3- (benzylaminocarbonyl) -5- (imidazol-1-yl) phenyl] fluorene-1-carboxamide (65 mg).

Mp: 240-249 ° C. IR (KBr, cm ⁻¹ ): 1668, 1647,
1600 MASS: 485 (M + 1) NMR (DMSO-d ₆ , δ): 4.24 (2H,
s), 4.54 (2H, d, J = 6 Hz),
7.17 (1H, s), 7.25-7.45 (7
H, m), 7.50-7.65 (2H, m),
7.74 (1H, s), 7.81 (1H, d,
J = 7 Hz), 7.88 (1H, s), 7.99
(1H, d, J = 6 Hz), 8.15 (1H, d, J = 6 Hz)
d, J = 8 Hz), 8.25 (2H, s), 8.3
0 (1H, s), 9.16 (1H, br.t,
J = 6 Hz), 10.70 (1H, s)

Example 31 3-Imidazol-1-ylaniline (80 mg) and 2,3-dihydrobenzofuran-7-carboxylic acid (98 mg)
mg), 4-dimethylaminopyridine (12 mg) and dichloromethane (2.5 ml) in a mixture of N- (3-dimesylaminopropyl) -N'-ethylcarbodiimide.
Hydrochloride (153 mg) (all dissolved) is added. Dilute with ethyl acetate (50 ml), water, saturated aqueous solution of sodium bicarbonate (3 times, 50 ml each time), brine (50 m
Wash with 1), dry over magnesium sulfate, filter and evaporate the solvent. The residue was purified by a silica gel column, eluted with dichloromethane-methanol, and recrystallized from diisopropyl ether to give N- [3-imidazol-1-yl) phenyl] -2,3-dihydrobenzofuran-7-carboxamide (92 mg). obtain. mp: 135-137 ° C. IR (KBr, cm ⁻¹ ): 3357, 1672 MASS: 306 (M + 1) NMR (DMSO-d ₆ , δ): 3.29 (2H,
t, J = 8.8), 4.77 (2H, t, J =
8.8), 7.00 (1H, dd, J = 7.6,
7.6), 7.13 (1H, s), 7.37
(1H, d, J = 9.0), 7.45-7.75
(5H, m), 8.00 (1H, dd, J = 1.
9, 1.9), 8.21 (1H, s), 9.94
(1H, s).

Example 32 The following compounds were obtained in the same manner as in Example 31. N-3- (5-methylimidazol-1-yl) phenyl-1-fluorenecarboxamide mp: 225-227 ° C IR (KBr, cm ⁻¹ ): 1666 MASS: 366 (M + 1) NMR (DMSO-d ₆ , δ) ): 2.20 (3H,
s), 4.21 (2H, s), 6.85 (1H,
s), 7.20 (1H, d, J = 7.8),
7.33-7.45 (2H, m), 7.50-7.6
5 (3H, m), 7.73-7.78 (2H,
m), 7.86-8.00 (3H, m), 8.1.
3 (1H, d, J = 6.7), 10.58 (1H
brs).

Example 33 The following compounds were obtained in the same manner as in Example 31. N-3- (oxazol-5-yl) phenyl-1-fluorenecarboxamide mp: 239-240 ° C IR (KBr, cm ⁻¹ ): 3307, 1647 MASS: 353 (M + 1) NMR (DMSO-d ₆ , δ): 4.22 (2H,
s), 7.32-7.62 (6H, m), 7.6.
8 (1H, s), 7.75-7.81 (2H,
m), 7.99 (1H, d, J = 7), 8.1
3 (1H, d, J = 6.7), 8.28 (1H,
br s), 8.49 (1H, s), 10.50 (1
H, s).

Example 34 The following compounds were obtained in the same manner as in Example 31. N-3- (thiazol-5-yl) phenyl-1-fluorenecarboxamide mp: 218-220 ° C. IR (KBr, cm ⁻¹ ): 3300, 1645 MASS: 369 (M + 1) NMR (DMSO-d ₆ , δ): 4.22 (2H,
s), 7.36-7.66 (6H, m), 7.7
5-7.84 (2H, m), 7.95-8.00
(1H, m), 8.11-8.17 (2H,
m), 8.30 (1H, s), 9.12 (1H,
s), 10.47 (1H, s).

Example 35 The following compounds were obtained in the same manner as in Example 31. 7-Chloro-N- [3- (imidazole-1-yl) phenyl] -1-fluorenecarboxamide mp: 239-241 ° C IR (KBr, cm ^-1 ): 1664 MASS: 386, 388 (Clisotopes, M)
+1) NMR (DMSO-d ₆ , δ): 4.25 (2H,
s), 7.14 (1H, s), 7.36-7.8
2 (8H, m), 8.01 (1H, d, J = 8.
2), 8.08-8.19 (3H, m), 10.57
(1H, s).

Example 36 The following compounds were obtained in the same manner as in Example 31. N- [3- (imidazole-1-yl) phenyl] -3
-(Oxazol-5-yl) benzamide mp: 167-169 ° C IR (KBr, cm ⁻¹ ): 1672 MASS: 331 (M + 1) NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.40 (1H, d, J = 9.0),
7.53 (1H, dd, J = 8.0, 8.0),
7.64-7.72 (2H, m), 7.78 (1
H, br d, J = 8.6), 7.84 (1H,
s), 7.97 (1H, dd, J = 8.0, 1.
6), 8.06 (1H, dd, J = 2.0, 2.
0), 8.20 (1H, s), 8.30 (1H, d
d, J = 1.8, 1.8), 8.54 (1H,
s), 10.60 (1H, s)

Example 37 The following compounds were obtained in the same manner as in Example 31. N- [3- (imidazole-1-yl) phenyl] -5
- methoxy-2-nitro-Benz amide mp: 77-84 ℃ IR (KBr, cm -1): 1683 MASS: 339 (M + 1) NMR (DMSO-d 6, δ): 3.95 (3H,
s), 7.13 (1H, s), 7.22-7.
29 (2H, m), 7.39 (1H, d, J =
8.2), 7.52 (1H, dd, J = 7.8,
7.8), 7.60-7.65 (2H, m),
7.90 (1H, dd, J = 1,1), 8.16
(1H, s), 8.22 (1H, d, J = 9.
4), 10.83 (1H, s).

Example 38 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazol-5-yl) phenyl] -3- (thiazol-4-yl) benzamide (as oxalate) mp: 136-138 ° C IR (KBr, cm ^{− 1} ): 1670 MASS: 361 (M + 1) NMR (DMSO-d ₆ , δ): 3.78 (3H,
s), 7.25-7.33 (2H, m), 7.5
0 (1H, dd, J = 7.9, 7.9), 7.64
(1H, dd, J = 7.8, 7.8), 7.83
−8.00 (3H, m), 8.18-8.25 (2
H, m), 8.33 (1H, d, J = 1),
8.56 (1H, s), 9.26 (1H, d,
J = 1), 10.53 (1H, s).

Example 39 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazol-5-yl) phenyl] -3- (thiazol-5-yl) benzamide (as fumarate) mp: 168-169 ° C IR (KBr, ^{cm -1): 1662 MASS: 361} (M + 1) NMR (DMSO-d 6, δ): 3.78 (3H,
s), 7.08 (1H, s), 7.26 (1H,
d, J = 7.9), 7.46 (1H, dd,
J = 7.9, 7.9), 7.63 (1H, dd,
J = 7.7, 7.7), 7.73-7.83 (2H,
m), 7.90-7.98 (3H, m), 8.2
2 (1H, s), 8.45 (1H, s), 9.1
6 (1H, s), 10.47 (1H, s) (fum
aric acid at 6.62 (2H,
s)).

Example 40 The following compounds were obtained in the same manner as in Example 31. N- [3- (imidazole-1-yl) phenyl] -3
-(Thiazol-5-yl) benzamide mp: 185-186 ° C IR (KBr, cm ^-1 ): 1664 MASS: 347 (M + 1) NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.40 (1H, d, J = 9.0),
7.53 (1H, dd, J = 8.0, 8.0),
7.64 (1H, dd, J = 7.7, 7.7),
7.68 (1H, s), 7.77 (1H, d, J =
8.0), 7.93-7.98 (2H, m), 8.
06 (1H, dd, J = 1, 1), 8.20 (1
H, s), 8.23 (1H, dd, J = 1,
1), 8.45 (1H, s), 9.17 (1H,
s), 10.58 (1H, s).

Example 41 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazole-5-yl) phenyl] -3- (3-methoxyphenyl) benzamide (as fumarate) mp: 90-93 ° C IR (KBr, cm ^-1) ): 1676 MASS: 384 (freeM + 1) NMR (DMSO-d 6, δ): 3.72 (3H,
s), 3.85 (3H, s), 6.90-7.1.
8 (2H, m), 7.22-7.54 (5H,
m), 7.60-8.00 (6H, m), 8.2
2 (1H, s), 10.44 (1H, s).

Example 42 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazole-5-yl) phenyl] -3- (3-methylphenyl) benzamide mp: 85-89 ° C IR (KBr, cm ^-1 ): 1670 MASS: 368 (M + 1) ) NMR (DMSO-d ₆ , δ): 2.41 (3H,
s), 3.72 (3H, s), 7.07 (1H,
d, J = 1.1), 7.20-7.29 (2H,
m), 7.36-7.50 (2H, m), 7.
54-7.67 (3H, m), 7.72 (1H,
s), 7.80-7.96 (4H, m), 8.2.
1 (1H, dd, J = 1.1), 10.43 (1
H, s).

Example 43 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazole-5-yl) phenyl] -3- (3-chlorophenyl) benzamide mp: 65-69 ° C IR (KBr, cm ^-1 ): 1670 MASS: 388 (M + 1) NMR (DMSO-d ₆ , δ): 3.72 (3H,
s), 7.07 (1H, d, J = 1.1),
7.26 (1H, d, J = 7.7), 7.42-
8.00 (11H, m), 8.26 (1H, br
s), 10.44 (1H, s).

Example 44 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazole-5-yl) phenyl] -3- (4-methylphenyl) benzamide mp: 110-111 ° C IR (KBr, cm ⁻¹ ): 1664 MASS: 368 (M + 1) ) NMR (DMSO-d ₆ , δ): 2.37 (3H,
s), 3.72 (3H, s), 7.07 (1H,
d, J = 1.1), 7.23-7.35 (3H,
m), 7.46 (1H, dd, J = 8.0,
8.0), 7.62 (1H, dd, J = 7.7,
7.7), 7.66-7.72 (3H, m), 7.
78-7.93 (4H, m), 8.21 (1H,
dd, J = 1, 1), 10.43 (1H, s).

Example 45 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazole-5-yl) phenyl] -3- (4-methoxyphenyl) benzamide mp: 98-100 ° C IR (KBr, cm ^-1 ): 1662 MASS: 384 (M + 1) ) NMR (DMSO-d ₆ , δ): 3.72 (3H,
s), 3.82 (3H, s), 7.05-7.1.
0 (3H, m), 7.25 (1H, d, J = 7.
9), 7.46 (1H, dd, J = 7.8,7.
8), 7.60 (1H, dd, J = 7.7,7.
7), 7.70-7.75 (3H, m), 7.80
−7.93 (4H, m), 8.18 (1H, d
d, J = 1, 1), 10.42 (1H, s).

Example 46 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazol-5-yl) phenyl] -3- (4-chlorophenyl) benzamide mp: 117-119 ° C IR (KBr, cm ^-1 ): 1662 MASS: 388 (M + 1) NMR (DMSO-d ₆ , δ): 3.72 (3H,
s), 7.07 (1H, d, J = 1.1),
7.25 (1H, d, J = 8.0), 7.46
(1H, dd, J = 7.9, 7.9), 7.54
−7.62 (2H, m), 7.65 (1H, dd,
J = 7.8, 7.8), 7.72 (1H, s),
7.79-7.88 (3H, m), 7.89-
8.01 (3H, m), 8.23 (1H, dd,
J = 1,1), 10.45 (1H, brs).

Example 47 The following compounds were obtained in the same manner as in Example 31. N-3- (1,2-dimethylimidazole-5-yl)
Phenyl-1-fluorenecarboxamide mp: 147-149 ° C IR (KBr, cm ^-1 ): 1674 MASS: 380 (M + 1) NMR (DMSO-d ₆ , δ): 2.37 (3H,
s), 3.57 (3H, s), 4.21 (2H,
s), 6.89 (1H, s), 7.17 (1
H, d, J = 7.8), 7.32-7.49 (3
H, m), 7.53-7.66 (2H, m),
7.73-7.88 (3H, m), 7.98 (1
H, d, J = 6.5), 8.12 (1H, J =
6.7), 10.44 (1H, s).

Example 48 The following compounds are obtained in the same manner as in Example 31. N-3- (2-ethyl-1-methylimidazole-5-
Yl) phenyl-1-fluorenecarboxamide mp: 112-113 ° C IR (KBr, cm ^-1 ): 1674 MASS: 394 (M + 1) NMR (DMSO-d ₆ , δ): 1.26 (3H,
t, J = 7.5), 2.72 (2H, q, J =
7.5), 3.58 (3H, s), 4.21 (2
H, s), 6.91 (1H, s), 7.18
(1H, d, J = 7.8), 7.35-7.49
(3H, m), 7.53-7.66 (2H,
m), 7.72-7.88 (3H, m), 7.98
(1H, d, J = 6.5), 8.12 (1H, d,
J = 6.7), 10.44 (1H, s).

Example 49 The following compounds are obtained in the same manner as in Example 31. N- [3- (imidazole-1-yl) phenyl] -3
- methoxy-2-nitrobenzamide mp: 184-185 ℃ IR (KBr, cm -1): 1676 MASS: 339 (M + 1) NMR (DMSO-d 6, δ): 3.95 (3H,
s), 7.12 (1H, brs), 7.38-
7.78 (7H, m), 7.91 (1H, br
s), 8.16 (1H, br s), 10.90
(1H, s).

Example 50 The following compounds were obtained in the same manner as in Example 31. N-3- (1,2-dimethylimidazole-5-yl)
Phenyl-3-phenyl-Baie Ends amide mp: 61-65 ℃ IR (KBr, cm -1): 1672 MASS: 368 (M + 1) NMR (DMSO-d 6, δ): 2.36 (3H,
s), 3.57 (3H, s), 6.88 (1H,
s), 7.17 (1H, d, J = 8.0),
7.40-7.56 (4H, m), 7.64 (1
H, dd, J = 7.7, 7.7), 7.76−
7.97 (6H, m), 8.23 (1H, br
s), 10.43 (1H, br s).

Example 51 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazole-5-yl) phenyl] -indeno [3,2-d] thiazol-7-carboxamide mp: 247-248 ° C IR (KBr, cm ^-1 ): 1660 MASS: 373 (M + 1 ) NMR (DMSO-d 6, δ): 3.72 (3H,
s), 4.25 (2H, s), 7.07 (1H,
d, J = 1.0), 7.25 (1H, Brd,
J = 7.9), 7.46 (1H, dd, J = 7.
8, 7.8), 7.58 (1H, dd, J =
7.5, 7.5), 7.70-7.74 (2H,
m), 7.81-7.92 (3H, m), 9.2
2 (1H, s), 10.47 (1H, s).

Example 52 The following compounds were obtained in the same manner as in Example 31. N- [3- (Imidazol-1-yl) phenyl] -indeno [3,2-d] thiazol-7-carboxamide mp: 242-244 ° C IR (KBr, cm ^-1 ): 1674 MASS: 359 (M + 1) NMR ( DMSO-d 6, δ): 4.25 (2H,
s), 7.14 (1H, d, J = 1.0),
7.40 (1H, d, J = 7), 7.52 (1
H, dd, J = 8.0, 8.0), 7.59-
7.77 (4H, m), 7.91 (1H, dd,
J = 7.4, 1.0), 8.06 (1H, d
d, J = 1.9, 1.9,), 8.18 (1H,
d, J = 1.0), 9.22 (1H, s), 1
0.58 (1H, s).

Example 53 The following compounds were obtained in the same manner as in Example 31. 3-ethoxy-N- [3- (imidazole-1-yl)
Phenyl] benzamide mp: 124-126 ° C IR (KBr, cm ⁻¹ ): 1666 MASS: 308 (M + 1) NMR (DMSO-d ₆ , δ): 1.37 (3H,
t, J = 6.9), 4.12 (2H, q, J =
6.9), 7.12-7.20 (2H, m),
7.36-7.57 (5H, m), 7.67 (1
H, s), 7.77 (1H, d, J = 8.
2), 8.05 (1H, dd, J = 1.8,
1.8), 8.18 (1H, s), 10.40
(1H, s).

Example 54 The following compounds were obtained in the same manner as in Example 31. N- [3- (1-Methylimidazol-5-yl) phenyl] indeno [3,2-d] pyrimidine-6-carboxamide mp: 227-229 ° C IR (KBr, cm ^-1 ): 1664 MASS: 368 (M + 1) NMR ( DMSO-d 6, δ): 3.73 (3H,
s), 4.35 (2H, s), 7.07 (1H,
d, J = 0.8), 7.27 (1H, d, J
= 7.9), 7.47 (1H, dd, J = 7.8,
7.8), 7.72-7.86 (3H, m),
7.93 (1H, dd, J = 1.7, 1.7),
8.06 (1H, d, J = 6.8), 8.28
(1H, dd, J = 6.8, 0.7), 9.03
(1H, s), 9.21 (1H, s), 10.5
5 (1H, s).

Example 55 The following compounds were obtained in the same manner as in Example 31. N- [3- (Imidazol-1-yl) phenyl] indeno "3,2-d" pyrimidine-6-carboxamide mp:> 300 ° C IR (KBr, cm ^-1 ): 1676 MASS: 354 (M + 1) _{NMR (DMSO-d 6, δ} ): 4.36 (2H,
s), 7.14 (1H, br s), 7.40
(1H, d, J = 9.0), 7.54 (1H, d
d, J = 8.0, 8.0), 7.68-7.80
(3H, m), 8.06-8.10 (2H, m),
8.20 (1H, brs), 8.29 (1H, brs)
dd, J = 6.7, 0.9), 9.04 (1
H, s), 9.21 (1H, s), 10.68 (1
H, s).

Example 56 The following compounds were obtained in the same manner as in Example 31. N- [3- (imidazole-1-yl) phenyl] -4
-Phenylbenzamide mp: 196-197 ° C IR (KBr, cm ^-1 ): 1664 MASS: 340 (M + 1) NMR (DMSO-d ₆ , δ): 7.14 (1H,
s), 7.33-7.58 (5H, m), 7.
68 (1H, dd, J = 1.2, 1.2),
7.76-7.89 (5H, m), 8.07-8.
12 (3H, m), 8.19 (1H, s), 1
0.50 (1H, brs).

Example 57 N, N-Dimethylformamide (0.01 ml) was added to a suspension of 1-fluorenecarboxylic acid (168 mg) and oxalyl chloride (0.17 ml) in dichloromethane (3 ml).
And stir for 2 hours. The solvent of the obtained solution is distilled off to obtain a crude acid chloride. 3- (1,2,4-triazo-
(L-1-yl) aniline (128 mg) and pyridine (0.20 ml) in dichloromethane (2 ml) are suspended in a dichloromethane (2 ml) solution of the acid chloride solution obtained above.
ml) The solution is added dropwise and stirred for 1 hour. The mixture is diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The separated organic layer is dried over sodium sulfate, and the solvent is distilled off. Column chromatography of the residue
(25 g of silica gel, eluted with 2% methanol in dichloromethane), and N- [3- (1,2,4-
Triazol-1-yl) phenyl] fluorenecarboxamide (0.175 g) is obtained. APCI-mass; m / z 353 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ; 4.23 (2
H, s), 7.3-7.6 (6H, m), 7.7-
8.0 (2H, m), 7.98 (1H, d, J =
6.7 Hz), 8.13 (1H, d, J = 7.3H)
z), 8.26 (1H, s), 8.44 (1H,
s), 9.28 (1H, s), 10.61 (1H,
s)

Example 58 N, N'-dimethylformamide (0.01 ml) was added to a suspension of 1-fluorenecarboxylic acid (147 mg) and oxalyl chloride (0.15 ml) in dichloromethane (3 ml).
And stir for 2 hours. The solvent of the obtained solution is distilled off to obtain a crude acid chloride. 1-methyl-5- (3-aminophenyl) -1,3,4-triazole (122 mg)
And pyridine (0.17 ml) in dichloromethane (2 m
A solution of the acid chloride obtained above in dichloromethane (2 ml) is added dropwise to the suspension in 1) and stirred for 1 hour. The mixture is diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The separated organic layer is dried over sodium sulfate, and the solvent is distilled off. The residue was purified by column chromatography (using 25 g of silica gel, eluted with 2% methanol in dichloromethane), and N- [3- (1-methyl-1,3,4-triazol-2-yl) phenyl] was used.
Fluorenecarboxamide (0.151 g) is obtained. APCI-mass; m / z 367 (M + H ⁺ ) NMR (DMSO-d6): δ; 3.78 (3H,
s), 4.22 (2H, s), 7.3-7.7 (6H,
m), 7.77 (1H, d, J = 6.8HZ),
7.89 (1H, d, J = 7.7 Hz), 8.13
(1H, d, J = 7.7 Hz), 8.22 (1H, d, J = 7.7 Hz)
s), 8.59 (1H, s), 10.55 (1H,
s)

Example 59 3- (benzimidazol-1-yl) aniline (10
0 mg) and pyridine (0.12 ml) in dichloromethane (2 ml) are added dropwise with a solution of fluorenecarboxylic acid chloride (109 mg) in dichloromethane (2 ml) and stirred for 1 hour. The mixture is diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The separated organic layer is dried over sodium sulfate, and the solvent is distilled off. The residue was purified by column chromatography (silica gel 25 g, eluted with 2% methanol in dichloromethane) and N- [3- (benzimidazol-1-yl) phenyl] fluorenecarboxamide (0.132)
g). ESI-mass; m / z 402 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ; 4.22 (2
H, s), 7.3-7.5 (5H, m), 7.6-
7.9 (6H, m), 7.9-8.1 (2H, m),
8.14 (1H, d, J = 7.7 Hz), 8.21
(1H, s), 8.61 (1H, s), 10.66
(1H, s)

Example 60 To a solution of 1-fluorenecarboxylic acid (0.068 g) in dichloromethane (2 ml) was added oxalyl chloride (84 μl) and a catalytic amount of N, N'-dimethylformamide (two drops in succession at room temperature). After stirring at room temperature for hours, the reaction mixture was evaporated under reduced pressure to remove the solvent, and the residue was diluted with dichloromethane (2 m
1) to obtain 1-fluorenecarboxylic acid chloride. To a solution of 3- (1-benzylimidazol-5-yl) aniline (80 mg) in dichloromethane (2 ml) is added pyridine (0.13 ml) and the acid chloride solution at 0 ° C. After stirring at 0 ° C. for 1 hour, the reaction mixture is diluted with dichloromethane, washed successively with an aqueous potassium carbonate solution (10%) and brine, and dried over potassium carbonate. The solvent was distilled off to give a residue, which was purified by chromatography on silica gel (50 ml), eluting with 0% -3% methanol and dichloromethane to give N- (1-benzylimidazole-5). -Yl) phenyl-1-fluorenecarboxamide (160 mg) is obtained. APCI-mass; 442 (m / z, [M + H] ⁺ ) NMR (DMSO-d ₆ , δ): δ; 4.19 (2
H, s), 5.38 (2H, s), 6.90-8.
20 (18H, m), 10.40 (1H, s)

Example 61 To a solution of carbazole-1-carboxylic acid (0.13 g) in dichloromethane (20 ml) was added 3- (imidazole-1-).
Yl) aniline (98 mg) and 1-ethyl-3- (3-
(Dimethylaminopropyl) carbodiimide hydrochloride (0.18 g) is added at room temperature. After stirring at room temperature for 18 hours, the reaction mixture is taken up in a mixture of water and dichloromethane. The separated organic layer is washed successively with water and brine, and dried over potassium carbonate. The solvent was evaporated under reduced pressure to give a residue, which was purified by chromatography on silica gel (50 ml), eluting with 0% -5% methanol and dichloromethane to give N- (3-imidazole- 1-ylphenyl) carbazole-1-carboxamide (0.118
g). LD-mass; 353.2 (m / z, [M + H] ⁺ ) NMR (DMSO-d ₆ , δ); 7.10-7.48
(5H, m), 7.55 (1H, t, J = 8.0)
Hz), 7.63-7.79 (2H, m), 7.79
−7.94 (1H, m), 8.05-8.24 (4
H, m), 8.40 (1H, d, J = 7.4H
z), 10.59 (1H, s), 11.54 (1H,
s)

Example 62 A solution of 3-ethyl-2-methylindole-7-carboxylic acid (0.15 g) in dichloromethane (5 ml) was added to a solution of 3-ethyl-2-methylindole-7-carboxylic acid (0.15 g) in dichloromethane (5 ml).
(Imidazol-1-yl) aniline (0.12 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.28 g) are added at room temperature. 1
After stirring at room temperature for 8 hours, the reaction mixture is taken up in a mixture of water and dichloromethane. The separated organic layer is washed successively with water and brine, and dried over potassium carbonate. The solvent was distilled off under reduced pressure to obtain a residue, which was pulverized with methanol to give N- (3-
Imidazol-1-ylphenyl) -3-ethyl-2-
Methyl indole-7-carboxamide (0.127
g). APCl-mass; 345 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , δ); 1.15 (3H,
tJ = 7.4 Hz), 2.37 (3H, s),
2.68 (2H, q, J = 7.4 Hz), 7.00
−7.20 (2H, m), 7.36 (1H, d,
J = 9.2 Hz), 7.52 (1H, t, J
= 8.1 Hz), 7.60-7.92 (4H,
m), 8.10-8.30 (2H, m), 10.
41 (1H, s), 10.80 (1H, s)

Example 63 2,3-Dimethylindole-7-carboxylic acid (0.1
To a solution of 2 g) in dichloromethane (5 ml) was added 3- (imidazole-1-yl) aniline (0.10 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g). Add at room temperature. After stirring at room temperature for 18 hours, the reaction mixture is taken up in a mixture of water and dichloromethane. The separated organic layer is washed successively with water and brine, and dried over potassium carbonate. The solvent is distilled off under reduced pressure,
The residue was obtained and purified by chromatography on silica gel, eluting with 0% -5% methanol and dichloromethane to give N- (3-imidazole-1-ylphenyl).
This gives -2,3-dimethylindole-7-carboxamide (0.118 g). APCl-mass; 331
(M / z, [M + H] ⁺ ) NMR (DMSO-d ₆ , δ); 2.19 (3H,
s), 2.37 (3H, s), 7.01-7.2.
1 (2H, m), 7.30-7.91 (6H,
m), 8.05-8.23 (2H, m), 10.
41 (1H, s), 10.80 (1H, s)

Example 64 A suspension of 2,3-cyclopentenoindole-7-carboxylic acid (141 mg) and 1-hydroxybenzotriazole (114 mg) in dichloromethane (5 ml) was treated with 1-ethyl- 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (201 mg) is added dropwise and stirred for 3 minutes. 3- (imidazole-1-yl) aniline (111 mg) and 4-dimethylaminopyridine (9
4 mg) and stir for 5 days. The residue was evaporated and the residue was purified by column chromatography (silica gel 25 g, eluted with 2% methanol in dichloromethane) to give N- [3- (imidazol-1-yl) phenyl] -2,3-. Cyclopentenoindole-7-carboxamide (115 mg, 47.9%) is obtained. M / z 343 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ; 2.4-2.6
(2H, m), 2.7.30 (4H, m),
7.08 (1H, d, J = 7.7 Hz), 7.1
4 (1H, s), 7.3-7.7 (4H, m),
7.73 (1H, d, J = 7.7 Hz), 7.8
−7.9 (1H, m), 8.1-8.2 (2H,
m), 10.43 (1H, s), 11.02 (1
H, s)

Example 65 9-Methylcarbazole-1-carboxylic acid (0.103
g) in dichloromethane (2 ml) solution and oxalyl chloride (0.12 ml) and N, N-dimethylformamide (2
Drops) are added sequentially at room temperature. After stirring at room temperature for 1 hour, the solvent of the reaction mixture was distilled off under reduced pressure, and the residue was taken up in dichloromethane (5 ml) to obtain a solution of 9-methylcarbazole-1-carboxylic acid chloride. 3- (imidazole-
1-yl) aniline (73 mg) in dichloromethane (2
pyridine (0.18 ml) and the acid chloride solution at 0 ° C. After stirring at 0 ° C. for 1 hour, the reaction mixture was diluted with dichloromethane and aqueous potassium carbonate (10%)
And brine, and dried over potassium carbonate. The solvent was distilled off to give a residue, which was purified by chromatography on silica gel (50 ml), eluting with 0% -3% methanol and dichloromethane to give N- (3-imidazo-
1-ylphenyl) -9-methylcarbazole-1
-Obtain carboxamide (84 mg). LD-mass; 367.2 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , δ); 3.85 (3H,
s), 7.14 (1H, s), 7.20-7.4
8 (3H, m), 7.48-7.74 (5H,
m), 7.74-7.88 (1H, m), 8.0
5-8.14 (1H, m), 8.14-8.30
(2H, m), 8.35 (1H, d, J = 1
H), 10.96 (1H, s)

Example 66 3- (3-carboxyphenyl) cyclohexene (19
N, N-dimethylformamide (0.01 ml) is added to a suspension of 9 mg) and oxalyl chloride (0.2 ml) in dichloromethane (2 ml), and the mixture is stirred for 2 hours. The solvent of the obtained solution is distilled off to obtain a crude acid chloride. 3- (Imidazol-1-yl) aniline (157 mg) and pyridine (0.24 ml) in dichloromethane (2 ml) suspension in dichloromethane (2 ml) of the acid chloride obtained above
The solution is added dropwise and stirred for 1 hour. The mixture is diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The separated organic layer is dried over sodium sulfate, and the solvent is distilled off. The residue was purified by column chromatography (silica gel 25 g, eluted with 2% methanol in dichloromethane) to give N- [3- (cyclohexene-3-
Yl) benzoyl] -3- (imidazole-1-yl)
Obtain aniline (0.156 g). APCl-mass; m / z 344 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ 1.7-2.0
(2H, m), 2.0-2.4 (4H, m),
2.8-3.0 (1H, m), 5.6-6.0 (2
H, m), 7.13 (1H, s), 7.3-
7.6 (4H, m), 7.67 (1H, s),
7.7-7.9 (3H, s), 8.04 (1H,
s), 8.19 (1H, s), 10.40 (1
H, s)

Example 67 2,4-Dimethoxy-5-nitrobenzoic acid (552 m
g) and N, N-dimethylformamide (0.01 ml) are added to a suspension of oxalyl chloride (0.5 ml) in dichloromethane (10 ml) and stirred for 30 minutes. The solvent of the obtained solution is distilled off to obtain a crude acid chloride. 3- (Imidazol-1-yl) aniline (387 mg) and pyridine (0.59 ml) in dichloromethane (7.5 ml) were suspended in dichloromethane (7.5 ml).
ml) The solution is added dropwise and stirred for 1 hour. The mixture is diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The separated organic layer is dried over sodium sulfate, and the solvent is distilled off. Column chromatography of the residue
(Silica gel 25 g, 2% methano-
Eluting with dichloromethane), N- (2,4-dimethoxy-5-nitrobenzoyl) -3- (imidazole-1)
-Yl) aniline (0.742 g) is obtained. M / z 369 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ; 4.08 (3
H, s), 4.10 (3H, s), 6.98
(1H, s), 7.13 (1H, s), 7.3
8 (1H, d, J = 9.0 Hz), 7.50 (1
H, t, J = 8.0 Hz), 7.7-7.8 (2
H, m), 7.97 (1H, s), 8.20 (1
H, s), 8.36 (1H, s), 10.25
(1H, s)

Example 68 2-methoxy-5-phenylbenzoic acid (0.286 g)
Oxalyl chloride (1.5 ml) and N, N-dimethylformamide (2
Drops) are added sequentially at room temperature. After stirring for 1 hour at room temperature, the solvent of the reaction mixture is evaporated under reduced pressure and the residue is taken up in dichloromethane (5 ml) to give a solution of 2-methoxy-5-phenylbenzoyl chloride. 3- (imidazole-1)
-Yl) aniline (0.2 g) in dichloromethane (5 m
l) To the solution is added pyridine (0.52 ml) and the acid chloride solution at 0 ° C. After stirring at 0 ° C. for 1 hour, the reaction mixture is diluted with dichloromethane, washed successively with an aqueous potassium carbonate solution (10%) and brine, and dried over potassium carbonate. The residue was obtained by distilling off the solvent, triturated with diisopropyl ether, and treated with N- (3-imidazole-1-ylphenyl)-.
2-methoxy-5-phenylbenzamide (0.335
g). LD-mass; 370.2 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , d); 3.96 (3H,
s), 7.13 (1H, s), 7.22-7.6.
0 (6H, m), 7.60-8.10 (7H,
m), 8.19 (1H, s), 10.04 (1
H, s)

Example 69 A suspension of 2-methyl-1- (3-nitrophenyl) imidazole (80 mg) in methanol (10 ml) was added.
% Palladium on activated carbon (10%, 10 mg)
Stir under a hydrogen atmosphere for 1.5 hours. The mixture is filtered and the solvent is distilled off. The obtained crude aniline derivative was dissolved in dichloromethane (10 ml), and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (1
50 mg) and fluorene-1-carboxylic acid (83 mg)
Add. After stirring at room temperature for 70 minutes, the mixture is poured into sodium bicarbonate to obtain an organic layer. The obtained solution was dried over sodium sulfate, the solvent was distilled off, the residue was purified by chromatography on silica gel, and eluted with chlorofilm methanol (0-2%, v / v) to give N- [3 −
(2-Methylimidazol-1-yl) phenyl] fluorene-1-carboxamide (30 mg) is obtained. mp: 223-227 ℃ IR (KBr, cm -1): 1674, 1603 MASS: 366 (M + 1) NMR (DMSO-d 6, δ): 2.33 (3H,
s), 4.21 (2H, s), 6.93 (1
H, d, J = 1 Hz), 7.20 (1H, d,
J = 9 Hz), 7.31 (1H, d, J = 1H
z), 7.35-7.70 (5H, m), 7.7
5 (1H, d, J = 7 Hz), 7.86 (1H,
d, J = 8 Hz), 7.90-8.05 (2H,
m), 8.13 (1H, d, J = 8 Hz),
10.57 (1H, s)

Example 70 N- [3- (ethoxycarbonyl) -5- (imidazo-
1-yl) phenyl] fluorene-1-carboxamide (1.44 g) in ethanol (50 ml).
An N sodium hydroxide aqueous solution (5.1 ml) is added, and the mixture is stirred at 60 ° C. for 1 hour. After cooling, 1N hydrochloric acid (5.1 ml)
Is added to the resulting solution. The resulting precipitate is collected and washed sequentially with ethanol and water to give 3- (fluoren-1-carboxamide) -5- (imidazole-1-yl) benzoic acid (1.30 g). mp:> 300 ° C. IR (KBr, cm ⁻¹ ): 1707, 1664,
^{1608 MASS: 394 (M-1} -) NMR (DMSO-d 6, δ): 4.24 (2H,
s), 7.16 (1H, s), 7.30-7.4
5 (2H, m), 7.50-7.70 (2H,
m), 7.70-7.90 (3H, m), 7.9
9 (1H, d, J = 6 Hz), 8.15 (1H, d, J = 6 Hz)
d, J = 7 Hz), 8.25-8.35 (2H,
m), 8.45 (1H, d, J = 2 Hz), 1
0.72 (1H, s), 13.0-14.0 (1
H, br. s)

Example 71 A suspension of 3- (fluoren-1-carboxamide) -5- (imidazole-1-yl) benzoic acid (100 mg) in dichloromethane (10 ml) and N, N-dimethylformamide (1 ml). In the suspension, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (97 m
g) and morpholine (44 μl) are added. After stirring at room temperature for 6 hours, the mixture was poured into aqueous sodium hydrogen carbonate solution,
Obtain an organic layer. The obtained solution was dried over sodium sulfate, the solvent was distilled off, the residue was purified by chromatography on silica gel, and chloroform-methanol (0-2) was used.
%, V / v) to give N- [3- (morpholinocarbonyl) -5- (imidazol-1-yl) phenyl] fluorene-1-carboxamide (103 mg). mp: 148-156 ° C IR (KBr, cm ^-1 ): 1676, 1604 MASS: 465 (M + 1) NMR (DMSO-d ₆ , δ): 3.30-3.80
(8H, m), 4.23 (2H, s), 7.1
6 (1H, s), 7.30-7.50 (3H,
m), 7.55-7.65 (2H, m), 7.7
0-7.90 (3H, m), 7.99 (1H,
d, J = 7 Hz), 8.10-8.20 (2H,
m), 8.26 (1H, s), 10.66 (1
H, s)

Example 72 The following compounds were obtained in the same manner as in Example 71. N- [3- (anilinocarbonyl) -5- (imidazo-
Ru-1-yl) phenyl] fluorene-1-carboxamide mp: 263-266 ° C. IR (KBr, cm ⁻¹ ): 1657, 1603 MASS: 471 (M + 1) NMR (DMSO-d ₆ , δ): 4.25 (2H,
s), 7.10-7.25 (2H, m), 7.
30-7.45 (4H, m), 7.50-7.65
(2H, m), 7.70-7.90 (4H,
m), 7.90-8.05 (2H, m), 8.1
5 (1H, d, J = 7 Hz), 8.30-8.3
5 (3H, m), 10.20-11.00 (2H,
br. m)

Example 73 The following compounds were obtained in the same manner as in Example 71. N- [3- (dimethylaminocarbonyl) -5- (imidazol-1-yl) phenyl] fluorene-1-carboxamide mp: 130-140 ° C IR (KBr, cm ^-1 ): 1673, 1616,
1604 MASS: 423 (M + 1 ) NMR (DMSO-d 6, δ): 3.00 (3H,
s), 3.03 (3H, s), 4.23 (2H,
s), 7.15 (1H, s), 7.30-7.
50 (3H, m), 7.50-7.70 (2H,
m), 7.70-7.90 (3H, m), 7.
99 (1H, d, J = 6 Hz), 8.10-8.
20 (2H, m), 8.25 (1H, s), 1
0.65 (1H, s)

Example 74 1,2-Bis (tert-butoxycarbonyl) -3-
Concentrated hydrochloric acid (10 ml) is added to a solution of (2,2-dimethoxyethylamino) -3- [3- (fluoren-1-carboxamido) phenyl] guanidine (0.18 g) in methanol (10 ml). The mixture is stirred for 1 hour at room temperature and partitioned between sodium bicarbonate and chloroform. The chloroform layer was dried over sodium sulfate, the solvent was distilled off, the residue was purified by chromatography on silica gel, and chloroform-methanol (0-10%, v
/ V) to give N- [3- (2-aminoimidazole-1-yl) phenyl] fluorene-1-carboxamide (30 mg). mp: 195-198 ° C IR (KBr, cm ⁻¹ ): 1653, 1608 MASS: 367 (M + 1) NMR (DMSO-d ₆ , δ): 4.20 (2H,
s), 5.40 (2H, br. s), 6.57
(1H, d, J = 2 Hz), 6.84 (1H, d, J = 2 Hz)
d, J = 2 Hz), 7.19 (1H, d, J =
7Hz), 7.35-7.65 ((5H, m),
7.70-7.80 (2H, m), 7.90-8.
00 (2H, m), 8.13 (1H, d, J =
7Hz), 10.51 (1H, s)

Example 75 N- (3-Imidazol-1-yl) phenyl-3-methoxy-2-nitroverbenzamide (1.36 g)
A mixture of iron (1.0 g), ammonium chloride (0.1 g) in ethanol (10 ml) and water (5 ml) is refluxed for 1 hour and heated. After cooling, the mixture is filtered through Celite, and the solvent is distilled off. 50 ml each of a saline solution and dichloromethane are added, and the mixture is collected and extracted again with dichloromethane (twice, 25 ml each). The organic layers are combined, dried over magnesium sulfate, filtered, and the solvent is distilled off. Purify on a silica gel column (eluted with dichloromethane-methanol),
Recrystallization from ethanol gives 2-amino-N- (3-imidazole-1-yl) phenyl-3-methoxybenzamide (0.65 g) as white crystals. mp: 161-162 ° C IR (KBr, cm ^-1 ): 3481, 3334,
1649 MASS: 309 (M + 1 ) NMR (DMSO-d 6, δ): 3.83 (3H,
s), 6.09 (2H, br s), 6.62
(1H, dd, J = 8.0, 8.0), 6.9
8 (1H, d, J = 7.0), 7.12 (1
H, d, J = 1.3), 7.30-7.37 (2
H, m), 7.48 (1H, dd, J = 8.
0, 8.0), 7.66 (1H, dd, J =
1.3, 1.3), 7.71 (1H, d, J =
8.7), 8.01 (1H, dd, J = 2.0,
2.0), 8.17 (1H, s), 10.17
(1H, brs).

Example 76 The following compounds are obtained in the same manner as in Example 75. 2-amino-N- (3-imidazol-1-yl) phenyl-5-methoxybenzamide mp: 186-187 ° C IR (KBr, cm ^-1 ): 1660 MASS: 309 (M + 1) NMR (DMSO-d ₆ , δ): 3.74 (3H,
s), 5.92 (2H, brs), 6.74
(1H, d, J = 8.9), 6.94 (1H,
dd, J = 8.9, 2.8), 7.12 (1H,
d, J = 1.0), 7.21 (1H, d, J
= 2.9), 7.35 (1H, d, J = 9),
7.48 (1H, dd, J = 8.0, 8.
0), 7.65-7.71 (2H, m), 7.9
7. (1H, dd, J = 2.0, 2.0),
18 (1H, s), 10.19 (1H, s).

Example 77 N- (2,4-dimethoxy-5-nitrobenzoyl)-
3- (imidazole-1-yl) aniline (368 m
g) of methanol (5 ml) and tetrahydrofuran (5
suspension in 10% palladium-carbon (w / w,
Hydrogenate under a hydrogen atmosphere for 4 hours, 50% wet, 100 mg). The catalyst was removed by filtration, the solvent of the filtrate was distilled off, and the residue was crystallized from isopropanol-isopropyl ether.
(2,4-dimethoxy-5-aminobenzoyl) -3-
(327 mg) of (Imidazol-1-yl) aniline are obtained. APC-mass; m / z 339 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ: 3.89 (3
H, s), 3.97 (3H, s), 4.56
(2H, s), 6.72 (1H, s), 7.12
(1H, s), 7.23 (1H, s),
3-7.4 (1H, m), 7.47 (1H, t,
J = 8.0 Hz), 7.70 (1H, s),
7.76 (1H, d, J = 8.8 Hz), 7.9
6 (1H, s), 8.21 (1H, s), 1
0.16 (1H, s)

Example 78 N- (2,4-Dimethoxy-5-aminobenzoyl)-
3- (imidazole-1-yl) aniline (135 m
To a suspension of g) and pyridine (0.1 ml) in tetrahydrofuran (5 ml) was added 4-drifluoromethylbenzenesulfonyl chloride (98 mg), and the mixture was stirred for 12 hours. The mixture is poured into water, taking into account the precipitate that has formed, washed with water, dried and treated with N- [2,4-dimethoxy-5-
(173 mg) of (4-trifluoromethylbenzenesulfonyl) aminobenzoyl] -3- (imidazol-1-yl) aniline is obtained. M / z 547 (M + H ⁺ ) NMR (DMSO-d ₆ , δ): δ; 3.47 (3
H, s), 3.99 (3H, s), 6.66.
(1H, s), 7.13 (1H, s), 7.3
6 (1H, d, J = 8.0 Hz), 7.48 (1
H, t, J = 8.0 Hz), 7.7-8.0 (8
H, m), 8.22 (1H, s), 9. 84
(1H, s), 10.09 (1H, s)

Example 79 To a stirred solution of N- (3-imidazole-1-ylphenyl) -2-methoxy-5-phenylbenzamide (38 mg) in methylene chloride (1 ml) was added boron tribromide in methylene chloride (1 ml). 1M, 1 ml) solution at -60 ° C. The reaction mixture is left for 4 hours until it reaches room temperature. The solvent was distilled off, the residue was triturated with diisopropyl ether, and N- (3-imidazole-1-ylphenyl) -2-hydroxy-5-yl was added.
Obtain phenylbenzamide (51.6 mg). LD-mass: 356.3 (m / z, [M +
H] ⁺ ) NMR (DMSO-d ₆ , δ); 7.13 (1H,
d, J = 8.5 Hz), 7.25-7.90 (9
H, m), 7.96 (1H, t, J = 1.7H)
z), 8.15-8.40 (3H, m), 9.7
1 (1H, s), 10.77 (1H, s), 1
1.71 (1H, brs)

Example 80 N- [3- (cyclohexen-3-yl) benzoyl]
-3- (Imidazol-1-yl) aniline (74m
A suspension of g) in ethanol (2 ml) was treated with palladium on carbon (10% w / w, 50% wet, 37 mg).
For 6 hours in a hydrogen atmosphere. The catalyst was removed by filtration, the solvent of the filtrate was distilled off, and N- (3-cyclohexylbenzoyl) -3- (imidazole-1-yl) aniline (58
mg). APCl-mass; m / z 346 (M + H ⁺ ) NMR (DMSO-d ₆ , δ); 1.2-1.6 (5
H, m), 1.7-1.9 (5H, m), 2.
6-2.8 (1H, m), 7.13 (1H, s),
7.3-7.6 (4H, m), 7.67 (1H,
s), 7.7-7.9 (3H, m), 8.04.
(1H, s), 8.18 (1H, s), 10.3
9 (1H, s)

Example 81 N- (3-Imidazol-1-ylphenyl) carbazol-1-carboxamide (47.4 mg) was added to a mixed solution of tetrahydrofuran (5 ml) and methanol (1 ml). Add hydrochloric acid in dioxane (4N, 0.1 m) at room temperature. The solvent was distilled off under reduced pressure, and the residue was pulverized with diisopropyl ether to obtain N- (3-imidazole-1-ylphenyl) carbazol-1-carboxamide hydrochloride (47.7 mg). LD-mass; 353.2 (m / z, [M (fre
e form) + H] ⁺ ) NMR (DMSO-d ₆ , δ); 7.11-7.80
(6H, m) 7.83-8.08 (2H, m
m), 8.08-8.31 (3H, m), 8.3
1-8.50 (2H, m), 9.61 (1H,
s), 10.80 (1H, s), 11.53 (1
H, s)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 249/08 511 C07D 249/08 511 263/32 263/32 277/28 277/28 401/12 401/12 403/12 403 / 12 405/12 405/12 409/12 409/12 413/12 413/12 417/12 417/12 487/04 137 487/04 137 498/04 521/00 521/00 498/04 112Q (72) Inventor Masaki Tomishima 2-2-1-1420 Aoki, Higashinada-ku, Kobe (72) Inventor Hiroshi Miyake 86, Jodoji Nishidacho, Sakyo-ku, Kyoto-shi

Claims (1)

[Claims] 1. The general formula: (Wherein, R ¹ is a heterocyclic group which may have a suitable substituent, R ² is hydrogen, a lower alkyl group, a lower alkoxy group or an acyl group, and R ³ is a group which has a suitable substituent. A phenyl group or a pyridyl group optionally having a suitable substituent.) And a salt thereof.