WO2007026720A1 - Ring-fused pyrazole derivative - Google Patents

Abstract

A ring-fused pyrazole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof: (1) wherein n represents 2 or 3; A represents the formula: -O- or the like; B represents a C1-10 alkylene group or the like; C represents a single bond or the formula: -O-; R1 represents a hydrogen atom, a pyrrolidinyl group or the like; R4, R5 and R6 independently represent a hydrogen atom, a halogen atom or the like; D1=D2 represents the formula: -CH=CH- or the like; E represents the formula: -O- or -NH- or the like; G represents a C1-10 alkylene group or the like; and R7 represents a hydrogen atom, a phenyl group or the like. The derivative or salt can inhibit the enzymatic activity of Lck involved in the abnormal activation of an immunocyte and is effective against the rejection in organ transplantation or an immune/allergic disease such as atopic dermatitis and asthma.

Description

 Specification

 Fused pyrazole derivatives

 Technical field

 [0001] The present invention relates to a fused pyrazole derivative that inhibits tyrosine kinase, and a salt thereof.

 Background art

 [0002] Tyrosine kinase is a signaling molecule that controls cell activation, growth, and differentiation, and it has been suggested that its abnormal activity is involved in canceration and immune responses. To date, more than 100 types of tyrosine phosphate enzymes have been discovered, and they are classified by structure into cytoplasmic, membrane-bound, and receptor types.

 [0003] Lymphocyte-specific protein tyrosine kinase (hereinafter abbreviated as Lck) is a membrane-bound tyrosine phosphate enzyme that is specifically expressed in T cells. Suppression of sputum is expected to have therapeutic effects on immune allergic diseases such as rejection during organ transplantation and atopic dermatitis / asthma.

 [0004] As Lck inhibitors, pyrazole pyrimidine derivatives (see Patent Document 1), isoxazole derivatives (see Patent Document 2), 2,4-diaminopyrimidine derivatives (see Patent Document 3), imidazoquinoxaline derivatives (Patent Document 4) See, 5) -aminovirazole derivatives (see Patent Document 5) and the like are not disclosed compounds having the structure of the present invention.

 [0005] Although a COX2 inhibitor (see Patent Document 6) has been reported as a fused pyrazole derivative, there is no disclosure of the compound of the present invention and no report as an Lck inhibitory action.

 [0006] Patent Literature l: WO03 / 080064

 Patent Document 2: US2003207873

 Patent Document 3: US2003191307

 Patent Document 4: WO99 / 09845

 Patent Document 5: WO97 / 40019

 Patent Document 6: WO01 / 16138

Disclosure of the invention Problems to be solved by the invention

[0007] An object of the present invention is to provide a drug that inhibits the enzymatic activity of Lck involved in abnormal activity of immunocompetent cells. Specifically, it aims to provide drugs for rejection during organ transplantation, immunity such as atopic dermatitis and asthma, and allergic diseases.

 Means for solving the problem

[0008] As a result of intensive studies for the above purpose, the present inventors have found that the novel fused ring pyrazole derivative has the ability to inhibit the enzymatic activity of Lck, and completed the present invention.

[0009] The present invention is indicated by the following 1 to 5.

[0010] 1. Formula (1)

[0011] [Chemical 1]

[0012] (wherein η represents 2 or 3,

Α is a single bond, formula O—, formula OCO—, formula NR ²¹ —, formula NR ²² CO—, or formula NR ²³ CONR ²⁴ − (where R ²¹ , R ²² , R ²³ and R ²⁴ are each independently , Hydrogen atom, or C

 1 represents an alkyl group. )

 8

 B is a single bond, a C alkylene group, a C cycloalkylene group, or a C alkylene group.

 1-10 3-10 2-10

 Represents a group in which any carbon atom is substituted with a C cycloalkylene group;

 3-10

 C represents a single bond or formula o,

R ¹ represents a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi Dino group, piperidino group substituted with C alkyl group, piperidyl group, C alkyl group

1-6 1-6

Piperidinyl, morpholino, and morpholino substituted with C alkyl groups

 1-6

Group, morpholinyl group, morpholinyl group substituted with C alkyl group, piperazinyl group,

 1-6

 Piperazinyl group substituted with C alkyl group or hydroxy C alkyl group, C alkyl

1-6 1-6 2-10 Canol group, carboxy group, strong rubamoyl group, C alkoxycarbonyl group, pyridyl

 2- 10

Group, pyridyl group substituted with C alkyl group, pyrimidyl group, substituted with C alkyl group

1-6 1-6

A pyrimidyl group or a formula — NR ³¹ R ³² (wherein R ³¹ and R ³² are each independently a hydrogen atom, a C alkyl group, a hydroxy C alkyl group, an amino C alkyl group, a mono C alkyl group)

1-8 2-6 2-6 1-6 Mino C alkyl group, di C alkyl amino C alkyl group, or dihydroxy C alkyl

2-6 1-6 2-6 2-6 represents a group. )

R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group,

 1-6 1-6

 D = D represents the formula —CH = CH—, formula—S—, or formula—NH,

 1 2

E is a single bond, Formula—O—, Formula—NR ⁶¹ —, Formula—OCO—, Formula—OSO—, Formula—NR ⁶² C

 2

O, wherein - OCOO, formula - NR ⁶³ SO-, wherein - OCONR ⁶⁴ -, wherein - NR ⁶⁵ CONR ⁶⁶

 2

One, the formula CONR ⁶⁷ -, wherein COO -, wherein NR ⁶⁸ COO -, wherein NR ⁶⁹ CSNR ⁷⁰ -, wherein - CR ⁷¹ R ⁷² 0-, or formula ^{- CR 73 R 74 NR 75 -} ( wherein, R ^61, R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ , R ⁶⁶ , R ⁶ R ⁶⁸ , R ⁶⁹ , R ⁷ °, R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ and R ⁷⁵ are each independently a hydrogen atom, or C

 1-8 represents an alkyl group. )

 G is a single bond, a C alkylene group, a C cycloalkylene group, or a C alkylene group.

 1-10 3-10 2-10

Represents a group in which any carbon atom is substituted with a C cycloalkylene group;

 3-10

R ⁷ is a hydrogen atom, a formula — NR ⁸¹ R ⁸² (where R ⁸¹ and R ⁸² are each independently a hydrogen atom or C

 1 represents an alkyl group. ), Indolyl group, N—C alkylindolyl group, benzofural

-6 1-6

Group, benzothiophenyl group, or formula (2)

[Chemical 2]

(In the formula, X and Y each independently represent a carbon atom or a nitrogen atom, and R ⁸ and R ⁹ are respectively Independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or C

1-6 represents a 1-alkoxy group, J represents a single bond or formula o, R ^1Q represents a hydrogen atom, C alkyl

6 1-8 group, hydroxy C alkyl group, amino C alkyl group, mono C alkylamino C

 2-6 2-6 1-6 2-6 Indicates an alkyl group, diC alkylamino C alkyl group, or dihydroxy C alkyl group

 1-6 2-6 2-6. ). Or a pharmaceutically acceptable salt thereof.

 2. n is 2 or 3,

A is a single bond, formula O—, formula OCO—, formula NR ²¹ —, formula NR ²² CO—, or formula NR ²³ CONR ²⁴ — (wherein R ²¹ , R ²² , R ²³ and R ²⁴ are each independently , Hydrogen atom, or C

 1- represents an alkyl group. )

 8

 B is a single bond, C alkylene group, C cycloalkylene group, or C alkylene group

 1-10 3-10 2-5

A group in which the carbon atom is substituted with a C cycloalkylene group,

 3-6

 C represents a single bond or formula o,

R ¹ is a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi

 1-6

Dino group, piveryl group, morpholino group, C alkyl group substituted with C alkyl group

 1-6 1-6

Or piperazinyl group substituted with hydroxy C alkyl group, C alkanol group, force

 1-6 2-10

Ruboxy group, rubamoyl group, C alkoxycarbonyl group, pyridyl group, or formula

 2-10

NR ³¹ R ³² (wherein R ³¹ and R ³² are each independently a hydrogen atom, C alkyl group, hydroxy C

 1-8 2 represents an alkyl group or a di-C alkylamino C alkyl group. )

 -6 1-6 2-6

R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group,

 1-6 1-6

 D = D force Formula 1 CH = CH- or Formula 1 S

 1 2

E is a single bond, Formula—O—, Formula—NR ⁶¹ —, Formula—OSO—, Formula—NR ⁶² CO—, Formula—OC

 2

R⁶⁹、 R⁷°、 R⁷¹、 R⁷²、 R⁷³、 R⁷⁴及び R⁷⁵はそれぞれ独立に、水素原子、又は C アルキル基を示す。 )を示し、 OO, formula OCONR ⁶⁴ , formula NR ⁶⁵ CONR ⁶⁶ , formula CONR ⁶⁷ , formula COO, formula NR ⁶⁸ COO, formula NR ⁶⁹ CSNR ^7Q , formula CR ⁷¹ R ⁷² 0—or formula CR ⁷³ R ⁷⁴ NR ⁷⁵ — (formula Medium, R ⁶¹ , R ⁶² , R ⁶⁴ , R ⁶⁵ , R ⁶⁶ , R ⁶⁷ ,

^{R 69, R 7 °, R} 71, R 72, R 73, R 74 and R ⁷⁵ each independently represent a hydrogen atom, or a C alkyl group. )

 1-8

 G represents a single bond, a C alkylene group, or a C cycloalkylene group,

1-10 3-10 R ⁷ is a hydrogen atom, formula NR ⁸¹ R ⁸² (where R ⁸¹ and R ⁸² are each independently a hydrogen atom or C

 1 represents an alkyl group. ), Indolyl group, N—C alkylindolyl group, or formula (2) (formula

-6 1-6

X and Y are carbon atoms, R ⁸ and R ⁹ are each independently a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group, and J is a single bond.

 1-6 1-6

R ^1Q represents a hydrogen atom. The fused ring pyrazole derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof.

 [0016] 3. n represents 2 or 3,

 A represents a single bond, Formula O—, Formula OCO—, Formula NH—, Formula NHCO—, or Formula N HCONH,

 B is a single bond, C alkylene group, C cycloalkylene group, or C alkylene group

 1-10 3-10 2-5

 A group in which the carbon atom is substituted with a C cycloalkylene group,

 3-6

 C represents a single bond or formula o,

R ¹ is a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi

 1-6

 Dino group, piveryl group, morpholino group, C alkyl group substituted with C alkyl group

 1-6 1-6

 Or piperazinyl group substituted with hydroxy C alkyl group, C alkanol group, force

 1-6 2-10

 Ruboxy group, rubamoyl group, C alkoxycarbonyl group, pyridyl group, or formula

 2-10

NR ³¹ R ³² (wherein R ³¹ and R ³² are each independently a hydrogen atom, C alkyl group, hydroxy C

 1-8 1 represents an alkyl group or a di-C alkylamino C alkyl group. )

 -6 1-6 2-6

R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group,

 1-6 1-6

 D = D force Formula 1 CH = CH

 1 2

 E represents a single bond, formula —O—, formula —NH—, or formula NHCO,

 G represents a single bond,

R ⁷ is a hydrogen atom, or formula (2) (wherein X and Y are carbon atoms, R ⁸ and R ⁹ are hydrogen atoms, J is a single bond, and R ^1Q is a hydrogen atom. A fused pyrazole derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof.

[0017] 4. n is 2,

A is a single bond, Formula —O—, Formula —NH—, Formula NHCO—, or Formula NHCONH Show

 B is any carbon of a C 8 aralkylene group, a C cycloanolylene group, or a C 3 arylene group.

1-10 3-10 2-5

A group in which an atom is substituted with a C cycloalkylene group,

 3-6

 C represents a single bond,

R ¹ is a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi

 1-6

Dino group, piveryl group, morpholino group, C alkyl group substituted with C alkyl group

 1-6 1-6

Or a piperazyl group substituted with a hydroxy C alkyl group, or the formula NR ³¹ R ³² (wherein

 1-6

, R ³¹ and R ³² are each independently a hydrogen atom, a C alkyl group, a hydroxy C alkyl group,

 1-8 2-6

Or a di C alkylamino C alkyl group. )

 1-6 2-6

R ⁴ , R ⁵ and R ⁶ represent a hydrogen atom,

D = D force Formula 1 CH = CH

 1 2

 E represents the formula O—

G represents a single bond,

R ⁷ is represented by the formula (2) (wherein X and Y represent a carbon atom, R ⁸ and R ⁹ represent a hydrogen atom, J represents a single bond, and R ^1Q represents a hydrogen atom). A condensed virazole derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof.

 5. n is 2,

 A represents the formula O,

 B represents a single bond or a C anoalkylene group,

 1-10

 C represents a single bond or formula O

R ¹ represents a hydrogen atom, a pyridyl group, or a formula —NR ³¹ R ³² (wherein R ³¹ and R ³² each independently represents a hydrogen atom or a C alkyl group);

 1-8

R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or a C alkoxy group,

 1-6

 D = D force formula CH = CH

 1 2

 E represents Formula O, Formula NH-, Formula OCOO, Formula OCONH-, Formula NHCONH-, Formula-COO, Formula-NHCOO, Formula-CHO, or Formula-CHNH,

 twenty two

 G represents a single bond, a C alkylene group, or a C cycloalkylene group,

 1-10 3-10

R ⁷ is a hydrogen atom, or formula (2) (wherein X and Y are carbon atoms, R ⁸ and R ⁹ are respectively Independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or C

1-8 represents a 1-alkoxy group, J represents a single bond, and R ^1Q represents a hydrogen atom. )

6

 A condensed ring pyrazole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof. The invention's effect

 [0019] The compound of the present invention inhibits the enzyme activity of Lck, which is involved in the abnormal activity of immunocompetent cells. Therefore, the rejection of organ transplantation, immunity / alergy such as atopic dermatitis / asthma, etc. Useful for treatment of disease.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0020] In the present invention, the C alkyl group is a linear or branched a-b having from b to a carbon atom.

 A chain alkyl group is meant. For example, a C alkyl group has 1 to 8 carbon atoms

 1-8

That means a linear or branched alkyl group, methyl group, Echiru radical, n-propyl group, an isopropyl radical, _n-butyl group, isobutyl group, tert-butyl group, sec-butyl radical, n-pentyl group, isopentyl group, A neopentyl group, an n-octyl group, etc. can be mentioned.

 [0021] The C alkylene group is a linear or branched alkyle having a to b carbon atoms a to b

 Means a group. For example, a C alkylene group is a straight chain having 1 to 10 carbon atoms.

 1-10

 Alternatively, it means a branched alkylene group, and examples thereof include a methylene group, a methylmethylene group, a dimethylmethylene group, an ethylene group, a propylene group, and a 2,2-dimethylpropylene group.

 [0022] C cycloalkylene group means a cyclic alkylene group having b from carbon atoms a to b

 To do. For example, a C cycloalkylene group is a cyclic alkyl having 3 to 10 carbon atoms.

 3-10

 Means a butene group such as cyclobutane-1,1-diyl group, cyclopentane-1,1-diyl group, cyclohexane-1,1,2 diyl group, cyclohexane-1,1,4 diyl group, etc. .

 [0023] The C alkanoyl group is a linear or branched al force having 2 to 10 carbon atoms.

 2-10

 It means a neutral group, and examples thereof include a acetyl group, a propiol group, an n-butyryl group, an isobutyryl group, a valeryl group, and an otatanyl group.

[0024] C alkoxycarbonyl group is linear or branched having 1 to 9 carbon atoms In which the alkoxy group and the carbonyl group are combined, for example, a methoxycarbon group, an ethoxycarbon group, an n-propoxycarbol group, an isopropoxycarbon group, and an n-butoxycarbon group. , Isobutoxycarbol group, tert-butoxycarbol group, sec-butoxycarbol group, n-pentyloxycarboro group, isopentyloxycarboro group, neopentyloxycarboro group, n —Octyloxycarboxyl group.

[0025] Hydroxy C alkyl group is a linear or branched chain having 2 to 6 carbon atoms.

 2-6

 It means a droxyalkyl group, and examples thereof include a hydroxyethyl group, a hydroxypropyl group, and a 2,2-dimethyl-1-hydroxypropyl group.

[0026] An amino C alkyl group is a linear or branched amino having 2 to 6 carbon atoms.

 2-6

 An alkyl group means an aminoethyl group, an aminopropyl group, or a 2,2-dimethyl-3-aminopropyl group.

 [0027] Mono C alkylamino C alkyl group means mono C alkylamino group and C alkyl group

 1-6 2-6 1-6 2-6 means a complex form, and examples thereof include a methylaminoethyl group and a tert-butylaminoethyl group.

[0028] The di C alkylamino C alkyl group is a di C alkylamino group and a C alkyl group.

 1-6 2-6 1-6 2-6 is a complex form, and examples thereof include a dimethylaminoethyl group and a jetylaminoethyl group.

 [0029] The dihydroxy C alkyl group is linear or branched having 2 to 6 carbon atoms.

 2-6

 And a 2,3-dihydroxypropyl group and a 2,4-dihydroxybutyl group.

 [0030] The compound of the present invention can be synthesized, for example, by the following production method. In the scheme, E and G are as defined above.

 Scheme 1

[0031] [Chemical 3]

(1- _C )

 Process (1-2)

 [0032] Step (1-1): Pyrazole derivative 1 a in the presence of a base such as potassium carbonate, cesium carbonate, or sodium bicarbonate in a solvent such as dimethylformamide or tetrahydrofuran [Reference: WO2002080926, WO2001019829, Heterocycles (1987) 26 (3) 613-616, Journal of Heterocyclic hemistry (1990) 27 (3) 647-660, Journal of Medicinal Cnemistry (1997) 40 (22) 3601-3616)] and haloalkyl bromobenzene derivatives 1b (formula Hal represents chlorine atom, bromine atom or iodine atom), whereby compound 1d can be produced.

 Step (1-2): In a solvent such as tetrahydrofuran or dioxane, a phosphine reagent such as triphenylphosphine or tributylphosphine or a azo reagent such as jetyl azodicarboxylate is added to pyrazole derivative 1-a. Compound 1-d can be produced by carrying out Mitsunobu reaction with hydroxyalkyl bromobenzene derivative 1-c.

 [0034] Step (1-3): Compound l-d is mixed with a phosphine such as binap or xanthophos in a solvent such as dioxane, diglyme or toluene in the presence of a catalyst such as paradimacetate or trisdibenzylideneacetone palladium. L-e can be produced by reacting a base such as cesium carbonate or sodium butoxide in the presence of a fin ligand.

 [0035] Step (14): In a solvent such as dimethyl sulfoxide and tert-butanol, the compound le is subjected to a hydrolysis reaction in the presence of a base such as potassium hydroxide, potassium carbonate, and a hydrogen peroxide solution. Thus, compound 1- can be produced.

 [0036] Scheme 2

[0037] [Chemical 4]

 (2-d)

Step (2-1): Compound 1 in Scheme 1 fCA is Formula 0—, B-force methylene, C is a single bond, R ¹ is a hydrogen atom 2-a is dichloromethane, 1, 2— Compound 2-b can be produced by reacting with boron tribromide in a solvent such as dichloroethane.

[0039] Step (2-2): Compound 2-b in a solvent such as tetrahydrofuran or dioxane, a phosphine reagent such as triphenylphosphine or tributylphosphine, or an azo reagent such as jetylazodicarboxylate The compound 2-c can be produced by carrying out Mitsunobu reaction with various alcohols represented by the formula Ri—C—B—OH. Further, instead of an alcohol represented by the formula Ri—C—B OH, an alkyl halide represented by the formula R ¹ —CB Hal (where Hal represents a chlorine atom, a bromine atom or an iodine atom) and a compound 2— Compound 2c can be produced by reacting b in a solvent such as chloroform, tetrahydrofuran, or dimethylformamide in the presence of a base such as triethylamine, potassium carbonate, or cesium carbonate.

Step (2-3): Compound 2b is converted to carboxylic acid represented by the formula R ¹ —COOH and dimethylformamide, tetrahydrofuran, chloroform, etc. in a solvent such as dicyclohexylcarbodiimide, Minopropyl) force to react in the presence of condensing agent such as 1 3 ethylcarbodiimide hydride chloride, 1-hydroxybenzotriazole, or in formula R ¹ —COC1 The compound 2-d can be produced by reacting in the presence of a base such as pyridine and triethylamine in a solvent such as the acid chloride shown and a solvent such as black form, tetrahydrofuran and dimethylformamide.

 Scheme 3

 [0041] [Chemical 5]

Step (3-1): Compound 2-b of Scheme 2 is reacted with trifluoromethanylsulfonyl chloride in a solvent such as tetrahydrofuran or dioxane in the presence of a base such as triethylamine or diisopropylethylamine. Compound 3—a can be produced.

 [0043] Step (3-2): Compound 3— In a solvent such as dioxane, diglyme and toluene, a catalyst such as para-diacetate or trisdibenzylideneacetone palladium is added to phosphine such as binap or xantphos. Compound 3-b can be produced by hydrolysis with benzophenone imine in the presence of a fin ligand in the presence of a base such as cesium carbonate or sodium butoxide.

[0044] Step (3-3): Compound 3-b is converted to dicarboxylic acid in a solvent such as carboxylic acid represented by the formula Ri-C-B-COOH and dimethylformamide, tetrahydrofuran, chloroform, etc. Bodiimide, 1— (3-Dimethylaminopropyl) -3-ethyl carbodiimide hydrate In the presence of a base such as pyridine and triethylamine in a solvent such as acid chloride represented by the formula R 1 -CB-COC1 and a solvent such as tetrahydrofuran, tetrahydrofuran, etc. Compound 3-c can be produced by reaction.

 [0045] Step (3-4): In the compound 3-b, an isocyanate represented by the formula Ri-C-B-NCO is mixed with a base such as pyridine or triethylamine in a solvent such as tetrahydrofuran or chloroform. Compound 3-d can be produced by reacting in the presence.

 Scheme 4

 [0046] [Chemical 6]

 (4-c)

[0047] Step (4-1): Compound 2 in Scheme 2— in which R ⁵ and R ⁶ are hydrogen atoms, D = D force Formula—CH

 1 2

= CH—, E is represented by the formula NR ⁶¹ —, R ⁶¹ is a hydrogen atom, G is a single bond, R ⁷ is a hydrogen atom. Compound 4 a in a solvent such as tetrahydrofuran, 1, 2 dichloroethane, sodium triacetoxy Compound 4b can be produced by reacting with an aldehyde represented by the formula R ⁷ — G, 1 CHO in the presence of a reducing agent such as borohydride or sodium cyanoborohydride. In the scheme, G ′ represents a single bond or a C alkylene group. [0048] Step (4 2): Compound 4a is an acid chloride represented by the formula R ⁷ — G— C OC1 in a solvent such as tetrahydrofuran, 1, 2 dichloroethane, dimethylformamide or the like in the presence of a base such as triethylamine or pyridine. Compound 4c can be produced by reacting with. In addition, carboxylic acid represented by compound 4a and R ⁷ -G-COOH can be converted into dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3 ethylcarbodiimide hydride in a solvent such as dimethylformamide, tetrahydrofuran, or chloroform. Compound 4-c can be produced by reacting in the presence of a condensing agent such as oral chloride or 1-hydroxybenzotriazole.

 [0049] [Chemical 7]

[0050] Step (5-1): Compound 2 in Scheme 2— in which R ⁵ and R ⁶ are hydrogen atoms, D = D force Formula— CH

 1 2

= CH-, E is the formula -COO-, G is a single bond, methanol compound 5-a where R ⁷ is represented by a methyl group, in a solvent such as tetrahydrofuran, sodium hydroxide, a base such as potassium hydroxide The compound 5-b can be produced by hydrolysis using the compound 5-b.

 [0051] Step (5-2): Compound 5— The carboxylic acid represented by b and the formula R—G—L (where L is

 7 1 1

OH, phenol represented in one NHR ^67), alcohol, Amin, or § - phosphorus-dimethylformamide, tetrahydrofuran, Kishirukarubo diimide into solvent dicyclohexyl such black hole Holm, 1- (3-dimethyl § amino propyl) -3 E Compound by reacting in the presence of condensing agent such as tilcarbodiimide hydride chloride and 1-hydroxybenzotriazole. 5—c (wherein L is —O—, —NR ⁶⁷ —) can be produced.

 2

 [0052] Step (5-3): Compound 5a is reacted with a reducing agent such as lithium aluminum hydride or sodium aluminum hydride in a solvent such as tetrahydrofuran or dioxane to give compound 5d. Can be manufactured.

[0053] Step (5-4): By reacting compound 5-d with paratoluenesulfurol cation in a solvent such as chloroform or toluene in the presence of a base such as triethylamine or dimethylaminopyridine. Compound 5—d can be produced.

[0054] Step (5-5): Compound 5d in the presence of a base such as triethylamine in a solvent such as black mouth form or dimethylformamide, R—G—M (wherein M is —OH, —NHR) ⁷⁵⁾ der

 7 1 1

The compound 5-e (wherein M is 1 O, 1 NR ⁷⁵ ) can be produced by reacting with phenol, alcohol, amine, or phosphorus.

 2

 [0055] A pharmaceutical comprising the compound of the present invention as an active ingredient can be administered systemically or locally orally or subcutaneously, intramuscularly, intravenously, transdermally, or the like. The dose of the compound of the present invention varies depending on the disease, symptoms, age, sex, body weight, route of administration, etc., but it is 0.01 to 100 mg / kg body weight / day for adults, which is once or several times a day. Can be administered separately.

 [0056] Examples and test examples are shown below to illustrate the compounds of the present invention in more detail.

 Example 1

 [0057] 2- (4 phenoxyphenol) 9.10 dihydro-4H pyrazo mouth "5.1-bl" l, 3l Benzodiazepine 3 Carboxamide (Compound No. 1)

(1) In a dimethylformamide (5 ml) solution of 5 amino-3- (4 phenol)-1H pyrazole-4-carbo-tolyl (1.13 g, 4. O9 mmol) obtained according to the production method described in WO2002080926 2 Bromophenethyl bromide (1.13 g, 4.29 mmol) and potassium carbonate (847 mg, 6.14 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. 2 Bromophenethyl bromide (0.49 g, 1.86 mmol) and potassium carbonate (400 mg, 2.90 mmol) were further added, and the mixture was stirred at 80 ° C. for 2 hours. Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water, saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the resulting residue into a silica gel column (developing solvent; ethyl acetate: _n —Hexane = 1: 4) By purifying with 4) Light yellow amorphous 5 Amino 1 1 (2 Bromo-ruethyl) 3 — (4 Phenolic Cipher) -1H pyrazole-4-carbo-tolyl (744 mg) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 3.29 (t, J = 6.81 Hz, 2 H) 3.89 (s, 2 H) 4.21 (t, J = 6.81 Hz, 2 H) 7.01-7.92 (m, 13 H)

[0058] (2) 5 Amino 1- (2 bromophenyl) 3- (4 phenoxyphenyl)-1H pyrazole-4-carbo-tolyl (744 mg, 1.62 mmol), trisdibenzylideneacetone obtained in (1) above A solution of palladium (92 mg, O.lOmmol), racemic binap (62 mg, 0.1 Ommol), cesium carbonate (1.06 g, 3.24 mmol) in dioxane (15 ml) was stirred at 100 ° C for 15 hours. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; ethyl acetate: _n- hexane =; L: 4) to give 2- (4 phenoxyphenol) -1,9 as a colorless solid. 10 Dihydro-4H pyrazo mouth [5,1-b] [l, 3] benzodiazepine-1-carbo-tolyl (90 mg) was obtained.

 1H NMR (300 MHz, CDC13) δ ppm 3.07-3.39 (m, 2 H) 4.41-4.50 (m, 2 H) 6.7 3 (br.s, 1 H) 6.73-7.91 (m, 13 H)

[0059] (3) 2- (4 phenoxyphenol) obtained in (2) above 9, 10 dihydro-4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine-3 carbo-tolyl (90 mg 0.24 mmol) in dimethyl sulfoxide (2 ml) was charged with potassium carbonate (100 mg, 0.72 mmol) and 30% aqueous hydrogen peroxide (0.2 ml) and stirred at 60 ° C. for 30 minutes. Add water to the reaction solution, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the resulting residue on a silica gel column (developing solvent; ethyl acetate: chloride). Purified by oral form = 1: 9) and recrystallized (ethyl acetate) to give colorless title compound 2— (4 phenoxyphenol) 9, 10 dihydro-4H pyrazo [5, 1—1)] [1 , 3] Benzodiazepine-3-carboxamide (45 mg) was obtained.

 Melting point: 2332. 5-233. 0 ° C

 Example 2

 [0060] 2— (4-Phenoxyphenol) 1. 5. 6. 7. 12—Tetrahydropyrazo mouth “5.1-bl” 1.3 l Benzodiazocine 3 Carboxamide (Compound No. 2)

(1) 5-Amino-3- (4 Phenylphenol)-1H Pyrazole-4-Bromophenol in a solution of 4-carbotolyl (1.99 g, 7.19 mmol) in dimethylformamide (10 ml) Propyl bromide (2.00 g, 7.19 mmol) and potassium carbonate (1.49 g, 10.79 mmol) were added, and the mixture was stirred at 60 ° C for 30 min. Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water, saturated Japanese brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue. NH silica gel column chromatography [NH silica gel; NH— DM1020 (Fuji Serial Co., Ltd.)] (Developing solvent: Ethyl acetate: n-hexane = 1: 4) Purification by colorless amorphous 5-amino-1- (4-phenoxyphenol) 1- (3-phenol -Rupropyl) 1 1H-pyrazole-4-carbo-tolyl (0.91 g) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 2.21 (qt, J = 7.47Hz, 2 H) 2.84 (t, J = 7.47Hz, 2 H) 3.96 (t, J = 7.47 Hz, 2 H) 4.24 (br. s, 2 H) 7.00-7.91 (m, 13 H)

[0061] (2) 5-amino-3- (4-phenoxyphenol) 1- (3-phenol oral pill) obtained in (1) above—1H pyrazole-4-carbo-tolyl (0.86 g, 1.82 mmol) , Tris-dibenzylideneacetone palladium (101 mg, O. l lmmol), racemic binap (68 mg, O. l lm mol), cesium carbonate (1.19 g, 3.64 mmol) in dioxane (15 ml) was heated to reflux for 30 hours. . Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained on a silica gel column (developing solvent; ethyl acetate: n-Hexane = 15:85) and purified by light yellow amorphous 2- (4-phenoxyphenol) 1, 5, 6, 7, 12-tetrahydrovirazolo [5, 1- b] [l, 3] Benzodiazocine 1-carbo-tolyl (72 mg) was obtained.

 1H NMR (300 MHz, CDC13) δ ppm 1.85 (m, 2 H) 2.69 (m, 2 H) 4.02 (m, 2 H) 6.43 (brs, 1 H) 7.00-7.93 (m, 13 H)

[0062] (3) 2- (4 phenoxyphenol) -1,5, 6, 7, 12-tetrahydropyrazo mouth obtained in (2) above [5, 1- b] [l, 3] benzodiazocine 3— To a solution of carbo-tolyl (62 mg, 0.16 mmol) in dimethyl sulfoxide (2 ml) was added potassium carbonate (65 mg, 0.47 mmol) and 30% hydrogen peroxide (0.4 ml), and the mixture was stirred at 80 ° C for 1 hour. . Water was added to the reaction solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated to recrystallize the residue (ethyl acetate). The title compound 2- (4phenoxyphenol) -1,5,7,12-tetrahydrovirazolo [5,1-b] [l, 3] benzodiazocine 3 carboxamide (28 mg) was obtained as colorless crystals. Melting point: 220. 5-221. 0 ° C

 Example 3

 [0063] 7 Methoxy-1- (4-phenoxyphenol) -9.10 Dihydro-1 4H Pyrazo mouth "5.1

 -bin.31 Benzodiazepine 3 Carboxamide (Compound No. 3)

 (1) 5-Amino-3- (4-phenoxyphenol)-1H Pyrazole-1-4-Carbotolyl (3.74 g, 14.3 mmol) in dimethylformamide (50 ml) in 2-bromo-5-methoxyphenethyl Bromide (3.96 g, 14.3 mmol) and potassium carbonate (2.97 g, 21.5 mmol) were added and stirred at 80 ° C. for 3 hours. Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained on a silica gel column (developing solvent; ethyl acetate: n —Hexane = 1: 2) Purification by light yellow solid 5 amino-1 (2 bromo-5-methoxyphenyl) -3- (4 phenoxyphenol) 1 1H pyrazole 1 4-carbo-tolyl (2 16g) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 3.23 (t, J = 6.81 Hz, 2 H) 3.69 (s, 3 H) 3.94 (b rs, 2 H) 4.20 (t, J = 7.03 Hz, 2 H) 6.57 -7.90 (m, 12 H)

 [0064] (2) 5 amino-11 obtained in (1) above (2 bromo-5-methoxyphenyl) -3 — (4 phenoxyphenol) 1 1H pyrazole 1 4-carbo-tolyl (2.12 g, 4 35 mmol), trisdibenzylideneacetone palladium (239 mg, 0.26 mmol), racemic bi-up (163 mg, 0.26 mmol), cesium carbonate (2.84 g, 8.7 mmol) in diglyme (100 ml) at 160 ° C. For 1 hour. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; ethyl acetate: n-hexane = 1: 1) to give a colorless solid 7-methoxy-2- (4-phenoxyphenol) 9, 10 Dihydro-1 4H pyrazo mouth [5, 1 — b] [l, 3] benzodiazepine 3 carbo-tolyl (1.43 g) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 3.18-3.23 (m, 2 H) 3.81 (s, 3 H) 4.41-4.46 (m, 2 H) 6.59 (brs, 1 H) 6.74-7.90 (m, 12 H )

[0065] (3) 7-methoxy-2- (4 phenoxyphenol) -1,9 dihydro-4H pyrazotone obtained in (2) above [5, 1-b] [l, 3] benzodiazepine 3-carbo- To a solution of tolyl (1.23 g, 3.01 mmol) in dimethyl sulfoxide (60 ml) was added potassium carbonate (1.25 g, 9.04 mmol) and 30% hydrogen peroxide (8.36 g). Stir for hours. Add water to the reaction, Extraction with ethyl acetate, washing (in order of water, saturated brine), drying (anhydrous magnesium sulfate), filtration, and concentration, the resulting residue was silica gel column (developing solvent; ethyl acetate: n-hexane = 1: By purifying in 2), the title compound 7-methoxy-2- (4-phenoxyphenyl) -1,9,10 dihydro-4H pyrazot [5, 1-b] [l, 3] benzodiazepine 1- Carboxamide (1.03 g) was obtained.

 Melting point: 202. 0- 203. 0 ° C

 Example 4

 [0066] 7 Hydroxy 2- (4 phenoxyphenol) 9. 10 Dihydro 4-H pyrazo mouth "5.

 1 bl “l.31 Benzodiazepine 3 Carboxamide (Compound No. 4 · 4)

 7-Methoxy-1-2- (4-Phenoxyphenol) -1,9,10 Dihydro-1-4ΗPyrazo Mouth [5, 1 —b] [l, 3] Benzodiazepine I 3-Carboxamide (1.00 g, 2.35 mmol) A 1M boron tribromide-dichloromethane solution (11.8 ml, 11.8 mmol) was added to the form (150 ml) solution, and the mixture was stirred at 78 ° C. for 2 hours and at room temperature for 1 hour. Pour the reaction mixture into ice water, separate and concentrate the black mouth form layer. The title compound in the form of pale yellow crystals 7 Hydroxy-2- (4-phenoxyphenol) 1, 9, 10 Dihydro-1 4H Pyrazo mouth [5, 1— b ] [l, 3] benzodiazepine 3 carboxamide (1.20 g) was obtained.

 Melting point: 265. 0- 265. 5 ° C

 Example 5

 [0067] 6-Methoxy-2- (4-phenoxyphenol) -9.10 Dihydro-1 4H Pyrazo mouth "5.1

 -bin.31 Benzodiazepine 3 Carboxamide (Compound No. 5)

(1) 5-Amino-3- (4-phenoxyphenol)-1H Pyrazole-4-bromo-tolyl (12. 92 g, 46. 80 mmol) in dimethylformamide (100 ml) in 2 bromo-4-methoxyphenethyl Bromide (16.39 g, 56.16 mmol) and potassium carbonate (9.70 g, 70.20 mmol) were added, and the mixture was stirred at 80 ° C. for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was silica gel column (developing solvent; ethyl acetate: _By purifying with _n- hexane = 1: 1), light yellow solid 5 amino 1- (2-bromo 4-methoxyphenethyl) 3-(4 phenoxyphenol) 1 1H pyrazole 1 4-carbo- Obtained Trill (12. 31g) It was.

 1H NMR (200 MHz, CDC13) δ ppm 3.21 (t, J = 6.81 Hz, 2 H) 3.79 (s, 3 H) 3.89 (b rs, 2 H) 4.15 (t, J = 6.81 Hz, 2 H) 6.73 -7.90 (m, 12 H)

 [0068] (2) 5 Amino 1- (2 bromo-4-methoxyphenethyl) 1 3- (4-phenoxyphenol) 1 1H pyrazole-4-carbo-tolyl (12. 15 g, obtained in (1) above, 24. 99mmol), trisdibenzylideneacetone palladium (1.37g, 1.50mmol), racemic bi-nut (933mg, 1.50mmol), cesium carbonate (16.28g, 49.98mmol) in diglyme (6 OOml) solution. The mixture was stirred at 160 ° C for 5 hours. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; ethyl acetate: n-hexane = 1: 1) to give a colorless solid 6-methoxy-1- (4-phenoxyphenol) 9, 10 Dihydro-1 4H pyrazo mouth [5, 1 — b] [l, 3] benzodiazepine 3 carbo-tolyl (6.15 g) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 3.16-3.21 (m, 2 H) 3.80 (s, 3 H) 4.41-4.46 (m, 2 H) 6.52-7.90 (m, 12 H) 6.73 (s, 1 H )

 [0069] (3) 6-Methoxy-2- (4 phenoxyphenol) -1,9 dihydro-4H pyrazotone obtained in (2) above [5, l-b] [l, 3] benzodiazepine 3-carbo- To a solution of tolyl (6.15 g, 15.07 mmol) in dimethyl sulfoxide (100 ml) was added potassium carbonate (6.25 g, 45.20 mmol), 30% hydrogen peroxide water (43 ml), and 50 ° C. Stir for 1 hour. Add water to the reaction mixture, extract with black mouth form, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter and concentrate the resulting residue on a silica gel column (developing solvent: ethyl acetate) The title compound 6-methoxy-2- (4 phenoxyphenol) 9, 10 dihydro 4H pyrazot [5, 1-b] [l, 3] benzodiazepine 3 canoleboxamide (5.68 g) was obtained by purifying with Obtained.

 Melting point: 174. 0- 175. 0 ° C

 Example 6

 [0070] 6 Hydroxy 2- (4 phenoxyphenol) 9. 10 Dihydro 4-H pyrazo mouth “5.

 1 bl “l.31 Benzodiazepine 3 Carboxamide (Compound No. 6)

6-Methoxy-1-2- (4 phenoxyphenol) -1,9,10 Dihydro-1 4H Pyrazo Methyl [5, 1 —b] [l, 3] Benzodiazepine 3-Carboxamide (5.55 g, 13. 02 mmol) A 1M boron tribromide-dichloromethane solution (65 ml, 65 mmol) was added to the rurum (500 ml) solution, and the mixture was stirred at −78 ° C. for 1 hour and at room temperature for 2 hours. The reaction mixture is poured into ice water, and the black mouth form layer is separated and concentrated to give the title compound 6 PYHYDRO-2- (4-Phenoxyphenol) 1, 9, 10 Dihydro-4H Pyrazo [5, 1— b] [l, 3] benzodiazepine-3-carboxamide (6.27 g) was obtained.

 Melting point: 295. 0- 296. 0 ° C

 Example 7

 [0071] 7-Γ2- (Dimethylamino) ethoxy 1— 2— (4 Phenoxyphenol) 9. 10 Dihydro — 4H Pyrazo mouth “5. l-bl” l.31 Benzodiazepine-3 Carboxamide (Compound No. 7 )

7 Hydroxy-2- (4 phenoxyphenol) 9, 10 Dihydro-4H Pyrazo Mouth [5, 1 1)] [1,3] Benzodiazepine-3-carboxamide (300111 ₈ , 0.728 mmol) in dimethylformamide (5 ml ) To the solution was added 2 dimethylaminoethyl chloride hydrate chloride (15 7 mg, 1.09 mmol), potassium carbonate (1.01 g, 7.28 mmol), 80. The mixture was stirred at C for 2 hours. Add water to the reaction mixture, extract with chloroform, wash (in order of water and saturated saline), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained on a silica gel column (developing solvent; The residue obtained by purification with form: methanol = 10: 1) was recrystallized from n-hexane-chloroform to give the title compound 7- [2 (dimethylamino) ethoxy] -2— (4 Phenoxyphenyl) 1, 9, 10 Dihydro-1 4H Pyrazocine [5, 1-b] [l, 3] benzodiazepine 3 Carboxamide (143 mg) was obtained.

 Melting point: 208. 5-210. 5 ° C

 Example 8

[0072] According to the production method of Example 7, 7 hydroxy 2- (4 phenoxyphenyl) 9, 10-dihydro-4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 3-carboxamide Or 6 Hydroxy-2- (4-phenoxyphenol) 9, 10 Dihydro-4H Pyrazo Mouth [5, l-b] [1,3] Benzodiazepine 3 Carboxamide vs. 2 Dimethylaminoethyl chloride Hydride Chloride Instead of N- (2-chloroethyl) pyrrolidine hydrochloride mouthpiece, 3 dimethinoreaminopropinorechloridenoide mouth chloride, 1 chloro-4-methinole Pentane, dimethylaminomethylpropyl chloride, 2 chloroacetamide, tert butyl chloroacetate, ethyl 4 chlorobutyrate, 3- (chloromethinole) pyridine hydride chloride, crocin acetone, 2- (chloromethinole) pyridine nodule chloride, 4 (Chloromethinole) pyridine Hydride Chloride, 3 Dimethylamino-2 Methylpropyl Chloride Hydride Chloride, 3 Chloromethyl 1-methylbiperidine, N— (2-Chloroethyl) piberidine Hydride Chloride, N— (2-Chloroethyl) morpholine Hydro Chloride, 2- (2-Chloroethyl) 1-Methylpyrrolidine Hydride Chloride, (1-Chloromethylolecyclopentylmethyl) dimethylamine Hydride Chloride, 2-Dibutylaminoethyl Chloride The following compounds of the present invention were obtained by using iodochloride or 2-dipropylaminoethyl chloride hydrate chloride.

[0073] 2— (4 Phenoxyphenol) 1 7— (2 Pyrrolidine 1-Iloxy) 1, 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No.) 8)

 Melting point: 185. 0- 195. 0 ° C

[0074] 2— (4-Phenoxyphenol) 1 7— (2 Piperidine 1 1-yloxy) 1, 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide ( Compound number 9)

 Melting point: 195.5-198. 5 ° C

[0075] 7- [3- (Dimethylamino) propoxy] 2— (4-Phenoxyphenol) 1, 9, 10 Dihydric Mouth — 4H Pyrazo Mouth [5, 1- b] [1, 3] Benzodiazepine 3 Carboxamide (Compound No. No. 10)

 Melting point: 187.5-194. 5 ° C

[0076] 7— (2 amino 1-2-oxoethoxy) 2— (4 phenoloxy) 1,9,10 Dihydric mouth—4H Pyrazo mouth [5, 1— b] [1, 3] benzodiazepine 3 carboxamide (Compound No.) 11)

 Melting point: 145. 5- 147. 0 ° C

[0077] Ethyl 4— {[3— (Aminocarbol) 1 2 — (4 Phenyloxy) 1 9, 10 Dihydro 4H Pyrazo Mout [5, 1—b] [l, 3] Benzodiazepine 7 yl] Oxy} butyric acid ester ( (Compound No. 12)

 Melting point: 177. 5- 179. 0 ° C

[0078] 2— (4-Phenoxyphenol) 1 7— (Pyridine 1-3-ylmethoxy) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 13 )

 Melting point: 209. 0—210. 0 ° C

[0079] 7— (2 Morpholine 4-yloxy) 1 2-— (4 Phenyloxy) 1, 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 14 )

 Melting point: 191.5-193.0 ° C

[0080] 7- [2- (1-Methylpyrrolidine-2-yl) ethoxy] —2— (4 Phenoxyphenol)

 9, 10 Dihydro-4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 3—force noreboxamide (Compound No. 15)

 Melting point: 189.5-191.5 ° C

[0081] 7— [3— (Dimethylamino) —2-Methylpropoxy] —2— (4-Phenoxyphenyl)

9, 10 Dihydro-4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 3—force nolevoxamide (Compound No. 16)

 Melting point: 184.5—186.0 ° C

[0082] 6— [(4-Methylpentyl) oxy] 2— (4 Phenyloxy) 1, 9, 10 Dihydro

—4H Pyrazo mouth [5, 1—1)] [1,3] Benzodiazepine-3—carboxamide (Compound No. 1

7)

 Melting point: 92. 0—95. 0 ° C

[0083] 6— [2— (Dimethylamino) ethoxy] —2— (4-phenoxyphenol) 1, 9, 10 Dihydro —4H Pyrazo Mout [5, 1-1)] [1,3] Benzodiazepine-3-carboxamide (Composite number 1 8)

 Melting point: 189.5-194. 0 ° C

[0084] 2— (4-Phenoxyphenyl) 1 6— (2 Pyrrolidine 1-Ilethyloxy) 1, 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. No. 19)

 Melting point: 157. 0-161. C

[0085] 6— [(3-Dimethylamino) propoxy] 2— (4-Phenoxyphenol) 1, 9, 10 Dihydr Mouth 4H Pyrazo Mout [5, 1- b] [1, 3] Benzodiazepine 3 Carboxamide (Compound No. (No. 20)

 Melting point: 143.0-146.0. C

[0086] 6— (2 amino 1-2-oxoethoxy) 2— (4 phenoloxy) 1,9,10 Dihydrone—4H Pyrazomouth [5, 1— b] [1, 3] benzodiazepine 3 Carboxamide (Compound No. twenty one)

 Melting point: 277.0-229.5. C

[0087] Tert Butyl {[3— (Aminocarbole) 1 2— (4-Phenoxyphenol) 1 9, 10 Dihydro 4H Pyrazo Mout [5, 1-b] [l, 3] Benzodiazepine 1 6 Inole ] Oxy} acetate (compound no. 22)

 Melting point: 149. 0- 152. 0 ° C

[0088] Yetyl 4— {[3— (Aminocarbol) 1 2— (4 Phenooxyl) 1 9, 10 Dihi Draw 4H Pilazo Mout [5, 1 1)] [1,3] Benzodiazepine 6— Ru] oxy} ester butyrate (Compound No. 23)

 Melting point: 133.5-136. 0 ° C

[0089] 2— (4-Phenoxyphenyl) 1- 6- (Pyridine 1-ylmethoxy) 1, 9, 10 Dihydro

4H Pirazo mouth [5, 1— b] [l, 3] benzodiazepine 3 carboxamide (Compound No. 24

)

 Melting point: 196. 5-205.0. C

[0090] 6— (2-Oxopropoxy) 1-2— (4 Phenoxyphenyl) -1,9,10 Dihydro-4H

—Virazolo [5, 1— b] [l, 3] benzodiazepine— 3 Carboxamide (Compound No. 25) Melting point: 160. 5-163. 5 ° C

[0091] 2— (4 Phenoxyphenol) 1 7— (Pyridine 1 2 IV Remethoxy) 1 9, 10 Dihydro 1

4H Pyrazo mouth [5, l—b] [l, 3] benzodiazepine— 3 carboxamide (Compound No. 26

) Melting point: 219. 0- 220. 0 ° C

[0092] 2— (4 Phenoxyphenol) 1 7— (Pyridine 1-4-ylmethoxy) 1,9,10 Dihydro-1 4H Pyrazo Mout [5, 1—b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 27)

 Melting point: 234. 0- 234. 5 ° C

[0093] 7-({1-[(Dimethylamino) methyl] cyclopentyl} methoxy) 2— (4 phenoxyphene 2-nore) 9, 10 dihydro-4H pyrazo mouth [5, 1-1)] [1,3] benzodiazepine-3 —Canore boxamide (Compound No. 28)

 Melting point: 173.5-174. 5 ° C

[0094] 6— [3— (Dimethylamino) -2-methylpropoxy] 2— (4-Phenoxyphenol) —9

, 10 Dihydro-1 4H Pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 1 3-carboxamide

(Compound No. 29)

 Melting point: 119. 0—120. 5 ° C

[0095] 6— [(1-Methylbiperidine-3-yl) methoxy] — 2— (4 Phenoxyphenyl) 9,

10 Dihydro 4H pyrazo mouth [5, 1— b] [l, 3] benzodiazepine 3 canoleboxamide (Compound No. 30)

 Melting point: 198. 5- 200. 0 ° C

[0096] 2— (4 Phenoxyphenyl) 1 6— (2 Piperidine 1 1-yloxy) 1 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound) (Number 31)

 Melting point: 134. 5-136. 0 ° C

[0097] 6— (2 Morpholine 1-4-Retoxy) 1 2— (4 Phenyloxy) 1 9, 10 Dihydro 4H Pyrazo Mout [5, 1—b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 32 )

 Melting point: 163.5-164. 5 ° C

[0098] 6— [2— (1-Methylpyrrolidine-2-yl) ethoxy] —2— (4 Phenyloxy)

9, 10 Dihydro-4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 3—force noreboxamide (Compound No. 33) Melting point: 142. 5-144. 5 ° C

[0099] 6- ({1 [(Dimethylamino) methyl] cyclopentyl} methoxy) 2— (4 Phenoxyphenol Ninore) 9, 10 Dihydro-4H Pyrazo Mout [5, 1-1)] [1,3] Benzodiazepine-3— Canole boxamide (Compound No. 34)

 Melting point: 83. 5-86. 0 ° C

 [0100] 7— [2— (Dibutylamino) ethoxy] —2— (4 Phenyloxy) 1,9,10 Dihydro —4H—Pyrazolone [5, l—b] [l, 3] Benzodiazepine-3 —Carboxamide (Compound No. 3 5)

 Melting point: 183. 0— 184. 5 ° C

[0101] 7— [2— (Dipropylamino) ethoxy] —2— (4 Phenyloxy) 1, 9, 10 Dihydrone — 4H Pyrazomouth [5, 1 — b] [1, 3] Benzodiazepine 3 Carboxamide (Compound No. No. 36)

 Melting point: 183.5-185.0 ° C

 Example 9

 [0102] 6- (3 oxobutoxy) -2- (4 phenoxyphenyl) 9. 10 Preparation of dihydro-4H pyrazolo "5, 1- bl" 1, 31 benzodiazepine 3 carboxamide (Compound No. 37) Example 7 6- [2— (2-Methyl- [1,3] dioxane 2-yl) ethoxy] -2— (4 phenoloxy) 9, 10 Dihydro-4H pyrazot [ To a suspension of 5,1-b] [l, 3] benzodiazepine-3-carboxamide (248 mg, 0.47 mmol) in tetrahydrofuran was added at room temperature with a 4M dioxane hydrochloride solution and stirred for 1 hour. Add sodium aqueous solution, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate, and purify the residue by silica gel column. By recrystallization from form, the title compound 6- (3- Xoxobutoxy) 2- (4 phenoxyphenol) 9,10 Dihydro-l 4H Pyrazolo [5, l-b] [l, 3] benzodiazepine-3 carboxamide (81 mg) was obtained.

 Melting point: 156. 0-159. 0 ° C

 Example 10

[0103] According to the production method of Example 9, 6- [2- (2-methyl- [1,3] dioxane 2-yl) Toxi] — 2— (4 Phenoxyphenol) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [1,3] Benzodiazepine-3 Instead of carboxamide, 2— (4 Phenoxyphenol ) —6— [2— (Tetrahydro-1H-pyran-2-yloxy) ethoxy] —9, 10 Dihydro — 4H Pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 1 3-carboxamide, {[3 — (Aminocarbole) 1 2— (4 Phenoxyphenyl) 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1 b] [1, 3] Benzodiazepine 6 yl] oxy} Acetic acid tert butyl ester or 2— (4 phenoxyphenyl) 7- [2- (tetrahydro 1 2H pyran 1 2-yloxy) ethoxy] —9, 10 dihydro 1 4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 1 3-carbox The following compounds of the present invention were obtained by using samide.

 [0104] 6— (2 Hydroxyoxy) 1 2— (4-Phenoxyphenol) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, l—b] [l, 3] Benzodiazepine-3 Carboxamide ( Compound number 38) Melting point: 160. 5— 162. 5 ° C

 [0105] {[3— (Aminocarbole) 1 2— (4-Phenoxyphenol) 1, 9, 10 Dihydro 1 4H—Pyrazolo [5, 1—b] [l, 3] Benzodiazepine-6 Il] oxy} acetic acid

 (Compound No. 39)

 Melting point: 129.0—133. 5 ° C

 [0106] 7— (2 Hydroxyoxy) 1 2— (4-Phenoxyphenol) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, l—b] [l, 3] Benzodiazepine-3 Carboxamide ( Compound number 40) Melting point: 200. 5- 201. 5 ° C

 Example 11

 [0107] 4-ΙΓ3- (Aminocarbol) 2— (4-Phenoxyphenol) 9. 10 Dihydro 1 4H Pyrazo Mouth “5.1 — bl” l, 31 Benzodiazepine 6-yl 1oxy 1 Butyric acid (compound) No. 41)

4 {[3— (Aminocarbole) —2— (4 Phenyloxyphenyl) -1,9,10 Dihydro-1 4H Pyrazo mouth [5, 1—b] [obtained in accordance with the production method of Example 7 l, 3] Benzodiazepine-6-yl] oxy] butyric acid ethyl ester (317 mg, 0.60 mmol) in tetrahydrofuran-methanol monohydrate (24-12-12 ml) was calcined with potassium hydroxide (101 mg, 1.81 mmol). And stirred at room temperature for 3 hours. Add 1M hydrochloric acid to the reaction, extract with ethyl acetate, wash (water, Saturated saline solution), dried (anhydrous magnesium sulfate), filtered, and concentrated to purify the residue by silica gel column (developing solvent; black mouth form: methanol = 10: 1). The title compound 4 [3--rubbermoyl 2- (4 phenoxyphenol) 9, 10-dihydro 4H pyrazot [5,1-b] [1,3] benzodiazepine 6-yloxy] butyric acid (288 mg) was obtained.

 Melting point: 204. 5-207. 5 ° C

 Example 12

 [0108] 4-ΙΓ3- (Aminocarbol)-2- (4 Phenoxyphenol) 9. 10 Dihydro-1 4H Pyrazo mouth "5.1-bl" l.31 Benzodiazepine 7-yl 1oxy} butyric acid (compound No. 42)

 According to the production method of Example 11, 4 — {[3— (Aminocarbole) —2— (4 phenoxyphene), 10, 10 dihydro-4H pyrazo mouth [5, 1—b] [l, 3] Instead of benzodiazepine 6-yl] oxy] butyric acid ethyl ester 4— {[3— (aminocarbol) —2— (4 phenoloxyl) 9, 10, dihydro 1 4H pyrazo mouth [5, 1— b ] [l, 3] Benzodiazepine 7-yl] oxy} By using butyric acid ethyl ester, the title compound 4— {[3— (aminocarbol) 2— (4 phenoloxyl) 9, 10 dihydrol 4H The pyrazo mouth [5, 1-b] [l, 3] benzodiazepine-7yl] oxy} butyric acid was obtained.

 Melting point: 213. 5-214. 5 ° C

 Example 13

 [0109] 6- (4 Amino-4-oxobutoxy) 2— (4 Phenyloxyphenol) 9. 10 Dihydro 4H Pyrazo Mouth “5.1 — bl” l.31 Benzodiazepine 3 Carboxamide (Compound No. 43)

4— {[3— (Aminocarbol) 2— (4 Phenoxyphenol) 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1—1)] [1,3] Benzodiazepine-6-yl] oxy} butyric acid (144111 ₈ , 0.29 mmol) in a dimethylformamide (5 ml) solution of 1 (3 dimethylaminopropyl) 3-ethylcarbodiimide hydride chloride (83 mg, 0.43 mmol), 1-hydroxybenzotriazole (59 mg 0.43 mmol), salt-ammonium (46 mg, 0.87 mmol), and riethyramine (292 mg, 2.9 mmol) were added and stirred at room temperature for 24 hours. Add water to the reaction solution. Extraction with ethyl acetate, washing (in order of water, saturated brine), drying (anhydrous magnesium sulfate), filtration and concentration, the residue obtained was NH-silica gel column chromatography [NH silica gel; NH-DM1020 (Fuji cereal Ltd.)] (developing solvent; black mouth form: ethyl acetate = 1: 9-1: 1) to give colorless crystalline title compound 6- (4 amino-4-oxobutoxy) 2- (4 phenoxyphenol) ) 9, 10 Dihydro-1 4H Pyrazo mouth [5, 1-b] [l, 3] benzodiazepine 3 carboxamide (124 mg) was obtained.

 Melting point: 203. 0- 204. 5 ° C

 Example 14

 [0110] 7- (4 Amino-4-oxobutoxy) 2— (4 Phenyloxyphenol) 9. 10 Dihydro 4H Pyrazo Mouth “5.1 — bl” l.31 Benzodiazepine 3 Carboxamide (Compound No. 44)

 According to the production method of Example 13, 4 — {[3— (Aminocarbole) —2— (4 phenoxyphene) 9,10 dihydro-4H pyrazo mouth [5, 1—b] [l, 3] Benzodiazepine 1 6-yl] oxy} Instead of butyric acid 4 {[3 (Aminocarbol) 2— (4 Phenoxyphenyl) —9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3 ] By using benzodiazepine 7-inore] oxy} butyric acid, the title compound 7- (4-amino-4-oxobutoxy)-2- (4 phenoxyphenol) -9, 10 dihydro-4H pyrazot [5, l —B] [l, 3] benzodiazepine 3-carboxamide was obtained.

 Melting point: 248. 5-250. 0 ° C

 Example 15

 [0111] 6 — “(1-methylbiperidine 1- 4-yl) oxy Ί 2-— (4-phenoxyphenol) 9. 1

0 Dihydro-4H Pirazo Mouth “5.1-bl” l.31 Benzodiazepine 3 Carboxamide (I [^ ^ 45)

 6 Hydroxy 2- (4 phenoxyphenol) 9, 10 Dihydro mono 4H Pyrazo mouth [5,

1-b] [l, 3] benzodiazepine 1-carboxamide (200 mg, 0.485 mmol), triphenyl-phosphine (191 mg, 0.73 mmol), 4 hydroxy-1-1-methylpiperidine (84 mg, 0.73 mmol) in tetrahydrofuran ( 5ml) Add 40% toluene solution (318mg, 0.73mmol) of Jetylazodicarboxylate in ice-cooled solution and stir at room temperature for 20 hours. It was. The reaction solution was purified by silica gel column chromatography [developing solvent; black mouth form: methanol = 20: 1, then black mouth form: methanol = 5: 1] to give the title compound 6- [(1-methylbiperidine as colorless crystals). 1-yl) oxy] 2- (4 phenoxyphenol) 9, 10-dihydro 4H pyrazo mouth [5, 1-b] [1, 3] benzodiazepine 3 canoleboxamide (52 mg).

 Melting point: 162.0—164.0 ° C

 Example 16

 [0112] In accordance with the production method of Example 15, instead of 4-hydroxy 1-methylbiperidine, 3-dimethylamino-2,2 dimethylpropanol, 2 jetylaminoethanol or 3-jetylamino-2,2- The following compounds of the present invention were obtained by using dimethylpropanol.

 [0113] 6— [3— (Dimethylamino) — 2, 2 Dimethylpropoxy] 2— (4-Phenoxyphenyl)

) -9, 10 Dihydro-4H—Pirazo Mouth [5, 1—1)] [1,3] Benzodiazepine-3—Canoreboxamide (Compound No. 46)

 Melting point: 107.5—108.5 ° C

[0114] 6— [2— (Jetylamino) ethoxy] —2— (4-Phenoxyphenol) 1, 9, 10 Dihydro

—4H—Pirazo mouth [5, l—b] [l, 3] benzodiazepine-3—carboxamide (Compound No. 4

7)

 Melting point: 53. 5-54. 0 ° C

[0115] 6- [3— (Jetylamino) 1, 2, 2 Dimethylpropoxy] 2— (4-Phenoxyphenol) 9, 10 Dihydro-1 4H Pyrazo mouth [5, 1- b] [l, 3] Benzodiazepine 1 —Carboxamide (Compound No. 48)

 Melting point: 67. 0— 69. 0 ° C

[0116] 6— {[6— (Jetylamino) hexyl] oxy} — 2— (4-Phenoxyphenol) 1, 9, 10 Dihydro 4H pyrazo mouth [5, 1— b] [l, 3] benzodiazepine 3 canoleboxamide (Yeong compound number 49)

 Melting point: 129. 0—130. 0 ° C

Example 17 [0117] 4— ί “3— (Aminocarbol) 2— (4 Phenyloxyl) 9. 10 Dihydro 1 4 ピ ラ Pirazo Mouth“ 5. 1— bl “l, 31 Benzodiazepine 6-yl 1 Oxytonk Mouth Hexacarbol 1¾ report of acid (Compound No. 50)

 4— {[3— (Aminocarbol) —2— (4 Phenoxyphenol) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] obtained according to the production method of Example 15. ] [l, 3] benzodiazepine 6yl] oxytonk hexane carboxylic acid methyl ester is hydrolyzed according to the production method of Example 11 to give the title compound 4 {[3 (aminocarbol) -2- ( 4-Fenoxyphenyl) 1,9,10 Dihydro-4H Pyrazo Mouth [5, 1-b] [l, 3] Benzodiazepine 6-yl] oxytonk Hexanecarboxylic acid was obtained.

 Melting point: 142.5—149. 5 ° C

 Example 18

 [0118] 3— (Aminocarbol)-2- (4 Phenoxyphenol) 9. 10 Dihydro-1 4H Pirazolo “5.1-131” 1,31 Benzodiazepine-7-yl 4-methylbiperazine 1 Production of carboxylic acid ester (Compound No. 51)

 7 Hydroxy-2- (4 phenoxyphenol) 9, 10 Dihydro-1 4H Pyrazo mouth [5, 1- b] [l, 3] Benzodiazepine 3-Carboxamide (200 mg, 0.48 mmol) in chloroform (3 ml) At room temperature, N-methylbiperazine 4 strength ruberamoyl mouth hydride mouth chloride (145 mg, 0.73 mmol), triethylamine (0.33 ml, 2.4 mmol), 4 dimethylamino pyridine (5.9 mg, 0.05 mmol) ) And stirred for 1 hour 30 minutes. Water was added to the reaction solution, extracted with black mouth form, washed (in order of water and saturated saline), dried (anhydrous magnesium sulfate), filtered and concentrated, and the residue obtained was recrystallized from black mouth form ethyl acetate. The title compound in the form of colorless crystals 3 (Aminocarbol) 2— (4 Phenoxyphenol) 9, 10 Dihydro-4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 7-Inole 4 Methylbiperazine 1 Carboxyl The acid ester (178 mg) was obtained.

 Melting point: 260. 5- 261. 5 ° C

 Example 19

[0119] According to the production method of Example 18, 7 hydroxy-2- (4 phenoxyphenol) -9, 10 dihydro-4H-pyrazo mouth [5, l-b] [l, 3] benzodiazepine 3-carboxamide or 6 Hydroxy-2- (4 phenoxyphenol) 9, 10 Dihydro-4H Pyrazo Mouth [5, 1 b] [1, 3] Benzodiazepine 3 Carboxamide vs N-Methylbiperazine 4 Carbamoyl Muclide Mouth Chloride or Nicotinoyl Muclide The following compounds of the present invention were obtained by using hydride chloride.

 [0120] 3— (Aminocarbol) 1 2— (4 Phenyloxy) 1 9, 10 Dihydro 1 4H Pyrazolo [5, 1— b] [l, 3] Benzodiazepine 1 6-yl 4-Methylbiperazine 1 1-Carbonate (Compound No. 52)

 Melting point: 93.0-98.5 ° C

[0121] 3— (Aminocarbol) 1 2 — (4 Phenyloxy) 1 9, 10 Dihydro-1 4H Pyrazolo [5, 1-1)] [1,3] Benzodiazepine-7-yl Nicotinate (I compound number

53)

 Melting point: 262. 0- 263. 0 ° C

 Example 20

 [0122] 3- (Aminocarbol) 2— (4 Phenoxyphenol) 9. 10 Dihydro-4H pyrazolo “5.1-bl” l, 3l Benzodiazepine-7-yl 1-Methylbiperidine-1-Carbonic acid Establishing ester (Compound No. 54)

7 Hydroxy 2- (4 phenoxyphenol) 9, 10 Dihydro 1 4H Pyrazo mouth [5, 1 1)] [1,3] Benzodiazepine-3-canoleboxamide (64111 ₈ , 0.16 mmol), 1-methinole-piperidine 4-Carboxylic acid hydride chloride (84 mg, 0.47 mmol) in dimethylformamide (3 ml) at room temperature, 1 (3 dimethylaminopropyl) 3 ethylcarbodiimide hydride chloride (44 mg, 0.23 mmol), 1 -Add hydroxybenzotriazole (31 mg, 0.23 mmol), triethylamine (0.22 ml, 1.6 mmol) 90. The mixture was stirred at C for 3 hours. Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained by NH silica gel chromatography [NH silica gel; NH DM1020 (Fuji Serial Co., Ltd.)] (Developing solvent; chloroform: ethyl acetate = 1: 9) and purified by purification using colorless crystals of the title compound 3— (aminocarbole) 2— (4 phenoxyphenol) 9, 10 Dihydro-1 4H Pyrazo Mout [5, 1 1)] [1,3] Benzodiazepine-7-Inole 1-Methinorebiperidine-4 Steal (43 mg) was obtained.

 Melting point: 249. 0- 250. 0 ° C

 Example 21

 [0123] In accordance with the production method of Example 20, 7 hydroxy-1- (4 phenoxyphenyl) -1,9,10 dihydro-4H-pyrazo mouth [5, l -b] [l, 3] benzodiazepine 3-carboxamide or 6 Hydroxy 1- (4 phenoxyphenol) 9, 10 Dihydro 1 4H Pyrazo Mouth [5, 1 b] [1, 3] Benzodiazepine 3 Carboxamide vs 1 Methylbiperidine 4 Carboxylic Acid Hyde Mouth Chloride The following compounds of the present invention were obtained by using N dimethylglycine.

 [0124] 3— (Aminocarbol) 1 2— (4 Phenyloxyl) 1 9, 10 Dihydro 1 4H— Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 1 6-il N, N Dimethylglycinate ester (Compound No. 55)

 Melting point: 214. 0- 215. 0 ° C

 [0125] 3— (Aminocarbole) 1 2— (4 Phenyloxy) 1 9, 10 Dihydro 1 4H Pyrazolo [5, 1—b] [l, 3] Benzodiazepine 1 7-yl N, N Dimethyl Glycine ester (Compound No. 56)

 Melting point: 225. 0- 227. 0 ° C

 Example 22

 [0126] 6-Γ4- (Dimethylamino) butoxy 1— 2— (4 Phenyloxyphenol) 9. 10 Dihydro —4H Pyrazo mouth “5. l-bl” l.31 Benzodiazepine-3 Carboxamide (Compound No. 5 ¾¾ notice of 7)

(1) 7 Hydroxy-2- (4 phenoxyphenol) 9, 10 Dihydro-4H pyrazot [5, 1-b] [l, 3] Benzodiazepine 3-Carboxamide (200 mg, 0.485 mmol) in dimethylformamide 1. Add 1,4 dibromobutane (314 mg, 1.455 mmol) and potassium carbonate (80 mg, 0.582 mmol) to the (3 ml) solution. The mixture was stirred at C for 3 hours. Dimethylformamide was distilled off and purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1) to give oily 6- (4-bromobutoxy)-2- (4-phenoxyphenol- 9, 10 Dihydro-1 4H Pyrazo mouth [5, 1- b] [l, 3] Benzodiazepine 3-Carbo Xamide (154 mg) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 1.85-2.11 (m, 4 H) 3.16-3.21 (m, 2 H) 3.49 (t, J = 6.4 Hz, 2 H) 3.98 (t, J = 6.4 Hz, 2 H) 4.40-4.45 (m, 2 H) 5.31 (brs, 1 H) 6. 49-7.55 (m, 12 H) 9.98 (brs, 1 H)

[0127] (2) 6- (4 Bromobutoxy) 2— (4 Phenyloxyphenyl) 9, 10 0 Dihydro 4H Pyrazo Mout [5, 1- b] [1, 3] Benzodiazepine 3 obtained in (1) above To a solution of canoleboxamide (154 mg, 0.281 mmol) in ethanol (2 ml) was added 2M dimethylamine methanol solution (0.7 ml, 1.4 mmol), and the mixture was stirred at room temperature for 20 hours. Evaporate the solvent and purify with NH silica gel chromatography [NH silica gel; NH—DM1020 (Fuji cereals)] (developing solvent; black mouth form: _n —hexane = 4: 1), n— Recrystallized from hexane-chloroform to give colorless title compound 6— [4 (dimethylamino) butoxy] 2— (4 phenoxyphenol) -9,10 dihydro-4H pyrazot [5, l—b] [l, 3] Benzodiazepine 3-force nolevoxamide (66 mg) was obtained.

 Melting point: 123. 5-124. 5 ° C

 Example 23

 [0128] According to the production method of Example 22, 7 hydroxy-2- (4 phenoxyphenyl) -9, 10 dihydro-4H-pyrazo mouth [5, l-b] [l, 3] benzodiazepine 3-carboxamide or 6 Hydroxy-1- (4 phenoxyphenol) 9, 10 Dihydro-4H Pirazo Mouth [5, 1 1)] [1,3] Benzodiazepine-3-Carboxamide instead of 1, 4 Dibromobutane 1, 2 Use dibromoethane or 1,3 dibromopropane, instead of 2M dimethylamine methanol solution, 40% methylamine methanol solution, N, N, N, monotrimethylethylenediamine, 2- (methylamino) ethanol, pyrrolidine, N-methylbiperazine, N Hydroxyethylpiperazine, jetylamine, piperidine, morpholine, N, N jetylethylenediamine, N, N jetyl N'—n-butylethylenediamine, By using the Le Amin, or propylamine to give the compound of the invention that follows.

[0129] 7— [4— (Dimethylamino) butoxy] —2— (4 Phenyloxyphenol) 1, 9, 10 Dihydro —4H—Pyrazolone [5, l—b] [l, 3] Benzodiazepine-3 —Carboxamide (Compound No. 5 8) Melting point: 192. 0- 193.5 ° C

[0130] 7— [2— (Methylamino) ethoxy] —2— (4 Phenyloxy) 1, 9, 10 Dihydro-1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 59 )

 Melting point: 180.5—181.5 ° C

[0131] 7— {2— [[2 (Dimethylamino) ethyl] (methyl) amino] ethoxy} 2— (4-Fenoxy shift) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [ l, 3] benzodiazepine 1 3 carboxamide (Compound No. 60)

 Melting point: 154. 0-155. 5 ° C

[0132] 7— {2— [(2 Hydroxyethyl) (methyl) amino] ethoxy} 2— (4 Phenoxyphenol Ninore) 9, 10 Dihydro-4H Pyrazo Mout [5, 1-1)] [1,3] Benzodiazepine-3-canole boxamide (Compound No. 61)

 Melting point: 177. 5- 178. 5 ° C

[0133] 2— (4 Phenoxyphenyl) 1 6— (4 Pyrrolidine 1-Ilbutoxy) 1 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No.) 62)

 Melting point: 110. 5- 112. 0 ° C

[0134] 6— [2— (4-Methylbiperazine 1-yl) Ethoxy] —2— (4 Phenyloxy)

 9, 10 Dihydro-4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 3—force noreboxamide (Compound No. 63)

 Melting point: 170. 0- 171. 0 ° C

[0135] 6— {2— [4— (2-Hydroxyethyl) piperazine 1-yl] ethoxy} 2-— (4-phenoxyphenyl) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b ] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 64)

 Melting point: 154. 0- 155. 0 ° C

[0136] 6— {2— [(2 Hydroxyethyl) (methyl) amino] ethoxy} 2— (4 Phenoxyphenol Ninore) 9, 10 Dihydro-4H Pyrazo Mout [5, 1-1)] [1,3] Benzodiazepine-3—canole boxamide (Compound No. 65) Melting point: 94. 0- 96. 0 ° C

[0137] 6— {2— [[2 (Dimethylamino) ethyl] (methyl) amino] ethoxy}-2- (4-Phenoxy shift) 1, 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 1 Carboxamide (Compound No. 66)

 Melting point: 97.5—99.5 ° C

[0138] 6— [2— (Methylamino) ethoxy] —2— (4-phenoxyphenol) 1, 9, 10 Dihydro

4H Pirazo mouth [5, 1— b] [l, 3] benzodiazepine 3 Carboxamide (Compound No. 67

)

 Melting point: 149. 0- 150. 0 ° C

[0139] 6— [4— (Jetylamino) butoxy] —2— (4-phenoxyphenol) 1, 9, 10 dihydro —4H—pyrazo [5, l—b] [l, 3] benzodiazepine 3-Carboxamide (Compound No. 6 8)

 Melting point: 73. 5-76. 0 ° C

 [0140] 2— (4-Phenoxyphenyl) 1 6— (4-Piperidine 1-Ilbutoxy) 1 9, 10 Dihydro 4H Pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 69)

 Melting point: 108.5—109.5 ° C

[0141] 6- (4-Morpholine 4-ylbutoxy) 1 2- (4-Phenoxyphenol) 1, 9, 10 Dihydro 4H Pyrazo Mout [5, 1- b] [l, 3] Benzodiazepine 3 Carboxamide (Compound) (Number 70)

 Melting point: 93.5—96. 0 ° C

 [0142] 2— (4-Phenoxyphenyl) 1- 6— (3 Piperidine 1-ylpropoxy) 1, 9, 10- Dihydro 4H Pyrazo Mout [5, 1- b] [l, 3] Benzodiazepine 3 Carboxamide ( (Composite number 71)

 Melting point: 123. 0- 124. 0 ° C

[0143] 6- [3— (4-Methylbiperazine 1-yl) propoxy] —2— (4-Phenoxyphenol) 9, 10 Dihydro-4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 1-carboxamide (Compound No. 72) Melting point: 65. 5-67. 0 ° C

 [0144] 6— (3 Morpholine 4-ylpropoxy) 1 2- (4 Phenyloxy) 1, 9, 10- Dihydro 4H Pyrazo Mout [5, 1- b] [l, 3] Benzodiazepine 3 Carboxamide (Item No. 73)

 Melting point: 129. 5- 131. 0 ° C

[0145] 6— [3— (Jetylamino) propoxy] 2 — (4 Phenyloxy) 1, 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 74 )

 Melting point: 116. 0- 117. 5 ° C

[0146] 7— [2— (Jetylamino) ethoxy] —2— (4 Phenyloxyphenyl) 1, 9, 10 Dihydro —4H—Pyrazolone [5, l—b] [l, 3] Benzodiazepine-3 —Carboxamide (Compound No. 7 5)

 Melting point: 185. 0— 186. 0 ° C

[0147] 7— (2— {[2 (Dimethylamino) ethyl] amino} ethoxy) -2- (4 phenoxyphenyl)

 9, 10 Dihydro-4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 3—force noreboxamide (Compound No. 76)

 Melting point: 165. 0— 166. 0 ° C

[0148] 7- (2 {Butyl [2 (dimethylamino) ethyl] amino} ethoxy} 2— (4-Phenoxyphenyl) 9, 10 Dihydro-4H Pyrazo Mout [5, 1–1)] [1,3] Benzodiazepine-3 —Carboxamide (Compound No. 77)

 Melting point: 173. 0- 174. 0 ° C

[0149] 7- [2- (4-Methylbiperazine 1-yl) ethoxy] —2— (4 Phenoxyphenyl)

 9, 10 Dihydro-4H Pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 3—Strengthen boxamide (Compound No. 78)

 Melting point: 185. 5- 187. 0 ° C

[0150] 7— [2— (Ethylamino) ethoxy] —2— (4 Phenyloxy) 1, 9, 10 Dihydro

4H Pirazo mouth [5, 1— b] [l, 3] benzodiazepine 3 Carboxamide (Compound No. 79

) Melting point: 175. 5- 176. 0 ° C

[0151] 2— (4 Phenoxyphenol) 1 7— [2— (Propylamino) ethoxy] —9, 10 Dihydro —4H—Pyrazo Mout [5, l—b] [l, 3] Benzodiazepine-3 —Carboxamide (Compound number 8 0)

 Melting point: 235. 0- 237. 0 ° C

 Example 24

 [0152] 6- (2 Aminoethoxy) 2— (4 Phenoxyphenol) 9. 10 Dihydro-1 4H Pyrazolo “5.1 — bl” l.31 Preparation of benzodiazepine 3 carboxamide (Compound No. 81) (1) In accordance with the production method of Example 7, 7 hydroxy 2— (4 phenoxyphenol) 9, 10 dihydro-4H pyrazolo [5, 1—b] [l, 3] benzodiazepine 3 instead of force noreboxamide 6 hydroxy 1 2— (4 phenoxyphenol) 9, 10 Dihydro 1 4H— Pyrazo Mouth [5, 1—1)] [1,3] Benzodiazepine 3- Carboxamide, 2 Dimethylaminoethyl chloride Instead of using 2- (Boc amino) ethyl bromide, tert-butyl (2— {[3— (aminocarbol) 2— (4-phenoxyphenol 2-nore) 9, 10 dihydro 1 4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 6-yl] oxy It was obtained Le) force Rubameto.

 1H NMR (200 MHz, CDC13) δ ppm 1.46 (s, 9 H) 3.16-3.21 (m, 2 H) 3.53 (q, J = 5.3 Hz, 2 H) 4.00 (t, J = 5.3 Hz, 2 H) 4.40-4.45 (m, 2 H) 4.97 (brs, 1 H) 5.32 (brs, 2 H) 6.53-7.54 (m, 12 H) 9.99 (brs, 1 H)

[0153] (2) tert butyl (2— {[3 (Aminocarbol) 2- (4 Phenol thiophene) 1 9, 10 Dihydro 1 4H Pyrazo Mouth obtained in (1) above [5, 1— b Trifluoroacetic acid (10 ml) was added to a solution of [l, 3] benzodiazepine-6-yl] oxy} ethyl) and rubamate (200 mg, 0.36 mmol) in chloroform (10 ml), and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction mixture, add saturated aqueous sodium hydrogen carbonate solution, extract with black mouth form, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter and concentrate the residue obtained on the silica gel column. (Development solvent; methanol: chloroform = 1: 2), purified by recrystallization (n-hexane-chloroform), and the title compound 6- (2 aminoethoxy)-2- ( 4—Phenoloxy) 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 1 -Carboxamide (53 mg) was obtained.

 Melting point: 78. 0-81. 5 ° C

 Example 25

 [0154] In accordance with the production method of Example 24, instead of 6-hydroxy-2- (4-phenoxyphenol) -9,10 dihydro-4H pyrazot [5, 1-b] [1,3] benzodiazepine 3 carboxamide 7 Hydroxy 2- (4 phenoxyphenol) 1, 9, 10 Dihydro 1 4H-virazolo [5, l-b] [l, 3] benzodiazepine-3-carboxamide The compound of

 7- (2 Aminoethoxy) 2— (4 Phenoxyphenol) 9, 10 Dihydro 1 4H Pyrazolo [5, l—b] [l, 3] Benzodiazepine-3 Carboxamide (Compound No. 82) Melting point: 201. 0-202. 0 ° C

 Example 26

 [0155] 6- (3 aminopropoxy) -2- (4 phenoxyphenol) 9. 10 Dihydro-4H— Pyrazo mouth “5. l-bl“ l, 31 Benzodiazepine— 3 Carboxamide (Compound No. 83)

 (1) In accordance with the production method of Example 7, 7 Hydroxy-2- (4 phenoxyphenol) -9, 10 0 Dihydro 4H pyrazolo [5, 1- b] [1, 3] benzodiazepine 3 Carboxamide instead In addition, 6-hydroxy-1- (4 phenoxyphenol) 9, 10 dihydro-1 4H pyrazolo [5, 1—1)] [1,3] benzodiazepine-3-carboxamide, 2 dimethylaminoethyl chloride By using N- (3-bromopropyl) phthalimide instead of chloride, 6- [3— (1,3 Dioxo-1,3 dihydro-1,2H-isoindole —2-yl) propoxy] —2— ( 4 Phenoxyphenyl) 9, 10 Dihydro-l 4H Pyrazolo [5, 1-b] [1, 3] benzodiazepine 3 Carboxamide was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 2.07-2.31 (m, 2 H) 3.14-3.18 (m, 2 H) 3.91 (t, J = 6.81 Hz, 2 H) 4.01 (t, J = 5.93 Hz, 2 H) 4.38-4.44 (m, 2 H) 5.31 (br.s, 2 H) 6.39-7.87 (m, 16 H) 9.90 (s, 1 H)

[0156] (2) 6- [3— (1,3 Dioxo 1,3 dihydro-2H-isoindole-2-yl) propoxy] obtained in (1) above—2— (4 phenoloxyphenyl) 9, 10 Dihydro-1 4H— Add a hydrazine hydrate (0.07 ml, 1.4 mmol) to a suspension of 1,4 dioxane (5 ml) in pyrazot [5, 1- b] [l, 3] benzodiazepine 3-force nolevoxamide (140 mg, 0.23 mmol). In addition, the mixture was stirred at 100 ° C for 15 hours. The reaction solution was concentrated, black mouth form was added, and the fixed substance was removed by filtration. The residue obtained by concentrating the black mouth form solution is purified by NH silica gel column chroma KNH silica gel; NH-DM1020 (Fuji Serial Co., Ltd.) (developing solvent; black mouth form) and recrystallized (ethanol). Title compound of colorless crystals 6- (3-aminopropoxy) -2- (4 phenoloxy) 9, 10 Dihydro-4H pyrazo mouth [5, 1- b] [1, 3] benzodiazepine 3 carboxamide (44 mg) Got.

 Melting point: 76.5—79. 0 ° C

 Example 27

 [0157] 6 Amino 1-(4 Phenyloxy) 1 9. 10 Dihydro 1 4H Pirazo mouth "5.1-b 1" 1.31 Benzodiazepine 3 Carboxamide (Compound No. 84)

 (1) 6-hydroxy 2- (4 phenoxy phenol) 1, 9, 10 dihydro 4-H pyrazo mouth [5, 1-1)] [1,3] benzodiazepine-3-canoleboxamide (2. 05 g, 5.0 mmol) , 4 To a suspension of dimethylaminopyridine (2.00 g, 16.4 mmol) in tetrahydrofuran (45 ml) was added trifluoromethanesulfuryl chloride (1 ml, 10.4 mmol) under ice-cooling, and the mixture was brought to room temperature. And stirred for 1 hour. Further, trifluoromethanesulfonyl chloride (1.0 ml, 9.5 mmol) was added and stirred for 1 hour. The reaction mixture was filtered and the residue obtained by concentrating the filtrate was treated with NH silica gel column chromatography [NH silica gel; NH—DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1 ) To give colorless crystals of 3- (amino carbo) -1- (4-phenoxyphenol) -1,9,10 dihydro-1 4H pyrazo mouth [5, 1 —b] [l, 3] benzodiazepine 6-yl trifluoromethanesulfonate (2.03 g) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 3.24-3.29 (m, 2 H) 4.46-4.51 (m, 2 H) 5.35 (brs, 2 H) 7.02-7.54 (m, 12 H) 10.23 (brs, 1 H )

[0158] (2) 3- (Aminocarbole) obtained in (1) 2— (4 Phenoxyphenol) —9, 10 —Dihydro-4H pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 6-yl trifluoromethanesulfonate (2. 46 g, 4.5 mmol), benzophenone imine (4.10 g, 22.6 mmol) , A suspension of trisdibenzylideneacetone palladium (415 mg, 0.45 mmol), racemic binap (281 mg, 0.45 mmol), cesium carbonate (3.06 g, 9.39 mmol) in toluene (50 ml) at 120 ° C for 1 hour Heated to reflux for 30 minutes. Further, trisdibenzylideneacetone paradium (415 mg, 0.45 mmol), racemic binap (281 mg ゝ 0.45 mmol) and cesium carbonate (3.06 g, 9.39 mmol) were added and heated to reflux for 2 hours. After allowing to cool, water was added to the reaction mixture, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained was tetrahydrofuran (50 ml), ethanol ( 2M hydrochloric acid (20ml) was added and stirred at room temperature for 30 minutes. Add 1M sodium hydroxide aqueous solution to the reaction mixture, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter and concentrate the residue obtained on NH silica gel. Column chromatography [NH silica gel; NH—DM1020 (Fuji cereals)] (developing solvent; black mouth form: n-hexane = 99: 1) purified by recrystallization (methanol) to give colorless title compound 6 Amino-2- (4 phenoxyphenol) 1,9,10 Dihydro-1 4H Pyrazo Mout [5, 1-b] [l, 3] Benzodiazepine 3 Canoleboxamide (312 mg) was obtained.

Melting point: 238. 5-239. 5 ° C

Example 28

6 — “(N.N dimethyldalysyl) amino 1— 2— (4 phenoxyphenyl) 1 9. 10 dihydr 4H pyrazo mouth“ 5. l-biri.31 benzodiazepine 3 carboxamide (compound no. 85)

6 Amino 1- (4 Phenyloxy) 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1- b] [1,3] Benzodiazepine 1 3-Carboxamide (293 mg, 0.712 mmol), N, N Dimethylglycine (110 mg, 1.07 mmol), 4 dimethylaminopyridine (174 mg, 1.42 mmol) in dimethylformamide (5 ml) at room temperature, 1 (3 dimethylaminopropyl) 3 ethylcarbodiimide hydride chloride (408 mg) 2.14 mmol) and 1-hydroxybenzotriazole (144 mg, 1.07 mmol) were added and stirred at room temperature for 20 hours. The precipitate was removed by filtration and the filtrate was concentrated. The resulting residue was subjected to NH silica gel column chromatography [NH silica gel; NH—DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 3: 1) And recrystallization (ethyl acetate) gave the title compound 6- [(N , N-dimethyldalysyl) amino] 2— (4 phenoxyphenol) 1,9,10 dihydro-1 4 H pyrazot [5,1—b] [l, 3] benzodiazepine 3 carboxamide (128 mg) was obtained. Melting point: 194. 0- 195. 0 ° C

 Example 29

 [0160] 2— (4-Phenoxyphenyl) 1 6 “(1-Pyrrolidine 1 1-Ilylacetyl) amino Ί—9. 1 0—Dihydro-4H Pyrazo mouth“ 5.1—Bl ”l.31 Benzodiazepine 3 Carboxamide () 86)

 6 Amino 1- (4 Phenyloxy) 1 9, 10 Dihydro 1 4H Pyrazocine [5, 1- b] [1,3] Benzodiazepine 1 3-Carboxamide (130 mg, 0.316 mmol) Chromium form (3 ml) To the solution were added chloroacetyl chloride (43 mg, 0.379 mmol) and triethylamine (160 mg, 1.58 mmol), and the mixture was stirred at room temperature for 1 hour. Pyrrolidine (112 mg, 1.58 mmol) was added to the reaction solution and stirred at 60 ° C. for 1 hour. The residue obtained by concentrating the reaction solution was purified by NH-silica gel column chromatography [NH silica gel; NH-DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: n-hexane = 1: 1), By recrystallization (ethyl acetate), the title compound 2- (4 phenoxyphenyl) 6 [((pyrrolidine-1-ylacetyl) amino) -9,10 dihydro-4H pyrazot [5, 1 — B] [l, 3] Benzodiazepine 3-force nolevoxamide (68 mg) was obtained.

 Melting point: 197. 0—198. 0 ° C

 Example 30

 [0161] According to the production method of Example 29, the following compound of the present invention was obtained by using 1-methylbiperazine or jetylamine instead of pyrrolidine.

 6— {[(4 Methylbiperazine 1-yl) acetyl] amino} 2— (4 Phenyloxyphenyl) 9, 10 Dihydro-4H Pyrazo Mout [5, 1- b] [l, 3] Benzodiazepine 3-Carboxamide (Compound No. 87)

 Melting point: 162.0—163.0 ° C

6 [(N, N Jetyldaricyl) amino] 2— (4-Phenoxyphenol) 1, 9, 10 Dihydro 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 88) Melting point: 154.4-155. 0 ° C

 Example 31

 [0162] 6 i “(tert-butylamino /) carbole 1-amino} -2- (4 phenoxyphenol) 9. 10

 Dihydro-4H Pirazo Mouth “5.1-bl” l .31 Preparation of benzodiazepine (Compound No. 89) 6 Amino 2- (4-Phenoxyphenyl) 1, 9, 10 Dihydro 1H 4H Pyrazo Mout [5, 1- b] To a solution of [1,3] benzodiazepine 3-carboxamide (32 mg, 0.078 mmol) in tetrahydrofuran (2 ml), tert-butyl isocyanate (39 mg, 0.389 mmol) and pyridine (62 mg, 0.78 mmol) were carotenized. The mixture was stirred for 20 hours at 60 ° C. The reaction solution was concentrated, purified by silica gel column chromatography (developing solvent; black form: methanol = 10: 1), recrystallized (black form), and colorless. Crystalline title compound 6— {[(tert-Butylamino) carbol] amino} — 2— (4 Phenoxyphenol) 1, 9, 10 Dihydro 1 4H Pyrazo mouth [5, 1— b] [1,3] Benzodiazepine (18 mg) was obtained.

 Melting point: 191.0-192.5 ° C

 Example 32

 [0163] 6 — “(ί“ 2— (Dimethylamino) ethyl 1amino} carbonyl) amino 1 2— (4-phenoxyphenyl) 9. 10 Dihydro-4Η pyrazo mouth “5. l-bl” 1.3 l benzodiazepine (compound ^^ -90)

6 Amamino 1- (4 phenoxyphenol) 1 9, 10 Dihydro 1 4H Pyrazo mouth [5, 1- b] [1,3] Benzodiazepine 1 3-carboxamide (123 mg, 0.399 mmol) tetrahydrofuran (5 ml) 2 Bromoethylisocyanate (65 mg, 0.432 mmol) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes and at 50 ° C. for 2 hours. The reaction solution was purified by silica gel column chromatography (developing solvent; chloroform form: methanol, 95: 5) and concentrated. To the obtained residue, 2M dimethylamine methanol solution (1.5 ml, 3. Ommol) was added, and the mixture was stirred in a sealed tube at 100 ° C (oil bath temperature) for 16 hours. The reaction mixture was concentrated, purified by silica gel column chromatography (developing solvent; chloroform: methanol = 3: 1), and recrystallized (n hexane ethyl acetate) to give the title compound 6-[({[ 2 (dimethylamino) ethyl] amino} carbonyl) amino] 2- (4 phenoxyphenol) 1,9,10 dihydro-1 4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 3-carboxamide (49 mg) Obtained. Melting point: 190. 0- 192. 0 ° C

 Example 33

 [0164] 6.7 Dimethoxy-2- (4-phenoxyphenol) 9.10 Dihydro-4H-pyrazo mouth

 5.1 Bl “1.31 Benzodiazepine 3 Carboxamide (Compound No. 91)

 (1) 5-amino-3- (4 phenoxyphenol) 1 1H pyrazole 4-carbo-tolyl (327 mg, 1.18 mmol), 2 bromo-4,5 dimethoxyphenethyl alcohol (36 7 mg, 1.4 mmol) To a solution of triphenylphosphine (368 mg, 1.4 mmol) in tetrahydrofuran (5 ml) was added 40% toluene solution (61 lmg, 1.4 mmol) of jetylazodicarboxylate under ice cooling, and the mixture was stirred at room temperature for 15 hours. . The reaction solution is concentrated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 7: 3) to give colorless crystals of 5-amino-1- (2 bromo-4,5-dimethoxyphenethyl). 3- (4 phenoxyphenol) 1H-pyrazole-4-carbo-tolyl (258 mg) was obtained.

 Melting point: 187. 0- 187. 5 ° C

 [0165] (2) According to the production method of Example 3, 5 amino-1 (2-promo 5-methoxyphenyl) — 3— (4 phenoloxy) — 1H instead of pyrazole-4-carbo-tolyl By using the 5 amino-1 (2 bromo-4,5 dimethoxyphenethyl) -3- (4 phenoxyphenol) -1 1H pyrazole 1-carbo-tolyl obtained in (1), the title compound in the form of colorless crystals 6, 7 Dimethoxy-2- (4 phenoxyphenol) 9, 10- Dihydro 4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 3 Forced norevoxamide was obtained Melting point: 196. 0—198. 0 ° C

 Example 34

 [0166] 7— “2 (Dimethylolamino) ethoxy 1 2—” 4 (2-methoxyphenoxy) phenyl Ί 9.

 10-dihydro 4H pyrazo mouth "5. l-biri.31 benzodiazepine 3 carboxamide () 92)

(1) 4- (2-methoxyphenoxy) benzoic acid (9.0 g, 36.8 mmol) in chloroform (60 ml) solution with thionyl chloride (8 ml, lOmmol) for 1 hour Heated to reflux. The reaction mixture was concentrated, and toluene (30 ml) and tetrahydrofuran (6 ml) were added. -Tolyl (2.43 g, 36.8 mmol), diisopropylethylamine (12.8 ml, 73.6 mmol)

) And stirred at room temperature for 15 hours. 1M hydrochloric acid (80 ml) was extracted from the reaction solution with sodium ketyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), and concentrated to give {hydroxy [4- (2 —Methoxyphenoxy) phenol] methylene} malono-tolyl (11.17 g) was obtained.

[0167] (2) {Hydroxy [4 (2-methoxyphenoxy) phenol] methylene} malono-tolyl (11.I7g, 36.5mmol) obtained in (1) above, 1,4 dioxane ( To a solution of 80 ml) and water (16 ml) were added sodium hydrogen carbonate (15.3 g, 182.5 mmol) and dimethyl sulfate (10.4 ml, 109.5 mmol), and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled, water was added, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), concentrated, and the resulting residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: Purification by _n- hexane = 1: 1) gave pale yellow {methoxy [4- (2-methoxyphenoxy) phenol] methylene} malono-tolyl (6.91 g).

[0168] (3) Suspension of {methoxy [4 (2-methoxyphenoxy) phenol] methylene} malononitrile (6.90 g, 22.5 mmol) obtained in (2) above in ethanol (80 ml) Hydrazine hydrate (2.8 ml) was added to the suspension and stirred at room temperature for 1 hour. The reaction mixture was concentrated and the resulting residue was recrystallized (n-hexane-ethyl acetate) to give colorless crystals of _5- amino- _3- [4- (2-methoxyphenoxy) phenol] — 1H pyrazole 4- Carbo-tolyl (5.66 g) was obtained. 1H NMR (600 MHz, CDC13) δ ppm 3.81 (s, 3 H) 6.96-7.65 (m, 8 H)

 [0169] (4) In accordance with the production method of Example 3, 5 amino-3- (4 phenoxyphenol) — 1H—pyrazole-4 carbo-tolyl instead of 5 amino-3— obtained in (3) above [ 4 (2-Methoxyphenoxy) phenol] — 1H pyrazole mono 4-carbo-tolyl, instead of 2-bromo-5-methoxyphenethyl alcohol, 4 bromo-3— (2 hydroxyschetil) By using phenol tert-butyldimethylsilyl ether, colorless amorphous 5-amino 1— {2— [2 bromo 5 (tert-butyldimethylsila- loxy) phenol] ethyl} 3— [4 (2-Methoxyphenoxy) phenol] 1H pyrazole 4 carbo-tolyl was obtained.

1H NMR (600 MHz, CDC13) δ ppm 0.10 (s, 6 H) 0.91 (s, 9 H) 3.19 (t, J = 6.88 Hz, 2 H) 3.83 (s, 3 H) 3.89 (s, 2 H) 4.19 (t, J = 6.88 Hz, 2 H) 6.52-7.84 (m, 11 H) [0170] (5) Obtained from (4) above 5 Amino-1 {2 -— [2 Bromo-5- (tert-butyldimethylsilanyloxy) phenol] ethyl} 3— [4- (2-Methoxyphenoxy) phenol] 1 H Pyrazole 4-Carbo- Tetra n-butylammonium fluoride 1M tetrahydrofuran solution (3.4 ml) was added to a tetrahydrofuran (20 ml) solution of tolyl (1.06 g, 1.71 mmol), and the mixture was stirred at room temperature for 2 hours. Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), and concentrate the residue. Silica gel column chromatography (developing solvent; ethyl acetate: _n — By purifying with hexane = 1: 1), the colorless amorphous 5-amino 1— [2— (2 bromo-5 hydroxyphenyl) ethyl] — 3— [4— (2-methoxyphenoxy) ) Phenol] — 1H Pyrazole-4-carbotryl (0.81 g) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 3.17 (t, J = 7.03 Hz, 2 H) 3.83 (s, 3 H) 3.96 (s, 2 H) 4.16 (t, J = 6.81 Hz, 2 H) 6.52- 7.87 (m, 11 H)

[0171] (6) 5 Amino 1 [2— (2 Bromo-5 hydroxyphenyl) phenyl] obtained in (5) above — 3— [4— (2-Methoxyphenoxy) phenol] — 1H Pyrazole 4-carbo-trinole (0.81 g, 1.60 mmol), dimethinoreminoethanolanol (214 mg, 2.40 mmol), triphosphine (631 mg, 2.40 mmol) in tetrahydrofuran (10 ml) in ice Under cooling, a 40% toluene solution (1.05 g, 2.4 mmol) of jetillazodicarboxylate was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated and purified by silica gel column chromatography (developing solvent; chloroform: methanol = 9: 1) to give a colorless amorphous 5-amino 1- {2- [2 bromo-5- (2 dimethylaminoethoxy) phenol. -Lu] ethyl} 3- [4- (2-Methoxyphenoxy) phenol] — 1H Pyrazole mono-4-carbo-tolyl (527 mg) was obtained.

 1H NMR (600 MHz, CDC13) δ ppm 2.28 (s, 6 H) 2.66 (t, J = 5.50 Hz, 2 H) 3.21 (t, J = 6.88 Hz, 2 H) 3.83 (s, 3 H) 3.87- 3.98 (m, 4 H) 4.18 (t, J = 6.88 Hz, 2 H) 6.59-7.85 (m, 11 H)

[0172] (7) 5-amino-1 {2- [2 bromo-5- (2 dimethylaminomethoxy) phenol] -ethyl} obtained in (6) above 3— [4— (2-methoxyphenoxy) Si) Fuel] — 1H—Villa Zole of sol-4-carbon-tolyl (516 mg, 0.895 mmol), trisdibenzylideneacetone palladium (49 mg, 0.054 mmol), racemic binap (34 mg, 0.054 mmol), cesium carbonate (583 mg, 1.79 mmol) 10 ml) solution was stirred at 170 ° C. for 2 hours. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; ethyl acetate: n-hexane = 1: 1, then chloroform: methanol = 9: 1) to give a colorless solid 7 — [2— (Dimethylamino) ethoxy] —2— [4— (2-Methoxyphenoxy) phenol] — 9, 1 0 -dihydro 4H pyrazo [5, 1— b] [1, 3] benzodiazepine 3 Carbo-tolyl (22 mg) was obtained.

 1H NMR (600 MHz, CDC13) δ ppm 2.36 (s, 6 H) 2.75 (br.s, 2 H) 3.17-3.19 (m, 2 H) 3.82 (s, 3 H) 4.06 (br.s, 2 H 4.41-4.42 (m, 2 H) 6.44 (s, 1 H) 6.77-7.83 (m, 11 H)

[0173] (8) 7- [2 (Dimethylamino) ethoxy] 2- [4 (2-methoxyphenoxy) phenol] obtained in (7) above, 9, 10 Dihydro-4H pyrazo mouth [5, 1 — B] [l, 3] Benzodiazepine 3 Carbo-tolyl (220 mg, 0.44 mmol) in dimethyl sulfoxide (5 ml) in potassium carbonate (184 mg, 1.33 mmol), 30% hydrogen peroxide solution (0.17 ml) ) And 50. Stir at C for 3 hours. Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained by NH silica gel chromatography [NH silica gel; NH - DM1020 (Fuji serial Ltd.) (developing solvent: acetic Echiru: _n - hexane = 3: 2) purification by recrystallization (methanol), the title compound as a colorless crystalline 7- [2 (Jimechiruamino) ethoxy ] 2- [4 (2-Methoxyphenoxy) phenol] -9, 10 Dihydro-1 4H Pyrazomouth [5,1-b] [l, 3] benzodiazepine 3 Carboxamide (36 mg) was obtained.

 Melting point: 193.5-194.0 ° C

 Example 35

[0174] According to the production method of Example 34, 5-amino 3- [4- (2-methoxyphenoxy) phenol]-1H instead of pyrazole 4-carbo-tolyl 5-amino 3- [( 4 phenoxy 2 trifluoromethyl) phenyl] 1H pyrazole 4 carbo-tolyl, 5 — amino 1 3 — [(3 methyl 4 phenoxy) phenyl] 1H pyrazole 4 carbo Nitryl, 5-amino 3— [(2-phenyl 4-phenol) phenol] 1H Pyrazole —4-carbo-tolyl, or 5-amino 3- (3-methoxy-1-phenyl phenol) 1H The following compounds of the present invention were obtained by using pyrazole 1-carbo-tolyl.

 [0175] 7— [2— (Dimethylamino) ethoxy] —2— [4 Phenyloxy 2- (trifluoromethyl) phenyl] 9, 10 Dihydro-4H Pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 3—Force Ruboxamide (Compound No. 93)

 Melting point: 175. 5- 178. 0 ° C

[0176] 7— [2— (Dimethylamino) ethoxy] —2— (3-Methyl 4-phenoxyphenol) 9, 1

0 dihydro 4H pyrazo mouth [5, 1—b] [1, 3] benzodiazepine 3 canoleboxamide (Compound No. 94)

 Melting point: 147. 0- 148. 0 ° C

[0177] 2— (2 Black mouth 4 Phenyloxy) 1 7— [2— (Dimethylamino) ethoxy] —9,

10 Dihydro 4H pyrazo mouth [5, 1— b] [l, 3] benzodiazepine 3 canoleboxamide (Compound No. 95)

 Melting point: 173. 0-174. 5 ° C

 Example 36

 [0178] 7 Methoxy-2- (3 methoxy-4-phenoxyphenol) 9. 10 Dihydro-4H— Pyrazo mouth “5.1-bl” l, 31 Benzodiazepine 3 Carboxamide (Compound No. 96)

 (1) {Methoxy [(2-methoxy-4-phenoxy) phenol] methylene} malono-tolyl (1.75 g, 5.7 mmol), 2- (2 bromo-5-methoxyphenyl) ethylhydrazine hydrochloride Triethylamine (4. Oml, 28.5 mmol) was added dropwise to an ethanol suspension of (1.99 g, 6.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 1) to give colorless crystals of 5-amino-1-(2-bromo-2-methoxyphenyl- Ru) ethyl] 3- (3-methoxy-4-phenyl) phenyl 1H pyrazole 4 carbo-tolyl (1.59 g) was obtained.

[0179] (2) The 5-amino-1 [2- (2 bromo-5-methoxyphenol)] obtained in (1) above. Cyl] 3— (3-Methoxy-4-phenoxyphenol) 1H Pyrazole 4 Carbo-tolyl (790 mg, 1.52 mmol), Trisdibenzylideneacetone palladium (82 mg, 0.09 mmol), Racemic binap (56 mg, 0.09 mmol), A solution of cesium carbonate (990 mg, 3.04 mol) in diglyme (20 ml) was stirred at 170 ° C. for 1 hour. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; ethyl acetate: _n— hexane = 1: 1) to give a light brown solid 7-methoxy-2- (3-methoxy-1- Phenoxyphenol) 9, 10-Dihydro 4H pyrazotone [5, 1-b] [l, 3] benzodiazepine 3 carbo-tolyl (50 Omg) was obtained.

[0180] (3) 7-methoxy 2- (3-methoxy-4-phenoxyphenol) obtained in (2) above 9, 10 dihydro-4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 3 canolepo -Toluene (300 mg, 0.68 mmol) in dimethyl sulfoxide (10 ml) was charged with potassium carbonate (284 mg, 2.05 mmol) and 30% hydrogen peroxide-hydrogen water (2 ml). Stir for hours. Water is added to the reaction solution, extracted with ethyl acetate, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue is subjected to silica gel column chromatography (developing solvent; acetate Echiru: _n - hexane = 70: purified by 30), the title compound as colorless crystals 7-methoxy one 2- (3-methoxy one 4 Fuenokishifue - Le) 9, 10-dihydro one 4H- pyrazol port [5 , 1-b] [l, 3] benzodiazepine 3 carboxamide (114 mg). Melting point: 215. 0— 216. 0 ° C

 Example 37

 [0181] 7 Methoxy-2- (4 methoxyphenyl) -9.10 Dihydro-1 4H Preparation of pyrazo mouth "5.1-bl" 1,31 benzodiazepine 3 carboxamide (Compound No. 97)

 In accordance with the production method of Example 3, 5 amino-3- (4-phenoxyphenyl) 1H pyrazo 1lu instead of 4-carbo-tolyl 5 amino- (4-methoxyphenol) 1 1H pyrazol 1 4 By using carbo-tolyl, the title compound in the form of colorless crystals 7 Methoxy-2- (4-methoxyphenol) -9, 10 Dihydro-4H Pyrazo mouth [5, l-b] [l, 3] benzodiazepine 3-strength of levoxamide It was.

 Melting point: 221. 0- 222. 0 ° C

Example 38 [0182] 7 Hydroxy-2- (4-hydroxyphenyl) 9. 10 Dihydro-4H Preparation of pyrazotone 5.1-bin.31 benzodiazepine 3-carboxamide (Compound No. 98)

 7-Methoxy-1-2- (4-Methoxyphenol) -1,9,10 Dihydro-1 4H Pyrazo-mouth [5, 1- b] [1,3] Benzodiazepine-one 3-Carboxamide (900 mg, 2. 47 mmol) To the (10 ml) solution, 1M boron tribromide-dichloromethane solution (7.4 ml) was added dropwise at −60 ° C. After the addition, the reaction was gradually raised to room temperature and stirred for 3 hours. Thereafter, water at ice temperature was added, and the precipitated solid was dissolved in methanol with 1-necked form (1-4). The organic layer was concentrated with silica gel and purified by silica gel column chromatography (developing solvent; black mouth form, then methanol: black mouth form = 1: 4). — (4 Hydroxyphenol) 1,9,10 Dihydro-1 4H Pyrazo Mout [5, 1-b] [l, 3] Benzodiazepine 3-Force Nolevoxamide (409 mg) was obtained.

 Melting point: 257. 0- 260. 0 ° C

 Example 39

 [0183] 2— (4 aminophenol) 1 7 Methoxy 1 9. 10 Dihydro 1 4H Pyrazo Mouth “5.1-bl”

 1.31 Manufacture of benzodiazepine 3 carboxamide (Compound No. 99)

 (1) In accordance with the production method of Example 3, 5 amino-3- (4 phenoxyphenol) 1H-pyrazole mono 4-h-carbazole instead of 5-amino mono (4-trophenol) 1H-pyrazole 4- —By using carbo-tolyl, light yellow crystalline 5-amino 1- [2— (2 bromo 5-methoxyphenyl) ethyl] — 3 — (4-trifluoro) mono 1H pyrazol 4 carbo-tolyl is obtained. It was.

 1H NMR (200 MHz, DMSO— D6) δ ppm 3.14 (t, J = 7.25 Hz, 2 H) 3.70 (s, 3 H) 4.23 (t, J = 7.03 Hz, 2 H) 6.74-8.37 (m, 9 H)

[0184] (2) 5 Amino 1 [2— (2 Bromo-5-methoxyphenyl) ethyl] obtained in (1) above —3— (4-Trophenyl) — 1H Pyrazole 4-Carbo-tolyl (337 mg) 0.996 mmol) of 2-propanol (10 ml), black mouth form (5 ml), and water (lml) were added with ammonium chloride (66 mg) and stirred at 100 ° C. for 4 hours. The reaction mixture was filtered through celite and the residue obtained by concentration was purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 2: 1) to give 5 amino-3- ( 4-aminophor) — 1— [2— (2 Bromo 5-methoxyphenyl) ethyl] —1H Pyrazole-4-force Lupo-tolyl (243 mg) was obtained.

 1H NMR (200 MHz, CDC13) δ ppm 3.22 (t, J = 6.81 Hz, 2 H) 3.67 (s, 3 H) 3.87 (br. S, 4 H) 4.17 (t, J = 6.81 Hz, 2 H) 6.55-7.76 (m, 7 H)

 [0185] (3) 5 Amino-3- (4 aminophenol) 1 [2- (2 Bromo-5-methoxyphenyl) ethyl] 1H Pyrazole-4-carbo-tolyl (442 mg, 1. 0,7 mmol), trisdibenzylideneacetone palladium (88 mg, O.096 mmol), racemic bi-up (60 mg, O.096 mmol), cesium carbonate (1.05 g, 3.21 mmol) in diglyme (1 Oml) solution at 170 ° C And stirred for 3 hours. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; ethyl acetate: n-hexane = 6: 4) to give a pale yellow solid 2- (4 aminophenol) -1-7-methoxy-one. 9, 10 Dihydro-1 4H Pyrazo mouth [5, 1-b] [1, 3] benzodiazepine 3 carbo-tolyl (137 mg) was obtained.

 1H NMR (600 MHz, DMSO— D6) δ ppm 3.03-3.05 (m, 2 H) 3.66 (s, 3 H) 4.23-4.25 (m, 2 H) 5.33 (s, 2 H) 6.53-7.45 ( m, 7 H) 9.19 (s, 1 H)

 [0186] (4) 2- (4 aminophenol) -7-methoxy 9, 10 dihydro-4H — virazolo obtained in (3) above 3--carbo- [5, 1- b] [l, 3] benzodiazepine To a solution of tolyl (120 mg, 0.362 mmol) in dimethyl sulfoxide (5 ml) was added potassium carbonate (150 mg, 1. O9 mmol) and 30% aqueous hydrogen peroxide (0.2 ml), and the mixture was stirred at 60 ° C. for 4 hours. Add water to the reaction solution, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained by silica gel column chromatography (developing solvent; ethyl acetate) : N-Hexane = 95: 5) By purifying with light gray crystals of the title compound 2- (4-aminophenol) -7-methoxy 9, 10 dihydro-4H pyrazot [5, l-b] [ l, 3] benzodiazepine-3-carboxamide (4211 ^) was obtained.

 Melting point: 265. 5- 267. 0 ° C

 Example 40

[0187] 2— (4 aminophenol) 1 7— “2— (Dimethylamino) ethoxy Ί—9.10 Dihydro 1 4 H pyrazo mouth“ 5. l-bl ”l.31 benzodiazepine-3 carboxamide ( Compound number 100) (1) 5 Amino 1- [2— (2 Bromo 5-methoxyphenyl) ethyl] 3— (4 Nitrophenol) — 1H Pyrazole 4-carbo-tolyl (10.0 g, 22.6 mmol), Tris Solution of benzylideneacetone palladium (1.24 g, 1.35 mmol), racemic bi-up (854 mg, 1.37 mmol), cesium carbonate (15.0 g, 46. Ommol) in diglyme (300 ml) at 170 ° C for 5 hours Stir. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; methanol: chloroform = 1: 10) to give 7-methoxy-1- (4-trophenol)-1 as a yellow solid. , 10 Dihydro-4H pyrazotone [5, 1-b] [l, 3] benzodiazepine-3-carbo-tolyl (1.79 g) was obtained.

[0188] (2) 7-Methoxy-1, 2- (4-trophenyl) 9,10 dihydro-4H pyrazo mouth obtained in (1) above [5, 1- b] [l, 3] benzodiazepine 3-Carbo-tolyl (1.00 g, 2.7 7 mmol) in dimethyl sulfoxide (50 ml) suspension in potassium carbonate (1.17 g, 8.74 mmol), 30% hydrogen peroxide solution (7.5 ml) ) And stirred at 55 ° C for 1.5 hours. Water was added to the reaction solution, and the precipitate was collected by filtration. 7-Methoxy-2— (4—-trophenol) -9,10 dihydro 4H pyrazo [5, 1—b] [l, 3 Benzodiazepine 3 canoleboxamide (0.774 g) was obtained.

 Melting point: 262. 0- 265. 0 ° C

 1H NMR (200 MHz, DMSO— D6) δ ppm 3.09-3.26 (m, 2 H) 3.73 (s, 3 H) 4.32-4.44 (m, 2 H) 6.74-7.03 (m, 3 H) 7.82 ( d, J = 8.8 Hz, 2 H) 8.30 (d, J = 8.8 Hz, 2 H) 9. 64 (s, 1 H)

 [0189] (3) 7-Methoxy 2- (4-trophenyl) -1,9 10 dihydro-4 H pyrazo mouth obtained in (2) above [5,1-b] [l, 3] benzodiazepine 1 —To a suspension of carboxamide (600 mg, 1.58 mmol) in black mouth form (12 ml) was added 1M boron tribromide dichloromethane solution (10. Oml, 10. Ommol), and the mixture was stirred at room temperature for 2.5 hours. Ice water was added to the reaction solution, and a mixed solution of ethyl acetate, methanol, and tetrahydrofuran was added. The organic layer is dried (anhydrous magnesium sulfate) and concentrated to form yellow crystals of 7-hydroxy 2- (4-trophenol) 9, 10 dihydro-4H pyrazot [5, 1- b] [l, 3] benzodiazepine 3— Strong norboxamide (742 mg) was obtained.

Melting point: 265. 0- 267. 0 ° C 1H NMR (200 MHz, DMSO— D6) δ ppm 3.05-3.14 (m, 2 H) 4.30-4.42 (m, 2 H) 6.59-6.69 (m, 2 H) 6.82 (d, J = 8.4 Hz, 1 H ) 7.82 (d, J = 9.2 Hz, 2 H) 8.30 (d, J = 8.8 Hz, 2 H) 9.18 (s, 1 H) 9.54 (s, 1 H)

[0190] (4) 7-hydroxy 2- (4-trophenyl) 9, 10 dihydro — 4H pyrazotone obtained in (3) above [5, l-b] [l, 3] benzodiazepine A suspension of carboxamide (2.41 g, 5.5 2 mmol), dimethylaminoethyl chloride hydrochloride (1.60 g, 5.55 mmol), carbonated rhodium (7.60 g, 55 mmol) in dimethylformamide (20 ml). The mixture was stirred at an outside temperature of 90 ° C for 2 hours. To the reaction solution, a mixed solution of black mouth form and methanol was filtered through Celite, and saturated brine was added. The organic layer is dried (anhydrous magnesium sulfate) and the residue obtained is purified with a silica gel column (developing solvent; black form: methanol = 10: 1) to give yellow crystals 7- (2 dimethylaminoethoxy) 2— (4-Trophele) 9,10 Dihydr Draw 4H Pyrazo Mout [5, 1—b] [1,3] Benzodiazepine 3 Canoleboxamide (800 mg) was obtained.

 Melting point: 178. 0—180. 0 ° C

 1H NMR (200 MHz, DMSO— D6) δ ppm 2.21 (s, 6 H) 2.60 (t, J = 5.7 Hz, 2 H) 3.12-3.22 (m, 2 H) 4.01 (t, J = 5.9 Hz, 2 H) 4.33-4.43 (m, 2 H) 6.76-6.96 (m, 3 H) 7.8 2 (d, J = 8.8 Hz, 2 H) 8.30 (d, J = 9.2 Hz, 2 H) 9.64 (s, 1 H)

[0191] (5) 7- (2 Dimethylaminoethoxy) 2- (4-trophenol) obtained in (4) above

 9, 10 Dihydro-4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 3-force noreboxamide (790 mg, 1.8 mmol) dissolved in methanol (12 ml) and tetrahydrofuran (12 ml), 10% Palladium carbon (400 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. To the reaction solution, a mixed solution of black mouth form and methanol was filtered through a celite, and saturated saline was added. The organic layer is dried (anhydrous magnesium sulfate) and concentrated to form a yellow crystal. Compound 2 -— (4-aminophenol) —7— [2- (dimethylamino) ethoxy] —9, 10 Dihydro 4H pyrazot [5 , 1-b] [l, 3] benzodiazepine 3 carboxamide (738 mg) was obtained.

 Melting point: 226. 0- 229. 0 ° C

Example 41 [0192] 2-Γ4- (Benzylamino) phenyl Ί 7 Methoxy 1 9. 10 Dihydro 1 4 ピ ラ Preparation of “5 l-biri.31 benzodiazepine 3 carboxamide (Compound No. 101)”

 2— (4 aminophenol) 1 7-methoxy 1,9,10 Dihydro 1 4H Pyrazo-mouth [5, 1- b] [1,3] Benzodiazepine 1 3-carboxamide (16.3 mg, 0.047 mmol) Ethane (2 ml) solution was charged with benzaldehyde (4.95 mg, 0.047 mmol), sodium triacetoxyborohydride (13.9 mg, 0.066 mmol) and acetic acid (0.0022 ml, 0.047 mmol) at room temperature. Stir for hours. Add a saturated aqueous solution of sodium bicarbonate to the reaction solution, extract with black-form, wash (in order of water and saturated saline), dry (anhydrous magnesium sulfate), filter and concentrate the residue obtained on a thin-layer silica gel column. Purification by chromatography (developing solvent; ethyl acetate: hexane = 1: 1) to give the title compound as colorless crystals 2— [4 (benzylamino) phenol] 7-methoxy 9, 10 dihydro-4H pyrazot [5, l —B] [l, 3] benzodiazepine 1 3 carboxamide (13.3 mg) was obtained.

 Melting point: 236. 0- 237. 0 ° C

 Example 42

 [0193] According to the production method of Example 41, the following compound of the present invention was obtained by using 1 methylindole-2 carboxaldehyde, 2 fluoro4 trifluoromethylbenzaldehyde instead of benzaldehyde.

[0194] 7-Methoxy-1- (4-— {[(1-Methyl-1H-indole-1-2-yl) methyl] amino} fe Ninore 9, 10 Dihydro-4H Pyrazo Mout [5, 1-1)] [ 1,3] Benzodiazepine-3-canole boxamide (Compound No. 102)

 Melting point: 237. 5-239. 5 ° C

[0195] 2— (4— {[2 Fluoro-4- (trifluoromethyl) benzyl] amino} phenol) 1 7-methyoxy 9, 10 dihydro-4H pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 3—Power Norboxamide (Compound No. 103)

 Melting point: 237. 5-239. 0 ° C

 Example 43

[0196] 2-Γ4- (Benzyloxy) phenyl 1—7 Methoxy 9. 10 Dihydro-4H Pyrazomouth “5._1—Production of bl [L3l Nzodiazepine 1-Carbox it ^ K (Compound No. 104) (1) To a suspension of [[4- (benzyloxy) phenol] (methoxy) methylene] malono-tolyl (4.91 g, 16.9 mmol) in ethanol (50 ml) was added 2- (2 bromo-5-methoxyphenol- Lu) ethylhydrazine hydrochloride (6.5 g, 20.3 mmol) was added, and triethylamine (11.8 ml, 84.5 mmol) was added under ice cooling. By stirring at room temperature for 1.5 hours and collecting the precipitate by filtration, colorless crystals of 5 amino-1- (2 bromo-5-methoxyphenyl) -3-3- (4 benzyloxyphenyl)-1H pyrazole-4- Carbo-tolyl (2.67 g) was obtained.

 [0197] (2) 5 amino-1- (2 bromo-5-methoxyphenyl) -3- (4-benzyloxyphenyl)-1H pyrazole-4-carbo-tolyl obtained in (1) above 5.4 g, 10.9 mmol), trisdibenzylideneacetone palladium (597 mg, 0.65 mmol), racemic binup (405 mg, 0.65 mmol), cesium carbonate (7 lg, 21.8 mmol) in diglyme (100 ml) ) The solution was stirred at 160 ° C for 1 hour. The residue obtained by concentrating the reaction solution was purified with a silica gel column (developing solvent; ethyl acetate: n-hexane = 1: 1) to give a colorless solid 2- [4- (benzyloxy) phenol] — 7-methoxy-1,9,10 dihydro-1,4 H pyrazo mouth [5, l-b] [l, 3] benzodiazepine, 3-carbo-tolyl (2.49 g) was obtained.

 [0198] (3) 2- [4 (Benzyloxy) phenol] -7-methoxy 9,10-dihydro 4H obtained from (2) above [5, 1- b] [1, 3 ] Benzodiazepine 3 Carbotolyl (2.49 g, 5.9 mmol) in dimethyl sulfoxide (100 ml) was charged with potassium carbonate (2.4 g, 17.7 mmol) and 30% hydrogen peroxide (2 ml). The mixture was stirred at 60 ° C for 3 hours. Add water to the reaction solution, extract with ethyl acetate, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained on a silica gel column (developing solvent; ethyl acetate). : n-Hexane = 1: 2) By purification with colorless crystals, the title compound 2— [4 (benzyloxy) phenol] —7-methoxy-1,9,10 dihydro-4H pyrazot [5, 1 — B] [l, 3] Benzodiazepine 3 carboxamide (2.46 g) was obtained.

 Melting point: 202. 5- 204. 0 ° C

 Example 44

 [0199] 2- (4-Hydroxyphenol) -7 Methoxy-9.10 Dihydro-4H Pyrazo Mouth “5.1-bl” 1.3 l Benzodiazepine 3 Carboxamide (Compound No. 105)

2— [4- (Benzyloxy) phenol] — 7—Methoxy-1,9,10 Dihydro-1,4H Pyrazo Add 5% 10% palladium on carbon (200 mg) to a solution of [5, 1-b] [l, 3] benzodiazepine 3-carboxamide (1.82 g, 4.13 mmol) in methanol (80 ml) tetrahydrofuran (40 ml), and add hydrogen. The mixture was stirred at 60 ° C for 2 hours. The residue obtained by concentrating the filtrate obtained by filtering the reaction solution through Celite was subjected to NH silica gel column chromatography [NH silica gel; NH-DM1 020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1) ) To give the title compound 2— (4-hydroxyphenyl) 7-methoxy-9,10 dihydro-1,4H, pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 1— Carboxamide (1.08 g) was obtained.

 Melting point: 283. 0- 284. 0 ° C

 Example 45

 [0200] 2-ί4-Γ (2.6 Dichloroguchi benzyl) amino Ί-Fell 1-7 Methoxy 9.10 Dihydro

 4Η Pirazo mouth `` 5. l-biri.31 benzodiazepine 3 canoleboxamide

 1¾ report of (Compound No. 106)

 2— (4 aminophenol) 1 7-methoxy 1,9,10 dihydro 1 4H pyrazo mouth [5,1—b] [1,3] benzodiazepine-3—force nolevoxamide (100 mg, 0.286 mmol), Dimethylformamide (2 ml) suspension of 2,6 diclonal benzylbromide (69 mg, 0.288 mmol) and triethylamine (0.12 ml, 0.866 mmol) was stirred at 60 ° C. for 3 hours. Add water to the reaction mixture, extract with ethyl acetate, wash (in order of water and saturated saline), dry (anhydrous magnesium sulfate), filter and concentrate the residue obtained on a silica gel column (developing solvent; ethyl acetate: By purifying with n-hexane = 7: 3), the title compound 2— {4 [(2,6 Dichlorodiethyl) amino] phenol} —7-methoxy-1,9,10 dihydro 1 4H pyrazo mouth [5, 1 b] [1, 3] benzodiazepine 3 carboxamide (1 Omg) was obtained.

 Melting point: 214.5—216. 0 ° C

 Example 46

[0201] In accordance with the production method of Example 45, 2- (4 aminophenol) -7-methoxy-9,10 dihydro-4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 1 —Carboxamide, 2— (4-hydroxyphenol) 1 7-Methoxy-1,9,10 Dihydro-1,4H Pyrazo mouth [5, 1—b] [l, 3] Benzodiazepine 1 3-Carboxamide or 2— (4-Aminophenol -Le) 7— [2— (Jimee Tyramino) ethoxy]-9, 10 Dihydro-4H Pyrazo Mouth [5, 1—b] [l, 3] Benzodiazepine 3—For power nolevoxamide, 2, 6 Diclo Mouth Benzyl bromide instead of Benzoyl Muclide , Benzylchlorophenolate, 3-phenylpyropiochloride, phenylisocyanate, benzylisocyanate, phenolchloroformate, 2-chlorobenzoyl chloroformate, 2-methoxyphenolchloroformate, Phenyl isothiocyanate, dimethylaminoethyl chloride, p-toluene sulfochloride, tert butyl isocyanate, cyclohexino lysocyanate, 2, 6 Diclonal phenyl isocyanate, 2-isopropylphenyl isocyanate, 2-bromophenol Ruisocyanate, 2-trifluoromethylphenol isocyanate The following compounds of the present invention were obtained by using 2,6 dimethylphenol isocyanate, 2,6-difluorophenol isocyanate, or 2-methoxyphenol isocyanate.

 [0202] 2— [4 -— (Benzylamino) phenol] — 7—Methoxy-1, 9, 10 Dihydro-4H Pyrazo Mout [5, l—b] [l, 3] Benzodiazepine-3 Carboxamide Compound No. 107) Melting point: 286. 5- 288. 0 ° C

 [0203] [4— (3 aminocarbol) 1 7-methoxy 1 9, 10 dihydro 1 4H pyrazo mouth [5, 1— b] [l, 3] benzodiazepine 2 yl) phenol] carnomic acid benzyl ester (Yu Compound Number 108)

 Melting point: 244. 5-246. 5 ° C

[0204] 7-Methoxy-1- 2— {4— [(3Flpropiool) amino] phenol} — 9, 10 Dihydric Mouth — 4H Pyrazo Mouth [5, 1— b] [1, 3] Benzodiazepine 3 Carboxamide (Compound No. 109)

 Melting point: 258. 0- 259. 5 ° C

[0205] 2— {4 [(Arylinocarbole) amino] phenol} — 7-methoxy-1,9,10 dihydro-4H

—Virazolo [5, l—b] [l, 3] Benzodiazepine 3-Carboxamide (Compound No. 110) Melting point: 297. 0- 299. 0 ° C

[0206] 2— (4 {[(Benzylamino) carbol] amino} phenol)-7 Methoxy 9, 10 Dihydrin — 4H Pyrazo [5, 1- b] [1, 3] Benzodiazepine 3 Carboxamide ( (Compound No. 111) Melting point: 280. 0- 294. 0 ° C (decompose)

[0207] 2- {4-[(2, 6 Dichlorobenzyl) amino] phenol} — 7— [2— (Dimethylamino) ethoxy] — 9, 10 Dihydro-4H pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 1-carboxamide (Compound No. 112)

 Melting point: 199.5-200. 0 ° C

[0208] 4— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mouth [5, 1— b] [l, 3] Benzodiazepine 2 yl) phenol] carnominic acid Fuel ester (Compound No. 113)

 Melting point: 190. 0- 192. 0 ° C

[0209] 4— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 2 Fil) Phell] Power Rubamic acid 2 Black mouth benzyl ester (Compound No. 114)

 Melting point: 236. 0- 237. 0 ° C

[0210] 2-Methoxyphenyl {4-— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1

4H-pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 1 file] force} rubamate (compound number 115)

 Melting point: 190. 0-192. 5 ° C

[0211] 4— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 2 yl] Fuel (Compound No. 11

6)

 Melting point: 271.0-272.5 ° C

[0212] 4— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 2 yl] phenol Benzylcarbamate (compound (Number 11 7)

 Melting point: 181.0-183.0 ° C

[0213] 4— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mouth [5, 1— b] [l, 3] Benzodiazepine 2 yl] Fuel (Compound No. 11 8) Melting point: 229. 5-230. 5 ° C

[0214] 4— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 2 yl] phenol Benzyl carbonate (compound) (Number 1 19)

 Melting point: 209. 5-211. 5 ° C

[0215] 2— {4 [(Alanilinocarbonoyl) amino] phenol} — 7-methoxy-1,9,10 dihydro —4H pyrazo mouth [5, 1-1)] [1,3] benzodiazepine 3-Carboxamide (Compound No. 120)

 Melting point: 177. 0- 178. 0 ° C

[0216] Benzyl (41- (Aminocarbol) 7- [2 (Dimethylamino) ethoxy] -9, 10 Dihydro-4H Pyrazo Mout [5, 1-b] [l, 3] Benzodiazepine 2-yl} Fe- ) Carbamate (Compound No. 121)

 Melting point: 219. 0-221. 0 ° C

[0217] 2— {4 [(Arylinocarbole) amino] phenol} — 7— [2 (Dimethylamino) ethoxy]

9, 10 Dihydro-4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine 3—force noreboxamide (Compound No. 122)

 Melting point: 241. 5-243. 5 ° C

[0218] 2— {4— [2— (Dimethylamino) ethoxy] phenol} — 7-methoxy-1,9,10 dihydro-4

H Pirazo mouth [5, 1— b] [l, 3] benzodiazepine (Compound No. 123)

 Melting point: 155. 0- 156. 5 ° C

[0219] 4— [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 2 yl] Ferle 4 Methylbenzenesulfonate (Compound number 124)

 Melting point: 179. 0—180. 0 ° C

[0220] 2— (4— {[(tert-butylamino) carbol] amino} phenol) — 7-methoxy-9, 10-dihydro 4H pyrazo mouth [5, 1— b] [l, 3] benzodiazepine 3 Carboxamide (Compound No. 125)

Melting point: 148. 5— 150. 5 ° C [0221] 2— (4— {[(Cyclohexylamino) carbol] amino} phenol) 1 7-methoxy-1,9,10 dihydro 4H pyrazo mouth [5, 1— b] [l, 3] benzodiazepine 3 Canoleboxamide (Compound No. 126)

 Melting point: 295. 0- 297. 5 ° C

[0222] 2— [4— ({[(2,6 dichlorophenol) amino] carbol} amino) phenol] — 7— [2— (Dimethylamino) ethoxy] —9, 10 Dihydro-4H Pirazo mouth [5, 1—b] [l, 3] benzodiazepine 3 carboxamide (Compound No. 127)

 Melting point: 255. 0-256. 5

[0223] 7— [2 (Dimethylamino) ethoxy] 2— [4 ({((2 isopropylphenol) amino) force (Lolol) amino) phenol] — 9, 10 Dihydro-4H pyrazo [ 5, 1—b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 128)

 Melting point: 259. 0— 261. 0 ° C

[0224] 2— [4— ({[(2 bromophenol) amino] carbol} amino) phenol] — 7— [2— (dimethylamino) ethoxy] —9, 10 dihydro-4H pyrazot [5, 1—b] [l, 3] Benzodiazepine-3 Carboxamide (Compound No. 129)

 Melting point: 261. 0- 263. 0

[0225] 7- [2- (Dimethylamino) ethoxy] —2— {4— [({[2— (Trifluoromethyl) phenol] amino} carbol) amino] phenol} — 9, 10 Dihydro-4H pyrazo mouth [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide (Compound No. 130)

 Melting point: 258. 5-260. 5 ° C

[0226] 7— [2 (Dimethylamino) ethoxy]-2- [4- ({[(2,6 Dimethylphenol) amino] Force Lupol} Amino) phenol] — 9, 10 Dihydro-4H pyrazol Mouth [5, 1—b] [l, 3] Benzodiazepine 3-Carboxamide (Compound No. 131)

 Melting point: 257. 0- 259. 0 ° C

[0227] 2-[4-({[(2, 6 Difluorophenol) amino] carbol} amino) file] — 7— [2—

 (Dimethylamino) ethoxy] —9,10 Dihydro-4H pyrazo mouth [5, 1—b] [l, 3] benzodiazepine—3-carboxamide (Compound No. 132)

Melting point: 257. 0- 259. 0 [0228] 7— [2 (Dimethylamino) ethoxy] 2— [4 ({(((2-Methoxyphenol) amino) carbol} amino) phenol] -9, 10 Dihydro-4H pyrazo mouth [5, l—b] [l, 3] benzodiazepine— 3-carboxamide (Compound No. 133)

 Melting point: 129. 0- 132. 0 ° C

 Example 47

 [0229] 2-ί4-Γ (2.6 Dichlorobenzyl) amino 1- 7-Hydroxy 9.10 Dihydro 4 4 Pyrazo mouth "5.1- bl" l.31 Benzodiazepine 3 Carboxamide (Compound No. 34)

 2- {4-[(2, 6 dichlorobenzyl) amino] phenol} — 7-methoxy-1,9,10 dihydro — 4H pyrazo mouth [5, 1— b] [l, 3] benzodiazepine 1 3-carboxamide ( 1M Boron tribromide-dichloromethane solution (5. Oml, 5. Ommol) was added to a suspension of 501 mg, 0.985 mmol) in black mouth form (10 ml) and stirred at room temperature for 15 hours. Ice water was added to the reaction solution, and a mixed solution of ethyl acetate, methanol, and tetrahydrofuran was added. The organic layer is dried (anhydrous magnesium sulfate) and the residue is purified by NH silica gel column chromatography [NH silica gel; NH-DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black form: methanol = 9: 1). The title compound 2— {4 [(2,6 dicyclobenzyl) amino] phenol} —7 hydroxy-1,9,10 dihydro-4H pyrazo [5, 1— b] [l , 3] benzodiazepine 3-force nolevoxamide (287 mg) was obtained.

 Melting point: 265. 0-266. 5 ° C

 Example 48

 [0230] 2-ί4-Γ (2.6 Dichlorobenzyl) amino Ί-Fell 1-7— (Pyridine 1-ylmethoxy) -9.10 Dihydro 4Η Pyrazo mouth “5.1-131” 1.31 Benzodiazepine-3 —Kaboki Samide (Chemical ^ 35)

2- {4-[(2, 6 dichlorobenzyl) amino] phenol} — 7 hydroxy-1,9,10 dihydro 4Η-pyrazo mouth [5, 1-1)] [1,3] benzodiazepine-3-carboxamide (50111 ₈ , 0.101 mmol), 3- (chloromethyl) pyridine hydride chloride (32 mg, 0.195 mmol), potassium carbonate (82 mg, 0.593 mmol) in dimethylformamide (2 ml) suspension at 80 ° C And stirred for 2 hours. Add water to the reaction mixture, add ethyl acetate, extract the organic layer, dry (anhydrous Magnesium sulfate), concentrated, and the residue is purified by NH silica gel column chromatography [NH silica gel; NH-DM 1020 (Fuji Serial Co., Ltd.)] (developing solvent; ethyl acetate: hexane = 3: 1), and recrystallized (ethyl acetate) Chloroform hexane) to give colorless crystals of the title compound 2— {4 -— [(2,6 dichlorobenzyl) amino] phenol} — 7— (Pyridine-1-3-normethoxy) 9, 10 Dihydro-4H The pyrazo mouth [5, 1-1)] [1,3] benzodiazepine-3-carboxamide (22 mg) was obtained.

 Melting point: 243.0-245. 0 ° C

 Example 49

 [0231] In accordance with the production method of Example 48 and Example 9, by using 2- (2-bromoethoxy) tetrahydro-2H-pyran instead of 3- (chloromethyl) pyridine hydride chloride. The following compounds of the present invention were obtained.

 2- {4-[(2,6-Dichlorobenzyl) amino] phenol} — 7— (2-Hydroxyethoxy) -9, 10 Dihydro-4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3—Power Norevoxamide (Compound No. 136)

 Melting point: 224. 5- 227. 0

 Example 50

 [0232] 7— “2 (Dimethylamino) ethoxy 1 2— (4-Hydroxyphenyl) 9. 10 Dihydro —4H Pyrazo Mouth“ 5.1-131 ”1.31 Benzodiazepine-3-carboxamide (Compound No. 1 37)诰

(1) 4- [3- (Aminocarbol) 7-methoxy-1,9,10 dihydro-4H-pyrazo mouth [5, l-b] [l, 3] benzodiazepine 2-yl] phenol 4 methylbenzenesulfonate A 1M boron tribromide-dichloromethane solution (8.3 ml) was added dropwise at 60 ° C to a solution of 280 mg (0.55 mmol) in chlorophenol (5 ml). After the addition, the reaction was gradually raised to room temperature and stirred for 14 hours. Then, saturated sodium bicarbonate water was added at ice temperature to adjust to pH 8-9, and then the organic layer was extracted by adding chloroform and methanol, dried (anhydrous magnesium sulfate), and concentrated to obtain a residue of NH silica gel. Purification by column chromatography [NH silica gel; NH—DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1) yields 4- (3— (amino carbo) of pale yellow crystals. ) —7 Hydroxy— 9, 10 Dihydro— 4H The pyrazo mouth [5, l-b] [l, 3] benzodiazepine 2-yl] phenol 4 methylbenzene sulfonate (15 lmg) was obtained.

 1H NMR (600 MHz, DMSO— D6) δ ppm 2.39 (s, 3 H) 3.03-3.05 (m, 2 H) 4.25-4.27 (m, 2 H) 6.58-7.72 (m, 11 H) 9.13 ( s, 1 H) 9.58 (s, 1 H)

 [0233] (2) 4 [3 (Aminocarbol) 7 Hydroxy 9, 10 Dihydrol 4H Pyrazo Mout [5, 1-b] [l, 3] Benzodiazepine 1- Dimethyl] formaldehyde (20 ml) in 4 [methyl] benzene sulfonate (151 mg, 0.3 lmmol), dimethylaminoethyl chloride hydrochloride (135 mg, 0.94 mmol), potassium carbonate (429 mg, 3. lmmol) The suspension was stirred at an external temperature of 90 ° C for 1 hour. A mixture of black mouth form and methanol was added to the reaction mixture, and the mixture was filtered through celite, and saturated brine was added. The organic layer was dried (anhydrous magnesium sulfate) and the resulting residue was subjected to NH silica gel column chromatography [NH silica gel; NH—DM1020 (Fuji Serial Co., Ltd.)] (developing solvent: black mouth form: methanol = 9: 1) 4 {3 -— (Aminocarbonyl) -7- [2- (dimethylamino) ethoxy] —9,10 dihydro-4H pyrazo [5, 1—b] [l, 3 Benzodiazepine 2-yl} Ferre 4 Methylbenzenesulfonate (34 mg) was obtained.

 1H NMR (600 MHz, CDC13) δ ppm 2.35 (s, 6 H) 2.44 (s, 3 H) 2.73 (br. S, 2 H) 3.1 7-3.19 (m, 2 H) 4.05 (t, J = 5.5 Hz, 2 H) 4.39-4.41 (m, 2 H) 5.10 (br.s, 2 H) 6.73-7.73 (m, 11 H) 9.77 (s, 1 H)

[0234] (3) 4 (Aminocarbole) -7- [2- (dimethylamino) ethoxy] —9,10 Dihydro-1H obtained from (2) above [5, 1—b] [l, 3] Benzodiazepine-2-yl} Phenyl 4-methylbenzenesulfonate (34 mg, 0.06 mmol) in ethanol / tetrahydrofuran / water mixed solution of potassium hydroxide (110 mg, 2. Ommol), 60 ° The mixture was stirred at C for 2 hours. The reaction mixture was concentrated, adjusted to pH 8 with 1N aqueous hydrochloric acid, and then added with black mouth form. The organic layer was dried (anhydrous magnesium sulfate) and the resulting residue was subjected to NH—silica gel column chromatography [NH silica gel; NH—DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1) The title compound 7- [2— (Dimethylamino) ethoxy] —2— (4-hydroxyphenol) — 9, 10 Dihydro-4H pyrazo mouth [5, 1— b ] [1,3] Benzodiazepine 3 Carboxamide (18mg) Got.

 Melting point: 226. 0- 227. 5

 Example 51

 [0235] 2— (4 linolephenol) 1 7 Methoxy 1 9. 10 Dihydro 1 4H Pyrazo mouth “5.1 — b 1” 1.31 Benzodiazepine 3 Carboxamide (Compound No. 138)

 A solution of triphenylbismuth (96 mg, 0.218 mmol) and odobenzene diacetate (59 mg, 0.181 mmol) in chloroform (3 ml) was stirred at room temperature for 15 hours. 2- (4-aminophenol) -7-methoxy 9,10 dihydro-4H pyrazot [5, l-b] [l, 3] benzodiazepine-3-carboxamide (41 mg, 0.12 mmol), copper acetate ( II) (4 mg, 0.02 mmol) and dimethylformamide (lml) were added and stirred at room temperature for 2 hours. Add water to the reaction mixture, extract with black mouth form, wash (in order of water, saturated saline), dry (anhydrous magnesium sulfate), filter, and concentrate the residue obtained in a silica gel column (developing solvent; Purification by ethyl acetate: n-hexane = 2: 1) gave the title compound (29 mg) as yellow crystals.

 Melting point: 230. 0-231. 0 ° C

 Example 52

 [0236] According to the production method of Example 51, 2- (4 aminophenol) -7-methoxy-9,10 dihydr 4H pyrazo mouth [5, 1-b] [l, 3] benzodiazepine 3 carboxamide Instead of 2- (4 aminophenol) 1 6-methoxy 1 9, 10 dihydro 1 4H pyrazo mouth [5, 1-b] [1,3] benzodiazepine 1 3-carboxamide, A compound was obtained.

 2— (4-Linophenol) 1 6-Methoxy 1,9,10 Dihydro 1 4H Pyrazo Mout [5, 1— b] [1,3] Benzodiazepine-3 Carboxamide (Compound No. 139)

 Melting point: 247. 0- 249. 0 ° C

 Example 53

[0237] 2- (4-Anilinophenyl) -6— “2 (Dimethylaminoethoxy) 1— 9. 10 Dihydro-4H pyrazo mouth“ 5.1 — bl ”l, 31 Benzodiazepine 3 Carboxamide (Compound No. 14 0) Manufacture (1) 2— (4 linolephenol) 1 6-methoxy 1,9,10 dihydro 1 4H pyrazo mouth [5, 1 —b] [l, 3] benzodiazepine 1 3-carboxamide (1. Og, 2. 1M Boron tribromide-dichloromethane solution (11.8 ml) was added dropwise to a suspension of 35 mmol) of black mouth (100 ml) at 78 ° C. After the addition, the reaction was gradually raised to room temperature and stirred for 14 hours. did. Then, after adjusting the pH to 15% aqueous sodium hydroxide solution at ice temperature, add organic mixture of chloroform and methanol, extract the organic layer, wash (in order of water, saturated saline), and dry ( Anhydrous magnesium sulfate), filtered and concentrated to 2— (4-linophenol) -6 hydroxy 9, 10 dihydro 4H pyrazot [5, 1— b] [l, 3] benzodiazepine 3 canoleboxamide (90 Omg).

 1H NMR (200 MHz, DMSO— D6) δ ppm 3.06-3.10 (m, 2 H) 4.27-4.32 (m, 2 H) 6.32-7.38 (m, 12 H) 8.41 (s, 1 H) 9.41 (s, 1 H) 9.98 (s, 1 H)

[0238] (2) 2- (4-linophenol) -one 6-hydroxy-1, 9,10-dihydro-- 4H pyrazotone [5, 1- b] [l, 3] benzodiazepine obtained in (1) above A suspension of 3-carboxamide (150 mg, 0.36 mmol), dimethylaminoethyl chloride hydrochloride (79 mg, 0.55 mmol) and carbonated lithium (498 mg, 3.6 mmol) in dimethylformamide (3 ml) was brought to 150 ° C. And stirred for 3 hours. The reaction solution was filtered through celite and washed with chloroform. The filtrate obtained was concentrated and purified by NH silica gel column chromatography [NH silica gel; NH-DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9 : Purified in 1), recrystallized from black form-hexane to give the title compound 2- (4-linophenol) 6- [2- (dimethylaminoethoxy)]- 9, 10 Dihydro-1 4H Pyrazomouth [5, 1-b] [l, 3] benzodiazepine-3 carboxamide (92 mg) was obtained.

 Melting point: 201. 0- 202. 5 ° C

 Example 54

[0239] In accordance with the production method of Example 53, 2- (4-linophenyl) -6-methoxy-9,10 dihydro-4H-pyrazo mouth [5, 1- b] [l, 3] Benzodiazepine 3 carboxamide or 2- (4-linophenol) 1 7-methoxy-1,9,10 dihydro-1 4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 3-carboxamide, dimethylaminoethyl chloride By using hydrochloric acid salt or 3- (chloromethyl) pyridine hydrochloride, the following compounds of the present invention can be obtained. Obtained.

 [0240] 2— (4-Alinophenol) 1 6— (Pyridine 1 3-ylmethoxy) 1 9, 10 Dihydro 1 4 H Pyrazo Mout [5, l—b] [l, 3] Benzodiase Pin-3 Carboxamide (Compound No. 141)

 Melting point: 210. 0- 211. 5 ° C

[0241] 2— (4-Linophenol) 1 7— [2— (Dimethylamino) ethoxy] —9, 10 Dihydro-4H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide ( Compound number 14 2)

 Melting point: 207. 0- 208. 0 ° C

[0242] 2— (4-Alinophenol) 1 7— (Pyridine 1 3-ylmethoxy) 1 9, 10 Dihydro 1 4 H Pyrazo Mout [5, 1— b] [l, 3] Benzodiazepine 3 Carboxamide ( Compound No. 143)

 Melting point: 229. 5-231. 0 ° C

 Example 55

 [0243] 6 Methoxyl 2— ί4 “Methyl (phenyl) aminophenol” — 9. 10 Dihydrol 4Η— Pyrazo Mouth “5.1 — Bl” l, 31 Benzodiazepine 3 Carboxamide (Compound No. 144) Iron making

2- (4-Linophenol) 1 6-Methoxy-1,9,10 Dihydro-1 4H Pirazo Mout [5, 1- b] [1,3] Benzodiazepine 3-Carboxamide (110 mg, 0.26 mmol), 36- Sodium cyanoborohydride (49 mg, 0.78 mmol) and acetic acid (0.1 ml) were added to a suspension of 38% formaldehyde aqueous solution (l ml) in acetonitrile (5 ml), and the mixture was stirred at room temperature for 19 hours. Add water to the reaction mixture, extract with chloroform, wash (in order of water and saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue, and use NH silica gel column chromatography [NH silica gel. NH— DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1), purified by recrystallization from ethyl hexane acetate to give the title compound 6- Methoxy-2- {4 [^ (tyl (phenol) amino] phenol} -9, 10- dihydro 4H pyrazo [5, 1- b] [1, 3] benzodiazepine 3 canoleboxamide (19 mg) was obtained . Melting point: 167. 5-169. 5 ° C

 Example 56

 [0244] 2— “4 (ayulinocarbole) phenol Ί 7 methoxy 9. 10 dihydro 4H virazolo“ 5.1 — bl ”l.31 Preparation of benzodiazepine 3 carboxamide (Compound No. 145) (1) Implementation In accordance with the production method of Example 1, 5-amino-3- (4 phenoxyphenyl)-1H-pyrazole-5-amino-3-(4-methoxycarbonylphenol) 1H pyrazole instead of 4-carbitolyl By using 4-carbo-tolyl, methyl 4- [3-- (aminocarbol) 1- 7-methoxy-1,9,10 dihydro-1 4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 2 —Ill] got benzoate.

 1H NMR (200 MHz, DMSO— D6) δ ppm 3.12-3.23 (m, 2 H) 3.73 (s, 3 H) 3.88 (s,

3 H) 4.32-4.42 (m, 2 H) 6.76-6.98 (m, 3 H) 7.69 (d, J = 8.8 Hz, 2 H) 8.04 (d, J = 8.

(4 Hz, 2 H) 9.71 (s, 1 H)

 [0245] (2) Methyl 4- [3 (aminocarbol) -7-methoxy-9,10 dihydro-4H-pyrazo mouth obtained in (1) above [5, 1- b] [l, 3 ] Benzodiazepine 2yl] Benzoate (47 mg, 0.08 mmol) in tetrahydrofuran (4 ml) methanol (3 ml) mixed with aqueous solution of potassium hydroxide (22 mg, 0.4 mmol) (3 ml) at room temperature For 3 hours. The reaction solution is acidified with 1N aqueous hydrochloric acid, and then added with ethyl acetate, and the organic layer is extracted, washed (in order of water and saturated brine), dried (anhydrous magnesium sulfate), filtered, and concentrated. — [3— (Aminocarbol) 1 7-Methoxy 1 9, 10 Dihydro 1 4H Pyrazo Mout [5, 1-b] [l, 3] Benzodiazepine-2-yl] benzoic acid (20 mg) was obtained.

 1H NMR (200 MHz, DMSO— D6) δ ppm 3.15-3.20 (m, 2 H) 3.74 (s, 3 H) 4.34-4.39 (m, 2 H) 6.78-8.04 (m, 7 H) 9.74 ( s, 1 H)

[0246] (3) 4- [3- (Aminocarbole) -7-methoxy 9, 10 dihydro-4H-pyrazo mouth obtained in (2) above [5, l-b] [l, 3] benzo Diazepine-2-yl] benzoic acid (107111 ₈ , 0.28 mmol), aline (28.7 mg, 0.3 lmmol), in a dimethylformamide (2 ml) solution of 1 (3 dimethylaminopropyl) 3) Ethylcarbodiimide hydride chloride (80.5 mg, 0.42 mmol) and 1-hydroxybenzotriazole (56.8 mg, 0.42 mmol) were added and stirred at room temperature for 16 hours. Add water to the reaction mixture and mix with chloroform and methanol. Extract the residue with liquid, wash (in order of water, saturated brine), dry (anhydrous magnesium sulfate), filter, and concentrate the residue. NH silica gel column chromatography [NH silica gel; NH-DM1020 (Fuji Serial Co., Ltd.)] (Developing solvent; Chlo-mouth form: Methanol = 1: 9) to purify the colorless compound of the title compound 2- [4 (A-linocarbonyl) phenyl] 7-methoxy 9,10 dihydro-4H pyrazo mouth [5, 1-b] [l, 3] benzodiazepine 3-force noreboxamide (61 mg) was obtained.

 Melting point:> 300 ° C

 Example 57

 [0247] In accordance with the production method of Example 56, benzyl alcohol was used in place of aline to obtain the following compound of the present invention.

 Benzyl 4— [3— (Aminocarbol) 7-Methoxy-1,9,10 Dihydro-1 4H Pyrazo Mouth [5,1—b] [l, 3] Benzodiazepine 2-yl] benzoic acid ester (Compound No. 146 ) Melting point: 233. 5- 225. 0 ° C

 Example 58

 [0248] 2— “4 (Hydroxymethyl) phenyl 1 7 Methoxy 9.10 Dihydro-4H Pyrazomouth” 5.1—bl “1.3 l Benzodiazepine 3 Carboxamide (Compound No. 147) Preparation Methyl 4 [3 (Aminocarbol ) 7-Methoxy 9, 10 Dihydro-4H Pyrazo Mouth In a suspension of tetrahydrofuran (200 ml) in [5,1—b] [l, 3] benzodiazepine-2-yl] benzoate (1.28 g, 3.3 mmol) Lithium aluminum hydride (464 mg, 9.8 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours.Methanol and 1N aqueous hydrochloric acid solution were successively added to the reaction mixture under ice-cooling, and the filtrate was obtained by Celite filtration. Water is added to the mixture, and a mixture of black mouth form and methanol is added. The organic layer is extracted, washed (in order of water and saturated saline), dried (anhydrous magnesium sulfate), filtered, and concentrated. Silica gel column chromatography (developing solvent; black mouth form: me By purifying with Nord = 5: 1), the title compound 2— [4 (Hydroxymethyl) phenol] 7-Methoxy 9, 10 Dihydro-4H Pyrazo Mout [5, l -b] [l, 3] Benzodiazepine 3 carboxamide (1.08 g) was obtained.

 Melting point: 227. 0- 230. 0 ° C

Example 59 [0249] 7 Methoxy-1-2- “4- (Phenoxymethyl) phenol 1-9.10 Dihydro-4H-pyrazo Mouth“ 5. l-bl “l, 31 Benzodiazepine 3 Preparation of carboxamide (Compound No. 148) ( 1) 2— [4 (Hydroxymethyl) phenol] — 7—Methoxy 9, 10 Dihydro-1 4H—Vilazolo [5, 1— b] [l, 3] Benzodiazepine 1 3-carboxamide (400 mg, 1. lmmol ) In a chloroform suspension of paratoluene sulfochloride (25 lmg, 1.3 mmol), triethylamine (0.46 ml, 3.3 mmol), 4- (dimethylamino) pyridine (13.4 mg, 0.11 mm ol) The reaction mixture was purified by NH silica gel column chromatography [NH silica gel; NH-DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; ethyl acetate: hexane = 7: 3). As a result, the colorless solid 2- [4 (chloromethyl) phenyl] -7-methoxy-9,10 dihydro 4H pyrazo port give [5, 1- b] [l, 3] Benzojiazepin 3- force Rubokisamido a (99 mg).

 1H NMR (200 MHz, CDC13) δ ppm 3.19-3.24 (m, 2 H) 3.80 (s, 3 H) 4.42-4.47 (m, 2 H) 4.64 (s, 2 H) 5.22 (br.s, 2 H ) 6.71-7.61 (m, 7 H) 9.81 (s, 1 H)

[0250] (2) 2- [4 (Chloromethyl) phenol] -7-methoxy 9, 10 dihydro 4H-pyrazo mouth obtained in (1) above [5, 1-1)] [1, 3] Benzodiazepine-3-carboxamide (50111 ₈ , 0.096 mmol), phenol (10.9 mg, 0.12 mmol), sodium chow sodium (2.9 mg, 0.02 mmol), potassium carbonate (66.3 mg, 0. 48 mmol) suspension of dimethylformamide (2 ml) was stirred at 90 ° C. for 4 hours. The reaction solution was filtered through Celite and washed with chloroform. The filtrate obtained was concentrated, and NH silica gel column chromatography [NH silica gel; NH DM 1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1 Purified in 1) and recrystallized from chloroform-form hexane to give the title compound 7-methoxy-2- [4 (phenoxymethyl) phenol] -9, 10 Dihydro-4H pyrazolo [5, 1-b] [1, 3] benzodiazepine 3 carboxamide (16 mg) was obtained.

 Melting point: 244. 0- 245. 0 ° C

 Example 60

 [0251] In accordance with the production method of Example 59, the following compounds of the present invention were obtained by using aline instead of phenol.

2— [4 (Alinomethyl) phenol] 7—Methoxy 9, 10 Dihydro-4H 5, l—b] [l, 3] benzodiazepine-3 carboxamide (Compound No. 149) Melting point: 202. 5-204. 5 ° C

 Example 61

 [0252] 7— “2 (Dimethylamino) ethoxy 1 2—“ 4- (Hydroxymethyl) phenyl 1 —9. 10—Dihydro 1 4H Pyrazo Mouth “5. l-bl” 1 .31 Benzodiazepine 1 3 Carboxamide (Compound • i 50)

 (1) 2-[4 (Hydroxymethyl) phenol]-7-Methoxy 9, 10 Dihydro 1 4H-Villazolo [5, 1-1)] [1, 3] Benzodiazepine-3-canoleboxamide (22511 ^, To a suspension of 0.0617 mmol) of black mouth form (23 ml), 1M boron tribromide-dichloromethane solution (3.09 ml) was added dropwise at -78 ° C. Stir. Then, after adjusting the pH to 15% aqueous sodium hydroxide solution under ice temperature, add the black mouth form and methanol mixture, extract the organic layer, wash (in order of water and saturated saline), The residue obtained by drying (anhydrous magnesium sulfate), filtration, and concentration was subjected to NH silica gel column chromatography [NH silica gel; NH—DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1) 2- [4 (Hydroxymethyl) phenol]-7 -Hydroxy 9, 10 Dihydro-1 4H Pyrazo Mout [5, 1- b] [l, 3] Benzodiazepine 1-Carboxamide (70 mg )

[0253] (2) 2- [4- (Hydroxymethyl) phenol] -7 Hydroxy 9, 10 Dihydro 4H Pyrazo Mout [5, 1- b] [1, 3] Benzodiazepine obtained in (1) above 3 Suspension of canoleboxamide (66 mg, 0.188 mmol), dimethylaminoethyl chloride hydrochloride (81 mg, 0.564 mmol), potassium carbonate (260 mg, 1.88 mmol) in dimethylformamide (1.5 ml) at an external temperature of 90 The mixture was stirred at ° C for 2 hours. A mixture of black mouth form and methanol was added to the reaction mixture, and the mixture was filtered through serate, and saturated brine was added. The organic layer was dried (anhydrous magnesium sulfate) and the resulting residue was subjected to NH silica gel column chromatography [NH silica gel; NH-DM1020 (Fuji Serial Co., Ltd.)] (developing solvent; black mouth form: methanol = 9: 1 ) To give colorless crystals of 7- [2 (dimethylamino) ethoxy] 2- [4 (hydroxymethyl) phenol] —9, 10 dihydro-4H pyrazo [5, 1- b] [l, 3] Benzodiazepine 1-carboxamide (12 mg) was obtained. Melting point: 210. 5-215. 5 ° C

 Example 62

 [0254] In accordance with the production method of Example 1, 5 amino-3- (4 phenoxyphenyl) 1H pyrazo 1lu instead of 4-carbo-tolyl 5 amino-3- (2 chael) — 1H pyrazol By using 1-luo 4-carbo-tolyl, 7-methoxy-l 2-(2 chael) 9, 10 dihydro 4H pyrazo mouth [5, 1- b] [l, 3] benzodiazepine 3 canoleboxamide (Compound No. 151 )

 Melting point: 234. 0- 236. 0 ° C

 Example 63

 [0255] In accordance with the production method of Example 7, 5 amino-3- (4 phenoxyphenyl) 1H pyrazo 1lu instead of 4-carbo-tolyl 5 amino-3- (2-chael) — 1H By using pyrazol 4-luo-carbo-tolyl, 7- [2- (dimethylamino) ethoxy] -2 2- (2 chael) 9, 10 dihydro-4H pyrazo mouth [5, l-b] [l, 3 Benzodiazepine-3-carboxamide (Compound No. 152) was obtained.

 Melting point: 177. 0-178. 5 ° C

 The structural formulas and NMR values of the present compounds 1-152 are shown in Tables 1 to 22 below.

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Test example

 A method for measuring the Lck inhibitory activity of the compound of the present invention will be described.

96 μl of Lck enzyme substrate mixture 25 μ1, ATP mixture 20 μ1 and test substance solution 5 μ1 In addition to Glyaction plate, it was incubated at room temperature for 1 hour. After stopping the reaction by adding 10 OmM phosphoric acid solution 200 1 as a reaction terminator, the entire amount of the reaction solution was transferred to a multiscreen (MAPHNB50 manufactured by Millipore) and washed 4 times with lOOmM phosphoric acid 200 1. After drying, 20 μ 1 of microcinch 0 (Perkin Elma Co., Ltd. 6013611) was added, and the radioactivity was measured by Top Count (Perkin Elmer Co., Ltd.). The ratio of the radioactivity when the test substance is added to the radioactivity when the test substance is not applied is calculated, and the IC value is calculated from the inhibition rate at each concentration, which is used as an index of the inhibitory activity. . The results are shown in Table 23.

 50

 Test substance solution: The test substance was dissolved in dimethyl sulfoxide (DMSO) and diluted to a final concentration of 50 pM-1 / zM. The final concentration of DMSO was 1%. Lck enzyme substrate mixture: Lck (upstate # 14-442) 12ng / well, substrate peptide (poly (L-glu-L-tyr) Sigma P0275) Dissolved in Atsy buffer to a final concentration of 25μΜ I let you.

 ΑΤΡ Mixture: ΑΤΡ (Oriental Yeast LTD45142000) Final concentration 5 μM / well,

[Γ - ³³ Ρ] ΑΤΡ dissolved in mediation Si buffer such that (Amersham Biosciences ΑΗ9968) 0.1 μ Ci / well.

 Atsey buffer: 50 mM Hepes pH 7.5, 50 mM KC1, 25 mM MgCl, 5 mM MnCl

 twenty two

, 100 M Na VO, ImM DTT, 0.01% CHAPS, 50 μg / ml BSA

 3 4

[0279] [Table 23]

Compound number to so (nM) Compound number ICso (nM) Compound number so (nM)

001 8.3 058 1.6 101 18.1

002 76.7 059 1.5 102 51.4

003 7.5 060 1.4 103 16.2

004 3.6 061 1.5 104 3ο.4

005 13.6 1.9 106 5.0

006 3.9 063 1.0 108 44.6

007 3.1 064 1.6 1 10 11.0

010 1J 065 1.3 1 1 1 15.7

01 1 8.7 067 1.0 1 12 3.6

013 4 068 0.8 1 13 15,5

014 2.3 069 0.9 1 14 27.4

015 1.9 071 115 14.4

016 2.4 072 1.3 116 6.4

018 1.9 073 2.1 117 8.1

021 1 1.1 074 2.4 118 4.5

024 9.5 075 1.2 1 19 5.5

026 4.7 076 1.9 120 13.7

027 3.9 077 2.0 121 3.8

028 1.7 078 4.6 122 5.3

031 1.9 079 5,2 126 13.7

033 2.8 080 8,0 1 ku 7 3,5

034 10.8 081 1,2 129 4,4

038 5.9 082 1.1 130 3.1

039 9.0 083 2,4 131 7.7

040 3.2 084 9,7 132 2.2

042 3.5 085 1,9 133 7.1

043 7.8 086 6,0 134 3.5

044 2.7 087 6.9 135 3.4

045 3.4 088 4.8 136 0.7

047 1.0 089 4.5 137 3.9

048 3.4 090 5.1 138 8.5

050 24.6 091 12.1 139 27.3

051 3.1 092 8.7 140 3.3

053 5.5 094 9.8 142 1.4

054 2.1 095 1 1.1 143 9.3

055 5.0 096 3,9 148 9.8

056 3.2 099 23.1 149 17.2

057 2,4 100 7.7 152 14.2 Industrial applicability

 The compound of the present invention inhibits Lck's enzyme activity, which is involved in the abnormal activity of immunocompetent cells, so that it can treat rejection during organ transplantation and immune and allergic diseases such as atopic dermatitis and asthma. It can be used as a medicine.

Claims

Claim Formula (1) [Chemical 1]

 (Where n represents 2 or 3, A is a single bond, formula O—, formula OCO—, formula NR ²¹ —, formula NR ²² CO—, or formula NR ²³ CONR ²⁴ — (wherein R ²¹ , R ²² , R ²³ and R ²⁴ are each independently , Hydrogen atom, or C  1- represents an alkyl group. )  8  B is a single bond, a C alkylene group, a C cycloalkylene group, or a C alkylene group.  1-10 3-10 2-10 Represents a group in which any carbon atom is substituted with a C cycloalkylene group;  3-10  C represents a single bond or formula o, R ¹ represents a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi  1-6 Dino group, piperidino group substituted with C alkyl group, piperidyl group, C alkyl group  1-6 1-6 Piperidinyl, morpholino, and morpholino substituted with C alkyl groups  1-6 Group, morpholinyl group, morpholinyl group substituted with C alkyl group, piperazinyl group,  1-6  Piperazinyl group substituted with C alkyl group or hydroxy C alkyl group, C alkyl 1-6 1-6 2-10 Canol group, carboxy group, strong rubamoyl group, C alkoxycarbonyl group, pyridyl  2- 10 Group, pyridyl group substituted with C alkyl group, pyrimidyl group, substituted with C alkyl group 1-6 1-6 A pyrimidyl group or a formula — NR ³¹ R ³² (wherein R ³¹ and R ³² are each independently a hydrogen atom, a C alkyl group, a hydroxy C alkyl group, an amino C alkyl group, a mono C alkyl group) 1-8 2-6 2-6 1-6 Mino C alkyl group, di C alkyl amino C alkyl group, or dihydroxy C alkyl 2-6 1-6 2-6 2-6 represents a group. ) R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group,  1-6 1-6  D = D represents the formula —CH = CH—, formula—S—, or formula—NH,  1 2 E is a single bond, Formula—O—, Formula—NR ⁶¹ —, Formula—OCO—, Formula—OSO—, Formula—NR ⁶² C  2 O, formula-OCOO, formula-NR ⁶³ SO-, formula-OCONR ^64- , formula-NR ⁶⁵ CONR ⁶⁶  2 One, the formula CONR ⁶⁷ -, wherein COO -, wherein NR ⁶⁸ COO -, wherein NR ⁶⁹ CSNR ⁷⁰ -, wherein - CR ⁷¹ R ⁷² 0-, or formula ^{- CR 73 R 74 NR 75 -} ( wherein, R ^61, R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ , R ⁶⁶ , R 6 R ⁶⁸ , R ⁶⁹ , R ⁷ °, R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ and R ⁷⁵ are each independently a hydrogen atom, or C  1-8 represents an alkyl group. )  G is a single bond, a C alkylene group, a C cycloalkylene group, or a C alkylene group.  1-10 3-10 2-10  Represents a group in which any carbon atom is substituted with a C cycloalkylene group;  3-10 R ⁷ is a hydrogen atom, a formula — NR ⁸¹ R ⁸² (where R ⁸¹ and R ⁸² are each independently a hydrogen atom or C  1 represents an alkyl group. ), Indolyl group, N—C alkylindolyl group, benzofural -6 1-6  Group, benzothiophenyl group, or formula (2)  [Chemical formula 2] λ. 9 (2) (In the formula, X and Y each independently represent a carbon atom or a nitrogen atom, and R ⁸ and R ⁹ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or C 1-6 represents a 1-alkoxy group, J represents a single bond or formula -o, R ^1Q represents a hydrogen atom, C alkyl 6 1-8 group, hydroxy C alkyl group, amino C alkyl group, mono C alkylamino C  2-6 2-6 1-6 2-6 Indicates an alkyl group, diC alkylamino C alkyl group, or dihydroxy C alkyl group  1-6 2-6 2-6  The ). Or a pharmaceutically acceptable salt thereof. [2] n represents 2 or 3, A is a single bond, formula O—, formula OCO—, formula NR ²¹ —, formula NR ²² CO—, or formula NR ²³ CONR ²⁴ — (wherein R ²¹ , R ²² , R ²³ and R ²⁴ are each independently , Hydrogen atom, or C 1- represents an alkyl group. ) B is a single bond, C alkylene group, C cycloalkylene group, or C alkylene group  1-10 3-10 2-5  A group in which the carbon atom is substituted with a C cycloalkylene group,  3-6  C represents a single bond or formula o, R ¹ is a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi  1-6  Dino group, piveryl group, morpholino group, C alkyl group substituted with C alkyl group  1-6 1-6  Or piperazinyl group substituted with hydroxy C alkyl group, C alkanol group, force  1-6 2-10  Ruboxy group, rubamoyl group, C alkoxycarbonyl group, pyridyl group, or formula  2-10 NR ³¹ R ³² (wherein R ³¹ and R ³² are each independently a hydrogen atom, C alkyl group, hydroxy C  1-8 2 represents an alkyl group or a di-C alkylamino C alkyl group. )  -6 1-6 2-6 R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group,  1-6 1-6  D = D force Formula 1 CH = CH- or Formula 1 S  1 2 E is a single bond, Formula—O—, Formula—NR ⁶¹ —, Formula—OSO—, Formula—NR ⁶² CO—, Formula—OC  2 OO, Formula OCONR ⁶⁴ , Formula NR ⁶⁵ CONR ⁶⁶ , Formula CONR ⁶⁷ , Formula COO, Formula NR ⁶⁸ COO, Formula NR ⁶⁹ CSNR ^7Q , Formula CR ⁷¹ R ⁷² 0—, or Formula CR ⁷³ R ⁷⁴ NR ⁷⁵ — (Formula ^{among, R 61, R 62, R} 64, R 65, R 66, R 67, R 68, R 69, R 7 °, R 71, R 72, R 73, R 74 and R ⁷⁵ are each independently a hydrogen Represents an atom or a C alkyl group.  1-8  G represents a single bond, a C alkylene group, or a C cycloalkylene group,  1-10 3-10 R ⁷ is a hydrogen atom, formula NR ⁸¹ R ⁸² (where R ⁸¹ and R ⁸² are each independently a hydrogen atom or C  1 represents an alkyl group. ), Indolyl group, N—C alkylindolyl group, or formula (2) (formula -6 1-6 X and Y are carbon atoms, R ⁸ and R ⁹ are each independently a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group, and J is a single bond.  1-6 1-6 R ^1Q represents a hydrogen atom. The condensed pyrazole derivative represented by the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof.  [3] n represents 2 or 3,  A represents a single bond, Formula O—, Formula OCO—, Formula NH—, Formula NHCO—, or Formula N HCONH,  B is a single bond, C alkylene group, C cycloalkylene group, or C alkylene group 1-10 3-10 2-5 A group in which the carbon atom is substituted with a C cycloalkylene group,  3-6  C represents a single bond or formula o, R ¹ is a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi  1-6 Dino group, piveryl group, morpholino group, C alkyl group substituted with C alkyl group  1-6 1-6 Or piperazinyl group substituted with hydroxy C alkyl group, C alkanol group, force  1-6 2-10 Ruboxy group, rubamoyl group, C alkoxycarbonyl group, pyridyl group, or formula  2-10 NR ³¹ R ³² (wherein R ³¹ and R ³² are each independently a hydrogen atom, C alkyl group, hydroxy C  1-8 2 represents an alkyl group or a di-C alkylamino C alkyl group. )  -6 1-6 2-6 R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C alkyl group, or a C alkoxy group,  1-6 1-6  D = D force Formula 1 CH = CH  1 2  E represents a single bond, formula —O—, formula —NH—, or formula NHCO, G represents a single bond, R ⁷ is a hydrogen atom, or formula (2) (wherein X and Y are carbon atoms, R ⁸ and R ⁹ are hydrogen atoms, J is a single bond, and R ^1Q is a hydrogen atom. The condensed ring pyrazole derivative represented by the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof. n represents 2,  A represents a single bond, formula —O—, formula —NH—, formula NHCO—, or formula NHCONH,  B is any carbon of a C 8 aralkylene group, a C cycloanolylene group, or a C 3 arylene group. 1-10 3-10 2-5 A group in which an atom is substituted with a C cycloalkylene group,  3-6  C represents a single bond, R ¹ is a hydrogen atom, a pyrrolidyl group, a pyrrolidinyl group substituted with a C alkyl group, piperi  1-6 Dino group, piveryl group, morpholino group, C alkyl group substituted with C alkyl group  1-6 1-6 Or a piperazyl group substituted with a hydroxy C alkyl group, or the formula NR ³¹ R ³² (wherein  1-6 , R ³¹ and R ³² are each independently a hydrogen atom, a C alkyl group, a hydroxy C alkyl group,  1-8 2-6 Or a di C alkylamino C alkyl group. )  1-6 2-6 R ⁴ , R ⁵ and R ⁶ represent a hydrogen atom, D = D force Formula 1 CH = CH  1 2  E represents the formula O— G represents a single bond, R ⁷ is represented by the formula (2) (wherein X and Y represent a carbon atom, R ⁸ and R ⁹ represent a hydrogen atom, J represents a single bond, and R ^1Q represents a hydrogen atom). The condensed pyrazole derivative represented by the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof. n represents 2,  A represents the formula O,  B represents a single bond or a C anoalkylene group,  1-10  C represents a single bond or formula O R ¹ represents a hydrogen atom, a pyridyl group, or a formula —NR ³¹ R ³² (wherein R ³¹ and R ³² each independently represents a hydrogen atom or a C alkyl group);  1-8 R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or a C alkoxy group,  1-6  D = D force formula CH = CH  1 2  E represents Formula O, Formula NH-, Formula OCOO, Formula OCONH-, Formula NHCONH-, Formula-COO, Formula-NHCOO, Formula-CHO, or Formula-CHNH,  twenty two  G represents a single bond, a C alkylene group, or a C cycloalkylene group,  1-10 3-10 R ⁷ is a hydrogen atom or formula (2) (wherein X and Y are carbon atoms, R ⁸ and R ⁹ are each independently a hydrogen atom, a halogen atom, a trifluoromethyl group, C Alkyl group or C 1-8 represents a 1-alkoxy group, J represents a single bond, and R ^1Q represents a hydrogen atom. ) 6 A fused pyrazole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof: