CN1391476A

CN1391476A - Vasopressin agonist formulation and process

Info

Publication number: CN1391476A
Application number: CN00816009A
Authority: CN
Inventors: J·K·尤恩; R·W·桑德斯; M·B·法齐
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1999-09-27
Filing date: 2000-09-26
Publication date: 2003-01-15
Also published as: MXPA02003191A; WO2001022969A2; AU7615200A; JP2003510280A; EP1216045A2; WO2001022969A3; CA2385971A1

Abstract

This invention provides novel formulations for vasopressin agonist compounds, or a pharmaceutically acceptable salt thereof, having general structure (I), and processes for making them, the formulations comprising from about 1% to about 20% of active ingredient, from about 1% to about 18% of a surfactant component, from about 50% to about 80% of a component of one or more polyethylene glycols, from about 1% to about 20% of a component of one or more sucrose fatty acid esters and/or polyvinylpyrrolidone and, optionally, one or more preservatives or antioxidants.

Description

Vasopressin agonist formulation and method

The application relates to the novel formulation of a class three ring vasopressin agonist chemical compounds and its pharmaceutically acceptable salt, and the method for preparing described preparation.The invention particularly relates to the oral formulations of these chemical compounds.

Background of the present invention

Many methods that prepare liquid or semi-solid encapsulated pharmaceutical formulation have been introduced in this area.Author Shah etc. are in Bull.Tech./Gattefosse Rep. (1996), and 89, introduced the hard gelatin capsule technology among the 27-38, be particularly useful for increasing that indissoluble is separated or the difficult bioavailability that absorbs the drug.

United States Patent (USP) the 4th, 620, No. 974 (Hersh etc.) have mentioned the hard gelatin capsule that comprises the telescopic two joint medicated caps that contain lubricant, and described lubricant comprises that molecular weight is approximately the Polyethylene Glycol of 200-900 and is present in the mixture of described composition with the concentration of about 0.5-25% weight.

WO 96/40071 (Lamberti) discloses the micro-capsular method and apparatus of preparation.WO96/41622 (Tanner etc.) has mentioned and has been suitable for encapsulated suspension in gelatine capsule, especially comprises the liquid phase of the solid phase of solid particle and this solid phase that can suspend.

United States Patent (USP) the 5th, 641, No. 512 (Cimiluca) have mentioned the analgesic of Perleization, and wherein said housing contains xanthine derivative such as caffeine.

United States Patent (USP) the 4th, 578, No. 391 (Kawata etc.) have introduced the Unctuous compositions that is used for antitumor drug, said composition contains at least a little oil-soluble or water solublity antitumor drug, at least a fat or oil and at least a solubilising adjuvant in the oiliness solvent, and described solvent is selected from the sucrose ester of crown ether, lecithin, Polyethylene Glycol, propylene glycol, vitamin E, polyoxyethylene alkyl ether and fatty acid.

EP 0 815 854 A1 disclose translucent substantially, the semisolid filler that is used for Perle, and described semi-solid thing is enough viscid, so that at room temperature can not it is extracted out from capsule with syringe holder.

United States Patent (USP) the 4th, 744, No. 988 (Brox) proposed to comprise the Polyethylene Glycol of gelatin housing, softening agent and filling and the Perle of lower polyol and at least a active substance, its characteristic is sorbitol (sorbital) or the anhydro sorbitol that described housing contains 4-40%, the Polyethylene Glycol of employed half weight at least is that to have mean molecule quantity be that 600 Polyethylene Glycol and described capsule filling contain the glycerol and/or 1 that reaches as high as 20% weight, 2-propylene glycol.

It is about 5 that WO 95/19579 (Dhabhar) has proposed to have specific viscosity-average molecular weight by use, 000-25, and 000 polyvinylpyrrolidone makes insoluble drug be dissolved in method in the mixture of Polyethylene Glycol and propylene glycol.

The present invention's general introduction

The invention provides the oral formulations of three ring vasopressin agonist chemical compounds or its pharmaceutically acceptable salt, this chemical compound is independent in this article or optional jointly to be called " active component ", and they have following structure:

Wherein: each independently is CH or nitrogen for A, B, E, G; D independently is C-W or nitrogen; R ¹Be 2-7 carbon atom alkanoyl, be selected from CN, COOH, CONH ₂,-≡-H ,-≡-R ⁹Group, or be selected from the part of following group: R ², R ³And R ⁵Each independently is the straight chained alkyl of hydrogen, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, the cycloalkyl of a 3-7 carbon atom or the perfluoroalkyl of 1-6 carbon atom; R ⁴Be branched alkyl, a 3-7 carbon atom of straight chained alkyl, a 3-7 carbon atom of hydrogen, a 1-6 carbon atom cycloalkyl, a 2-7 carbon atom alkoxyalkyl or be selected from the acyl substituent of following group: the alkenoyl of the alkanoyl of 2-7 carbon atom, a 3-7 carbon atom, cycloalkanes acyl group, aroyl or the Arylalkanoyl of a 3-7 carbon atom; Each independently is alkoxyalkyl, the halogen (comprising chlorine, bromine, fluorine and iodine) of perfluoroalkyl, a 2-7 carbon atom of cycloalkyl, a 1-6 carbon atom of branched alkyl, a 3-7 carbon atom of straight chained alkyl, a 3-7 carbon atom of hydrogen, a 1-6 carbon atom, alkoxyl, hydroxyl, the CF of a 1-6 carbon atom for X and Y ₃Or the perfluoroalkyl of 2-6 carbon atom; W is hydrogen, halogen (especially chlorine, bromine or iodine), alkyl, the alkoxyalkyl of a 2-7 carbon atom, the hydroxyalkyl or the CH of a 1-6 carbon atom ₂NR ⁶R ⁷R ⁶And R ⁷Each independently is the straight chained alkyl of hydrogen, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom; Or R ⁶And R ⁷With CH ₂NR ⁶R ⁷Nitrogen-atoms together, form optional one or more other the heteroatomic 5 or 6 yuan of rings that contain, for example, but be not limited to following group:

R ⁸It is the straight chained alkyl of 1-6 carbon atom; R ⁹It independently is the straight chained alkyl of hydrogen, a trimethyl silyl or 1-6 carbon atom; Or its pharmaceutically acceptable salt, ester or prodrug.

The chemical compound of the preferred active component of preparation of the present invention is the chemical compound with following formula:

Wherein: each independently is CH or nitrogen for A and B; D is C-W or nitrogen; R ¹Be the alkanoyl of 2-7 carbon atom or be selected from following group

R ², R ³And R ⁵Each independently is the straight chained alkyl of hydrogen, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, the cycloalkyl of a 3-7 carbon atom or the perfluoroalkyl of 1-6 carbon atom; R ⁴, X, Y, W, R ⁶, R ⁷And R ⁸As defined above; Or its pharmaceutically acceptable salt.

For above define and the mentioned chemical compound of this paper for; except that other explanation, aroyl comprises benzoyl, the naphthoyl as can independently being replaced by one or more substituent group that is selected from following group: alkoxyl, the CF of the straight chained alkyl of hydrogen, halogen, cyano group, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, a 1-6 carbon atom ₃Or phenyl.

Described 4-hetaroylpyrazol refers to that carbonyl directly is attached to the aroyl that has on one or two heteroatomic 5 yuan of heterocyclic carbon atoms that are selected from nitrogen, oxygen, sulfur, for example 2-thiophene acyl group.The heterocycle of described 4-hetaroylpyrazol also can be the group of furan, pyrroles, 2H-pyrroles, imidazoles, pyrazoles, isothiazole, isoxazole, thiophene, pyrazoline, imidazolidine or pyrazolidinyl including, but not limited to aryl moiety wherein.Described heteroaryl can independently be replaced by one or more substituent group that is selected from following group: the straight chained alkyl of hydrogen, halogen, cyano group, a 1-6 carbon atom or the branched alkyl of 3-7 carbon atom.

Described Arylalkanoyl refers to that carbonyl is directly connected on the alkyl of 1-6 carbon atom (it is replaced by the aryl end group), for example phenylacetic acid.Described aryl can independently be replaced by one or more substituent group that is selected from following group: alkoxyl, the CF of the straight chained alkyl of hydrogen, halogen, cyano group, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, a 1-6 carbon atom ₃The perhaps phenyl of phenyl or replacement, wherein said substituent group is selected from the straight chained alkyl of halogen, cyano group, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, alkoxyl, the CF of a 1-6 carbon atom ₃

Except that other explanation, described halogen can be selected from fluorine, chlorine, bromine or iodine.

The definition that those skilled in the art will appreciate that formula (I) chemical compound (is worked as R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, X or Y comprise asymmetric carbon) comprise have that the following stated is active, all possible stereoisomer and composition thereof.Especially, it comprises having described active any optical isomer and diastereomer; And racemic and that split, enantiomeric pure R and S stereoisomer; And other mixture of R and S stereoisomer and pharmaceutically acceptable salt thereof.Can obtain optical isomer with pure form by the standard isolation technics.Also be appreciated that the R of formula (I) chemical compound ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, X or Y definition comprise have that the following stated is active, all possible regional isomer and composition thereof.Can obtain this pure class regional isomer by the known standard isolation methods of this field technique personnel.

The active component of the preparation of the present invention of preferred group is the chemical compound in the following subgroup: the chemical compound that a) has following general formula

Wherein A, B, W, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, X and Y as defined above; B) have the chemical compound of following general formula:

Wherein A, B, R ¹, R ², R ³, R ⁴, R ⁵, R ⁹, X and Y as defined above; And c) have the chemical compound of following general formula:

Wherein A, B, R ¹, R ², R ³, R ⁴, R ⁵, R ⁹, X and Y as defined above.

Be appreciated that above subgroup a)-c) also comprises following subgroup: wherein: each independently is CH or nitrogen for A and B; R ¹Be the alkanoyl of 2-7 carbon atom or be selected from following group:

R ², R ³And R ⁵Each independently is the straight chained alkyl of hydrogen, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, the cycloalkyl of a 3-7 carbon atom or the perfluoroalkyl of 1-6 carbon atom; And R ⁴, X, Y, W, R ⁶, R ⁷And R ⁸As defined above; Or its pharmaceutically acceptable salt.

The particularly preferred chemical compound of more than organizing a) is that wherein W is H, and A and B respectively are CH and R ¹Be the alkanoyl of 2-7 carbon atom or the chemical compound that is selected from above listed part (a) and (b), (e), (f), (g), (h), (i) or group (k).

Pharmaceutically acceptable salt comprises that described acid for example is lactic acid, citric acid, acetic acid, tartaric acid, succinic acid, maleic acid, malonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulfonic acid and similar known acceptable acid by the organic and deutero-salt of mineral acid.

Most preferred preparation is described hereinly to have as active component [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl-(5H among the present invention, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl] preparation of ketone or its pharmaceutically acceptable salt, this chemical compound has following structure:

Preparation of the present invention is used for the treatment of in the method that wherein needs the active people of vasopressin agonist or other mammiferous disease, symptom or disorder.Described Therapeutic Method comprises at disease, symptom or disorder releasing factor VIII and Feng ideally. the prestige Willebrand factor enters blood circulation, discharge the former activation factor of tectotype fibrinolysin (t-PA) enters blood circulation or influence kidney and keep moisture and urinate spissated method.Described Therapeutic Method comprises hemophilia including, but not limited to treatment people or other mammiferous diabetes insipidus, enuresis nocturna, nocturia, urinary incontinence or hemorrhage and coagulopathy.

Use the method for described preparation to comprise the momentary delayed urination alleviation that makes people or other mammalian body, if desired, this method also can be thought control or treat momentary delay acraturesis.Think that described method comprises the treatment of alleviating momentary delayed urination, this treatment is independently and is not included in the treatment of the symptom that is called enuresis nocturna and nocturia.

In order to obtain the concordance of administration, preferred compositions of the present invention is a unit dosage form.Suitable unit dosage form preferably includes tablet or capsule, also is preparation easily and effective although it will be appreciated by those skilled in the art that semisolid of the present invention or gel.Described unit dosage form can comprise The compounds of this invention and the preferred 2-50mg of 0.1-1000mg.The unit dosage form that is more preferably comprises 1-25mg, more preferably the chemical compound of the present invention of 1-10mg.Chemical compound of the present invention can be at oral administration in approximately 0.01-100mg/kg or the preferred 0.1-10mg/kg dosage range.Described compositions can the administration every day 1-6 time, and administration every day is 1-4 time usually.

Compositions of the present invention can be with preparations such as other conventional carrier or excipient such as filler, disintegrating agent, binding agent, lubricant, flavoring agents.

Preparation of the present invention comprises (%w/w): a) active component or its pharmaceutically acceptable salt of about 1-20%, preferably approximately 1-16%, more preferably this active component of about 5-16%; B) surfactant component of about 1-18%, preferably approximately 1-5%, more preferably approximately 5-15% or approximately 5-18%, most preferably approximately 5-10% or the approximately surfactant component of 8-12%; C) one or more of about 50-80% are planted the composition of Polyethylene Glycol (PEG), and preferably approximately one or more of 55-70% are planted Polyethylene Glycol; And d) about 1-20%, preferably approximately 5-15% and the more preferably following composition of about 8%-12%:

I) one or more plant sucrose fatty acid ester; Or

Ii) polyvinylpyrrolidone (PVP), it is about 15-90 as defined K value in USP/NF, and preferred K value is about 17 polyvinylpyrrolidone; Or

Iii) one or more kind sucrose fatty acid ester and the compositions of PVP as defined above.

The Polyethylene Glycol composition can comprise one or more kind PEG polymer, preferably can buy the PEG polymer between the PEG 200-PEG 4,000 that obtains, and promptly those have the PEG polymer of mean molecule quantity at about 190-4800.Preferred PEG polymer is that mean molecule quantity is about 190-3450, most preferably is about 400-1540.Preferred PEG polymer is that to have mean molecule quantity be the PEG 400 of about 380-420 and has the PEG 1,000 that mean molecule quantity is about 950-1050.In the PEG composition, ratio high and low-molecular-weight PEG kind is preferably about 2.5: 1-1: 2.5, and more preferably about 1: 1.For example, the admixture of preferred in the present invention PEG polymer comprises 1: 1 the admixture of PEG 400 and PEG 1000.Preferential select to have or near the PEG mixture of ingredients of the fusing point of the mammal physiological temp of accepting described preparation.Preferably the range of viscosities that has under 37 ℃ is about 140-1500 centipoise, more preferably is 300 mixture to the ultimate constituent of about 800 centipoise scopes under 37 ℃.

Spendable surfactant comprises but is not limited to polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate) in the preparation of the present invention; polysorbate 60; polysorbate 40; polyoxyethylene sorbitan monoleate; sorbester p17 sorbitan oleate (ICI Americas product; Wilmington, Delaware); sorbimacrogol oleate 100; polysorbate 85; Polysorbate 120; bile acid and their salt (being defined in 13 editions 1341-1342 pages or leaves of The Extra Pharmacopoeia by Martindale) are as sodium taurocholate; the deoxidation sodium taurocholate; chenodeoxy cholic acid; ursodesoxycholic acid and pluronic gram (P1uronic) or poloxamer (poloxamer) are as pluronic gram F68; pluronic gram L44; the compositions of pluronic gram L101 or the above one or more kind composition.The present invention preferably uses independent polyoxyethylene sorbitan monoleate or itself and one or more to plant other combinations-of surfactants.

The sucrose fatty acid ester that uses among the present invention comprise can buy obtain comprise monoesters, diester and three esters or its mixture or the admixture of sucrose with the ester that is used to prepare composition for oral liquid known in the art.The particular instance that is used for the present invention's ester is sucrose monolaurate, sucrose list myristinate, P-1570, sucrose monostearate, sucrose distearate, sucrose tristearate, sucrose three myristinates and sucrose tripalmitate or its compositions.

Except these compositions, the antioxidant or the antiseptic of other enhancing or protectiveness can be joined in the present composition, they can account for 4% of weight of formulation at most.Example can comprise ascorbic palmitate, benzylalcohol, butylated hydroxyanisol (BHA), Yoshinox BHT (BHT) etc.The example of these compositions comprises that concentration is that BHA and the concentration of about 0.3-2.5% (%w/w) is the BHT of about 0.005-0.15% (%w/w) in preparation of the present invention, preferred BHA and the mixture of BHT in this scope.Other embodiment comprises about 0.2% BHT.

The preparation of the present invention that uses one or more to plant antioxidant or antiseptic comprises:

A) active component or its pharmaceutically acceptable salt of about 1-20%, preferably this active component is about 1-16%, more preferably about 5-16%;

B) surfactant component of about 1-18%, the preferably approximately surfactant component of 5-15%, more preferably approximately 5-10% or the approximately surfactant component of 8-12%;

C) one or more of about 50-80% are planted Polyethylene Glycol (PEG) compositions, and preferably approximately one or more of 55-70% are planted poly-diethanol;

D) about 1-20%, preferably approximately one or more of 5-15% plant sucrose fatty acid ester or as defined K value be about 15-90, preferably the K value is about 17 polyvinylpyrrolidone (PVP) in USP/NF; With

E) one or more of about 0.1-4% are planted antiseptic or antioxidants, for example approximately the BHA of 0.3-2.5% (%w/w) and/or the approximately BHT of 0.005-0.15% (%w/w).

An embodiment preferred of the present invention provides pharmaceutical formulation, and it comprises:

A) active component of about 5-16%;

B) surfactant component of about 5-10%;

C) one or more of about 55-70% are planted Polyethylene Glycol compositions;

D) approximately 5-15% have as defined K value among the USP/NF for about 15-90, preferably to have the K value be about 17 polyvinylpyrrolidone (PVP); With

E) the approximately BHA of 0.3-2.5% (%w/w) and the approximately BHT of 0.005-0.15% (%w/w).

Preferred preparation of the present invention is encapsulated in airtight shell after preparation, in for example soft or hard gelatin capsule.During preparation of the present invention also can be made liquid or semi-liquid preparations and incapsulates.Equally, use composition and/or temperature in the tolerance interval, described preparation can be made gel or solid before encapsulated.The present invention describes in detail

The reactive compound that uses in the preparation of the present invention can prepare according to one of universal method shown below.

As shown in the scheme I; with acetyl group aroyl (4-hetaroylpyrazol) halogen of suitable replacement, aroyl (4-hetaroylpyrazol) chlorine of preferred formula (2); in the presence of alkali such as pyridine or trialkylamine such as triethylamine; in aprotic organic solvent such as dichloromethane or oxolane; three of processing formula (1) encircle benzodiazepine under-40 to 50 ℃ of temperature, obtain the derivant of formula (3) acidylate.Exist according to Lin etc. J.Het.Chem., 14, the method in 345 (1977) with the dialkyl amide of formula (4) two alkanols that contract, in aprotic organic solvent such as dichloromethane, is handled (3) at 0 ℃ in the temperature range of solvent refluxing, obtain the ketenes of formula (5).With the hydrazine that hydroxylamine or formula (6) replace, in acetic acid, in the temperature range of solvent refluxing, handle (5) in room temperature, obtain the target compound of formula (I), wherein A, B, D, E, G, X, Y, R ²And R ⁴As defined above, R ¹Be to be selected from (f) defined above, (g) or (j) to organize heterocyclic heterocyclic moiety.

Acetyl group aroyl (4-hetaroylpyrazol) chlorine of the preferred replacement of scheme I Chinese style (2) can be by using thionyl chloride in room temperature arrives the solvent refluxing temperature range; or with oxalyl chloride in aprotic solvent such as dichloromethane or oxolane; in the presence of the dimethyl formamide of catalytic amount, in 0-40 ℃ of scope, handle corresponding carboxylic acid and prepare easily.

Preferred dialkylamine two alkanols that contract can be bought and obtain or for known in the document or can prepare easily according to the method for similar document (Kantlehner, W.Chem.Ber.105,1340 (1972)).

The preferred three ring benzodiazepine of formula (1) are 10,11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (Albright etc., United States Patent (USP) the 5th, 536, No. 718, on July 16th, 1996 issued), 10,11-dihydro-5H-pyrazolo [5,1-c] [1,4] benzodiazepine (Cecchi, L. etc. J.Het.Chem.20,871 (1983) and 10,11-dihydro-5H-tetrazolo [5,1-c] [1,4] benzodiazepine (Klaubert, D.H., J.Het.Chem.22, 333 (1985)).Scheme I

The method that is used for formula (3) intermediate preparation at following scheme II explanation another kind.Scheme II

Thereby; with bromo aroyl (4-hetaroylpyrazol) halogen of suitable replacement, aroyl (4-hetaroylpyrazol) chlorine of preferred formula (8); in the presence of organic base such as pyridine or trialkylamine such as triethylamine; in aprotic organic solvent such as dichloromethane or oxolane; three of processing formula (1) encircle benzodiazepine under-40 to 50 ℃ of temperature, obtain the intermediate of the acyl groupization of formula (9).Make the mono-substituted terminal acetylene of straight chained alkyl of intermediate (9) and mono-substituted terminal acetylene such as trimethyl silyl or 1-6 carbon atom subsequently, close in the presence of palladium (II) and the Copper diiodide (I) at pyridine and catalyst such as chlorination two (triphenylphosphine), in organic base such as triethylamine as solvent, in the manometer tube of sealing, in the temperature range of room temperature to 100 ℃, exist according to Martinez etc. basically J.Med.. Chem.Method coupling in 35,620 (1992).Then with the acetylene intermediate of the formula (10) that obtains by with 1% sulphuric acid in the aprotic organic solvent oxolane saturated as usefulness Mercury bisulfate. (II), at room temperature, exist according to Reed etc. basically J.Org.ChemMethod in 52,3491 (1987) is handled aquation, obtains the acyl compounds of required formula (3), and wherein A, B, D, E, G, X and Y are as defined above and R ⁹It is the straight chained alkyl of a hydrogen or 1-6 carbon atom.Perhaps, incite somebody to action wherein R ⁹Be the chemical compound 9 of trimethyl, in ether solvents such as oxolane, handle, obtain wherein R with tetrabutylammonium ⁹It is the chemical compound (10) of hydrogen.

The preferred acylating agent of scheme II Chinese style (8) can by with thionyl chloride room temperature in the scope of the reflux temperature of solvent or with oxalyl chloride in aprotic organic solvent such as dichloromethane or oxolane; in the presence of the dimethyl formamide of catalytic amount, aryl (heteroaryl) carboxylic acid of handling the formula (7) of suitable replacement under 0-40 ℃ temperature obtains easily.

The acetylene intermediate of protecting among the scheme II can be bought and obtain, or known in the art, maybe can by with this area in the similar method of method easily prepare.

As shown in the scheme III, the intermediate acetyl compounds (3) of scheme I also can exist according to Kosugi etc. basically Bull.Chem.Soc.Jpn., 60Method in 767 (1987), bromo aryl (heteroaryl) chemical compound of the formula (9) by scheme II and (α-ethoxy ethylene base) trialkyltin, preferably (α-ethoxy ethylene base) tributyl tin closes in the presence of the palladium (II) in the chlorination two (triphenyl phosphorus) of catalytic amount, in aprotic organic solvent such as toluene, prepare to the Stille coupling under the reflux temperature of solvent in room temperature.Scheme III

The preparation of acetyl compounds (3) also can exist according to Cabri etc. Tetrahedron Lett., 32, the method in 1753 (1991) is finished vinyl alkyl ethers such as vinyl butyl ether palladium catalysis arylation by the aryl halide intermediate with formula (9).

(a-alkoxy vinyl) trialkyltin intermediate of scheme III can buy and obtain, or is known in the art, maybe can by with this area in the similar method of method easily prepare.

The R of scheme I therein ⁴Be under the situation of hydrogen, described heterocyclic nitrogen can be according to reaction alkylation or the acidylate described in the scheme IV.Scheme IV

Thereby, with formula (I, R ⁴Be H) pyrazole compound by with highly basic such as sodium hydride or hydrofining and alkylating agent such as alkyl halide, preferred alkyl chlorine (alkyl bromide or alkyl iodide) in aprotic organic solvent such as dimethyl formamide or oxolane, is handled alkylation in 0-80 ℃ of temperature range, obtain chemical compound (I, R ¹=(f) or (g)), wherein A, B, D, E, G, X, Y and R ²As defined above, R ⁴Be alkyl or acyl moiety.Perhaps; chemical compound (I) passes through with preferred acyl chlorides of carboxylic acid halides or carboxylic acid anhydrides; in the presence of amine alkali such as pyridine or the preferred triethylamine of trialkylamine; in aprotic organic solvent such as dichloromethane or oxolane, (when using pyridine, there is not other solvent) as alkali; in the temperature range of room temperature, handle acidylate at-40 ℃, obtain wherein A, B, D, E, G, X, Y and R ²As defined above, R ⁴It is the chemical compound (I) of alkyl or acyl moiety.Formula (I, R ⁴Be H) the alkylation of chemical compound or the acidylate mixture that generates regional isomer, wherein R ²Be hydrogen and R ¹Be to be selected from above the definition and (f) of following explanation respectively or (g) organize heterocyclic heterocyclic moiety.

The general formula of scheme I (I) chemical compound, wherein A and B are carbon, R ²Be H and R ¹Be the heterocyclic moiety that is selected from heterocyclic as defined above (g) group, can prepare according to the universal method shown in the plan V.Plan V

Thereby, the halogenated aryl of suitable replacement (heteroaryl) carboxylate, bromo (or iodo) methyl ester and the dialkyl amido propine of preferred formula (11), preferred 1-dimethylamino propine, catalyst such as chlorination two (triphenylphosphine) close palladium (II) and Copper diiodide (I) in the presence of, in organic base such as triethylamine, in the temperature range of room temperature to 80 ℃, exist according to Alami etc. basically as solvent Tetrahedron Lett., 34, in 6403 (1993) and Sanogashira etc. exist Tetrahedron Lett.,Method coupling in 4467 (1975) obtains the acetylene intermediate of the replacement of general formula (12).Subsequently by using oxidant, with the method for oxidation of many standards (Albini, A., Synthesis,263 (1993)) any in or with diepoxide for example reagent (Murray, R.W. Chem.Rev.1187 (1989)), in aprotic organic solvent such as dichloromethane, under subambient temperature, handle, described intermediate (12) is changed into its N-oxide.Not with the intermediate N divided oxide from but its original place reset be that the ketenes of general formula (13), described solvent comprise following any solvent or its combination or aqueous solvent: any C by handle (preferred heating) with hydroxylic solvent ₁-C ₈Straight or branched alkylol, ethylene glycol, Polyethylene Glycol, 1,2-propylene glycol, polypropylene glycol, glycerol, 2-methyl cellosolve, cellosolvo, 2,2,2-TFE, benzylalcohol, phenol or any for well known by persons skilled in the art, contain one or more free hydroxyl group (OH) substituent suitable solvent.

Plant solvents, contain one or more dicyandiamide solutions of planting cosolvents and also can be used for this N-oxide and reset the process that obtains required enamine ketone with one or more.Here the cosolvent of being mentioned can be defined as the diluent of primary solvent and can be selected from: hydrocarbon is pentane, hexane or heptane for example; Aromatic hydrocarbons is benzene, toluene or dimethylbenzene for example; Ether is ether, oxolane, diox or dimethoxy-ethane for example; Chlorohydrocarbon is dichloromethane, chloroform, dichloroethanes or sym-tetrachloroethane for example; Or other conventional solvent for example ethyl acetate, N, dinethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, acetone etc.

Can be by amine n-oxide being imported in the suitable hydroxylic solvent, preferably stir simultaneously, under about room temperature or approximately room temperature changes amine n-oxide into enamine ketone to finishing between the reflux temperature of solvent.In other cases, amine n-oxide is imported in the hydroxylic solvent, preferably stir simultaneously, can in the presence of acceptable catalyst such as palladium (II) catalyst or copper (I) catalyst, at room temperature or in room temperature between the reflux temperature of solvent, finish.

Described method provides the new method of the synthetic enamine ketonic compound in hydroxylic solvent (end product of its influence reaction) by propargyl amine or their N-oxide.The synthetic new method of described enamine ketone provides the alternative method easily of existing method and has further enlarged the scope of the raw material that can change enamine ketone product into.

Although the propargyl amine n-oxide change into enamine ketone product really cutter reason also do not have strictly to determine that as if it similar with two kinds of known methods: the heat of propargyl amine n-oxide [2,3]-sigmatropic rearrangement (Craig etc., Tetrahedron Lett.4025,1979; Hallstrom etc., Tetrahedron Lett.667,1980; Khuthier, A-H etc., J.Chem.Soc.Chem. Commun.9,1979) and some isoxazole change into enamine ketone (Liguori etc., Tetrahedron 44, 1255,1988).

With the hydrazine (6) that replaces in acetic acid, handle the mixture that (13) produce the regional isomerism chemical compound of the general formula (14) of different ratios and (15) in the temperature range that refluxes in room temperature.The main isomer separation of formula (14) also is hydrolyzed to subsequently the carboxylic acid of required formula (16) by chromatography and/or method for crystallising.

Then by with the similar method of the above method, change intermediate (16) the acidylate material of formula (17) into, preferred acyl chlorides (acylbromide or acyl iodides) or mixed anhydride.By any the above method, with three ring benzodiazepine of acylating agent (17) acidylate formula (1), obtain the chemical compound of required formula (I) then, wherein A, B are CH and D, E, G, X, Y and R ⁴As defined above, R ²Be hydrogen and R ¹Be to be selected from the following stated (g) to organize heterocyclic heterocyclic moiety.

Equally, with the hydrazine of non-replacement (6, R ⁴Be H) in acetic acid, in the scope of the reflux temperature of solvent, handle (13), obtain the intermediate pyrazoles ester of formula (18) in room temperature.In the case, as shown in the plan V I, described heterocyclic azanylization or acidylate can be obtained the chemical compound of formula (I), wherein R ²Be hydrogen and R ¹Be to be selected from as defined above (f) to organize heterocyclic heterocyclic moiety.Plan V I

Thereby, with highly basic such as sodium hydride or hydrofining and alkylating agent such as alkyl halide, preferred alkyl chlorine (alkyl bromide or alkyl iodide), in aprotic solvent such as dimethyl formamide or oxolane, in 0-80 ℃ of temperature range, handle, with the intermediate ester alkylation of formula (18), obtain the mixture of the regional isomer of the formula (14) of different ratios and (15).By chromatography and/or crystallization with the main region isomer separation of formula (15) and the carboxylic acid that is hydrolyzed to required formula (19) subsequently, then by with the above similar method, change it into acylating agent, preferred acyl chlorides or mixed anhydride.Use the acidylate material of formula (20) that three of formula (1) is encircled the chemical compound that benzodiazepine acidylates obtain required formula (I), wherein A, B, D, E, G, X, Y and R then ⁴As defined above, R ²Be hydrogen and R ¹Be to be selected from (f) defined above to organize heterocyclic heterocyclic moiety.

The chemical compound of general formula (I), wherein R ¹Be to be selected from R defined above ¹(h) organize heterocyclic heterocyclic moiety, can as shown in plan V II, prepare.Plan V II

At first with hydrazine in acetic acid, at the malonaldehyde of room temperature suitable replacement of processing formula (21) in the scope of the reflux temperature of solvent, use potassium permanganate then in alkaline aqueous solution, at room temperature oxidation intermediates pyrazoles under the temperature of the backflow of solvent, obtain the carboxylic acid intermediate of formula (22).By method similar to the above, change acid (22) into acylating agent, preferred acyl chlorides (acylbromide or acyl iodides) or mixed anhydride.At last, make the acylating agent of formula (23) and three ring benzodiazepine reactions of formula (1), obtain the chemical compound of formula (I), wherein A, B, D, E, G, X, Y and R ⁴As defined above and R ¹Be to be selected from as defined above (h) to organize heterocyclic heterocyclic moiety.

The R of plan V II therein ⁴Be under the situation of hydrogen, can be according to the method shown in above with described heterocyclic nitrogen alkylation or acidylate.

The malonaldehyde of preferred formula (21) and the hydrazine of plan V II can be bought and obtain or known in the art, perhaps can be by being similar to Knorr etc. At J.Org.Chem., 49, 1288 (1984) and Coppola etc. exist J.Het.Chem., 11, the preparation method method of known compound described in 51 (1974) easily prepares.

The intermediate carboxylic acid of the formula of plan V II (22), wherein Y as defined above and R ⁴Be not hydrogen, another preparation method shown in the plan V III.Plan V III

The organotin reagent that makes formula (25) in the Stille coupling reaction with aryl (heteroaryl) halogen of suitable replacement, the bromide or the iodide of preferred formula (28), close in the presence of palladium (0) and the Copper diiodide (I) as four (triphenyl phasphines) at catalyst, in organic aprotic solvent such as dimethyl formamide, in room temperature to 150 ℃ temperature range, exist according to Farina etc. substantially J.Org.Chem., 59, 5905 (1994) the middle similar approach reactions of finding.In aquiferous ethanol or oxolane,, obtain the carboxylic acid of required formula (22) with sodium hydroxide or lithium in room temperature ester basic hydrolysis with the formula (26) that obtains in the scope of the reflux temperature of solvent.

Equally, the R group organotin reagent of the formula of alkyl (25) preferably wherein, by using halogenation trialkyltin, preferred tributyltin chloride (or bromination tributyl tin), metallization reagent such as lithium alkylide as just-butyl lithium, the second month in a season-butyl lithium or tert-butyl lithium in the presence of, in aprotic organic solvent such as ether,-40 ℃ in the temperature range of room temperature, exist according to Martina etc. Synthsis, similar method described in 8,613 (1991) is with the 4-bromo N-alkyl pyrazole metallization preparation easily of formula (24).

The 4-bromo pyrazoles that the preferred N-alkyl of formula (24) replaces, by using alkyl halide, preferred alkyl chlorine (alkyl bromide or alkyl iodide), in the presence of highly basic such as lithium hydride, sodium hydride or hydrofining, in aprotic organic solvent such as dimethyl formamide or oxolane, in 0-80 ℃ temperature range, 4-bromo pyrazolidinylization is prepared easily.Perhaps, the alkylation of 4-bromo pyrazoles can be with above mentioned alkylating agent and highly basic metal base such as Lithium hydrate, sodium hydroxide or potassium hydroxide, at phase transfer catalyst (Jones, R.A.Aldrichimica ACTA, 9 (3), 35,1976) as carrying out under zephiran chloride dimethyl myristyl ammonium or the existence of zephiran chloride trimethyl ammonium.

The diazotising of the corresponding substituted aniline of aryl (heteroaryl) the iodine through type (27) of preferred formula (28) is reacted in acidic aqueous media by corresponding diazol and iodine and potassium iodide subsequently, exists according to Street etc. basically J.Med.Chem., 36, 1529 (1993) and Coffen etc. exist J. Org. Chem., 49, the method in 296 (1984) prepares easily.

Another preparation method of the chemical compound of general formula (I) is shown in the scheme IX.Scheme IX

With three ring benzodiazepine of formula (1) with the fluoro aroyl of halo aroyl (4-hetaroylpyrazol) halogen of suitable replacement, preferred formula (29) or fluoro (chloro) aroyl chloride of mixing; in the presence of alkali such as triethylamine or diisopropylethylamine; in aprotic organic solvent such as dichloromethane or oxolane; handle between the reflux temperature of solvent at-40 ℃, obtain the derivant (30) of acidylate.

Perhaps, described acidylate material can be the mixed anhydride of carboxylic acid as mentioned above, and as by 2,4,6-trichloro-benzene formyl chloride exists according to Inanaga etc. in solvent such as dichloromethane Bull.Chem. Soc.Jpn, 52, the method prepared in reaction in 1989 (1979).Three ring benzodiazepine with formula (1); in solvent such as dichloromethane; in the presence of organic base such as 4-dimethylaminopyridine,, obtain the intermediate acylated derivatives (30) of scheme IX at 0 ℃ of mixed anhydride of handling described general formula (29) in the scope of the reflux temperature of solvent.

Then, the chemical compound of formula (30) is used heterocyclic lithium, sodium or the potassium salt of the suitable replacement of formula (31), in polar non-proton organic solvent such as dimethyl formamide or oxolane, handle in the scope of the reflux temperature of solvent in room temperature, obtain the chemical compound of general formula (I), wherein A, B, D, E, G, X, Y, R ², R ³And R ⁵As defined above, R ¹Be (a) and (b), (c), (d), (l), (n) or the heterocyclic moiety (o) that is selected from above definition.

The intermediate of formula (30) and the intermediate salt condensation of formula (31) produce the regional isomer of the general formula (I) of different ratios, and it separates by chromatography and/or method for crystallising.

The assorted aroyl chloride of the fluoro aroyl of the replacement of preferred formula (29) and fluoro (or chloro) can be bought and obtain or known in the art, maybe can easily prepare by the similar method that is used for known compound in the document.

Heterocyclic lithium, sodium or the potassium salt of formula (31), can be by using highly basic such as lithium hydride, sodium hydride, hydrofining or metal alkoxide,-40 ℃ in the temperature range of room temperature, heterocycle preparation as described in aprotic organic solvent is handled in as dimethyl formamide or oxolane.

Perhaps, can be at the chemical compound of the general formula (I) described in the scheme IX according to preparing in the method shown in the scheme X.Scheme X

Thereby,,, in alcoholic solvent such as methanol, in the presence of the dimethyl formamide of catalytic amount, handle as with oxalyl chloride (or thionyl chloride) with methods known in the art; Or by with methanol in the presence of acidic catalyst such as right-toluenesulfonic acid, in room temperature to the temperature range internal condensation that refluxes, with the fluorinated aryl or the esterification of fluoro (or chloro) heteroaryl carboxylic acid of the suitable replacement of formula (32).

Make heterocyclic lithium, sodium or the potassium salt of the suitable replacement of the ester of the formula (33) that obtains and formula (31), in polar non-proton organic solvent such as dimethyl formamide,, obtain the intermediate ester of formula (34) at the temperature range internal reaction of room temperature to 150 ℃.(33) produce the regional isomer of the formula (34) of different ratios with the condensation of (31), it separates through chromatography and/or method for crystallising.

Subsequently, with aqueous alkali such as Lithium hydrate, sodium hydroxide or potassium hydroxide, hydrolysis in methanol or oxolane obtains the carboxylic acid of formula (35) with the intermediate ester of (34).

Then, with any above-described method, change the intermediate carboxylic acid of formula (35) into acylating agent, the acyl chlorides or the mixed anhydride of preferred formula (36).

Subsequently,, make the three ring benzodiazepine of formula (1) and the intermediate acylation reaction of formula (36), obtain the chemical compound of the formula (I) of required scheme IX according to any above-described method.

Perhaps, can be according to the carboxylic acid for preparing in the method shown in the scheme XI in the replacement of the formula (35) described in the scheme X.Scheme XI

Thereby, lithium, sodium or the potassium salt of substituted heterocycle that makes the fluorinated aryl of formula (37) or fluoro (chloro) heteroaryl nitrile and formula (31) is in apolar aprotic solvent such as dimethyl formamide, at the temperature range internal reaction of room temperature to 150 ℃, obtain the intermediate of general formula (38).(37) produce the regional isomer of the formula (38) of different ratios with (31) reaction, it is through chromatography and/or Crystallization Separation.Formula (38, y ≠ CF ₃) the hydrolysis of intermediate nitrile preferentially adopt mineral acid such as sulphuric acid, in the temperature range of room temperature to 60 ℃, carry out.

Perhaps, the hydrolysis of described nitrile (38) can be by heating in ethanol, in the presence of highly basic metal base such as sodium hydroxide, be with or without phase transfer catalyst (Jones, R.A.AldrichimicaActa, 9 (3), 35,1976) as carrying out under the zephiran chloride dimethyl myristyl ammonium.

Then by with the above similar method, the carboxylic acid of the formula (35) that obtains is changed into the chemical compound of the formula (I) of required scheme IX.

Perhaps, the carboxylic acid of the replacement of the formula of scheme X (35) can be according to the method shown in the scheme XII, and order be used alkaline hydrogen peroxide, in dimethyl sulfoxide, exists according to Katritzky etc. basically Synthesis, the method in 949 (1989), the nitrile of processing formula (38), wherein A and B are CH and R ¹Not the alkanoyl, alkynyl, (b) of 2-7 carbon or (d), preferably use dilute sulfuric acid and sodium nitrite subsequently, exist according to Hanes etc. Tetrahedron, 51, the method in 7403 (1995) handles the amide preparation of the resulting formula of hydrolysis (38).Scheme XII

R wherein ¹Not (b) or (d)

Provide the method for optimizing of the carboxylic acid that the intermediate of the formula (35) that is used to prepare scheme X replaces among the scheme XIII, wherein R ¹Be to be selected from R as defined above ¹(a) organize heterocyclic heterocyclic moiety.Scheme XIII

With the aniline diazotising of the suitable replacement of formula (40), subsequently, with stannic chloride (II) in concentrated hydrochloric acid, according to Street etc. at J .Med.Chem., the method in 36,1529 (1993) obtains the intermediate hydrazonium salt hydrochlorate of formula (42) with the diazol reduction of the formula (41) that obtains.Subsequently, make the aldehyde derivatives (R wherein of formula (42) and formula (47) ²As defined above, R ³And R ⁵Be that H and P are dialkyl acetal such as acetyl group dimethylacetal) or the ketone of formula (47) (R wherein ², R ³And R ⁵With P be as defined above=O or (O-alkyl) ₂), in solvent such as methanol aqueous solution, at the temperature range internal condensation of room temperature to 100 ℃, obtain after the crystallization required formula (34, R ¹Be (a) and R ⁵Be H) intermediate ester, then it is changed into the chemical compound of the formula (I) as shown in above scheme X.

When Y is OCH ₃The time, the chemical compound of the general formula of described scheme I (I) can be easily as at demethylation as shown in the scheme XIV.Scheme XIV

Thereby making wherein, Y is OCH ₃The chemical compound and the Boron tribromide of formula (I) in organic solvent such as dichloromethane, react, obtain the phenol of corresponding formula (I), wherein Y is OH and A, B, D, E, G, X, R ²And R ³As defined above and R ¹Be that (a) that is selected from as above definition and following explanation organizes heterocyclic heterocyclic moiety.

Prepare wherein R according to scheme XV ¹Contain three heteroatomic chemical compounds.Scheme XV

Thereby; cyano group aroyl (4-hetaroylpyrazol) halogen with suitable replacement; aroyl (4-hetaroylpyrazol) chlorine of preferred formula (43) is in the presence of alkali, in aprotic organic solvent such as dichloromethane or oxolane; three of processing formula (1) ring benzodiazepine in-40 to 80 ℃ temperature range; obtain the intermediate nitrile of formula (46, scheme XVI), subsequently; it with mineral acid such as sulphuric acid, is hydrolyzed to the amide intermediate of general formula (44) under the temperature of room temperature to 50 ℃.Dialkyl amide with formula (4) contracts two alkanols in aprotic organic solvent such as dichloromethane or oxolane, handles described amide (44) in 0-80 ℃ temperature range, obtains the intermediate of formula (45).In acetic acid, in the temperature range that refluxes, handle (45) with the hydrazine of hydroxylamine or formula (6), obtain the target compound of required formula (I), wherein A, B, D, E, G, X, Y, R in room temperature ²And R ⁴As defined above and R ¹Be (e), (i) that is selected from above definition and the heterocyclic heterocyclic moiety of (k) organizing.

Another is used for the midbody acid amide (referring to scheme XV) of preparation formula (44), wherein A and B be CH and D be not the method for optimizing of CH shown in the scheme XVI and comprise with alkaline hydrogen peroxide in dimethyl sulfoxide, exist according to Katritzky etc. substantially Synthesis, the method in 949 (1989) is handled the nitrile of formula (46).Scheme XVI

Prepare wherein R ¹Comprise four hetero atoms and R ⁴The preferable methods of chemical compound of general formula (I) that is hydrogen is shown in the scheme XVII.Scheme XVII

With the nitrile intermediate of the formula (46) of scheme XVI with Hydrazoic acid,sodium salt and ammonium chloride in aprotic organic solvent such as dimethyl formamide, handle in the scope of the reflux temperature of solvent in room temperature, obtain the chemical compound of required formula (I), wherein A, B, D, E, G, X and Y as defined above, R ⁴Be hydrogen, R ¹Be that (m) that is selected from above definition organizes heterocyclic heterocyclic moiety.

The chemical compound of general formula (I), wherein D is that CW and W are hydrogen, can be as carrying out the Mannich condensation as shown in the scheme XVIII.Scheme XVIII Thereby, make the chemical compound of formula (I, D are CH) and the aqueous solution of formaldehyde or paraformaldehyde, the replacement amine and the glacial acetic acid of formula (47), in alcoholic solvent such as methanol, to the temperature range internal reaction that refluxes, obtain the Mannich alkali of corresponding formula (I), wherein A, B, E, G, X, Y, R in room temperature ², R ³, R ⁵, R ⁶And R ⁷As defined above; D is CW; W is the dialkyl aminoalkyl residue, preferred dimethylaminomethyl residue and R ¹Be (a), (c) that are selected from above definition, (e), (f), (g), (h), (i), (j), (k), (l), (m), (n) and (o) organize heterocyclic heterocyclic moiety.

Equally, wherein D is that the chemical compound of the general formula (I) of CH can carry out halogenation as shown in scheme XIX.Scheme XIX

Thereby, make formula (I, D is CH) chemical compound and N-halo butanimide such as N-chloro (bromo or iodo) butanimide, in polar non-proton organic solvent such as dichloromethane, at-80 ℃ of temperature range internal reactions to room temperature, obtain the halide derivative of corresponding general formula (I), wherein A, B, E, G, X, R ², R ³And R ⁵As defined above, D is CW, and W is halogen such as chlorine (bromine or iodine) and R ¹Be (a), (c) that are selected from above definition, (e), (f), (g), (h), (i), (j), (k), (l), (m), (n) and (o) organize heterocyclic heterocyclic moiety.

Biological activity according to following method test motif compound of the present invention.

Test compound is to the vasopressin V of normal conscious water load rat ₂The agonist effect:

Give male or female normotensive Sprague-Dawley rat (the Charles River Laboratories of 350-500g body weight, Inc., Kingston, NY) standard rodent (Purina Rodent Lab.Chow 5001) and arbitrarily drinking-water.In test day, rat is placed individually the metabolic cage that is equipped with device that feces and urine are separated and collects the container of urine.Give test compound or control drug with the 10mg/kg oral dose in the 10ml/kg capacity.Used solvent is to be dissolved in 2.5% dimethyl sulfoxide (DMSO) that boils 20% in the corn starch in advance.Give test compound after 30 minutes, with 30ml/kg water pipe is raised in the stomach of rat with feeding tube.Do not provide water or food at test period to rat.Give to collect urine 4 hours behind the test compound.When finishing in 4 hours, measure the urine amount.Use Fiske One-Ten permeability manometer (Fiske Associates, Norwood, MA, 02062) or AdvancedCRYOMATIC permeability manometer, (Advanced Instruments, Norwood MA) measure the osmotic pressure of urinating to the 3C2 type.Use the ion specificity electrode in the Beckman SYNCHRON EL-ISE electrolyte system analyser to carry out Na ⁺, K ⁺And Cl ^-Ion determination.The osmotic pressure of described urine will increase by ratio.In screening test, every kind of chemical compound uses two rats.If the difference of the urine amount of two rats, is then used the 3rd rat greater than 50%.

Test compound is to the vasopressin V of the normal conscious Brattleboro of the isozygotying rat that suffers from central diabetes insipidus ₂The agonist effect:

Give the male or female Brattleboro of isozygotying rat (HarlanSprague Dawley, Inc., Indianapolis, IN) the standard rodent (Purina RodentLab.Chow 5001) and arbitrarily drinking-water of 250-350g body weight.In test day, rat is placed individually the metabolic cage that is equipped with device that feces and urine are separated and collects the container of urine.Give test compound or control drug with the 1-10mg/kg oral dose in the 10ml/kg capacity.Used solvent is to be dissolved in 2.5% dimethyl sulfoxide (DMSO) that boils 20% in the corn starch in advance.Rat is arbitrarily drunk water.After giving test compound, collected urine 6 hours.When finishing in 6 hours, measure the urine amount.Use Fiske One-Ten permeability manometer (Fiske Associates, Norwood, MA, 02062) or Advanced CRYOMATIC permeability manometer, (Advanced Instruments, Norwood MA) measure the osmotic pressure of urinating to the 3C2 type.Use the ion specificity electrode in the BeckmanSYNCHRON EL-ISE electrolyte system analyser to carry out Na ⁺, K ⁺And Cl ^-Ion determination.Described animal model is mainly used in the assessment of described reactive compound usefulness and acting duration.The result of research lists in Table I.

Embodiment urine amount osmotic pressure rat type ^c

(% minimizing) ^a(% increase) ^b2 80％ (1mg/kg) 306％ (1mg/kg) CD3 58％ 240％ CD4 57％ 225％ CD5 56％ 231％ CD6 58％ 270％ CD7 13％ 137％ CD9A 70％ 325％ CD9B 21％ 168％ CD11 70％ 285％ CD12 69％ 330％ CD13 50％ 229％ CD14 86％ 406％ CD15 47％ 38％ CD16 88％ 400％ CD18 52％ 214％ CD20 25％ (1mg/kg) 152％ (1mg/kg) CD21 49％ 181％ CD22 80％ 322％ CD24 47％ 159％ CD25 87％ 979％ CD26 54％ 279％ CD27 76％ 183％ CD28 75％ 37％ CD29 66％ 305％ CD30 81％ 334％ BB31 72％ 298％ CD32 77％ 373％ CD33 68％ 362％ CD34 76％ 407％ BB35 63％ 308％ CD36 66％ 164％ BB37 71％ 370％ CD38 66％ 256％ BB39 69％ 253％ CD40 46％ 183％ CD41 69％ 240％ CD49 74％ 221％ BB50 53％ 223％ CD51 72％ CD52 66％ 261％ CD55 80％ 164％ CD57 77％ 288％ CD58 49％ 324％ CD59 80％ 607％ CD60 54％ 165％ CD61 59％ 245％ CD62 22％ 150％ CD63 27％ 214％ CD64 79％ 349％ CD71 84％ 264％ CD77 13％ 90％ CD78 21％ 115％ CD79 38％ 123％ CD81 82％ 490％ CD83 85％ 442％ CD84 56％ 291％ CD85 76％ 436％ CD86 5％ 86％ CD87 71％ 214％ CD88 68％ 226％ CD90 61％ 413％ CD91 22％ 69％ CD92 69％ 454％ CD95 68％ 300％ CD97 3％ 106％ CD99 43％ 205％ CD100 24％ 248％ CD101 76％ 376％ CD107 31％ 125％ CD108 30％ 145％ CD109 21％ 95％ CD115 66％ 229％ CD116 66％ 256％ CD117 68％ 311％ CD120A 66％ 269％ CD120B 67％ 272％ CD121 22％ 155％ CD123 88％ 663％ CD

^aExcept that other explanation, the minimizing % of urine amount under 10mg/kg with the contrast ratio.

^bExcept that other explanation, the change of osmotic pressure in contrast percentage ratio under 10mg/kg.

^cThe rat model that uses: Sprague-Dawley (CD) or Brattleboro (BB).

Below provide embodiment so that the present invention is described, but do not limit the scope of the invention.

Embodiment 1 (4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Oxalyl chloride (2.0g) is joined in dichloromethane (25ml) suspension of 4-fluoro-2-trifluoro acute pyogenic infection of nails yl benzoic acid (2.0g).Add two dimethyl formamides and described mixture was at room temperature stirred 18 hours.The solution evaporation that obtains is obtained rough acyl chlorides to dried.Be dissolved in the dichloromethane once more it and filtration.Described material evaporation is obtained liquid, then this liquid is dissolved in the hexane once more, filtration and evaporation obtain acyl chlorides, are light yellow viscous liquid, and it is not further purified and uses.

Dichloromethane solution (25ml) gradation of acyl chlorides (2.26g) is joined 10,11-dihydro-5H-pyrrolo-[2,1-c] in the mixture of [1,4] benzodiazepine (1.66g), dichloromethane (10ml) and diisopropylethylamine (1.30g), in ice bath, cool off.After at room temperature keeping 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.Filter through the anhydrous sodium sulfate drying dichloromethane solution and by hydrated magnesium silicate sodium short column, further use the dichloromethane eluting of several volumes.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration and obtain the 2.57g title compound, m.p.154-155 ℃.

Embodiment 2[4-(3-methyl-pyrazol-1-yl)-2-trifluoro acute pyogenic infection of nails base-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

The oil solution (0.15g) of 60% sodium hydride with hexane wash and add exsiccant dimethyl formamide (25ml), is added 3-methylpyrazole (0.25g) subsequently.After hydrogen stops to emit, add (4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.0g).This reactant mixture was heated 15 hours down in 110 ℃ in sand bath.This reactant mixture is poured on ice and adds saturated brine solution.Collecting precipitation thing after filtration.Rough product is dissolved in the dichloromethane and filters, further use the dichloromethane eluting of several additional volumes by hydrated magnesium silicate sodium short column.On hot plate, concentrate the organic layer that merges and add hexane simultaneously gradually.After the cooling, collect the raw product that crystal obtains 0.77g after filtration.Be further purified by the filtration of hydrated magnesium silicate sodium short column, add hexane subsequently, obtaining title compound is crystalline solid (0.66g), m.p.194-195 ℃.

Embodiment 3[4-(4-methyl-pyrazol-1-yl)-2-trifluoro acute pyogenic infection of nails base-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 2, use (4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.15g), 4-methylpyrazole (0.20g) and the dimethyl formamide (25ml) of ketone (0.8g), 60% sodium hydride, obtaining product (0.47g) is colourless amorphous solid, MS, m/z:437.3 (M+H) ⁺, 873.2 (2M+H) ⁺

Embodiment 4 (4-pyrazol-1-yl-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 2, use (4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.20g), pyrazoles (0.25g) and the dimethyl formamide (35ml) of ketone (1.0g), 60% sodium hydride, obtaining product (0.62g) is colourless amorphous solid, MS, m/z:423.2 (M+H) ⁺, 445.2 (M+Na) ⁺, 845.3 (2M+H) ⁺

Embodiment 5[4-(3-cyclopropyl-pyrazol-1-yl)-2-trifluoro acute pyogenic infection of nails base-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 2, use (4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.20g), 3-cyclopropyl pyrazoles (0.43g) and the dimethyl formamide (50ml) of ketone (1.42g), 60% sodium hydride, obtaining product (1.22g) is the crystal form solid, m.p.163-164 ℃.

Embodiment 6[4-(4-methyl-imidazoles-1-yl)-2-trifluoro acute pyogenic infection of nails base-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 2, use (4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.20g), 4-methylimidazole (0.25g) and the dimethyl formamide (25ml) of ketone (1.0g), 60% sodium hydride, obtaining title compound (0.66g) is amorphous solid, MS, m/z:437.2 (M+H) ⁺, 873.2 (2M+H) ⁺

Embodiment 7 (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-(4-[1,2,4] triazol-1-yl-2-trifluoro acute pyogenic infection of nails base phenyl)-ketone

Method with embodiment 2, use (4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.20g), 1,2 of ketone (1.0g), 60% sodium hydride, 4-triazole (0.20g) and dimethyl formamide (25ml), obtaining title compound (0.36g) is colourless amorphous solid, MS, m/z:424.2 (M+H) ⁺, 847.3 (2M+H) ⁺Embodiment 8 (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Oxalyl chloride (2.60g) is joined in dichloromethane (50ml) suspension of 2-chloro-4-fluorinated acid (3.44g).Adding two dimethyl formamides also at room temperature stirred this mixture 18 hours.It is viscosity grease (3.72g) that the solution evaporation that obtains is obtained rough 2-chloro-4-fluorobenzene formyl chloride.

Dichloromethane solution (25ml) gradation of rough 2-chloro-4-fluorobenzene formyl chloride (3.68g) is joined that stirring, ice-cold 10,11-dihydro-5H-pyrrolo-[2,1-c] in the solution of [1,4] benzodiazepine (2.76g), diisopropylethylamine (2.47g) and dichloromethane (50ml).After at room temperature 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.Filter the dichloromethane eluting of also further using several volumes with the anhydrous sodium sulfate drying dichloromethane solution and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration and obtain title compound (3.85g), m.p.110-112 ℃.

Embodiment 9[2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (isomer A) and [2-chloro-4-(5-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (isomer B)

Method 1: in the dimethyl formamide solution (25ml) of the oil solution (0.3g uses the hexane defat) of 60% sodium hydride, add 3-methylpyrazole (0.55g).When hydrogen emit stop after, add (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.70g).This reactant mixture was heated 18 hours in sand bath (125 ℃ of internal temperatures).Then reactant mixture is poured on ice and with saturated brine solution and further dilutes.The solid that goes out of collecting precipitation after filtration.This raw product is dissolved in the dichloromethane,, filters and further use the dichloromethane eluting of several volumes then by hydrated magnesium silicate sodium short column through anhydrous sodium sulfate drying.The eluent that merges refluxed on hot plate concentrate the while and add hexane gradually until obtaining opaque solution.Obtain amorphous solid after the cooling.Described material by second hydrated magnesium silicate sodium short column and evaporating solvent in a vacuum, is obtained the mixture of approximate 9: 1 ratios of regional isomer 9A and 9B, be amorphous glass shape thing (1.11g), MS, m/z:403.2 (M+H) ⁺

Method 2: under blanket of nitrogen, 0 ℃, be added dropwise to 3-methylpyrazole (5.50g) in the suspension (250ml) in the dry dimethyl formamide of 60% sodium hydride (3.00g) of pre-cooled, the hexane wash that stirring.This mixture is heated to room temperature.After gas stops to emit, add (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-the yl)-ketone (17.0g) of solid, shaped, with this mixture heated to 130 ℃ 1 hour.Reactant mixture is poured in the frozen water, after filtration collecting precipitation thing and air-dry.Described precipitate is dissolved in the dichloromethane, filters, use eluent ethyl acetate through anhydrous sodium sulfate drying and by the silica gel short column.The filtrate that merges evaporated in a vacuum obtain residual foam (18.5g).With regional isomer on silica gel through the low pressure column chromatography purification with separate, with the gradient mixture eluting of ethyl acetate-hexane (10: 90 to 25: 75), obtain the regional isomer of two purification:

Isomer A, [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (13.5g), be colourless amorphous solid; MS (EI), m/z:402 (M) ⁺With sample (0.5g) crystallization from ether, recrystallization obtains regional isomer A (0.275g) from ethanol subsequently, is colourless, lenticular solid, m.p.141-143 ℃.

Isomer B, [2-chloro-4-(5-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.93g), be colourless amorphous solid.With sample crystallization from ether, subsequently from methanol recrystallization to obtain regional isomer B be colourless spicule (1.4g), m.p.160-163 ℃; MS (EI), m/z:402 (M) ⁺, MS (+FAB), m/z:403 (M+H) ⁺Embodiment 10[2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Step a) 2-chloro-4-(3-methylpyrazole-1-yl) benzonitrile: (60% in oil to the sodium hydride that cools off (0 ℃); 2.0g) dimethyl formamide (50ml) suspension in gradation add 3-methylpyrazole (3.39g).After hydrogen stops to emit, add 2-chloro-4-fluoro benzonitrile (5.17g) and also this mixture was at room temperature stirred 18 hours.This mixture is poured on ice, also collects the precipitate that obtains after filtration with the saline dilution.Raw product is dissolved in the dichloromethane, makes crystallization by the filtration of anhydrous silicic acid magnesium sodium post and through adding hexane.Recrystallization obtains the 4.42g product from ethanol, m.p.148-150 ℃.

Step b) 2-chloro-4-(3-methylpyrazole-1-yl) Benzoylamide: the dimethyl sulfoxide that contains potassium carbonate (0.40g) (20ml) suspension of 2-chloro-4-(3-methylpyrazole-1-yl) benzonitrile (4.35g) of step a) is cooled off in ice bath.Add hydrogen peroxide (30%, 2.4ml) and with this mixture heat to room temperature more than 1 hour.Collect the precipitate obtain after filtration and from ethanol recrystallization, obtain the 2.44g product, be fine needle crystal, m.p.159-160 ℃; MS, m/z:235.9 (M+H) ⁺

Step c) 2-chloro-4-(3-methylpyrazole-1-yl) benzoic acid: the solution in 75% aqueous sulfuric acid (25ml) of 2-chloro-4-(3-methylpyrazole-1-yl) Benzoylamide (1.09g) of step b) cooled off in ice bath and add sodium nitrite (1.73g).This mixture is heated to room temperature more than 1 hour and be poured on ice.After filtration the collecting precipitation thing and be directly used in next step the reaction in.

Step d) [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H-10,11-dihydro-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone: 2-chloro-4-(3-methylpyrazole-1-yl) benzoic acid (0.69g) of step c) and mixture, oxalyl chloride (1.0g) and dimethyl formamide of dichloromethane (25ml) were at room temperature stirred 18 hours.This mixture is concentrated, be dissolved in the dichloromethane (25ml) and join and contain 10 of diisopropylethylamine (0.76g), in dichloromethane (25ml) mixture of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.51g).This mixture was at room temperature stirred 18 hours and wash with saturated sodium bicarbonate aqueous solution.Organic layer is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.With this solution concentration and with the material crystallization from ether that obtains, obtain the 0.67g product, m.p.137-138 ℃; MS, m/z:403.2 (M+H) ⁺, 805.8 (2M+H) ⁺

Embodiment 11[2-chloro-4-(4-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.3g uses the hexane defat), 4-methylpyrazole (0.48g) and the dimethyl formamide (25ml) of ketone (1.0g), 60% sodium hydride, obtain title compound (0.74g), be amorphous solid, MS, m/z:403.2 (M+H) ⁺, 425.2 (M+Na) ⁺, 805.3 (2M+H) ⁺

Embodiment 12[2-chloro-4-(4-methyl-imidazoles-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.3g uses the hexane defat), 4-methylimidazole (0.48g) and the dimethyl formamide (25ml) of ketone (1.0g), 60% sodium hydride, obtain title compound (0.38g), be amorphous solid, MS, m/z:403.3 (M+H) ⁺

Embodiment 13[2-chloro-4-(3-trifluoro acute pyogenic infection of nails base-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and oil solution (0.25g uses the hexane defat), 3-trifluoro acute pyogenic infection of nails base pyrazoles (0.61g) and the dimethyl formamide (25ml) of ketone (0.8g), 60% sodium hydride, obtaining title compound is amorphous solid, MS, m/z:457.2 (M+H) ⁺Embodiment 14[2-chloro-4-(1,2, the 4-triazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.5g of ketone (1.7g), 60% sodium hydride, use the hexane defat), 1,2,4-triazole (0.70g) and dimethyl formamide (50ml), obtain title compound (0.51g), be amorphous solid, MS, m/z:390.3 (M+H) ⁺, 779.3 (2M+H) ⁺

Embodiment 15 (2-chloro-4-pyrroles-1-base-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.3g uses the hexane defat), pyrroles (0.42g) and the dimethyl formamide (25ml) of ketone (1.7g), 60% sodium hydride, obtain title compound (0.60g), be amorphous solid, MS, m/z:388.2 (M+H) ⁺

Embodiment 16 (2-chloro-4-pyrazol-1-yl-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and oil solution (0.2g uses the hexane defat), pyrazoles (0.20g) and the dimethyl formamide (25ml) of ketone (1.0g), 60% sodium hydride, obtaining title compound is amorphous solid, MS, m/z:389.2 (M+H) ⁺, 777.1 (2M+H) ⁺Embodiment 17[2-chloro-4-(1H-imidazoles-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-fluoro phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.50g uses the hexane defat), imidazoles (0.50g) and the dimethyl formamide (25ml) of ketone (2.0g), 60% sodium hydride, obtain title compound (0.57g), be the brown amorphous solid, MS, m/z:389 (M+H) ⁺

Embodiment 18[2-chloro-4-(3-methylpyrazole-1-yl)-phenyl]-(3-methyl-5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Step a) 1-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-2,2,2-three fluoro-ethyl ketone: to ice-cold 10,11-dihydro-5H-pyrrolo-[2,1-c] be added dropwise to the dichloromethane solution of three fluoro acetic anhydrides (7.0g) in dichloromethane (75ml) solution of [1,4] benzodiazepine (5.62g) and diisopropylethylamine (4.0g).This mixture was at room temperature stirred 18 hours and water and saturated sodium bicarbonate aqueous solution washing.Organic layer is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtaining the 7.70g product is fine needle crystal, m.p.134-135 ℃, and MS m/z:281 (M+H) ⁺

Step b) 1-(3-dimethylaminomethyl-5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-2,2,2-three fluoro ethyl ketones: will be from the 1-(5H of step a), 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-2,2,2-three fluoro ethyl ketones (2.80g), Bis-dimethylamino methane (2.04g), paraformaldehyde (2.70g) and the mixture of acetic acid (1.20g) in the mixture of oxolane (50ml) and methanol (50ml) at room temperature stirred 18 hours.This mixture is concentrated in a vacuum, add entry and described aqueous mixture dichloromethane extraction.The extract that merges is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.This solution is concentrated in a vacuum and with residue crystallization from hexane, obtaining the 2.05g product is colorless solid, m.p.109-110 ℃, MS m/z:338.3 (M+H) ⁺

Step c) iodate trimethyl-(10-trifluoroacetyl group-10; 11-dihydro-5H-pyrrolo-[2; 1-c] [1; 4] benzodiazepine -3-base-methyl)-and ammonium: will be from the 1-(3-dimethylaminomethyl-5H of step b); 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-2; 2, the mixture in the dichloromethane (20ml) of 2-trifluoro ethyl ketone (1.83g) and iodomethane (1.0g) at room temperature stirred 18 hours.Add ether and collect the precipitate that obtains after filtration, obtaining the 2.54g product is colorless solid, m.p.140-155 ℃ (decomposition).

Step d) 10,11-dihydro-3-methyl-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine :

Divide two parts to join iodate trimethyl-(10-trifluoroacetyl group-10 sodium borohydride (2.6g) from step c); 11-dihydro-5H-pyrrolo-[2; 1-c] [1,4] benzodiazepine -3-base-methyl)-mixture of the backflow of ammonium (2.60g) in ethanol in.After 4 hours, this mixture is concentrated in a vacuum.Water is joined in the residue also with this mixture dichloromethane extraction.The extract that merges is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.This solution is concentrated in a vacuum and, obtain the 1.14g product residue crystallization from hexane, m.p.150-151 ℃, MS m/z:199.1 (M+H) ⁺

Step e) [2-chloro-4-(3-methylpyrazole-1-yl)-phenyl]-(3-methyl-5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone: will at room temperature stir 18 hours from the mixture in the dichloromethane (10ml) of 2-chloro-4-(3-methylpyrazole-1-yl)-benzoic acid (0.18g), oxalyl chloride (0.18g) and a dimethyl formamide of step d).This mixture concentrated in a vacuum and be dissolved in residue in the dichloromethane once more and concentrate again in a vacuum, obtain 2-chloro-4-(3-methyl-pyrazol-1-yl)-Benzenecarbonyl chloride..Slurry in the dichloromethane (25ml) of acyl chlorides is added dropwise to 10, in dichloromethane (25ml) solution of 11-dihydro-3-methyl-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.12g) and diisopropylethylamine (0.10g).This mixture was at room temperature stirred 18 hours and water and saturated sodium bicarbonate aqueous solution washing.Organic layer filters through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.This solution is concentrated in a vacuum and grind with ether, obtaining the 0.115g product is clear crystal, m.p.178-180 ℃, and MS m/z:417.3 (M+H) ⁺833.3 (2M+H) ⁺Embodiment 19 (2-chloro-4-trifluoro acute pyogenic infection of nails base-pyrimidine-5-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

2-chloro-4-(trifluoro acute pyogenic infection of nails base) pyrimidine-5-formyl chloride (2.57g) is joined ice-cold 10 gradually, 11-dihydro-5H-pyrrolo-[2,1-c] in dichloromethane (50ml) solution of [1,4] benzodiazepine (1.84g) and diisopropylethylamine (1.37g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column, with the further eluting of dichloromethane of several volumes.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtain title compound (3.22g), m.p.221-223 ℃.

Embodiment 20[2-(3-methyl-pyrazol-1-yl)-4-trifluoro acute pyogenic infection of nails base-pyrimidine-5-yl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dimethyl formamide (25ml) solution of the oil solution (0.15g uses the hexane defat) of 60% sodium hydride, add 3-methylpyrazole (0.25g).When hydrogen stops to emit, add (2-chloro-4-trifluoro acute pyogenic infection of nails base-pyrimidine-5-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (0.98g).This reactant mixture was heated 18 hours in sand bath (110 ℃ of internal temperatures).Then mixture is poured on ice and further and dilutes with saturated brine solution.Leach precipitate, be dissolved in the dichloromethane once more and through anhydrous sodium sulfate drying.Filter the further eluting of dichloromethane that purification is also used several volumes by hydrated magnesium silicate sodium short column.The eluent concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect solid after filtration, obtain title compound (0.54g), be clear crystal, m.p.202-204 ℃.Embodiment 21[2-(4-methyl-pyrazol-1-yl)-4-trifluoro acute pyogenic infection of nails base-pyrimidine-5-yl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Mode with the method 1 of embodiment 9, use (2-chloro-4-trifluoro acute pyogenic infection of nails base-pyrimidine-5-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.15g), 4-methylpyrazole (0.42g) and the dimethyl formamide (25ml) of ketone (0.98g), 60% sodium hydride, obtain title compound (0.73g), be crystalline solid, m.p.214-217 ℃.

Embodiment 221-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-ethyl ketone

4-acetylbenzoic acid (5.0g) and thionyl chloride (10ml) were also under reduced pressure removed volatile material in 0.75 hour in heating on the steam bath, under argon atmospher.Also removing volatile material again obtains rough acyl chlorides to add toluene, is reddish orange grease.Described chemical compound easily solidifies and is directly used in further conversion.

Dichloromethane solution (25ml) gradation of acyl chlorides (4.56g) is joined ice-cooled 10, in dichloromethane (100ml) solution of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4]-benzodiazepine (3.68g) and diisopropylethylamine (3.25g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered and with the dichloromethane eluting of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtain title compound (1.75g), m.p.135-137 ℃.

Embodiment 233-dimethylamino-1-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-2-propylene-1-ketone

With 1-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-reactant mixture of ethyl ketone (1.40g), uncle-butoxy-Bis-dimethylamino methane (5.0ml) and dichloromethane (10ml) stirred 18 hours.Leach the reddish orange precipitate, obtain title compound (1.22g), m.p.203-205 ℃.From reactant mixture, isolate more product (0.18g) by concentrating.

Embodiment 24[4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

With 3-dimethylamino-1-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-reaction mixture refluxed 7 hours of 2-third (prop)-1-ketone (1.0g), anhydrous hydrazine (0.20g) and glacial acetic acid (20ml) and be evaporated to dried.Rough residue is dissolved in the dichloromethane, with the saturated sodium bicarbonate aqueous solution washing and through anhydrous sodium sulfate drying.This solution is filtered by hydrated magnesium silicate sodium short column, with the dichloromethane eluting of several volumes.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration.Repeat described post processing method and obtain title compound (0.65g), m.p.219-221 ℃.

Embodiment 25[4-(1-methyl isophthalic acid H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Oil solution (0.35g to 60% sodium hydride, use the hexane defat) and the mixture of dimethyl formamide (20ml) in add [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and ketone (0.98g), add iodomethane (0.50g) after a few minutes.This reactant mixture was at room temperature stirred 18 hours, pour in the water then and use dichloromethane extraction.After the drying organic layer is filtered by hydrated magnesium silicate sodium short column, with the dichloromethane eluting of several volumes.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtain title compound (0.70g), m.p.194-195 ℃.Embodiment 26[4-(1-ethyl-1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 25, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.27g), dimethyl formamide (25ml) and the ethyl iodide (0.87g) of ketone (1.0g), 60% sodium hydride, obtain title compound (0.69g), be crystalline solid, m.p.180-183 ℃.

Embodiment 27[4-(1-propyl group-1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 25, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.30g), dimethyl formamide (25ml) and the propyl iodide (0.60g) of ketone (0.98g), 60% sodium hydride, obtain title compound (0.32g), be crystalline solid, m.p.159-161 ℃.

Embodiment 28[4-(1-butyl-1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 25, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-oil solution (0.30g), dimethyl formamide (25ml) and the 1-iodobutane (0.60g) of ketone (0.98g), 60% sodium hydride, obtain title compound (0.32g), be crystalline solid, m.p.122-123 ℃.

Embodiment 29[4-(1-methoxy-1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 25, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and oil solution (0.15g), dimethyl formamide (25ml) and the iodomethyl methyl ether (0.50g) of ketone (1.0g), 60% sodium hydride, obtain title compound (0.26g), be amorphous solid, MS, m/z:399.2 (M+H) ⁺, 797.2 (2M+H) ⁺

Embodiment 301-{3-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-pyrazol-1-yl }-ethyl ketone

In dry pyridine (10ml) solution of [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (0.50g), add acetic anhydride (0.20g).After at room temperature stirring 18 hours, this reactant mixture poured in the water and collecting precipitation thing after filtration.Be dissolved in raw product in the dichloromethane and through anhydrous sodium sulfate drying.This solution is filtered the dichloromethane eluting of reuse several volumes by hydrated magnesium silicate sodium short column.Eluent concentrated while on hot plate is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtain title compound (0.46g), m.p.192-194 ℃.

Embodiment 311-{3-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-pyrazol-1-yl }-third-1-ketone

Method with embodiment 30, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-solution and propionic andydride (0.10g) in the dry pyridine (10ml) of ketone (0.16g), obtain title compound (0.17g), be crystalline solid, m.p.150-152 ℃.

Embodiment 32[4-(1-cyclopropane carbonyl-1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dry pyridine (10ml) solution of [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.0g), add cyclopropanecarbonyl chloride (0.44g).After at room temperature stirring 18 hours, this reactant mixture poured in the water and collecting precipitation thing after filtration.Be dissolved in raw product in the dichloromethane and through anhydrous sodium sulfate drying.This solution is filtered the dichloromethane eluting of reuse several volumes by hydrated magnesium silicate sodium short column.Eluent concentrated while on hot plate is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtain title compound (0.88g), be crystalline solid, m.p.197-199 ℃.

Embodiment 331-{3-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-pyrazol-1-yl }-Ding-1-ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-solution and butyl chloride (0.32g) in the dry pyridine (10ml) of ketone (0.71g), obtaining title compound (0.54g) is solid, m.p.105-110 ℃; MS, m/z:424 (M) ⁺

Embodiment 34 (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and 4-[1-(thiophene-2-carbonyl)-1H-pyrazole-3-yl] phenyl }-ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-dry pyridine (10ml) solution and the thiophene-2-formyl chloride (0.25g) of ketone (0.5g), obtain title compound (0.41g), be crystalline solid, m.p.195-197 ℃; MS, m/z:464 (M) ⁺

Embodiment 35{4-[1-(5-fluoro-2-methyl-benzoyl)-1H-pyrazole-3-yl] phenyl }-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and dry pyridine (10ml) solution and the 2-methyl-5-fluorobenzene formyl chloride (0.22g) of ketone (0.35g), obtain title compound (0.11g), be amorphism, brown solid, MS, m/z:490 (M) ⁺

Embodiment 36{4-[1-(2-methyl-benzoyl)-1H-pyrazole-3-yl] phenyl }-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-dry pyridine (20ml) solution of ketone (0.71g) and neighbour-toluyl chlorine (o-toluyl chloride) (0.39g), obtain title compound (0.59g), be crystalline solid, m.p.170-173 ℃, MS, m/z:472 (M) ⁺

Embodiment 37{4-[1-(2-chloro-4-fluoro-benzoyl)-1H-pyrazole-3-yl] phenyl }-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

2-chloro-4-fluorobenzene formyl chloride (0.82g) gradation is joined [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-dichloromethane (25ml) solution of ketone (1.0g) and diisopropylamine (0.55g) in, it is cooled off in ice bath.Subsequently this reactant mixture is at room temperature stirred and spend the night.With the washing of this reactant mixture water and saturated sodium bicarbonate and through anhydrous sodium sulfate drying.This dichloromethane solution is filtered the dichloromethane eluting of the several different volumes of reuse by hydrated magnesium silicate sodium short column.Eluent is evaporated to dried, obtains the product of 1.06g, be solid, m.p.150-157 ℃; MS, m/z:510 (M) ⁺

Embodiment 38{4-[1-(2,4-dichloro--benzoyl)-1H-pyrazole-3-yl] phenyl }-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-dry pyridine (20ml) solution and 2 of ketone (0.71g), 4-dichlorobenzene formyl chloride (0.52g), obtain title compound (0.66g), be crystalline solid, m.p.180-182 ℃, MS, m/z:528 (M) ⁺Embodiment 392-(2,4-dichloro--phenyl)-1-{3-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-pyrazol-1-yl }-ethyl ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-dry pyridine (25ml) solution and 2 of ketone (0.71g), 4-dichlorobenzene chloroacetic chloride (0.56g), obtain title compound (0.20g), be crystalline solid, m.p.130-140 ℃, solidify m.p.180-182 ℃ again.

Embodiment 40{4-[1-(biphenyl-2-carbonyl)-1H-pyrazole-3-yl]-phenyl }-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and dry pyridine (20ml) solution and the 2-dibenzoyl chlorine (0.65g) of ketone (0.71g), obtain title compound (0.49g), be amorphous solid, MS, m/z:534 (M) ⁺

Embodiment 41{4-[1-(4 '-trifluoro acute pyogenic infection of nails base-biphenyl-2-carbonyl)-1H-pyrazole-3-yl]-phenyl }-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Method with embodiment 32, use [4-(1H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and the dry pyridine (20ml) and the 4 '-trifluoro acute pyogenic infection of nails base-2-dibenzoyl chlorine (0.71g) of ketone (0.71g), obtain title compound (0.59g), be amorphous solid, MS, m/z:602 (M) ⁺

Embodiment 423-dimethylamino-1-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-2-butylene-1-ketone

Under inert atmosphere, with 1-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-mixture of ethyl ketone (2.0g) and dimethyl acetylamide dimethyl acetal (15ml) refluxed 15 hours and under reduced pressure removes volatile matter.Should rough solid be dissolved in the dichloromethane and and filter, use the dichloromethane eluting of several volumes subsequently by hydrated magnesium silicate sodium short column.The eluent that merges is concentrated and add hexane gradually until crystallization occurring.Refrigerative solution is filtered, obtain title compound (1.03g), be crystalline solid, m.p.183-185 ℃.

Embodiment 43[4-(5-methyl isophthalic acid H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Anhydrous hydrazine (0.10g) is joined 3-dimethylamino-1-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-phenyl]-glacial acetic acid (25ml) solution of 2-butylene-1-ketone (0.50g) in.With this reaction mixture refluxed 18 hours, concentrate in a vacuum then.This solid is washed with dichloromethane extraction and with saturated sodium bicarbonate aqueous solution.This dichloromethane solution is filtered through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column, with the further eluting of dichloromethane of several volumes.The organic layer concentrated while on steam bath that merges is added hexane gradually, obtain opaque solution.Obtain amorphous solid after the cooling after filtration, obtain product (0.33g), MS, m/z:368 (M) ⁺

Embodiment 444-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-benzonitrile

4-cyanobenzoic acid (5.0g) and thionyl chloride (5.0ml) were heated 1 hour on steam bath, under reduced pressure remove all volatile matters.Add hexane and obtain rough crystallization acyl chlorides (5.30g) after filtration, it is not further purified and uses.

To 10, add 4-cyano-benzoyl chloride (2.97g) in the reactant mixture of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (3.68g), dichloromethane (100ml) and diisopropylethylamine (2.80g).After at room temperature keeping 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column, with the further eluting of dichloromethane of several volumes.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (5.05g), m.p.184-186 ℃.

Embodiment 454-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide

The 4-that will obtain from embodiment 44 (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-benzonitrile (0.5g) joins in the concentrated sulphuric acid (5ml) and this mixture was at room temperature stirred 18 hours, obtains pale yellow solution.This solution is poured on ice and through adding dense ammonium hydroxide alkalization.The solid that obtains is leached, be dissolved in the dichloromethane and and filter, with the further eluting of dichloromethane of several volumes by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (5.05g), m.p.226-228 ℃.

Embodiment 46N-(dimethylamino methylene)-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide

To reflux 4 hours and remove volatile matter in a vacuum from the mixture of 4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-the carbonyl)-Benzoylamide (1.25g) of embodiment 45 and dimethyl formamide dimethyl acetal (20ml) and obtain solid.This solid is dissolved in the dichloromethane also by the filtration of hydrated magnesium silicate sodium short column, with the further eluting of dichloromethane of several volumes.The organic layer that merges is concentrated on steam bath, add hexane gradually until crystallization occurring simultaneously.After the cooling, collect crystal after filtration, obtain title compound (1.40g), m.p.232-234 ℃.

Embodiment 47N-(1-dimethylamino ethylidene)-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide

To on steam bath, heat 4 hours from 4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-the carbonyl)-Benzoylamide (1.24g) of embodiment 45 and the mixture of dimethyl acetylamide dimethyl acetal (5.0ml).Cool off and be settled out crystalline solid in 18 hours, with its filtered and recycled.With this solid hexane wash, obtain product (1.54g), m.p.210-212 ℃; MS, m/z:400 (M) ⁺

Embodiment 48 (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-[4-(2H-[1,2,4] triazole-3-yl) phenyl]-ketone

Will be from N-(dimethylamino methylene)-4-(5H of embodiment 46,11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-mixture of Benzoylamide (1.0g), glacial acetic acid (15ml) and anhydrous hydrazine (0.16g) refluxed 15 hours and removes volatile matter in a vacuum.Add saturated sodium bicarbonate aqueous solution and reclaim the solid that forms after filtration.Also removing volatile matter in a vacuum obtained solid in 4 hours with this solids backflow.This solid is dissolved in the dichloromethane also by the filtration of hydrated magnesium silicate sodium short column, with the further eluting of dichloromethane of several volumes.The organic layer concentrated while on steam bath that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (0.39g), m.p.225-227 ℃; MS, m/z:355 (M) ⁺

Embodiment 49[4-(2-methyl-2H-[1,2,4] triazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

With the method identical with embodiment 48, use is from N-(dimethylamino methylene)-4-(5H of embodiment 46,11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-and glacial acetic acid (75ml) solution and the methylhydrazine (0.32g) of Benzoylamide (1.56g), obtaining title compound (0.10g) is solid, m.p.155-158 ℃, MS, m/z:369 (M) ⁺

Embodiment 50[4-(5-methyl-2H-[1,2,4] triazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

With the method identical with embodiment 48, use is from N-(1-dimethylamino ethylidene)-4-(5H of embodiment 47,11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-and glacial acetic acid (75ml) solution and the anhydrous hydrazine (0.25g) of Benzoylamide (1.00g), obtain title compound (0.20g), be amorphous solid, MS, m/z:369 (M) ⁺

Embodiment 51[4-(2,5-dimethyl-2H-[1,2,4] triazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

With the method identical with embodiment 48, use is from N-(1-dimethylamino ethylidene)-4-(5H of embodiment 47,11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-and glacial acetic acid (75ml) solution and the methylhydrazine (0.30g) of Benzoylamide (1.18g), obtaining title compound (0.33g) is solid, m.p.193-195 ℃, MS, m/z:383 (M) ⁺

Embodiment 52[4-(the 3-methyl [1,2,4] oxadiazole-5-yls)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Will be from N-(1-dimethylamino ethylidene)-4-(5H of embodiment 47,11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-glacial acetic acid (50ml) solution that contains hydroxy amine hydrochloric acid salt (0.40g) and potassium acetate (1.0g) of Benzoylamide (1.15g) refluxed 2 hours.Under reduced pressure remove all volatile matters and add saturated sodium bicarbonate aqueous solution.With this mixture with dichloromethane extraction and with extract through anhydrous sodium sulfate drying.This solution filtered by hydrated magnesium silicate sodium short column and with the further eluting of the dichloromethane of several volumes.The organic layer concentrated while on steam bath that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtain title compound (0.38g), m.p.177-179 ℃; MS, m/z:371.3 (M) ⁺, 741.3 (2M) ⁺

Embodiment 531-methyl-4-(4-aminomethyl phenyl)-1H-pyrazoles

The mixture of 2-(4-aminomethyl phenyl)-malonaldehyde (3.05g), dehydrated alcohol (40ml) and methylhydrazine (1.09g) was at room temperature stirred 18 hours and at room temperature removed volatile matter.Add entry also with this mixture dichloromethane extraction.Behind anhydrous sodium sulfate drying, this solution filtered by hydrated magnesium silicate sodium short column and with the further eluting of the dichloromethane of several volumes.The organic layer concentrated while on steam bath that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (2.91g), m.p.107-108 ℃.

Embodiment 544-(1-methyl isophthalic acid H-pyrazoles-4-yl)-benzoic acid

The mixture of 1-methyl-4-(4-aminomethyl phenyl)-1H-pyrazoles (1.70g), potassium permanganate (9.70g) and 1N sodium hydroxide (100ml) was refluxed 18 hours.This suspension is also cooled off through diatomite filtration.With this aqueous solution dichloromethane extraction, described dichloromethane is discarded.This aqueous solution is acidified to pH 5.5.The precipitate that obtains is difficult to filter, and therefore uses dichloromethane extraction.Behind the evaporating solvent, the solid recrystallization from acetone with obtaining obtains title compound (0.60g), m.p.274-275 ℃; MS m/z:202 (M) ⁺

Embodiment 55[4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Oxalyl chloride (0.30g) is joined in dichloromethane (25ml) suspension of 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-benzoic acid (0.46g).Adding two dimethyl formamides also at room temperature stirred this mixture 18 hours.The solution evaporation that obtains is extremely done, obtained rough acyl chlorides (0.57g), it is not further purified and uses.

Described acyl chlorides is joined 10, in dichloromethane (50ml) solution of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.37g) and diisopropylethylamine (0.58g).After at room temperature 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.Dichloromethane solution is filtered and with the further eluting of the dichloromethane of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (0.38g), m.p.200-201 ℃; MS, m/z:368 (M) ⁺

Embodiment 566-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-3-carboxylic acid

With 6-(1-formoxyl-2-hydroxyl vinyl) pyridine-3-carboxylic acid (1.93g) (EastmanChemicals) dehydrated alcohol (50ml) and the suspension of methylhydrazine (0.50g) at room temperature stirred 18 hours.This reactant mixture filtration is obtained product (1.30g).Filtrate evaporation is obtained solid, this solid recrystallization from ethyl acetate is obtained the analytic sample (0.55g) of title compound, m.p.262-264 ℃.

Embodiment 57[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridin-3-yl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Thionyl chloride (5.0ml) suspension of 6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-3-carboxylic acid (0.48g) was at room temperature stirred 2 hours.Under reduced pressure remove volatile matter, obtaining 6-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-3-formyl chloride is solid, and it is not further purified and uses.

With 10,11-dihydro-5H-pyrrolo-[2,1-c] dichloromethane (25ml) solution of [1,4] benzodiazepine (0.37g) and diisopropylethylamine (0.61g) is cooled to dichloromethane (25ml) solution that 0 ℃ and gradation add 6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-pyridine-3-formyl chloride.After at room temperature 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered and with the further eluting of the dichloromethane of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (0.31g), m.p.173-175 ℃; MS, m/z:370.3 (M+H) ⁺Embodiment 58[4-(pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dichloromethane (25ml) suspension of 4-(pyrazol-1-yl) benzoic acid (1.56g), add oxalyl chloride (1.04g) and a dimethyl formamide.This mixture at room temperature stirred obtained clear solutions in 18 hours.Under reduced pressure remove volatile material and obtain 4-(pyrazol-1-yl) Benzenecarbonyl chloride., be light yellow solid (1.58g) that it is not further purified and uses.

4-(pyrazol-1-yl) Benzenecarbonyl chloride. (0.75g) is joined 10, in the dichloromethane solution (25ml) of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.61g) and diisopropylethylamine (0.47g).After at room temperature 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered and with the further eluting of the dichloromethane of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration, obtain title compound (0.90g), m.p.179-181 ℃.

Embodiment 59[4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dichloromethane (25ml) suspension of 4-(3-methylpyrazole-1-yl) benzoic acid (1.84g), add oxalyl chloride (1.16g) and a dimethyl formamide.This mixture was at room temperature stirred 18 hours and under reduced pressure removed volatile material.Add dichloromethane, this solution is filtered and the vapourisation under reduced pressure solvent, obtain 4-(3-methylpyrazole-1-yl) Benzenecarbonyl chloride., be yellow oil (1.76g) that it is not further purified and uses.

4-(3-methylpyrazole-1-yl) Benzenecarbonyl chloride. is joined ice-cold 10, in dichloromethane (25ml) solution of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.55g) and diisopropylethylamine (0.44g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered and with the further eluting of the dichloromethane of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Obtain title compound (0.90g) after the cooling, be amorphous solid, MS, m/z:369 (M+H) ⁺

Embodiment 60[4-(4-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dichloromethane (15ml) suspension of 4-(4-methylpyrazole-1-yl)-benzoic acid (0.75g), add oxalyl chloride (0.50g) and a dimethyl formamide.This mixture was at room temperature stirred 18 hours and under reduced pressure removed volatile material.Be dissolved in residue in the hexane and through diatomite filtration.Evaporating solvent obtains 4-(4-methylpyrazole-1-yl) Benzenecarbonyl chloride. (0.77g) in a vacuum, and it is not further purified and uses.

4-(4-methylpyrazole-1-yl) Benzenecarbonyl chloride. (0.72g) is joined ice-cold 10, in dichloromethane (25ml) solution of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.60g) and diisopropylethylamine (0.48g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered and with the further eluting of the dichloromethane of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, filter the collection crystallization and obtain title compound (0.75g), m.p.179-181 ℃; MS, m/z:369 (M+H) ⁺

Embodiment 61[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dichloromethane (25ml) suspension of 4-(3-1-yl)-benzoic acid (1.34g), add oxalyl chloride (1.0g) and a dimethyl formamide.This mixture was at room temperature stirred 18 hours and under reduced pressure removed volatile material.Be dissolved in residue in the hexane and through diatomite filtration.Evaporating solvent obtains 4-(3-1-yl) Benzenecarbonyl chloride. (0.80g) in a vacuum, and it is not further purified and uses.

4-(3-1-yl) Benzenecarbonyl chloride. (0.75g) is joined ice-cold 10, in dichloromethane (25ml) solution of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.55g) and diisopropylethylamine (0.42g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered and with the further eluting of the dichloromethane of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Obtain title compound (0.79g) after the cooling, be amorphous solid, MS, m/z:383 (M+H) ⁺

Embodiment 62 (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-[4-(3-trifluoro acute pyogenic infection of nails base-pyrazol-1-yl)-phenyl]-ketone

Thionyl chloride (5.0ml) suspension of 4-(3-trifluoro acute pyogenic infection of nails base pyrazol-1-yl)-benzoic acid (1.45g) was heated 3 hours under refluxing.Under reduced pressure remove volatile material, be dissolved in residue in the dichloromethane and through diatomite filtration.Evaporating solvent obtains 4-(3-trifluoro acute pyogenic infection of nails base pyrazol-1-yl) Benzenecarbonyl chloride. (1.45g) in a vacuum, and it is not further purified and uses.

To 10, add 4-(3-trifluoro acute pyogenic infection of nails base pyrazol-1-yl) Benzenecarbonyl chloride. (1.40g) in dichloromethane (50ml) solution of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.88g) and diisopropylethylamine (0.66g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered the dichloromethane eluting of also further using several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (1.70g), m.p.166-167 ℃, MS, m/z:423.3 (M+H) ⁺, 845.4 (2M+H) ⁺Embodiment 63[4-(imidazoles-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Thionyl chloride (2.0ml) suspension of 4-(imidazoles-1-yl)-benzoic acid (0.90g) was heated 1 hour under argon atmospher, on steam bath.Under reduced pressure remove volatile material and obtain residue, through adding the hexane crystallization, obtaining 4-(imidazoles-1-yl) Benzenecarbonyl chloride. is hydrochlorate (1.17g), m.p.242-247 ℃ with this residue.

To 10,11-dihydro-5H-pyrrolo-[2,1-c] add 4-(imidazoles-1-yl) benzoyl chloride hydrochloride salt (1.12g) in dichloromethane (50ml) solution of [1,4] benzodiazepine (0.75), diisopropylethylamine (1.20g) and 4-dimethylaminopyridine (0.1g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution through anhydrous sodium sulfate drying, is filtered and with the further eluting of the dichloromethane of several volumes by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Collect crystal after the cooling after filtration, obtain title compound (0.57g), m.p.171-172 ℃, MS, m/z:354 (M+H) ⁺

Embodiment 64[4-(4-methyl-imidazoles-1-yl)-phenyl]-(5H, 11H-% cough up also [2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dichloromethane (25ml) suspension of 4-(4-methylimidazole-1-yl)-benzoic acid (0.80g), add oxalyl chloride (0.50g) and a dimethyl formamide.This mixture is at room temperature stirred 18 hours and under reduced pressure remove volatile material, obtain 4-(4-methylimidazole-1-yl) Benzenecarbonyl chloride. (1.02g), it is not further purified and uses.

4-(4-methylimidazole-1-yl) Benzenecarbonyl chloride. (0.99g) is joined ice-cold 10, in dichloromethane (25ml) solution of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.64g) and diisopropylethylamine (0.60g).After at room temperature stirring 18 hours, with this reactant mixture water and saturated sodium bicarbonate aqueous solution washing.This dichloromethane solution is filtered and with the further eluting of the dichloromethane of several volumes through anhydrous sodium sulfate drying and by hydrated magnesium silicate sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.Obtain title compound (0.52g) after the cooling, be solid, m.p.140-145 ℃, MS, m/z:369 (M+H) ⁺

Embodiment 654-bromo-2-chloro-essence of Niobe

Thionyl chloride (1.64ml) is added dropwise in the methanol suspension of 4-bromo-2-chlorobenzene formic acid (6.92g) and be heated to 60 ℃ 2 hours.Remove in a vacuum and desolvate, residue is dissolved in ethyl acetate once more, and order 0.5N sodium hydroxide (2x), water and salt water washing.Organic layer through anhydrous sodium sulfate drying and in a vacuum except that desolvating, is obtained title compound (7.8g). ¹HNMR(300MHz)，(DMSO-d ₆)δ：3.87(s，3H)，7.68-7.9(m，3H)。

Embodiment 662-chloro-4-(3-dimethylamino-propine-1-yl) essence of Niobe

In triethylamine (110ml) solution of the 4-bromo that is stirring-2-chlorobenzene methyl formate (18.69g), add 1-dimethylamino-2-propine (12.1ml), chlorination two (triphenylphosphine) close palladium (II) (1.26g) and Copper diiodide (I) (0.136g).This mixture slowly is heated to 60 ℃ and with this temperature maintenance 1 hour.This reactant is cooled to room temperature, washs with ethyl acetate through diatomite filtration and with the solid of collecting.Remove in a vacuum and desolvate, be dissolved in the residue that obtains in the ethyl acetate once more and water (3x) washing.The organic extract liquid that merges through anhydrous sodium sulfate drying and remove in a vacuum and desolvate, is obtained raw product.This raw product is gone up column chromatography purification at silica gel (225g), with 40% ethyl acetate/hexane eluting.Except that after desolvating, obtaining title compound is viscosity grease (17.7g) in a vacuum, MS (+FAB), m/z:252 (M+H) ⁺

Embodiment 672-chloro-4-(3-dimethylamino-2-propylene-1-ketone-1-yl) essence of Niobe

3-chloro benzylhydroperoxide (10.76g) is little by little joined in dichloromethane (40ml) solution of 2-chloro-4-(3-dimethylamino-propine-1-yl)-essence of Niobe (15.07g), adding speed makes this reaction remain on-20 ℃.This mixture was stirred 10-15 minute.With the N-oxide that obtains alkali alumina (215g) chromatography purification, with 10% ethanol/methylene eluting through activity I level.Evaporating solvent under 12-18 ℃ of temperature in a vacuum.The residue that obtains is dissolved in the methanol (100ml) and heating 18 hours when 60-65 ℃ is stirred down.Except that after desolvating, described product is gone up column chromatography purification at silica gel (190g), in a vacuum with 70% ethyl acetate/hexane eluting.Grind with the ether that contains some hexanes, obtain title compound, be solid (5.68g), m.p.92-96 ℃.

Embodiment 682-chloro-4-(1H-pyrazole-3-yl)-essence of Niobe

In ethanol (53ml) suspension of 2-chloro-4-(3-dimethylamino-2-propylene-1-ketone-1-yl)-essence of Niobe (13.67g), add a hydrazine hydrochloride (7.0g).This mixture was heated 1 hour under 75-80 ℃ of temperature in oil bath.Remove in a vacuum and desolvate.Be dissolved in the ethyl acetate residue that obtains and water and salt water washing, through anhydrous sodium sulfate drying and in a vacuum except that desolvating, obtaining title compound is rough solid (12g).The fusing point of purification of samples is 130-131 ℃.

Embodiment 692-chloro-4-(1-methyl isophthalic acid H-pyrazole-3-yl)-essence of Niobe

Under blanket of nitrogen, with 15 fens clockwise with dimethyl formamide (30ml) solution that adds 2-chloro-4-(1H-pyrazole-3-yl)-essence of Niobe (12.0g) in dimethyl formamide (6ml) suspension of the sodium hydride (3.05g, 60% dispersion liquid) of hexane wash.This mixture was at room temperature stirred 30 minutes.With being added dropwise to iodomethane (9.5ml) in 15 minutes.This mixture was at room temperature stirred 45 minutes.Add the iodomethane (5.16ml) of additional amount and with reactant restir 75 minutes.Reactant is also concentrated in a vacuum with the low amounts of water dilution.Extract with residue water (500ml) dilution and with amount of ethyl acetate (5x).The organic layer that merges is evaporated in a vacuum, obtain raw product (13.48g).Described raw product through silica gel (195g) column chromatography purification, with 15% ethyl acetate/hexane eluting, is obtained pure 1-methyl regional isomer (4.29g), obtain the mixture (4.6g) of 1-methyl and 2-methyl regional isomer subsequently.Described mixture of isomers is ground three times with hexane, obtain the sample (2.55g) of the pure 1-methyl regional isomer of additional amount, m.p.66.5-67 ℃; MS (+FAB), m/z:251 (M+H) ⁺

Embodiment 702-chloro-4-(1-methyl isophthalic acid H-pyrazole-3-yl)-benzoic acid

In methanol (32ml) solution of 2-chloro-4-(1-methyl isophthalic acid H-pyrazole-3-yl)-essence of Niobe (6.85g), add 2.5N sodium hydroxide solution (15.3ml).With this reactant be heated to 50 ℃ 1 hour.Remove in a vacuum and desolvate and, cooling and with 2N hydrochloric acid (24ml) acidify in ice bath in the residue water-soluble (250ml).The precipitate that obtains is filtered and dry colourless solid (6.3g), m.p.232-233 ℃ of obtaining; MS (+FAB), m/z:236 (M+H) ⁺

Embodiment 71[2-chloro-4-(1-methyl isophthalic acid H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Under blanket of nitrogen, 2-chloro-4-(1-methyl isophthalic acid H-pyrazole-3-yl)-benzoic acid (6.3g) and the dimethyl formamide of fully pulverizing (2.16ml) is suspended in the mixture of oxolane (70ml) and dichloromethane (15ml).Dichloromethane (5ml) solution that is added dropwise to oxalyl chloride (2.43ml) also stirs this reactant 1 hour.2-chloro-the 4-that obtains (1-methyl isophthalic acid H-pyrazole-3-yl)-Benzenecarbonyl chloride. suspension is not further purified and uses.

To 10, add diisopropylethylamine (7ml) in dichloromethane (15ml) suspension of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (4.93g).Positive pressure gas at nitrogen flows down with the suspension that added freshly prepd acyl chlorides in 15 minutes gradually.The reactant mixture of slight fever was stirred 50 minutes under blanket of nitrogen.Stir after 1 hour, this mixture is concentrated in a vacuum.Residue is dissolved in the dichloromethane water, 5% sodium bicarbonate and water washing.With salt water washing organic layer,, obtain raw product (10.95g) through anhydrous sodium sulfate drying and in a vacuum except that desolvating.With this raw product (200g) column chromatography purification on silica gel, with 25% ethyl acetate/hexane application of sample in post.With the ethyl acetate/hexane eluting of low polar impurity with 25-30%.With the ethyl acetate/hexane eluting of this product, obtain pure sample (7.42g) with 30-40%; After adding crystal seed described sample was ground 24 hours with the ether that contains some hexanes.It is crystalline solid (6.88g) that filtration obtains title compound, m.p.148.5-150 ℃, and MS (EI), m/z:402 (M) ⁺

Embodiment 722-chloro-4-(2-methyl isophthalic acid H-pyrazole-3-yl)-essence of Niobe

With with identical method described in the embodiment 68, use 2-chloro-4-(3-dimethylamino-2-propylene-1-ketone)-essence of Niobe (0.8g) and methylhydrazine (0.319ml) to prepare title compound.Main 2-methyl regional isomer is separated through silica gel column chromatography, ¹H NMR (300MHz), (DMSO-d ₆) δ: 3.87 (s, 3H), 3.89 (s, 3H), 6.58 (d, 1H), 7.5 (d, 1H), 7.62-7.93 (m, 3H).

Embodiment 732-chloro-4-(2-methyl isophthalic acid H-pyrazole-3-yl)-benzoic acid

With with identical method described in the embodiment 70, use 2-chloro-4-(2-methyl isophthalic acid H-pyrazole-3-yl)-essence of Niobe (0.464g) and 2.5N sodium hydroxide (1.04ml) to prepare title compound. ¹H?NMR(300MHz)，(DMSO-d ₆)δ：3.89(s，3H)，6.56(d，1H)，7.49(d，1H)，7.59-7.90(m，3H)。

Embodiment 74[2-chloro-4-(2-methyl isophthalic acid H-pyrazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

With with identical method described in the embodiment 71, use 2-chloro-4-(2-methyl isophthalic acid H-pyrazole-3-yl)-benzoic acid (3.98g) to obtain corresponding acyl chlorides also with 10,11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.293g) acidylate, obtaining title compound is foam, m.p.78-79 ℃; MS (EI), m/z:402 (M) ⁺Embodiment 752-chloro-4-cyano-benzoic acid methyl ester

2-chloro-4-Methyl anthranilate (13.95g) is suspended in the mixture of water (65ml) and concentrated hydrochloric acid (15.7ml).After at room temperature stirring 10 minutes, this suspension is cooled to 0 ℃.With the water that added sodium nitrite (5.71g) in 20 minutes gradually (37ml) solution, keeping reaction temperature is 0 ℃.After stirring 35 minutes under 0 ℃, through adding solid sodium carbonate (3.16g) this reactant mixture is partly neutralized, obtain the cold solution of diazol.

With 45-50 minute, (8.4g) and the diazonium salt solution more than adding gradually in the aqueous solution (112ml) of Cyanogran. (9.19g) to the copper cyanider (I) of pre-cooling.Keeping described diazonium salt solution temperature during adding is 0 ℃.The mixture that obtains was at room temperature stirred 18 hours.Leach precipitate, air-dry, be dissolved in the ethyl acetate (250ml) and remove by filter insoluble material.Through anhydrous magnesium sulfate drying and in a vacuum except that desolvating, obtaining raw product is brown solid (13.2g) with organic layer.Through silica gel (250g) column chromatography purification, with 5-10% ethyl acetate/hexane eluting, obtaining title compound (10.9g) is solid, m.p.90-92 ℃ with this raw product; MS (EI), m/z:195 (M) ⁺

Embodiment 762-chloro-4-cyanobenzoic acid

In methanol (150ml) solution of the 2-chloro-4-cyano-benzoic acid methyl ester (24.3g) that stirs, add 2.5N sodium hydroxide solution (54.5ml).After at room temperature stirring 45 minutes, remove in a vacuum and desolvate.Residue is soluble in water, cooling and with 2N hydrochloric acid (14ml) acidify in ice bath.The precipitate that obtains is filtered also drying in a vacuum, and obtaining title compound is solid (22.55g), m.p.154-158 ℃.

Embodiment 773-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-benzonitrile

Under 0 ℃, be added dropwise to dichloromethane (10ml) solution of oxalyl chloride (4.6ml) in the suspension in the mixture of the dichloromethane (40ml) of refrigerative 2-chloro-4-cyanobenzoic acid (9.1g) and dimethyl formamide (3.88ml).With 1 hour the reactant that stirs is heated to room temperature.The turbid solution of 2-chloro-4-cyano-benzoyl chloride is not further purified and uses.

Under blanket of nitrogen,, add the turbid solution of 2-chloro-4-cyano-benzoyl chloride in dichloromethane (35ml) suspension of 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (7.32g) and diisopropylethylamine (13.6ml) to 10 of stirring.After at room temperature 1 hour, this mixture is washed with dichloromethane dilution and order water, 5% sodium bicarbonate and 50% saturated brine.Behind anhydrous sodium sulfate drying, remove in a vacuum and desolvate, obtain raw product (18.0g).Through silica gel (250g) column chromatography purification, with 20% ethyl acetate/hexane, use 25% ethyl acetate/hexane eluting subsequently, obtaining title compound (13.56g) is the olive drab(O foam, MS (EI), m/z:347 (M) ⁺

Embodiment 783-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-benzoic acid

To adding 10N sodium hydroxide (1.02ml) in the alcohol suspension of 3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-benzonitrile (90.72g) and this mixture being heated 2 hours under backflow.Remove in a vacuum and desolvate, residue is soluble in water and make its acidify with 2N hydrochloric acid (4.7ml).With the precipitate that obtains with ethyl acetate extraction and with organic layer through anhydrous sodium sulfate drying.Except that after desolvating, foam was ground 18 hours and filtered with ether in a vacuum, obtain raw product (0.69g).This raw product is handled purification with active carbon in methanol.Crystallization obtains title compound from methanol, be pure solid (0.29g), and m.p.198-199 ℃, MS (EI), m/z:366 (M) ⁺

Embodiment 793-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide

Concentrated sulphuric acid (70ml) is joined in 3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-benzonitrile (12.85g).This mixture was stirred 3 hours down at 60 ℃, at room temperature stirred subsequently 18 hours.This reactant mixture is poured on ice and neutralizes with 30% ammonium hydroxide (184ml) down at 0 ℃.With the suspension ethyl acetate extraction that obtains.Filter aqueous mixture and extract again with ethyl acetate.The organic layer that merges through anhydrous sodium sulfate drying, is removed in a vacuum and desolvates.The mixture of residue with ether (50-60ml) and amount of ethyl acetate ground.Leach precipitate and obtain title compound, be crystalline solid (10.44g), m.p.211-212 ℃, MS (EI), m/z:365 (M) ⁺

Embodiment 80N-(1-dimethylamino ethylidene)-3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide

The suspension of 3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide (5.48g) and dimethyl acetylamide dimethyl acetal (10.97ml) was heated 20 minutes down at 90 ℃.Under reduced pressure remove excessive reagent, described title compound is not further purified and uses, MS (EI), m/z:434 (M) ⁺

Embodiment 81[2-chloro-4-(5-methyl-2H-[1,2,4] triazole-3-yl) phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-ketone

Acetic acid (4ml) solution that in acetic acid (4ml) solution of N-(1-dimethylamino ethylidene)-3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide (3.01g), adds anhydrous hydrazine (0.435ml).This reactant mixture was stirred 45 minutes under 85-90 ℃ of temperature.After removing acetic acid in a vacuum,, be neutralized to pH 7.0, use ethyl acetate extraction with sodium bicarbonate aqueous solution with this reactant mixture water (35-40ml) dilution.With salt water washing organic extract liquid,, obtain raw product (2.68g) except that desolvating in a vacuum through anhydrous sodium sulfate drying.This raw product is gone up column chromatography purification at silica gel (45g), with 70% ethyl acetate/hexane eluting, obtain pure product (2.5g), after it was ground with ether, obtaining title compound was solid (2g), m.p.211-212 ℃, and MS (EI), m/z:403 (M) ⁺Embodiment 82N-(dimethylamino methylene)-3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-Benzoylamide

With with identical method described in the embodiment 80, use 3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-and Benzoylamide (1.83g) and dimethyl formamide dimethyl acetal (5.3ml) preparation title compound, MS (EI), m/z:420 (M) ⁺

Embodiment 83[2-chloro-4-(2H-1,2,4-triazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

With with identical method described in the embodiment 81, use N-(dimethylamino methylene)-3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-and Benzoylamide (2.53g) and hydrazine (0.38ml) preparation title compound, m.p.174-177 ℃; MS (EI), m/z:389 (M) ⁺

Embodiment 84[2-chloro-4-(2-methyl-2H-[1,2,4] triazole-3-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-ketone

With with identical method described in the embodiment 48, use N-(dimethylamino methylene)-3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-and Benzoylamide (0.572g) and methyl hydrazine (0.149ml) preparation title compound, m.p.141-143 ℃; MS (EI): 403 (M) ⁺

Embodiment 854-[(2,5-dimethyl-2H-[1,2,4] triazole-3-yl)-2-chloro-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-ketone

With with identical method described in the embodiment 48, use N-(1-dimethylamino ethylidene)-3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-and Benzoylamide (0.51g) and methyl hydrazine (0.125ml) preparation title compound, m.p.197-199 ℃; MS (EI): 417 (M) ⁺

Embodiment 86[2-chloro-4-(1H-tetrazolium-5-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dimethyl formamide (2ml) solution of 3-chloro-4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-benzyl cyanogen (0.348g), add Hydrazoic acid,sodium salt (0.078g) and ammonium chloride (0.065g).With this mixture heated to 100 ℃ 18 hours.

Remove most of dimethyl formamide in a vacuum.With also alkalizing to pH 9.0 in the residue water-soluble (being approximately 8ml), use ethyl acetate extraction with 2.5N sodium hydroxide (0.6ml).Aqueous extract with 2N hydrochloric acid (1.1ml) acidify, is extracted again with ethyl acetate, also obtain raw product (0.350g) except that desolvating in a vacuum, be grease through anhydrous sodium sulfate drying.This oily product is ground with ether,, obtain pure sample with 40% ethyl acetate/hexane eluting by acid-treated filtered through silica gel.It is further ground and filter with ether, obtain sample (0.88g), m.p.218-220 ℃.MS(+FAB)391(M+H) ⁺。

Embodiment 87[2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(3-dimethylaminomethyl-5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

To [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H that stirs, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.61g), N, N, N ' adds 37% formalin (4ml) in methanol (25ml) solution of N '-tetramethyl diaminourea-methane (0.82g) and glacial acetic acid (0.48g).With this mixture heated to 40 ℃ 10 minutes.After at room temperature stirring 1 hour, this reactant is concentrated in a vacuum, be dissolved in the dichloromethane once more and order sodium bicarbonate aqueous solution and water (4x) extraction.Organic layer through anhydrous sodium sulfate drying, is filtered by silica gel plug (plug), use eluent ethyl acetate.Evaporating solvent obtains grease in a vacuum, it is ground with hexane obtain the 0.36g title compound, is colourless powder, m.p.100-102 ℃; MS (+FAB), m/z:482 (M+Na) ⁺, 460 (M+H) ⁺

Embodiment 88 (3-bromo-5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-[2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-ketone

With 10 minutes, under-78 ℃, to [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H that stirring, pre-cooling, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-add solid N-bromo-succinimide (0.712g) in dichloromethane (25ml) solution of ketone (1.61g).This reactant was heated to-40 ℃ with 30 minutes.Mixture is diluted with dichloromethane, order with saturated sodium bicarbonate aqueous solution (2 * 100ml) and water (100ml) extract.Organic layer through anhydrous sodium sulfate drying, is filtered by silica gel plug, and evaporating solvent obtains residue in a vacuum.Crystallization obtains the 1.47g title compound from ether, is colorless solid, m.p.148-149 ℃ (decomposition); MS (EI), m/z:480 (M) ⁺

Embodiment 89 (4-bromo-2-chlorophenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Dimethyl formamide (1) is joined in anhydrous tetrahydro furan (20ml) solution of 4-bromo-2-chlorobenzene formic acid (2.20g).Adding oxalyl chloride (1.46g) also extremely refluxes this mixture heated.The solution that obtains is cooled to room temperature and is evaporated to driedly, obtain rough 4-bromo-2-chlorobenzene formyl chloride, be golden viscous liquid, it is not further purified and uses.

To in ice bath refrigerative 10,11-dihydro-5H-pyrrolo-[2,1-c] be added dropwise to dichloromethane (20ml) solution of 4-bromo-2-chlorobenzene formyl chloride (2.42g) in dichloromethane (40ml) mixture of [1,4] benzodiazepine (1.44g) and triethylamine (0.95g).Stirred 22 hours after removing cryostat, with this reactant order water, saturated sodium bicarbonate aqueous solution, 0.5N hydrochloric acid and water washing.Dichloromethane solution through anhydrous sodium sulfate drying, is filtered, be evaporated to driedly then in a vacuum, obtain the canescence foam.Through flash chromatography purification on silica gel,, obtain white foam shape thing (3.02g), m.p.77-80 ℃ with hexane-ethyl acetate (2: 1) eluting; MS m/z:400 (M) ⁺Embodiment 90[2-bromo-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Step a) 4-fluoro-2-bromobenzene formyl chloride: dimethyl formamide (2) is joined in anhydrous tetrahydro furan (55ml) solution of 4-fluoro-2-bromobenzene formic acid (4.91g).Adding oxalyl chloride (3.41g) also extremely refluxes this mixture heated.The solution that obtains is cooled to room temperature, and evaporation obtains rough acyl chlorides in a vacuum, is golden viscous liquid, and it is not further purified and uses.

Step b) (4-fluoro-2-bromo phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-and ketone: will join 10 from dichloromethane (35ml) drips of solution of the 4-fluoro-2-bromobenzene formyl chloride (5.32g) of step a), 11-dihydro-5H-pyrrolo-[2,1-c] in dichloromethane (80ml) solution of [1,4] benzodiazepine (3.44g) and triethylamine (2.27g) and in ice bath, cool off.Stirred 16 hours after removing cryostat, with this reactant mixture order water, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.Dichloromethane solution through anhydrous magnesium sulfate drying, is filtered and evaporation in a vacuum, obtain pale red purple foam.Flash chromatography purification on silica gel with hexane-ethyl acetate (1: 1) eluting, obtains intermediate (4-fluoro-2-bromo phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone, be brown foam (6.91g) MS m/z:384 (M) ⁺This material is not further purified and is used for next step.

Step c) [2-bromo-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone: the oily aaerosol solution (0.20g) of 60% sodium hydride is used hexane wash, be suspended in then in the dimethyl formamide (15ml).In this suspension, add 3-methylpyrazole (0.41g).After hydrogen stops to emit, add (4-fluoro-2-bromo phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.74g) from step b).With this reactant mixture be heated to 130 ℃ 6 hours.After this reactant mixture is cooled to room temperature, pours into it in 50% saturated sodium-chloride water solution and use ethyl acetate extraction.Described ethyl acetate solution through anhydrous magnesium sulfate drying, is filtered and evaporation in a vacuum, obtain brown oil.Through the flash chromatography on silica gel purification,, obtain colorless solid (0.75g) with hexane-ethyl acetate (1: 1) eluting.Recrystallization obtains canescence crystalline solid (0.53g) from methanol, and m.p.141-142.5 ℃, MS m/z:446 (M) ⁺

Embodiment 91 (2,4-two fluoro-phenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Step a) 2,4-difluoro-benzene formyl chloride: under blanket of nitrogen, will contain 2 of several dimethyl formamides, dichloromethane (40ml) suspension of 4-difluoro-benzene formic acid (3.6g) drips oxalyl chloride (2.4ml) and handles.After gas stops to emit, this reactant mixture was refluxed 15 minutes again.This solution is evaporated in a vacuum dried, residue is not further purified and uses.

Step b) (2,4-difluoro-benzene base)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone: under blanket of nitrogen, to from rough 2 of step a), add solid 10 in the dichloromethane solution of 4-difluoro-benzene formyl chloride, 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (2.0g) and diisopropylethylamine (3.4ml).This reactant mixture changes yellowish orange into.After at room temperature stirring 10 minutes, with this reactant mixture water, 1N hydrochloric acid, 1N sodium hydroxide and salt water washing.Organic layer through anhydrous sodium sulfate drying and be evaporated to driedly, is obtained brown solid.This raw product is gone up column chromatography purification at silica gel (Merck-60), and with 20% ethyl acetate-hexane eluting, obtaining the 2.9g title compound is white foam shape thing.MS(EI，m/z)：324(M) ⁺。

Embodiment 92[2-fluoro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Under blanket of nitrogen, room temperature, will drip 3-methylpyrazole (0.62ml) with the suspension in the dry dimethyl formamide of 60% sodium hydride (0.31g) of hexane wash and handle.Continue to stir and stop to emit (10 minutes) until gas.(2,4-difluoro-benzene base) of disposable adding embodiment 91 step b)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (2.5g) also continues to stir until obtaining clear solutions.This mixture was heated 1 hour down at 130 ℃ in pre-warmed oil bath.After the cooling, this mixture is distributed between water and the ethyl acetate.With organic extract liquid through anhydrous sodium sulfate drying and be evaporated to dried.This raw product is gone up the rapid column chromatography purification at silica gel (Merck-60), and with 20% ethyl acetate-hexane eluting, the title compound that obtains 0.82g is a foam, with it through sonication crystallization from ethanol/hexane, m.p.192-193 ℃.MS(EI)m/z：386(M) ⁺。

Embodiment 934-(3-methyl-pyrazol-1-yl)-2-trifluoro acute pyogenic infection of nails base-essence of Niobe

Step a) 4-fluoro-2-trifluoro acute pyogenic infection of nails yl benzoic acid methyl ester: under blanket of nitrogen, dichloromethane (250ml) the suspension dropping oxalyl chloride (11.3ml) of 4-fluoro-2-trifluoro acute pyogenic infection of nails yl benzoic acid (25.6g) and several dimethyl formamides is handled.After gas stops to emit, this reactant mixture was refluxed 15 minutes again.With reactant cooling and adding methanol (50ml).Stir after 2 hours, reactant is concentrated in a vacuum, residue is distributed between dichloromethane and the water.Organic layer is washed through saturated sodium bicarbonate solution,, be evaporated to the dried 18.0g of obtaining title compound, be golden grease through anhydrous sodium sulfate drying.MS(EI)m/z：222(M) ⁺。

With 2N hydrochloric acid the water-bearing layer acidify is obtained colourless solid, collect described solid after filtration and obtain 7.5g benzene feedstock formic acid.

Step b) 4-(3-methyl-pyrazol-1-yl)-2-trifluoro acute pyogenic infection of nails base-essence of Niobe: under blanket of nitrogen, room temperature, will add dimethyl formamide (50ml) solution-treated of 3-methylpyrazole (7.75ml) with dry dimethyl formamide (150ml) hanging drop of 60% sodium hydride (3.85g) of hexane wash.Continue to stir and stop to emit (10 minutes) until gas.To join in the described clear solutions from dimethyl formamide (50ml) drips of solution of the 4-fluoro-2-trifluoro acute pyogenic infection of nails yl benzoic acid methyl ester (17.8g) of step a).Stir after 30 minutes, at room temperature with this reactant with the saturated ammonium chloride quencher and use ethyl acetate extraction.With organic extract liquid (3x) through anhydrous sodium sulfate drying and be evaporated to dried.Through silica gel (Merck 60) rapid column chromatography purification, with dichloromethane-hexane gradient (50%-75%) eluting, obtaining the 13.6g title product is colorless solid with raw product.m.p.59-61℃MS(EI，m/z)：284(M) ⁺。Embodiment 944-(3-methyl-pyrazol-1-yl)-2-trifluoro acute pyogenic infection of nails base-benzoic acid

To be dissolved in the methanol (10ml) from 4-(3-methylpyrazole-1-the yl)-2-trifluoro acute pyogenic infection of nails yl benzoic acid methyl ester (1.19g) of embodiment 93 step b) and add 2.5N sodium hydroxide solution (3.3ml).This reactant was heated 90 minutes under refluxing, be cooled to room temperature and be concentrated into dried in a vacuum.Residue is distributed between ethyl acetate and the 1N hydrochloric acid.The organic extract liquid that merges through anhydrous sodium sulfate drying, is concentrated in a vacuum and obtains the 1.14g title compound, be colorless solid.MS(FAB)m/z：271(M+H) ⁺。

Embodiment 95[4-(3-methylpyrazole-1-yl)-2-trifluoro acute pyogenic infection of nails base phenyl]-(5H, 11H-pyrazolo [5,1-c] [1,4] benzodiazepine -10-yl)-ketone

Will be from oxolane (5ml) solution of 4-(3-methyl-pyrazol-1-yl)-2-trifluoro acute pyogenic infection of nails yl benzoic acid (0.26g) of embodiment 94 with dimethyl formamide (0.020ml), use oxalyl chloride (0.090ml) subsequently) handle.This solution at room temperature stirred until gas stop to emit, this solution is heated to refluxed 10 minutes then.This sample is cooled to room temperature, is condensed into solid and also this solid is dissolved in the oxolane (25mL).This solution is joined (5H-10 is in oxolane (20ml) solution of 11-dihydro-pyrazolo [5,1-c] [1,4] benzodiazepine (0.143g) and triethylamine (0.150ml).This solution at room temperature stirred spend the night.Form precipitate.This sample is diluted with the dissolution precipitation thing with dichloromethane, then sample is concentrated into 1/3 of about initial volume in a vacuum.Described sample is distributed between dichloromethane and the saturated aqueous ammonium chloride.Sample is merged with dichloromethane extraction and with organic layer,, filter and simmer down to grease through anhydrous sodium sulfate drying.Through flash chromatography on silica gel, with 40% ethyl acetate/hexane to 100% ethyl acetate gradient elution, obtaining title compound is foam (0.30g) with described grease.The described material of portion recrystallization from acetone/hexane is obtained the viscosity flaky crystal, m.p.100-102 ℃.MS?m/z：437(M) ⁺。Embodiment 962-chloro-4-(3-methyl isophthalic acid H-pyrazol-1-yl)-essence of Niobe and 2-chloro-4-(5-methyl isophthalic acid H-pyrazol-1-yl)-essence of Niobe

To stir simultaneously with dimethyl formamide (5ml) suspension of the hydrofining (0.424g) of hexane wash with the disposable processing of 3-methyl-pyrazoles (0.85ml).After gas stops to emit, 2-chloro-4-fluorinated acid methyl ester (2.0g, 10.6) is joined in the described clear solutions and at 130 ℃ to descend to heat 15 minutes.This reactant mixture is cooled to room temperature and be distributed in ethyl acetate and saline between.With organic layer water, salt water washing and through anhydrous sodium sulfate drying.Remove to desolvate in a vacuum and obtain the 2.2g yellow oil.(note: the NMR spectrum analysis by raw product detects 20% ester hydrolysis).By silica gel (Merck 60) rapid column chromatography dichloromethane-hexane (2: 1) eluting, required regional isomer 2-chloro-4-(3-methyl isophthalic acid H-/pyrazol-1-yl)-essence of Niobe is separated from other isomer (following explanation), obtain the 1.55g title compound, be colorless solid.MS(EI?m/z：250/252(M) ⁺。

With the 5-regional isomer is that 2-chloro-4-(5-methyl isophthalic acid H-pyrazol-1-yl)-essence of Niobe separates with 2: 1 further eluting of dichloromethane-hexane by above silica gel (Merck 60) rapid column chromatography, obtains the 0.20g product, is colorless solid.MS(EI)，m/z：250/252(M) ⁺。

Embodiment 972-chloro-4-(3-methyl isophthalic acid H-pyrazol-1-yl)-benzoic acid

To at room temperature stir 18 hours from oxolane (20ml) solution of the 1M aqueous lithium hydroxide of 2-chloro-4-(3-methyl isophthalic acid H-the pyrazol-1-yl)-essence of Niobe (1.42g) of embodiment 96 and 6ml.This reactant mixture is distributed between ethyl acetate and the 1N hydrochloric acid.With organic layer water, salt water washing and through anhydrous sodium sulfate drying.Evaporating solvent obtains the 1.05g title compound in a vacuum, is colorless solid.m.p.192-193℃。MS(EI)，m/z：236/238(M) ⁺。Embodiment 98 (2,6-dichloropyridin-3-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

With 2, dichloromethane (25ml) solution of 6-dichloro-nicotinic acid (3.84g), oxalyl chloride (2.0g) and a dimethyl formamide at room temperature stirred 18 hours.With concentrated in a vacuum 2 of the 3.50g that obtains of this solution, 6-dichloro-nicotinoyl chlorine, its solution gradation in dichloromethane (25ml) is joined 10,11-dihydro-5H-pyrrolo-[2,1-c] in the ice-cold solution of the dichloromethane (50ml) of [1,4] benzodiazepine (2.15g) and diisopropylethylamine (2.03g).This mixture was at room temperature stirred 18 hours and wash with saturated sodium bicarbonate aqueous solution.Organic layer is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.The organic layer concentrated while on hot plate that merges is added hexane gradually until crystallization occurring.After the cooling, collect crystal after filtration and obtain the 2.65g title compound, be amorphous solid.m.p.115-130℃。MS?m/z：358.1(M+H) ⁺。

Embodiment 99 (2-chloro-6-pyrazol-1-yl-pyridin-3-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dimethyl formamide (25ml) suspension of the oil solution (0.1g) of 60% sodium hydride, be added dropwise to pyrazoles (0.15g).After hydrogen stops to emit, add (2,6-dichloropyridin-3-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (0.67g) and also this reactant mixture was heated 18 hours under 110 ℃ in sand bath.This mixture is poured on ice, with saline dilution and use dichloromethane extraction.The extract that merges is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.This solution concentrated in a vacuum and grind and obtain the 0.18g title compound, be colorless solid with ether.m.p.133-135℃。MS?m/z：390.8(M+H) ⁺，779.1(2M+H) ⁺。Embodiment 100[2-chloro-6-(3-methylpyrazole-1-yl)-pyridin-3-yl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dimethyl formamide (25ml) suspension of the oil solution (0.1g) of 60% sodium hydride, be added dropwise to 3-methylpyrazole (0.15g).After hydrogen stops to emit, add (2,6-dichloropyridin-3-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (0.67g) and also this reactant mixture was heated 18 hours under 110 ℃ in sand bath.This mixture is poured on ice, with saline dilution and use dichloromethane extraction.The extract that merges is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.Raw product through preparation property hplc (Dynamax c60 silicagel column) purification, with the hexane solution eluting of 40% acetic acid acetic acid, is obtained the 0.21g clear crystal.m.p.171-172℃。MS?m/z：404.2(M+H) ⁺，807.1(2M+H) ⁺。

Embodiment 101[2-chloro-6-(4-methylpyrazole-1-yl)-pyridin-3-yl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dimethyl formamide (25ml) suspension of the oil solution (0.1g) of 60% sodium hydride, be added dropwise to 3-methylpyrazole (0.45g).After hydrogen stops to emit, add (2,6-dichloropyridin-3-yl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.79g) and also this reactant mixture was heated 18 hours under 110 ℃ in sand bath.This mixture is poured on ice, with saline dilution and use dichloromethane extraction.The extract that merges is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.Raw product through preparation property hplc (Dynamax c60 silicagel column) purification, with the hexane solution eluting of 40% acetic acid acetic acid, is obtained the 0.26g clear crystal.m.p.155-156℃。MSm/z：404.2(M+H) ⁺，807.0(2M+H) ⁺。

Embodiment 102[2-chloro-4-(3-methyl isophthalic acid, 2,4-triazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dimethyl formamide (50ml) suspension of the oil solution (0.3g) of 60% sodium hydride, be added dropwise to the 3-methyl isophthalic acid, 2,4-triazole (0.45g).After hydrogen stops to emit, add 2-chloro-4-fluoro phenyl-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.70g) and also this reactant mixture was heated 18 hours under 110 ℃ in sand bath.This mixture is poured on ice, with saline dilution and use dichloromethane extraction.The extract that merges is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.Solution is concentrated in a vacuum and residue is ground with ether, obtaining the 1.25g title compound is clear crystal.m.p.191-193℃。MSm/z：404.1(M+H) ⁺。

Embodiment 103[4-(3-methyl isophthalic acid, 2,4-triazol-1-yl)-2-trifluoro acute pyogenic infection of nails base-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

In dimethyl formamide (50ml) suspension of the oil solution (0.3g) of 60% sodium hydride, be added dropwise to the 3-methyl isophthalic acid, 2,4-triazole (0.45g).After hydrogen stops to emit, add 4-fluoro-2-trifluoro acute pyogenic infection of nails base-phenyl-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.76g) and also this reactant mixture was heated 18 hours under 110 ℃ in sand bath.This mixture is poured on ice, with saline dilution and use dichloromethane extraction.The extract that merges is filtered through anhydrous sodium sulfate drying and by anhydrous silicic acid magnesium sodium short column.Solution is concentrated in a vacuum and residue is ground with ether, obtaining the 0.81g title compound is clear crystal.m.p.148-150℃。MSm/z：438.2(M+H) ⁺，875.8(2M+H) ⁺。

Embodiment 1044-diazanyl-2-methoxybenzoic acid methyl ester hydrochloride (1: 1) hydrate (2: 1)

Be lower than 0 ℃ speed with being cooled to-10 ℃, concentrated hydrochloric acid (110ml) suspension of 4-amino-2-methoxybenzoic acid methyl ester (21.74g) of stirring to keep reaction temperature, with water (45ml) solution-treated of pre-cooled sodium nitrite (8.5g).After adding is finished, this reactant mixture was stirred 10 minutes down at-2 ℃.Under-10 ℃, with this muddiness, orange solution is added dropwise in concentrated hydrochloric acid (67ml) solution of that vigorous stirring, pre-cooled stannic chloride (II) dihydrate (101g).The speed controlling that adds is lower than-5 ℃ keeping reaction temperature.After adding is finished, this lacteous suspension is warmed to room temperature and leaches solid.Described solid with the ether washing and through anhydrous sodium sulfate drying, is obtained the 52g raw product.(20g) is distributed between 2.5N sodium hydrate aqueous solution and the dichloromethane with this raw product.Organic layer is passed through diatomite filtration, with the salt water washing and through anhydrous magnesium sulfate drying.Filtering and evaporating solvent in a vacuum, obtain lacteous solid (7.1g), with its diethyl ether solution processing with 1 normal anhydrous hydrogen chloride, obtain title compound, is a hydrochlorate, m.p.76-79 ℃, and MS m/z:197 (M+H) ⁺

Embodiment 1052-methoxyl group-4-(3-methyl-pyrazol-1-yl)-essence of Niobe

Add acetyl group dimethylacetal (0.53g) in the solution in 1: 1 water/carbinol mixture (10ml) of the 4-diazanyl that an is stirring-2-methoxybenzoic acid methyl ester hydrochloride (0.88g) and a concentrated hydrochloric acid from embodiment 104.With this reactant be heated to 90 ℃ 5 minutes.This reactant is concentrated in a vacuum and is distributed between 1N sodium hydroxide (10ml) and the ethyl acetate (50ml).Remove organic layer and use the salt water washing, through anhydrous magnesium sulfate drying and filtration.Evaporating solvent obtains brown oil in a vacuum, with itself and former a collection of (0.54g) merges and from dipropyl ether recrystallization three times, obtain 2-methoxyl group-4-(3-methyl-pyrazol-1-yl)-essence of Niobe (0.5g).m.p.167-169℃，MS?m/z：246(M) ⁺。

Embodiment 1062-methoxyl group-4-(3-methyl-pyrazol-1-yl)-benzoic acid

To at room temperature handle with 1N Lithium hydrate (2.13ml) from oxolane (2.5ml) solution of 2-methoxyl group-4-(3-methyl-pyrazol-1-yl)-essence of Niobe (0.5g) of embodiment 105.After 14 hours, in a vacuum except that desolvating and under 0 ℃, being settled out title compound by adding 1N hydrochloric acid.Obtain the 0.42g title compound in a vacuum after the drying, be solid.MS?m/z：232(M) ⁺。Embodiment 107[2-methoxyl group-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Oxalyl chloride (0.17ml) is joined in anhydrous tetrahydro furan (10ml) solution of (3-methyl-pyrazol-1-yl) benzoic acid (0.41g) of the 2-methoxyl group-4-from embodiment 106 that stirring and dimethyl formamide (0.004ml).This reactant was heated 10 minutes down at 35 ℃.The solution that obtains is evaporated in a vacuum, obtain rough 2-methoxyl group-4-(3-methyl-pyrazol-1-yl)-Benzenecarbonyl chloride..With the dichloromethane coevaporation after, be dissolved in this acyl chlorides in the dichloromethane (10ml) and add 10,11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0.31g).Adding diisopropylethylamine (0.37ml) also at room temperature stirred this reactant 2 hours.With this reactant with dichloromethane dilution and water, use 1N salt acid elution subsequently.With organic layer salt water washing,, be concentrated into dried in a vacuum through anhydrous magnesium sulfate drying.Through silica gel rapid column chromatography purification, with hexane/ethyl acetate (2/1) eluting, obtaining the 0.35g title compound is colorless solid with solid residue.m.p.92-94℃。

Embodiment 108 (3-dimethylaminomethyl-5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-[2-methoxyl group-4-(3-methyl-pyrazol-1-yl)-phenyl]-ketone

To [2-methoxyl group-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H that is stirring from embodiment 107,11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-add N in warm methanol solution (10ml) solution of ketone (0.57g), N, N, N '-tetramethyl-diaminourea methane (0.392ml) and acetic acid (0.164ml).After adding 37% formalin (2.9ml), reactant was stirred 15 minutes.Mixture is concentrated in a vacuum and is distributed between dichloromethane and the sodium bicarbonate.Remove organic layer, with the salt water washing and through anhydrous magnesium sulfate drying.This solution is filtered and remove in a vacuum and desolvate.Residue through silica gel rapid column chromatography purification, is obtained solid with chloroform/methanol (50/1) eluting.With this solid recrystallization from acetone, obtaining title compound is colorless solid, m.p.196-198 ℃.Embodiment 109[2-hydroxyl-4-(3-methyl-pyrazol-1-yl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

To be dissolved in the dichloromethane (20ml) from [2-methoxyl group-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (0.82g) of embodiment 107 and be cooled to-78 ℃.Adding Boron tribromide (6.2ml) also stirs this reactant 5 minutes down at 0 ℃.Add ammonium hydroxide (15ml) and use dichloromethane extraction.With salt water washing organic layer and through anhydrous magnesium sulfate drying.Remove solid after filtration also in a vacuum except that desolvating.Through silica gel rapid column chromatography purification, with hexane/ethyl acetate (3/1 then 2/1) eluting, obtaining the 0.19g title compound is colorless solid with residue.m.p.134-136℃。

Embodiment 1102-chloro-4-iodo-essence of Niobe

Temperature was for-10 ℃ and stir into suspension in 4-amino-2-methoxyl group-essence of Niobe (22.97g) was cooled in concentrated hydrochloric acid (110ml).Keeping reaction temperature to be lower than 0 ℃ speed, water (45ml) solution of the sodium nitrite (98.71g) of pre-cooling is joined in the described mixture.After stirring 25 minutes under 0 ℃, be lower than-4 ℃ speed to keep reaction temperature, with water (50ml) solution-treated of reactant with potassium iodide (24.44g) and iodine (18.37g).Add ethyl acetate (100ml), mixture that should dead color during adding stirred 1 hour down at 0 ℃.Organic layer is carefully washed with the ethyl acetate dilution and with saturated sodium thiosulfate solution.With the clear color solution that obtains with the salt water washing and through anhydrous magnesium sulfate drying.Evaporating solvent obtains grease in a vacuum, and it through silica gel sucking filtration purification, is used hexane/ethyl acetate (50/1) eluting.The purification grease cooling curing that obtains obtains the 33.71g title compound.MS，m/z：296(M) ⁺。

Embodiment 1114-bromo-1-methyl isophthalic acid H-pyrazoles

In oxolane (200ml) suspension of the oil solution (11.67g) of 60% sodium hydride of pre-wash (oxolane), be added dropwise to oxolane (50ml) solution of 4-bromo pyrazoles (39.77g).This solution was at room temperature stirred 2 hours.Oxolane (50ml) solution that adds excessive iodomethane (33ml) with the speed that keeps increasing slightly temperature.With this reactant restir 2 hours.Under vacuum, remove and desolvate and in ether, stir residue.Wash through the sucking filtration disgorging and with ether.The organic layer that merges is evaporated in a vacuum, and the title compound that obtains 42.22g is a grease.MS?m/z：160(M) ⁺。

Embodiment 1121-methyl-4-tributyl stannyl-1H-pyrazoles

Under argon atmospher, keeping the speed of described temperature, the 1.6M in the hexane of (internal temperature＜-10 ℃) of pre-cooling just-add ether (50ml) solution in absolute ether (100ml) solution of butyl lithium (100ml) from 4-bromo-1-methyl isophthalic acid H-pyrazoles (23.42g) of embodiment 111.This reactant restir after 20 minutes, is added ether (50ml) solution of tributyltin chloride (43.4ml).The temperature of reactant is increased to 20 ℃.This reactant is removed insoluble substance with the ether dilution and through sucking filtration.Evaporating solvent in a vacuum, obtaining the 56g title compound is grease.MS?m/z：373(M+H) ⁺。In fine vacuum, under 170 ℃, by the stannum residue of residual volume being removed from described grease with the Kugelrohr apparatus distillation.

Embodiment 1132-chloro-4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-essence of Niobe

To close from 2-chloro-4-iodo-essence of Niobe (25.4g), 1-methyl-4-tributyl stannyl-1H-pyrazoles (31.77g), four (triphenylphosphines) of embodiment 110 palladium (0) (1.8g) and the dimethyl formamide solution (70ml) of the argon-degassed of the Copper diiodide (I) of catalytic amount 80 ℃ of heating 7 hours down.In a vacuum except that desolvating and residue being adsorbed on the silica gel.By silicagel pad sucking filtration purification, order will obtain solid residue with hexane, use hexane/ethyl acetate (2/1) eluting subsequently after the solvent evaporation, with its recrystallization from Di Iso Propyl Ether, obtain the 7.82g title compound, MS m/z:250 (M) ⁺Embodiment 1142-chloro-4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-benzoic acid

In from methanol (80ml) solution of 2-chloro-4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-essence of Niobe (6.25) of embodiment 113, add 1N sodium hydroxide solution (30ml).This reactant was heated 1 hour under refluxing.The volume of solvent is reduced 3/4 and residue is following to the acid treatment of 2N salt at 0 ℃ in a vacuum.Leach precipitate and dry in a vacuum, obtain the 5.84g title compound, MS m/z:237 (M+H) ⁺

Embodiment 115[2-chloro-4-(1-methyl isophthalic acid H-pyrazoles-4-yl) phenyl] (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Oxalyl chloride (0.49ml) is joined in anhydrous tetrahydro furan (20ml) solution of 2-chloro-4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-benzoic acid (0.41g) from embodiment 114 and dimethyl formamide (0.012ml).This reactant was heated 10 minutes down at 35 ℃.The solution that obtains is evaporated in a vacuum dried, obtains rough 2-chloro-4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-Benzenecarbonyl chloride..With the anhydrous methylene chloride coevaporation after, acyl chlorides is dissolved in the dichloromethane (20ml), add 10 subsequently, 11-dihydro-5H-pyrrolo-[2,1-c] [1,4] benzodiazepine (0-888g) and diisopropylethylamine (1.06ml).The solution that obtains was at room temperature stirred 2 hours.With this reactant with dichloromethane dilution and water, use 1N salt acid elution subsequently.With organic layer usefulness salt water washing and through anhydrous magnesium sulfate drying.Also be concentrated into the dichloromethane solution filtration dried in a vacuum.Through silica gel rapid column chromatography purification, with hexane/ethyl acetate (2/1) eluting, obtaining the 1.4g title compound is colorless solid with residue.m.p.105-109℃。

Embodiment 116[2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine -5-yl)-ketone

In dichloromethane solution (10ml) solution, add 5H-10 from 2-chloro-4-(3-methyl-pyrazol-1-yl)-Benzenecarbonyl chloride. (0.214g) of embodiment 18 step e, 11-dihydro-pyrazolo [5,1-c] [1,4] benzodiazepine (0.153g) and diisopropylethylamine (0.173ml).This reactant was at room temperature stirred 2 hours.With this reactant with dichloromethane dilution and water, use 1N salt acid elution subsequently.With organic layer usefulness salt water washing and through anhydrous magnesium sulfate drying.Dichloromethane solution is filtered and is concentrated in a vacuum drying.Through silica gel rapid column chromatography purification, with hexane/ethyl acetate (1/1) eluting, obtaining the 0.3g title compound is colorless solid with residue.m.p.187-188℃。

Embodiment 117[2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5,10-dihydro-4H-tetrazolo [5,1-c] [1,4] benzodiazepine -5-yl)-ketone

In dichloromethane (10ml) solution, add 10 from 2-chloro-4-(3-methyl-pyrazol-1-yl)-Benzenecarbonyl chloride. (0.18g) of embodiment 18 step e, 11-dihydro-5H-tetrazolo [5,1-c] [1,4] benzodiazepine (0.13g) and diisopropylethylamine (0.145ml).This reactant was at room temperature stirred 2 hours.With this reactant with dichloromethane dilution and water, use 1N salt acid elution subsequently.With organic layer usefulness salt water washing and through anhydrous magnesium sulfate drying.Also be concentrated into the dichloromethane solution filtration dried in a vacuum.Through silica gel rapid column chromatography purification, with hexane/ethyl acetate (1/1) eluting, obtaining the 0.14g title compound is colorless solid with residue.m.p.110-114℃。

Embodiment 1181-[4-(4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine -5-carbonyl)-phenyl]-ethyl ketone

With 5,10-dihydro-4H-pyrazolo [5,1-c] [1,4] benzodiazepine (0.555g), 4-acetylbenzene formyl chloride (0.657g) and N, dichloromethane (15ml) mixture of N-diisopropylethylamine (0.464g) at room temperature stirred 4 hours.Pour into this mixture in the water and use dichloromethane extraction.With dichloromethane extraction liquid saturated sodium bicarbonate, water and salt water washing and through anhydrous sodium sulfate drying.Extract filtered by the thin pad of hydrated magnesium silicate and with the filter bed washed with dichloromethane.With the concentrated in a vacuum 1.53g yellow solid that obtains of filtrate.Described solid is obtained the 0.747g title compound with the ethyl acetate grinding, be glassy mass, m.p.201-210 ℃.The mother liquid evaporation of self-grind and residue (0.30g) gone up chromatography at thick coating silica gel plate (200 microns) in the future, with hexane-ethyl acetate (1/1) as solvent.Solid ground with ethyl acetate and merge with the product of 0.747g initial separation.The solid that merges is precipitated from the mixture of dichloromethane-hexane, and obtaining the 0.73g product is glassy mass.

Embodiment 1191-[4-(4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine -5-carbonyl)-phenyl]-3-(dimethylamino)-third-2-alkene-1-ketone

With 1-[4-(4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine -5-carbonyl) phenyl] ethyl ketone (0.73g), uncle-butoxy be two-and mixture in the dichloromethane (10ml) of [dimethylamino] methane (0.964g) at room temperature stirred 2 days.This mixture is concentrated in a vacuum and, obtain the 0.65g title compound, be yellow crystals, m.p.225-230 ℃ residue crystallization from dichloromethane-hexane.

Embodiment 120[4-(1-methyl isophthalic acid H-pyrazole-3-yl) phenyl] (4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine -5-yl) ketone (isomer A) and [4-(2-methyl isophthalic acid H-pyrazole-3-yl) phenyl] (4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine -5-yl) ketone (isomer B)

With 1-[4-(4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepine -5-carbonyl) phenyl]-mixture in the 10ml ethanol of 3-(dimethylamino)-third-2-alkene-1-ketone (0.83g), hydrazine (0.198g) and acetic acid (0.336g) refluxed 4 hours.Remove volatile matter in a vacuum and residue is dissolved in the dichloromethane.With this solution with water, 1N sodium bicarbonate, water and salt water washing and through anhydrous sodium sulfate drying.This solution is washed filter bed by the thin pad filtration of hydrated magnesium silicate and with ethyl acetate.Filtrate is concentrated in a vacuum, obtain the 0.56g light yellow solid.This solid is gone up chromatography at thick coating silica gel plate (200 microns), as solvent, obtain the mixture that the 0.35g white solid is A and B (1: 4) with ethyl acetate.Multiple fractionation crystallization from ethyl acetate obtains the 89mg crystal, and m.p.155-156 ℃, the mixture (1: 6) that is A and B for mixture (9: 1) and the 65mg glassy mass of A and B.

Embodiment 1211-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-3-chlorophenyl]-ethyl ketone

Step a) in 20ml Carrius pipe, triethylamine (8.80ml) is joined (4-bromo-2-chlorophenyl)-pyridine (1.80ml) solution of (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (2.37g) in.With the solution that obtains with nitrogen purge 25 minutes, add then (trimethyl silyl) acetylene (1.67ml), chlorination two (triphenylphosphine) close palladium (II) (0.08g) and Copper diiodide (I) (0.01g).To fill it up with the triethylamine of nitrogen purge in the described pipe, sealing was also heated 80 hours under 90 ℃ in oil bath.Described solution is cooled to room temperature, in a vacuum evaporating solvent and residue is distributed between dichloromethane and the water.This dichloromethane extraction liquid through anhydrous sodium sulfate drying, is filtered and flashes in a vacuum brown foam.Flash chromatography purification on silica gel with hexane-ethyl acetate (1: 1) eluting, obtains intermediate acetylene, is canescence foam (2.11g) MS m/z:418 (M) ⁺This material is not further purified and uses in next step.

Step b) is saturated with 1% vitriolic tetrahydrofuran solution with Mercury bisulfate. (II).Oxolane (5ml) solution of intermediate acetylene (1.00g) tetrahydrofuran solution with the above-mentioned Mercury bisulfate. of 30ml (II) was stirred 50 hours.The Mercury bisulfate. (II) that adds additional amount (0.01g) and water (0.3ml).Stir after 120 hours, pour into this reactant mixture in the water and use dichloromethane extraction.This dichloromethane solution is used saturated sodium bicarbonate aqueous solution and water washing in proper order.Through anhydrous magnesium sulfate drying, filter and be evaporated to dried this dichloromethane solution, obtain brown solid.Through the flash chromatography on silica gel purification, with hexane-ethyl acetate (1: 1) eluting, obtain white solid (0.30g), m.p.98-100 ℃, MS m/z:364 (M) ⁺Embodiment 1221-[4-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-carbonyl)-3-chlorophenyl]-ethyl ketone

Tributyl (ethoxy ethylene base) stannum (1.17g) is joined (4-bromo-2-chlorophenyl)-toluene (10ml) solution of (5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.24g) in.The solution that obtains is used nitrogen purge 10 minutes, add chlorination two (triphenylphosphine) then and close palladium (II) (0.11g).Described reactant mixture is heated to backflow 24 hours.Solution is cooled to room temperature, adds 5% aqueous hydrochloric acid solution (10ml).Stir after 1 hour, mixture is filtered by Celite pad.Join ether (5ml) in the filtrate and with the mixture ethyl acetate extraction that obtains.Organic layer through anhydrous magnesium sulfate drying, is filtered also evaporation in a vacuum and obtains brown glass shape thing.Flash chromatography purification on silica gel with hexane-ethyl acetate (1: 1) eluting, obtains white solid (0.30g), MS m/z:364 (M) ⁺

Embodiment 123[2-chloro-4-(3-methyl-4-acetenyl-phenyl) (5H, 11H-pyrrolo-[2,1-c] [1,4]-benzodiazepine -10-yl)-ketone

At room temperature, will handle with the tetrahydrofuran solution of 1M tetrabutylammonium, remove the title compound that obtains 84% yield after desolvating, be orange/yellow solid from the intermediate acetylene of embodiment 121 steps A, m.p.84-86 ℃, MS, m/z:346 (M) ⁺The method for preparing pharmaceutical formulation

The present invention also comprises the method for preparing the above preparation.Method of the present invention may further comprise the steps:

A) the preferred employing mixed or stirring, PEG mixed forming first carrier mixture with surfactant component;

B) temperature of rising first carrier mixture is to about 75-95 ℃ scope, preferably approximately 80-90 ℃;

C) add active component to form the mixture of initial medicinal combination;

D) mixture of the initial medicinal combination of stirring preferably heats simultaneously till the mixture clarification of this initial medicinal combination, and preferred temperature is about 115-170 ℃, and preferably approximately 130-150 ℃, more preferably about 135-145 ℃;

E) if desired, initial Pharmaceutical composition is cooled to about 75-95 ℃, preferably approximately 80-90 ℃;

G) add a certain amount of sucrose fatty acid ester and/or polyvidone to form the mixture of final medicinal combination, preferably stir simultaneously till the mixture clarification of initial medicinal combination.

Under the situation of using optional antioxidant or antiseptic such as BHA, BHT etc., can adopt following steps:

A) the preferred employing mixed or stirring, and PEG composition (as the mixture of PEG 400 and PEG 1000) is mixed to form first carrier mixture with surfactant component (as polyoxyethylene sorbitan monoleate);

B) temperature that improves first carrier mixture arrives about 75-95 ℃, preferably approximately 80-90 ℃;

C) in first carrier mixture, add optional antioxidant or antiseptic composition to form second carrier mixture, mix till second carrier mixture is clear solutions with its stirring or with other method then;

D) add active component to form the mixture of initial medicinal combination;

E) mixture of the initial medicinal combination of stirring preferably heats simultaneously till the mixture clarification of initial medicinal combination, and preferred temperature is about 130-150 ℃, and more preferably temperature is about 135-145 ℃;

F) optional initial Pharmaceutical composition is cooled to temperature is about 75-95 ℃, preferably approximately 80-90 ℃;

G) add a certain amount of sucrose fatty acid ester and/or polyvidone to form the mixture of final medicinal combination, preferably stir simultaneously till the mixture clarification of final medicinal combination.

The viscosity and the form that it will be understood by those skilled in the art that finished product preparation can adopt interior composition of the scope of the invention and the temperature range in the course of processing to control.For example, liquid or semisolid compositions can prepare with mobile better PEG, surfactant and the PVP material in the scope of the invention.Gel, viscosity or semi-solid combination can and have the preparation of compositions of the PVP composition of higher K value with high-molecular weight PEG composition more.In addition, the processing method of grinding or other final product composition having can be cooled to described composition below their fusing point if desired.In order to form more granular primary composition, fluid composition of the present invention can be sprayed on refrigerative Tefion -coating surface forming little solid spherical thing, coating or collection are used for other processing separately for they.

Below provide specific indefiniteness embodiment is arranged in the scope of the invention.

Embodiment 150mg/ capsule: drug loading is 10% oral formulations

In the said preparation of embodiment 1, replace polyoxyethylene sorbitan monoleate, also can be with other Polysorbate series as polysorbas20,40 and 60, independent or combination with one another and/or be used in combination with polyoxyethylene sorbitan monoleate.

(%w/w) every capsules is every batch 20,000

(mg) capsules (g) active component: 10.42 50.00 1000.00 non-active ingredient: PEG 1000, NF 30.96 148.61 2,972.16 polyvidone USP K-17 10.00 48.00 960.00 polyoxyethylene sorbitan monoleates, NF 10.00 48.00 960.00BHT, NF 0.09 0.42 8.32BHA, NF 0.87 4.16 83.2PEG 400, NF ²In right amount to 100 in right amount to 480.00 in right amount to 9,600

1. with polyoxyethylene sorbitan monoleate, PEG 400 and PEG 1000 weighings and add in the suitable mixer, stir and heat to 85 ± 5 ℃ with the fixed blender in top.

2. add BHT and BHA very lentamente in mixer, in case form micelle.Continue down to stir at 85 ± 5 ℃ until forming clear solutions.

3. under 85 ± 5 ℃, add active component very lentamente in container, in case form micelle.Slowly temperature is risen to 125 ± 5 ℃ and stir and to dissolve fully until active component.

4. the solution with step 4 is cooled to 60 ± 5 ℃.

5. with polyvidone, USP, (Plasdone C-15 ISP) slowly joins in the step 5 in case form micelle K-17.

Described solution is heated to 85 ± 5 ℃.Stirring becomes clarification until solution.

6. under 38 ± 5 ℃, with Hoflinger and Karg (H﹠amp; K) (seal in No. 1 capsule by step 10) with the 480mg final mean annual increment solution for the 800L capsule filling machine.In the middle of sealing, cool off capsule body with cooling nitrogen by dry ice.

With gelatin solution with described capsule ring seal.

Embodiment 250mg/ capsule: drug loading is 10% oral formulations

In this preparation, except using surfactant (poloxamer 188), also can use other series of polymers such as pluronic to restrain L44, pluronic gram L101.

(%w/w) every capsules is every batch 20,000

(mg) capsules (g) active component: 10.42 50.00 1000.00 non-active ingredients: polyvidone USP K-17 10.00 48.00 960.00 (Plasdone C-15, ISP) poloxamer 188, NF 12.00 57.60 1152.00BHT, NF 0.09 0.42 8.32BHA NF 0.87 4.16 83.20PEG 400 NF are in right amount to 100 in right amount to 480.00 in right amount to 9600g

Except the poloxamer with 12% in said preparation replaces the polyoxyethylene sorbitan monoleate, the said preparation method preparation identical with embodiment 1 (50mg/ capsule) preparation.The weight of encapsulation object is 480mg.Embodiment 350mg/ capsule

Embodiment 3 provides the preparation of the compositions that adopts two or more surfactants.

(%w/w) every capsules (mg) is every batch 20,000

Capsules (g) active component: 10.64 51.07 1,021.44 non-active ingredient: PEG 1000, NF 28.60 137.28 2,745.60 polyvidone USP K-17 10.00 48.00 960.00 (Plasdone C-15, ISP) polysorbate 40, NF 5.00 24.00 480.00 poloxamers 188, NF 10.00 48.00BHT, NF 0.09 0.43 8.64BHA, NF 0.87 4.18 83.52PEG 400, NF in right amount to 100 in right amount to 480.00 in right amount to 9600.00

Except in step 1 with PEG 400 and PEG 1000 add two kinds of surfactant polysorbate 40s and poloxamer 188, use with the identical method of embodiment 1 (50mg/ capsule) to prepare the preparation of embodiment 3.The weight of encapsulation object is 480mg.Embodiment 425mg/ capsule: drug loading is 5% oral formulations

(%w/w) every capsules is every batch 20,000

(mg) capsules (g) active component: 5.49 25.00 500.00 non-active ingredient: PEG 1000, NF 32.66 148.61 2,972.16 polyvidone, USP K-17 10.55 48.00 960.00 (Plasdone C-15, ISP) polyoxyethylene sorbitan monoleate, NF 10.55 48.00 960.00BHT, NF 0.09 0.42 8.32BHA, NF 0.91 4.16 83.2PEG 400, NF ²In right amount to 100 in right amount to 455.00 in right amount to 9,100g

Except the heating-up temperature of lytic activity composition in the step 3 be 115 ± 5 ℃ replacing 120 ± 5 ℃, the preparation of embodiment 4 adopts the method identical with above 50mg/ capsule to prepare.The weight of encapsulation object is 455mg.Embodiment 5100mg/ capsule: drug loading is 15% oral formulations

(%w/w) every capsules is every batch 20,000

(mg) capsules (g) active component: 15.38 100.00 2,000.00 non-active ingredient: PEG 1000, NF 28.98 188.35 3,767.05 polyvidone, USP K-17 10.00 65.00 1,300.00 (Plasdone C-15, ISP) ³Polyoxyethylene sorbitan monoleate, NF 9.45 61.39 1,227.91BHT, NF 0.08 0.53 10.64BHA, NF 0.82 5.32 106.42PEG 400, NF in right amount to 100 in right amount to 650.00 in right amount to 13,000.00

Except the heating-up temperature of lytic activity composition in the step 3 be 145 ± 5 ℃ replacing 120 ± 5 ℃, the preparation of embodiment 5 adopts the step identical with above 50mg/ capsule to prepare.The weight of encapsulation object is 650mg, is No. 0 hard gelatin capsule.Embodiment 6150mg active component is in No. 00 capsule

(%w/w) the every finger 20,000 of every capsules

(mg) capsules (g) active component: 16.48 149.97 2,999.36 non-active ingredient: PEG 1000, NF 26.3 239.33 4,786.60 polyvidone, USP K-17 15 136.50 2,730.00 (Plasdone C-15, ISP) polyoxyethylene sorbitan monoleate, NF 9.32 84.81 1,696.24BHT, NF 0.08 0.73 14.56BHA, NF 0.81 7.37 147.42PEG 400, NF in right amount to 100 in right amount to 910.00 in right amount to 18,200.00

Except the heating-up temperature of lytic activity composition in the step 3 be 150 ± 5 ℃ replacing 145 ± 5 ℃, the preparation of embodiment 6 adopts the step identical with above 50mg/ capsule to prepare.The weight of encapsulation object is 910mg, is No. 00 hard gelatin capsule.

Can prepare the preparation of the specific embodiment 7-11 that lists in the following table 1 as mentioned above, contain the preparation of the compositions (as the adjuvant composition) of PEG 400, the PEG 1000 of 10% active component, variable concentrations, two kind of PVP composition that has 15 and 90 K value respectively and BHA and BHT with formation.

The active number 400 1000 K15 K90 compositions of table 1 embodiment PEG PEG PVP PVP BHT BHA NATC

(％)???(％)???(％)?(％)????(％)????(％)????(％)????(％)7????55.40??20.00??10.00?0.00????0.20????2.00????2.40????10.008????40.40??35.00??10.00?0.00????0.20????2.00????2.40????10.009????75.40??0.00???5.00??5.00????0.20????2.00????2.40????10.0010???65.40??10.00??0.00??10.00???0.20????2.00????2.40????10.0011???40.40??35.00??5.00??5.00????0.20????2.00????2.40????10.00

Equally, by described method, can prepare the preparation of following examples 12-32 with PEG 400, PEG 1000, PVP, active component, as the BHA of antioxidant or antiseptic and BHT and listed " other " supplementary element with K value 17.

The active BHA BHT other other of the real PEG PEG of table 2 PVP execute 400 1000 K-17 compositions example number 12 40.40 35.00 10.00 10.00 2.00 0.20 sodium taurocholate-

2.4013 75.40-5.00 10.21 2.00 0.20 sodium taurocholate PVP

2.40??????????K-90

5.0014 42.59 35.00 10.00 10.21 2.00 0.20--15 34.35 28.23 10.00 10.21 2.00 0.20 poloxamers 188-

15.0016 42.59 20.00 10.00 10.21 2.00 0.20 poloxamers 188-

15.0017 37.10 30.49 10.00 10.21 2.00 0.20 poloxamers 188-

10.0018 35.72 29.36 10.00 10.21 2.00 0.20 poloxamers 188-

12.5019 34.35 28.23 10.00 10.21 2.00 0.20 poloxamers 188-

15.0020 37.10 30.49 10.00 10.21 2.00 0.20 poloxamers 188-

10.0021 34.35 28.23 10.00 10.21 2.00 0.20 poloxamers 188-

15.0022 35.72 29.36 10.00 10.21 2.00 0.20 poloxamers 188-

12.5023 36.86 30.30 10.00 10.64 2.00 0.20 pluronics gram-

L44

10.0024 36.86 30.30 10.00 10.64 2.00 0.20 pluronics gram-

L101

10.0025 39.61 32.55 10.00 10.64 2.00 0.20 polysorbate40s-

5.0026 41.25 33.91 10.00 10.64 2.00 0.20 polysorbate40s-

2.0027 39.61 32.55 10.00 10.64 2.00 0.20 polysorbas20s-

5.0028 41.25 33.91 10.00 10.64 2.00 0.20 polysorbas20s-

2.0029 34.12 28.04 10.00 10.64 2.00 0.20 polysorbate40 poloxamers 188

5.00 10.0030 36.86 30.30 10.00 10.64 2.00 0.20 polysorbate40s-

10.0031 36.86 30.30 10.00 10.64 2.00 0.20 Tween 80s-

10.0032 34.12 28.04 10.00 10.64 2.00 0.20 Tween 80 poloxamers 188

5.00??????????10.00

Claims

1. Pharmaceutical composition, it comprises (% w/w): a) approximately active component or its pharmaceutically acceptable salt of 1%-20%, this active component has following structure:

Wherein: each independently is CH or nitrogen for A, B, E, G; D independently is C-W or nitrogen; R ¹Be 2-7 carbon atom alkanoyl, be selected from CN, COOH, CONH ₂,-≡-H ,-≡-R ⁹Group, or be selected from the part of following group:

R ², R ³And R ⁵Each independently is the straight chained alkyl of hydrogen, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, the cycloalkyl of a 3-7 carbon atom or the perfluoroalkyl of 1-6 carbon atom; R ⁴Be branched alkyl, a 3-7 carbon atom of straight chained alkyl, a 3-7 carbon atom of hydrogen, a 1-6 carbon atom cycloalkyl, a 2-7 carbon atom alkoxyalkyl or be selected from the acyl substituent of following group: the alkenoyl of the alkanoyl of 2-7 carbon atom, a 3-7 carbon atom, cycloalkanes acyl group, aroyl or the Arylalkanoyl of a 3-7 carbon atom; Each independently is alkoxyalkyl, the halogen (comprising chlorine, bromine, fluorine and iodine) of perfluoroalkyl, a 2-7 carbon atom of cycloalkyl, a 1-6 carbon atom of branched alkyl, a 3-7 carbon atom of straight chained alkyl, a 3-7 carbon atom of hydrogen, a 1-6 carbon atom, alkoxyl, hydroxyl, the CF of a 1-6 carbon atom for X and Y ₃Or the perfluoroalkyl of 2-6 carbon atom; W is hydrogen, halogen (preferred chlorine, bromine or iodine), alkyl, the alkoxyalkyl of a 2-7 carbon atom, the hydroxyalkyl or the CH of a 1-6 carbon atom ₂NR ⁶R ⁷R ⁶And R ⁷Each independently is the straight chained alkyl of hydrogen, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom; Or R ⁶And R ⁷With CH ₂NR ⁶R ⁷Nitrogen-atoms together, form optional one or more other the heteroatomic 5 or 6 yuan of rings that contain, for example, but be not limited to following group: R ⁸It is the straight chained alkyl of 1-6 carbon atom; R ⁹It independently is the straight chained alkyl of hydrogen, a trimethyl silyl or 1-6 carbon atom; B) surfactant component of about 1-18%; C) one or more of about 50-80% are planted Polyethylene Glycol compositions; And d) the following composition of about 1-20%:

I) one or more plant sucrose fatty acid ester; Or

Ii) the K value is the polyvinylpyrrolidone of about 15-90; Or

Iii) one or more plant the compositions of sucrose fatty acid ester and polyvinylpyrrolidone.

2. the Pharmaceutical composition of a claim 1, wherein said active component has following structure:

Wherein: each independently is CH or nitrogen for A and B; D is C-W or nitrogen; R ¹Be the alkanoyl of 2-7 carbon atom or be selected from following group: R ², R ³And R ⁵Each independently is the straight chained alkyl of hydrogen, a 1-6 carbon atom, the branched alkyl of a 3-7 carbon atom, the cycloalkyl of a 3-7 carbon atom or the perfluoroalkyl of 1-6 carbon atom; R ⁴, X, Y, W, R ⁶, R ⁷And R ⁸Such as in claim 1 definition; Or its pharmaceutically acceptable salt.

3 A pharmaceutical composition of claim 1, wherein said active ingredient is selected from: (4 - fluoro-2 - trifluoromethyl - phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine Miscellaneous -10 - yl) - methanone, [4 - (3 - methyl - pyrazol-1 - yl) -2 - trifluoromethyl - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, [4 - (4 - methyl - pyrazol-1 - yl) -2 - trifluoromethyl - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, (4 - pyrazol-1 --2 - trifluoromethyl-phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [4 - (3 - cyclopropyl - pyrazol-1 - yl) -2 - trifluoromethyl - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, [4 - (4 - methyl - imidazol-1 - yl) -2 - trifluoromethyl - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - (4 - [1,2,4) triazol-1 - -2 - trifluoromethyl-phenyl) - methanone, (2 - chloro-4 - fluoro-phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin- - 10 - yl) - methanone, [2 - chloro-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, [2 - chloro-4 - (5 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, [2 - chloro-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, [2 - chloro-4 - (4 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, [2 - chloro-4 - (4 - methyl - imidazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, [2 - chloro-4 - (3 - trifluoromethyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, [2 - chloro-4 - (1,2,4 - triazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, (2 - chloro-4 - pyrrol-1 - yl - phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine -10 - yl) - methanone, (2 - chloro-4 - pyrazol-1 - yl - phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine -10 - yl) - methanone, [2 - chloro -4 - (1H-imidazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [2 - chloro-4 - (3 - methyl-pyrazol-1 - yl) - phenyl] - (3 - methyl-5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, (2 - chloro-4 - trifluoromethyl - pyrimidin-5 - yl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [2 - (3 - methyl - pyrazol-1 - yl) -4 - trifluoromethyl - pyrimidin-5 - yl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, [2 - (4 - methyl - pyrazol-1 - yl) -4 - trifluoromethyl - pyrimidin-5 - yl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, 1 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - phenyl] - acetic Ketones, 3 - dimethylamino -1 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - Carbonyl) - phenyl]-2 - propen-1 - one, [4 - (1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine -10 - yl) - methanone, [4 - (1 - methyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [4 - (1 - ethyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [4 - (1 - propyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [4 - (1 - butyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [4 - (1 - methoxymethyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, 1 - {3 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - phenyl] - Pyrazol-1 - yl} - ethanone 1 - {3 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - phenyl] - Pyrazol-1 - yl} - propan-1 - one, [4 - (1 - cyclopropanecarbonyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, 1 - {3 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - phenyl] - Pyrazol-1 - yl} - butan-1 - one, (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - {4 - [1 - (thiophen-2 - carbonyl Yl)-1H-pyrazol-3 - yl]-phenyl} - methanone, {4 - [1 - (5 - fluoro-2 - methyl - benzoyl)-1H-pyrazol-3 - yl] - phenyl} - (5H, 11H-pyrazol Pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, {4 - [1 - (2 - methyl - benzoyl)-1H-pyrazol-3 - yl] - phenyl} - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, {4 - [1 - (2 - chloro-4 - fluoro - benzoyl)-1H-pyrazol-3 - yl] - phenyl} - (5H, 11H-pyrazol Pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, {4 - [1 - (2,4 - dichloro - benzoyl)-1H-pyrazol-3 - yl] - phenyl} - (5H, 11H-pyrrolo And [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, 2 - (2,4 - dichloro - phenyl) -1 - {3 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine Miscellaneous -10 - carbonyl) - phenyl] - pyrazol-1 - yl} - ethanone {4 - [1 - (biphenyl-2 - carbonyl)-1H-pyrazol-3 - yl] - phenyl} - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, {4 - [1 - (4'-trifluoromethyl - biphenyl-2 - carbonyl)-1H-pyrazol-3 - yl] - phenyl} - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, 3 - dimethylamino -1 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - Carbonyl) - phenyl] -2 - butene-1 - one, [4 - (5 - methyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, 4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - benzonitrile, 4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - benzamide, N-(dimethylamino-methylene) -4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine -10 - carbonyl) - benzamide, N-(1 - methylethylidene dimethylaminoethyl) -4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine Miscellaneous -10 - carbonyl) - benzamide, (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - [4 - (2H-[1,2,4] three Zol-3 - yl) - phenyl] - methanone, [4 - (2 - methyl-2H-[1,2,4] triazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepin -10 - yl) - methanone, [4 - (5 - methyl-2H-[1,2,4] triazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepin -10 - yl) - methanone, [4 - (2,5 - dimethyl-2H-[1,2,4] triazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, [4 - (3 - methyl [1,2,4] oxadiazol-5 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, 1 - methyl - 4 - (4 - methyl-phenyl)-1H-pyrazole, 4 - (1 - methyl-1H-pyrazol-4 - yl) - benzoic acid, [4 - (1 - methyl-1H-pyrazol-4 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, 6 - (1 - methyl-1H-pyrazol-4 - yl) - pyridine-3 - carboxylic acid, [6 - (1 - methyl-1H-pyrazol-4 - yl) - pyridin-3 - yl] - (5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepin -10 - yl) - methanone, [4 - (pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin- - 10 - yl) - methanone, [4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine Miscellaneous -10 - yl) - methanone, [4 - (4 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine Miscellaneous -10 - yl) - methanone, [4 - (3,5 - dimethyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - [4 - (3 - trifluoro-methyl Yl - pyrazol-1 - yl) - phenyl] - methanone, [4 - (imidazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin- - 10 - yl) - methanone, [4 - (4 - methyl - imidazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine Miscellaneous -10 - yl) - methanone, 4 - bromo-2 - chloro - benzoic acid methyl ester, 2 - chloro-4 - (3 - dimethylamino - propyn-1 - yl) benzoate, 2 - chloro-4 - (3 - dimethylamino-2 - propen-1 - one-1 - yl) - benzoic acid methyl ester, 2 - chloro -4 - (1H-pyrazol-3 - yl) - benzoic acid methyl ester, 2 - chloro-4 - (1 - methyl-1H-pyrazol-3 - yl) - benzoic acid methyl ester, 2 - chloro-4 - (1 - methyl-1H-pyrazol-3 - yl) - benzoic acid, [2 - chloro-4 - (1 - methyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, 2 - chloro-4 - (2 - methyl-1H-pyrazol-3 - yl) - benzoic acid methyl ester, 2 - chloro-4 - (2 - methyl-1H-pyrazol-3 - yl) - benzoic acid, [2 - Chloro-4 - (2 - methyl-1H-pyrazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, 2 - chloro-4 - cyano-benzoic acid methyl ester, 2 - chloro-4 - cyano-benzoic acid, 3 - chloro -4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - benzyl Nitrile, 3 - chloro -4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - benzoic Acid, 3 - chloro -4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - benzoic Amide, N-(1 - methylethylidene dimethylaminoethyl) -3 - chloro -4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - carbonyl) - benzamide, [2 - chloro-4 - (5 - methyl-2H-[1,2,4] triazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - methanone, N-(dimethylamino-methylene)-3 - chloro -4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - carbonyl) - benzamide, [2 - chloro -4 - (2H-1, 2,4 triazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepin -10 - yl) - methanone, [2 - Chloro-4 - (2 - methyl-2H-[1,2,4] triazol-3 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - methanone, 4 - [(2,5 - dimethyl-2H-[1,2,4] triazol-3 - yl) -2 - chloro - phenyl] - (5H, 11H-pyrrolo And [2,1-c] [1,4] benzodiazepin -10 - carbonyl) - methanone, [2 - chloro -4 - (1H-tetrazol-5 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [2 - chloro-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (3 - dimethylaminomethyl-5H, 11H- Pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, (3 - bromo-5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - [2 - chloro - 4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - methanone, (4 - bromo-2 - chloro-phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin- - 10 - yl) - methanone, [2 - bromo-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, (2,4 - difluoro - phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - Yl) - methanone, [2 - fluoro-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzene And diaza -10 - yl) - methanone, 4 - (3 - methyl - pyrazol-1 - yl) -2 - trifluoromethyl - benzoic acid methyl ester, 4 - (3 - methyl - pyrazol-1 - yl) -2 - trifluoromethyl - benzoic acid, [4 - (3 - methyl-pyrazol-1 - yl) -2 - trifluoromethyl-phenyl] - (5H, 11H-pyrazolo [5,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, 2 - chloro-4 - (3 - methyl-1H-pyrazol-1 - yl) - benzoic acid methyl ester and 2 - chloro-4 - (5 - methyl - 1H-pyrazol-1 - yl) - benzoic acid methyl ester, 2 - chloro-4 - (3 - methyl-1H-pyrazol-1 - yl) - benzoic acid, (2,6 - dichloro-pyridin-3 - yl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin- - 10 - yl) - methanone, (2 - chloro -6 - pyrazol-1 - yl - pyridin-3 - yl) - (5H, 11H-pyrrolo [2,1-c] [1,4] benzo- Diaza -10 - yl) - methanone, [2 - chloro -6 - (3 - methyl-pyrazol-1 - yl) - pyridin-3 - yl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, [2 - chloro -6 - (4 - methyl-pyrazol-1 - yl) - pyridin-3 - yl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, [2 - chloro-4 - (3 - methyl-1 ,2,4 - triazol-1 - yl) - phenyl] - (5H, 11H-pyrrolo [2,1 - c] [1,4] benzodiazepin -10 - yl) - methanone, [4 - (3 - methyl-1 ,2,4 - triazol-1 - yl) -2 - trifluoromethyl - phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - yl) - methanone, 4 - hydrazino-2 - methoxy-benzoate hydrochloride (1:1) hydrate (2:1) 2 - methoxy - 4 - (3 - methyl - pyrazol-1 - yl) - benzoic acid methyl ester, 2 - methoxy - 4 - (3 - methyl - pyrazol-1 - yl) - benzoic acid, [2 - methoxy-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] (5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepin -10 - yl) - methanone, (3 - dimethylaminomethyl-5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - Yl) [2 - methoxy-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - methanone, [2 - hydroxy - 4 - (3 - methyl - pyrazol-1 - yl] (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine Miscellaneous -10 - yl) - methanone, 2 - chloro-4 - iodo - benzoic acid methyl ester, 4 - bromo-1 - methyl-1H-pyrazole, 1 - methyl - 4 - alkyl tributylstannyl-1H-pyrazole, 2 - chloro-4 - (1 - methyl-1H-pyrazol-4 - yl) - benzoic acid methyl ester, 2 - chloro-4 - (1 - methyl-1H-pyrazol-4 - yl) - benzoic acid, [2 - chloro-4 - (1 - methyl-1H-pyrazol-4 - yl) phenyl] (5H, 11H-pyrrolo [2,1-c] [1,4] Benzodiazepin -10 - yl) - methanone, [2 - chloro-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (4H, 10H-pyrazolo [5,1-c] [1,4] benzene And diaza -5 - yl) - methanone, [2 - chloro-4 - (3 - methyl - pyrazol-1 - yl) - phenyl] - (5,10 - dihydro-4H-tetrazolo [5,1 - c] [1,4] benzodiazepin- -5 - yl) - methanone, 1 - [4 - (4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepin- -5 - carbonyl) phenyl] - acetic Ketones, 1 - [4 - (4H, 10H-pyrazolo [5,1-c] [1,4] benzodiazepin- -5 - carbonyl) phenyl] -3 - (di- Methylamino) - prop-2 - en-1 - one, [4 - (1 - methyl-1H-pyrazol-3 - yl) phenyl] (4H, 10H-pyrazolo [5,1-c] [1,4] - benzodiazepin Aza -5 - yl) methyl ketone, [4 - (2 - methyl-1H-pyrazol-3 - yl) phenyl] (4H, 10H-pyrazolo [5,1-c] [1,4] - benzodiazepin Aza -5 - yl) methyl ketone, 1 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) -3 - chlorobenzene Yl] - ethanone 1 - [4 - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin -10 - carbonyl) -3 - chlorobenzene Yl] - ethanone [2 - chloro-4 - (3 - methyl - 4 - ethynyl - phenyl) (5H, 11H-pyrrolo [2,1-c] [1,4] - phenyl And diaza -10 - yl) - methanone. ...

4. the Pharmaceutical composition of a claim 1, wherein said active component are [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone or its pharmaceutically acceptable salts.

5. the Pharmaceutical composition of a claim 1, it comprises (% w/w):

A) active component or its pharmaceutically acceptable salt of about 5-16%;

B) surfactant component of about 5-15%;

C) one or more of about 55-70% are planted Polyethylene Glycol compositions; With

D) the following composition of about 1-20%:

I) one or more plant sucrose fatty acid ester; Or

Ii) the K value is the polyvinylpyrrolidone of about 15-90; Or

Iii) one or more plant the compositions of sucrose fatty acid ester and polyvinylpyrrolidone as defined above.

6. the Pharmaceutical composition of a claim 1, wherein said surfactant component comprises polysorbate 20, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monoleate, sorbester p17 sorbitan oleate, sorbimacrogol oleate 100, polysorbate 85, Polysorbate 120, sodium taurocholate, deoxidation sodium taurocholate, chenodeoxy cholic acid, ursodesoxycholic acid, pluronic gram or poloxamer or their compositions.

7. the Pharmaceutical composition of a claim 1, wherein said one or more plant Polyethylene Glycol compositions and comprise that one or more kinds have the Polyethylene Glycol that mean molecule quantity is about 190-3450.

8. the Pharmaceutical composition of a claim 5, wherein said one or more plant Polyethylene Glycol compositions and comprise that one or more kinds have the Polyethylene Glycol that mean molecule quantity is about 400-1540.

9. the Pharmaceutical composition of a claim 5, wherein said one or more plant Polyethylene Glycol compositions and comprise that ratio is about 2.5: 1-1: 2.5 PEG 400 and the mixture of PEG 1000.

10. the Pharmaceutical composition of a claim 1, the K value of wherein said polyvinylpyrrolidone is about 17.

11. a Pharmaceutical composition, it comprises (% w/w): a) active component or its pharmaceutically acceptable salt of the claim 1 of about 1-20%; B) surfactant component of about 1-18%; C) one or more of about 50-80% are planted Polyethylene Glycol compositions; D) approximately one or more kind sucrose fatty acid ester or the K value of 1-20% are the polyvinylpyrrolidone of about 15-90; And e) one or more of about 0.1-4% are planted antioxidant or antiseptic.

12. the Pharmaceutical composition of a claim 11, wherein: a) described surfactant component comprises polysorbate 20, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monoleate, sorbester p17 sorbitan oleate, sorbimacrogol oleate 100, polysorbate 85, Polysorbate 120, sodium taurocholate, deoxidation sodium taurocholate, chenodeoxy cholic acid, ursodesoxycholic acid, pluronic gram or poloxamer or their compositions; B) described one or more kind Polyethylene Glycol compositions comprise that one or more kinds have the Polyethylene Glycol that mean molecule quantity is about 400-1540; C) described one or more kind antioxidants or antiseptic are selected from ascorbic palmitate, benzylalcohol, butylated hydroxyanisol or Yoshinox BHT or its compositions.

13. the Pharmaceutical composition of a claim 11, it comprises (% w/w): a) defined active component or its pharmaceutically acceptable salt in the claim 1 of about 5-16%; B) surfactant component of about 5-15%; C) one or more of about 55-70% are planted Polyethylene Glycol compositions; D) approximately one or more kind sucrose fatty acid ester or the K value of 1-20% are the polyvinylpyrrolidone of about 15-90; E) the approximately BHA of 0.3-2.5% (%w/w) and/or the approximately BHT of 0.005-0.15% (%w/w).

14. the Pharmaceutical composition of a claim 11, it comprises (% w/w): a) active component or its pharmaceutically acceptable salt of about 5-16%; B) surfactant component of about 5-15%, they comprise polysorbate 20, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monoleate, sorbester p17 sorbitan oleate, sorbimacrogol oleate 100, polysorbate 85, Polysorbate 120, sodium taurocholate, deoxidation sodium taurocholate, chenodeoxy cholic acid, ursodesoxycholic acid, pluronic gram or poloxamer or their compositions; C) approximately one or more kinds of 55-70% have the Polyethylene Glycol composition that mean molecule quantity is about 400-1540; D) approximately the K value of 1-20% is the polyvinylpyrrolidone (PVP) of about 15-90; And e) the approximately BHA of 0.3-2.5% (%w/w) and the approximately BHT of 0.005-0.15% (%w/w).

15. the Pharmaceutical composition of a claim 1, it is included in hard or the Perle.

16. a method of preparing Pharmaceutical composition, described Pharmaceutical composition comprise (% w/w): active component or its pharmaceutically acceptable salt of about 1-20%; The surfactant component of about 1-18%; Approximately one or more of 50-80% are planted the Polyethylene Glycol composition; And one or more kind sucrose fatty acid ester or the K value of about 1-20% are the polyvinylpyrrolidone of about 15-90; Or one or more plant the compositions of sucrose fatty acid ester and polyvinylpyrrolidone; Said method comprising the steps of:

A) surfactant component and one or more being planted the Polyethylene Glycol composition mixes to form first carrier mixture;

B) temperature of rising first carrier mixture is to about 75-95 ℃;

C) add active component or its pharmaceutically acceptable salt to form the mixture of initial medicinal combination;

D) stir the mixture of described initial medicinal combination till clarification;

E) if desired, described initial Pharmaceutical composition is cooled to about 75-95 ℃;

G) add a certain amount of one or more kind sucrose fatty acid ester and/or polyvidone to form the mixture of final medicinal combination.

17. the method for a claim 13, this method comprises the following steps:

B) the raise temperature to 80 ℃-about 90 ℃ of first carrier mixture;

D) raise the temperature of initial Pharmaceutical composition to about 135-145 ℃ and with its mixing or stir till the mixture clarification of described initial medicinal combination;

E) if desired, initial Pharmaceutical composition is cooled to about 80-90 ℃;

G) add a certain amount of sucrose fatty acid ester and/or polyvidone to form the mixture of final medicinal combination.

18. a method of preparing Pharmaceutical composition, described Pharmaceutical composition comprise (% w/w): active component claimed in claim 1 or its pharmaceutically acceptable salt of about 1-20%; The surfactant component of about 5-18%; Approximately one or more of 50-80% are planted the Polyethylene Glycol composition; Approximately one or more kind sucrose fatty acid ester or the K value of 1-20% are the polyvinylpyrrolidone of about 15-90; And one or more kind adjuvant of about 0.1-3%; Said method comprising the steps of:

A) one or more being planted the Polyethylene Glycol composition mixes with surfactant component to form first carrier mixture;

B) temperature of rising first carrier mixture is to about 75-95 ℃;

C) in first carrier mixture, add one or more kind antioxidants or antiseptic to form second carrier mixture;

D) add active component or its pharmaceutically acceptable salt to form the mixture of initial medicinal combination;

E) stir till the mixture clarification of initial medicinal combination;

F) if desired, initial Pharmaceutical composition is cooled to about 75-95 ℃;

G) to plant sucrose fatty acid ester or have K value be that the polyvinylpyrrolidone of about 15-90 is to form the mixture of final medicinal combination to one or more that add about 1-20%.

19. the method for claim 18, wherein: a) described surfactant component comprises polysorbate 20, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monoleate, sorbester p17 sorbitan oleate, sorbimacrogol oleate 100, polysorbate 85, Polysorbate 120, sodium taurocholate, deoxidation sodium taurocholate, chenodeoxy cholic acid, ursodesoxycholic acid, pluronic gram or poloxamer or their compositions; B) described one or more kind Polyethylene Glycol compositions comprise that one or more kinds have the Polyethylene Glycol that mean molecule quantity is about 400-1540; And c) described one or more kind antioxidants or antiseptic are selected from ascorbic palmitate, benzylalcohol, butylated hydroxyanisol or Yoshinox BHT or their compositions.

20. a method of preparing Pharmaceutical composition, described Pharmaceutical composition comprise (% w/w): about 1-20%'s as the defined active component of claim 1 or its pharmaceutically acceptable salt; The surfactant component of about 5-18%; Approximately one or more of 50-80% are planted the Polyethylene Glycol composition; Approximately the K value of 1-20% is the polyvinylpyrrolidone composition of about 15-90; And the antioxidant or the antiseptic composition of the Yoshinox BHT of the butylated hydroxyanisol of about 0.3-2.5% and about 0.005-0.15%; Said method comprising the steps of:

A) the preferred employing mixed or stirring, one or more planted Polyethylene Glycol compositions mix with surfactant component to form first carrier mixture;

B) temperature of rising first carrier mixture is to about 75-95 ℃;

C) in first carrier mixture, add antioxidant or antiseptic to form second carrier mixture;

E) temperature of the mixture of the described initial medicinal combination of rising is to approximately 130-150 ℃;

F) stir or the mixture that mixes initial medicinal combination till the mixture clarification of described initial medicinal combination;

G) make extremely approximately 75-95 ℃ temperature of initial Pharmaceutical composition;

H) add the polyvidone composition of about 1-20% to form the mixture of final medicinal combination.

21. the method for claim 18, wherein: a) described surfactant component comprises polysorbate 20, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monoleate, sorbester p17 sorbitan oleate, sorbimacrogol oleate 100, polysorbate 85, Polysorbate 120, sodium taurocholate, deoxidation sodium taurocholate, chenodeoxy cholic acid, ursodesoxycholic acid, pluronic gram or poloxamer or their compositions; And b) described one or more kind Polyethylene Glycol compositions comprise that one or more kinds have the Polyethylene Glycol that mean molecule quantity is about 400-1540.

22. a method of preparing Pharmaceutical composition, described Pharmaceutical composition comprise (% w/w): about 5-16%'s as the defined active component of claim 1 or its pharmaceutically acceptable salt; The surfactant component of about 5-15%; Approximately one or more of 55-70% are planted the Polyethylene Glycol composition; Approximately the K value of 5-15% is the polyvinylpyrrolidone composition of about 15-90; And the antioxidant or the antiseptic of the Yoshinox BHT of the butylated hydroxyanisol of about 0.3-2.5% and about 0.005-0.15%; Said method comprising the steps of:

B) temperature of rising first carrier mixture is to about 80-90 ℃;

C) in first carrier mixture, add antioxidant or antiseptic composition to form second carrier mixture;

E) temperature of the mixture of the described initial medicinal combination of rising is to approximately 135-145 ℃;

G) make extremely approximately 80-90 ℃ temperature of described initial Pharmaceutical composition;

H) add the polyvidone composition of about 5-15% to form the mixture of final medicinal combination.