MXPA02003191A - Vasopressin agonist formulation and process. - Google Patents

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 PROCESS FOR DEVELOPING THE SAME The application relates to new formulations for a class of tricyclic vasopressor agonist compounds, and pharmaceutically acceptable salts thereof as well as the processes for manufacturing the formulations. The invention relates in particular to orally administered formulations of these compounds.

BACKGROUND OF THE INVENTION The technique describes many methods for producing encapsulated liquid or semi-liquid pharmaceutical formulations. In Bull. Tech. / Gattefosse Rep. (1996), 89, 27-38, the authors Shah et al. describe the technology of hard gelatin capsules, particularly for use to improve the bioavailability of poorly soluble or poorly absorbed drugs. U.S. Patent No. 4,620,974 (Hersh et al.) Teaches a hard gelatin capsule comprising a two-piece telescopic layer with a lubricant comprising polyethylene glycol of a molecular weight between about 200 and about 900 present in admixture with the composition at a concentration of about 0.5 to about 25 weight percent.

REF: 136772 WO 96/40071 (Lamberti) describes methods and devices for producing capsules of minimum volume. WO 96/41622 (Tanner et al.) Teaches suspensions suitable for encapsulation in gelatin capsules, which particularly includes a solid phase of solid particles and a liquid phase capable of suspending the solid phase. The American Patent NO. 5,641,512 (Cimiluca) teaches analgesics encapsulated in soft gelatine capsules in which the caps contain a xanthine derivative, such as caffeine. U.S. Patent No. 4,578,391 (Kawata et al.) Discloses only compositions for antitumor agents comprising at least a sparingly soluble oil or a water soluble antitumor drug, at least one fat or oil, and at least one solubilizing adjuvant in a vehicle oily, selected from crowned ether, lecithin, polyethylene glycol, propylene glycol, vitamin E, polyoxyethylene alkyl ether, and sucrose esters of fatty acids. EP 0 815 854 A1 describes a semi-solid, substantially translucent filler material for a soft gelatin capsule, the semi-solid material being sufficiently viscous so that it can be extracted from the capsule with a syringe at room temperature. The American Patent NO. 4,744,988 (Brox) teaches soft gelatine capsules comprising a s * gelatin bushing, a softener and filler or filler of a polyethylene glycol and a lower polyhydric alcohol and at least one active substance, characterized in that the bushing contains from 4 to 40 percent sorbitan or sorbitan, at least half the weight of the The polyethylene glycol used is a polyethylene glycol having an average molecular weight of 600, and the filling of the capsule comprises up to 20 percent glycol and / or 1,2-propylene glycol. WO 95/19579 (Dhabhar) teaches a process for solubilizing hardly soluble pharmaceutical agents in a mixture of polyethylene glycol and propylene glycol using polyvinylpyrrolidone with an average molecular weight of specific viscosity of about 5,000 to about 25,000.

Summary of the Invention This invention provides orally administrable formulations for tricyclic vasopressin agonist compounds, or pharmaceutically acceptable salts thereof, singularly or collectively optionally referred to herein as "active ingredient" which have the structure: where: A, B, E, G are, independently CH or nitrogen; D is independently, C-W or nitrogen; R1 is alkanoyl of 2 to 7 carbon atoms, a group selected from CONH2, H, R9, or a selected portion of the group (a) (b) (c) «». «*« ..,. *! i * kt?;,:, • .ifcft-j "AtJtt _. (•) (j) (k) (l) 10 (m) (n) (o) R2, R3 and R5 are, independently hydrogen, straight-chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6. carbon atoms; R4 is hydrogen, straight-chain alkyl of 1 to 6 -0 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, or acyl substituent selected from the group consisting of alkanoyl of «.Aatürfi *» -_ .... í ... 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, cycloalkanoyl of 3 to 7 carbon atoms, aroyl or arylalkanoyl; X and Y are independently hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkyloxyalkyl of 2 to 7 carbon atoms, halogen (including chlorine, 'bromine', fluorine and iodine), alkoxy of 1 to 6 carbon atoms, hydroxy, CF3 or perfluoroalkyl of 2 to 6 carbon atoms; W is hydrogen, halogen (preferably chlorine, bromine or iodine), alkyl, alkoxyalkyl of 2 to 7 carbons, hydroxyalkyl of 1 to 6 carbons, or CH2NR6R7; R6 and R7 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms; or, taken together with the nitrogen atom of CH2NR6R7, R6 and R7 form a five or six member ring optionally containing one or more additional heteroatoms such as, but not limited to, those of the group: R8 is a straight-chain alkyl of 1 to 6 carbon atoms R9 is independently hydrogen, trimethylsilyl or a straight-chain alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt, ester or prodrug form thereof. Among the most preferred active ingredient compounds of formulations of this invention are those of the formula: where: A and B are, independently CH or nitrogen D is C-W or nitrogen; R1 is alkanoyl of 2 to 7 carbon atoms or a group selected from (a) (b) (e) (0 (g) (h) (i) (k) R2, R3 and R5 are, independently, hydrogen, straight-chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6. carbon atoms; R4, X, Y, W, R6, R7 and R8 are as defined above; or a pharmaceutically acceptable salt thereof. For the compounds defined and referred to above, unless otherwise noted, ? &? rk aroyl groups include, for example, benzoyl, naphthoyl which may be independently substituted with one or more substituents of the group of hydrogen, halogen, cyano, straight-chain alkyl of 1 to 6 carbon atoms, branched-chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF3 or phenyl. Heteroaryl groups refer to a (radical) carbonyl directly attached to a carbon atom of a five-membered heterocyclic ring having one or two heteroatoms selected from nitrogen, oxygen, sulfur, for example 2-thienoyl. The heterocyclic ring of the heteroaryl groups can also include, but is not limited to, groups in which the aryl moiety is a furan, pyrrole, 2H-pyrrole, imidazole group. pyrazole, isothiazole, isoxazole, thiophene, pyrazoline, imidazoline or pyrazolidine. The heteroaryl groups herein can be independently substituted with one or more substituents of the group of hydrogen, halogen, cyano, straight-chain alkyl of 1 to 6 carbon atoms, or branched-chain alkyl of 3 to 7 carbon atoms. The arylalkanoyl group herein refers to a carbonyl group or radical directly attached to an alkyl group of 1 to 6 carbon atoms which is terminally substituted by an aryl group, eg, acid phenylacetic The aryl group can be independently substituted with one or more substituents of the group of hydrogen, halogen, cyano, straight-chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, CF3, or phenyl or substituted phenyl wherein the substituents are selected from halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, CF3. The halogens referred to herein may be selected from fluorine, chlorine, bromine or iodine, unless otherwise specified. It is understood by those skilled in the art that the definition of compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, X or Y contains asymmetric carbons, encompassing all stereoisomers and possible mixtures of the same ones that have the activity discussed later. In particular, it encompasses any isomers and diastereomers; as well as the racemic and resolved enantiomerically pure R and S stereoisomers; as well as other mixtures of stereoisomers R and S and pharmaceutically acceptable salts thereof, which possess the indicated activity.

The optical isomers can be obtained in pure form by standard preparation techniques. It should also be understood that the definition of R1, R2, R3, R4, R5, R6, R7, X or Y of the compounds of formula (I) encompasses all possible regioisomers, and mixtures thereof possessing the activity discussed below. . Such regioisomers can be obtained pure by standard separation methods known to those skilled in the art. Also among the preferred active ingredient groups in the formulations of this invention are those in the subgroups: a) compounds having the general formula: where A, B, W, R1, R2, R3, R4, R5, R6, R7, R8, R9, X or Y are as defined above; b) compounds having the general formula: where A, B, R1, R2, R3, R4, R5, R9, X or Y are as defined above; and c) compounds having the general formula: where A, B, R1, R2, R3, R4, R5, R9X or Y are as defined above. It should be understood that subgroups a) -c) above also include subgroups where: A and B are, independently, CH or nitrogen; R1 is alkanoyl of 2 to 7 carbon atoms or a group selected from ,, .f .- »t (a) (b) (e) (f) R, R3 and R5 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, perfluoroalkyl of 1 to 6 atoms of carbon; and R4, X, Y, W, R6, R7 and R8 are as defined above; or pharmaceutically acceptable salt thereof. Among the particularly preferred compounds of group a), above, are those in which W is H, A and B are each CH, and R 1 is the alkanoyl group of 2 to 7 carbon atoms or a group selected from the portions (a), (b), (e), (f), (g), (h), (i), or (k), listed above. Pharmaceutically acceptable salts include those derived from organic and inorganic acids such as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic acid and also known acceptable acids.

Among the most preferred formulations of this invention are those described herein having as an active ingredient the [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo [2 , l] c] [1,4] benzodiazepin-10-yl) -methanenone, or pharmaceutically acceptable salts thereof having the structure: -A .i? The formulations of this invention are useful in methods for treating in humans or other animals, diseases, conditions or disorders in which the vasopressin agonist activity is desired. Those treatment methods include those for diseases, conditions or disorders that make it desirable to release a factor VIII and v Ion Willebrand factor in the circulatory system, release of tissue-type plasminogen activator (t-PA) into the bloodstream, or affect the renal conservation of water and urine concentration. Such methods of treatment include, but are not limited to, treatments for diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence or disorders of bleeding and coagulation in humans or other animals, including hemophilia. The methods of the present for which those formulations are used include facilitation in humans or other mammals and the temporary delay of urination, which may also be described as the control or treatment of the inability to temporarily delay urination, when desirable. It can be understood that this method includes treatments to facilitate the temporary delay of urination which are separate from and are not included in the treatment of conditions known as nocturnal enuresis and nocturia.

To obtain consistency in administration, it is preferred that a composition be in the form of a unit dose. The unit dosage forms preferably include tablets or capsules, although one skilled in the art will understand that the semisolids or gels of this invention are also readily produced and useful. Such unit dosage forms may contain from 0.1 to 1000 mg of a compound of the invention and preferably from 2 to 50 mg. Even more preferred unit dosage forms contain from 1 to 25 mg, more preferably from 1 to 10 mg, of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg / kg or preferably at a dose range of 0.1 to 10 mg / kg. Such compositions can be administered 1 to 6 times a day, more usually 1 to 4 times a day. The compositions of the invention can be formulated with other conventional carriers or excipients such as fillers, disintegrating agents, binders, lubricants, flavoring agents or the like. The formulations of this invention comprise (in% by weight / weight): a) from about 1% to about 20% active ingredient, or a pharmaceutically acceptable salt thereof, preferably from about 1% to about 16%, more preferably from about 5% to about 16% of this active ingredient; b) from about 1% to about 18% of a surfactant component, preferably from about 1% to about 5%, more preferably from about 5% to about 15% or from about 5% to about 18%, of more preferably from about 5% to about 10% or from about 8% to about 12% of the surfactant component; c) from about 50% to about 80% of a component of one or more polyethylene glycols (PEG), preferably from about 55% to about 70% of one or more polyethylene glycols; and d) from about 1% to about 20%, more preferably from about 5% to about 15% and more preferably between about 8% and about 12% of a component of: i) one or more fatty acid esters of sucrose; or ii) a polyvinylpyrrolidone (PVP) with a K value between about 15 and 90, preferably, with a K value of about 17 as defined in the USP / MF; or iii) a combination of one or more sucrose fatty acid esters and a PVP, as defined above. The polyethylene glycol component can be comprised of one or more PEG polymers, preferably commercially available PEG polymers between PEG 200 and PEG 4,000, ie, those PEG polymers having an average molecular weight of between about 190 and about 4800. More preferred are PEG polymers between average molecular weights of between about 190 to about 3450, more preferably between 400 and 1540. Among the preferred PEG polymers are PEG 400, which has an average molecular weight between about 380 and about 420, and PEG 1000 having an average molecular weight of between about 950 and about 1050. The ratio of PEG species of high and low molecular weight within the PEG component is, preferably, about 2.5. : 1 to about 1: 2.5, more preferably about 1: 1. As an example, a preferred mixture of PEG polymers within this invention would include a 1: 1 mixture of PEG 400 and PEG 1000. It may be preferable to choose a PEG component mixture having a melting point at or near the temperature physiological of the mammal to receive the formulation. The mixture of final components that * ¿¿. ± have a viscosity range of from about 140 to about 1,500 centipoise at 37 ° C may be preferred, most preferably a range from 300 to about 800 centipoise at 37 ° C. Surfactants that may be used with the formulations herein include, but are not limited to polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate), Polysorbate 60, Polysorbate 40, polysorbate 80, Sorbitan Oleate from Span 80, an ICI product America, Wilmington, Delaware, polysorbate 81, polysorbate 85, polyisobutyl 120, bile acids and salts defined by the Martindale The Extra Pharmacopoeia Thirty-fifth Edition on pages 1341-1342 such as Sodium taurocolates, Sodium deoxaurocholates, Chenodeoxycholic acid and ursodeoxycholic acid, and • pluronic or poloxamers such as Pluronic F68, Pluronic L44, Pluronic LlOl, or combinations of one or more of the foregoing. Polysorbate 80, itself or in combination with one or more other surfactants, is preferred for use with this invention. Sucrose fatty acid esters are useful with this invention include those commercially available and art recognized esters useful for orally administered pharmaceutical compositions, including monoesters, diesters and sucrose triesters or mixtures or combinations thereof. The examples Specific to esters useful with this invention are sucrose monolaurate, sucrose monomyristate, sucrose monopalminate, sucrose monostearate, sucrose distearate, sucrose tristearate, sucrose trimyristate and sucrose tripalmitate, or combinations thereof. In addition to these components, other preservative or antioxidant protectants or preservatives may be added to the compositions of this invention, which may account for up to about 4% by weight of the formulation. Examples may include ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc. Examples of those components in the formulations herein will include BHA at a concentration of about 0.3% to about 2.5% (% by weight / weight) and BHT at a concentration of about 0.005% to about 0.15% (% by weight / weight ), preferably with a mixture of BHA and BHT within those ranges. The additional embodiments comprise approximately 0.2% BHT. A formulation of this invention that uses one or more of those antioxidants or preservatives comprises: a) from about 1% to about 20% active ingredient, or a pharmaceutically salt thereof, preferably from about 1% up to _, _, _, _, _, _, _, _, _, _, _, _, _, _, _, _ about 16%, more preferably from 5% to about 16% of this active ingredient; b) from about 1% to about 18% of a surfactant component, preferably from about 5% to about 15% of the surfactant, more preferably from about 5% to about 10% from about 8% to about 12% of the surfactant component; c) from about 50% to about 80% of a component of 1 or more polyethylene glycols (PEG), preferably from about 55% to about 70% of one or more polyethylene glycols; d) from about 1% to about 20%, preferably from about 5% to about 15%, of one or more fatty acid esters of sucrose or polyvinylpyrrolidone (PVP) with a K value of between about 15 and 20 , preferably with a K value of about 17 as defined in the USP / NF; e) from about 0.1% to about 4% preservatives or antioxidants for example from about 0.3% to about 2.5% (% by weight / weight) of BHA and / or from about 0.005% to about 0.15% (% by weight / weight / ) of BHT. aÜ fc., A preferred embodiment of this invention provides a pharmaceutical formulation comprising: a) from about 5% to about 16% active ingredient; b) from about 5% to about 10% of a surfactant component; c) a component of about 55% to about 70% of one or more polyethylene glycols; d) from about 5% to about 15% polyvinylpyrrolidone (PVP) with a K value between about 15 and 90, preferably with a K value of about 17 as defined in the USP / NF; and e) from about 0.3% to about 2.5% (% by weight / weight) of BHA and from about 0.005% to about 0.15% (% by weight / weight) of BHT. Preferably, the formulations of this invention are closed in a sealed enclosure after manufacture, such as a soft or hard gelatin capsule. The formulations of this invention can be created as a liquid or semi-liquid formulation introduced into a capsule. Similarly, by using an acceptable range of component and / or temperatures, the formulation can be produced as a gel or solid prior to encapsulation.

Detailed Description of the Invention The active compounds useful in the formulations of the present invention can be prepared according to one of the general processes set forth below. As shown in Scheme I a tricyclic benzodiazepine of formula (1) is treated with an appropriately substituted acetylaroyl (heteroaroyl) halide, preferably an aroyl chloride (heteroaroyl) of formula (2) in the presence of a base such as pyridine or a trialkylamine such as triethylamine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at temperatures of -40 ° C to 50 ° C to produce the acylated derivative of formula (3). The treatment of (3) with a dialkyl dialkyl acetal of formula (4) in an aprotic organic solvent such as dichloromethane at temperatures ranging from 0 ° C to the reflux temperature of the solvent yields the enone of formula (5) according to to the procedure of Lin et al., J. Het. Chem., 14, 345 (1977). Treatment of (5) with hydroxylamine or a substituted hydrazine of formula (6) in acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent produces the objective compounds of formula (I) wherein A, B, D , E, G, X, Y, R2 and R4 are as defined above and R1 is a heterocyclic portion selected from group (f), (g) or (j) of heterocycles defined above.

Preferred substituted acetylaroyl (heteroaroyl) chlorides of formula (2) of scheme I are conveniently prepared by treating the corresponding carboxylic acids with thionyl chloride at temperatures ranging from room temperature to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0 ° C to 40 ° C. Preferred dialkylamide dialkylacetals are commercially available, or are known in the literature, or can conveniently be prepared according to procedures analogous to those of the literature. Kantlehner, W. Chem. Ver. 105, 1340 (1972). The preferred bicyclic benzodiazepines of formula (1) are 10, 11-dihydro-5H-pyrrolo [2, 1-] [1,] benzodiazepine (Albright et al., Patent No. 5,536,718, issued July 16, 1996), a 10,1-dihydro-5H-pyrazole [5, 1-c] [1,] benzodiazepine, Cecchi, L. et. al., J.Het. Chem., 20, 871 (1983) and 10,11-dihydro-5H-tetrazole [5, 1-c] [1,4] benzodiazepine, Klaubert, D.H. J. Het Chem., 22, 333 (1985).

REACTION SCHEME I (5) An alternative process of the process for the preparation of the intermediates of formula (3) is illustrated in the following Reaction Scheme (II).

REACTION SCHEME II (7) J = COOH J = adiarte portion (8) (9) Thus, a tricyclic benzodiazepine of formula (1) is treated with a bromine aroyl halide (heteroaroyl), suitably substituted, preferably an aroyl chloride (heteroaroyl) of formula (8) in the presence of an organic base such as pyrimidine or a íiLi? tÁ .-. krI? . : .. ^ J ??? ? trialkylamine such as trialkylamine in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at temperatures of -40 ° C to 50 ° C to produce the acylated intermediate of formula (9). The intermediate (9) is subsequently completed with a monosubstituted terminal acetylene such as trimethylsilyl or a straight chain alkyl of 1 to 6 carbon atoms, in the presence of thymidine and a catalyst such as bis (triphenylphosphine) palladium (II) chloride. ) and copper iodide (I) in an organic base such as triethylamine as a solvent, in a pressure tube sealed at temperatures that fluctuate from room temperature to 100 ° C essentially according to the procedure of Martinez et al., J. Med. Chem., 35, 620 (1992). The resulting acetylene intermediate of formula (10) is then hydrated by treatment with 1% sulfuric acid in an aprotic organic solvent such as tetrahydrofuran saturated with mercury (II) sulfate at room temperature essentially according to the procedure of Reed et al. al., J. Org. Che., 52, 3491 (1987) to provide the desired acyl compound of formula (3) where A, B, D, E, G, X and Y are as defined above, and R9 is hydrogen or a straight chain alkyl of 1 to 6 carbon atoms. Alternatively, compound 9 where R8 where trimethyl is treated with fluoride of tetrabulbutylammonium in an ether solvent such as tetrahydrofuran to give the compound (10) wherein R9 is hydrogen. The preferred acylating agents of formula (8) of Reaction Scheme II are conveniently prepared by treating an appropriately substituted aryl (heteroaryl) carboxyl acid of formula (7) with thionyl chloride at temperatures ranging from room temperature to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic organic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0 ° C to 40 ° C. The acetylene intermediaries protected from Reaction Scheme II are commercially available, or are "known in the art, can be readily prepared by procedures analogous to those of the art." As shown in Reaction Scheme III, the intermediate acetyl compounds (3) of the Scheme of Reaction I can also be prepared by the Stille coupling of a bromine aryl compound (heteroaryl) of formula (9) of Reaction Scheme II with a (α-ethoxyvinyl) trialkyl tin, preferably an (α-ethoxyvinyl) tributyltin, in the presence of a quantity rí? ái catalytic bis (triphenylphosphine) palladium (II) chloride in an aprotic organic solvent such as toluene at temperatures ranging from room temperature to that of refluxing a solvent, essentially according to the procedure of Kosugi et al., Bull. Chem. Soc. Jpn., 60, 767 (1987).

REACTION SCHEME III The preparation of the acetyl compound (3) can also be achieved via the palladium catalyzed arylation of a vinyl alkyl ether such as a vinyl butyl ether, with the aryl halide intermediate of formula (9) according to the Cabri et al. ., Tetrahedron Lett., 32, 1753 (1991). The (a-alkoxyvinyl) trialkyltin intermediates of Reaction Scheme III are ÍÉtédñ-í ^ k. they are commercially available, or are known in the art, or can be readily prepared by methods analogous to those of the art. In the case where R 4 in Reaction Scheme I is hydrogen, the heterocyclic nitrogen can be alkylated or acylated according to the reactions set forth in Reaction Scheme IV.

REACTION SCHEME IV, AiÉtáa Thus, the pyrazole compound of formula (I, R4 is H) is alkylated by treatment with a strong base such as sodium potassium hydride and an alkylating agent such as an alkyl halide, preferably a sodium chloride. alkyl (bromine or iodine) in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0 ° C to 80 ° C to produce the compound (I, R1 == (f) or (g)) where A, B, D, E, G, X, Y and R2 are as defined above, and R4 is an alkyl or acyl moiety. Alternatively, the compound (I) is acylated by treatment with a carboxylic acid halide, preferably a chlorine, or a carboxylic acid anhydride in the presence of an amine base such as pyridine or trialkylamine, preferably triethylamine , in an aprotic organic solvent such as dichloromethane or tetrahydrofuran without additional solvent when the pyridine is used as the base, at temperatures that fluctuate at -40 ° C at room temperature to produce the compound (I) where A, B, D , E, G, X, Y and R2 are as defined above, and R4 is alkyl or acyl. The alkylation or acylation of the compound of formula (I, R4 is H) leads to a mixture of regioisomers wherein R2 is hydrogen and R1 is a heterocyclic portion selected from any of groups (f) or (g) of heterocycles defined above and illustrated later, respectively. ímré ?.

(O (g) The compounds of general formula (I) of Reaction Scheme I where A and B are carbon, R 2 is H, and R 1 is a heterocyclic portion selected from the group (g) of heterocycles defined above, can be prepared according to the general process disclosed in Reaction Scheme V.

REACTION SCHEME V (11, A and B = carbon)) (12) J = COOCH (14) J = COOCH3 (15) J = COOCH3 (major) (minor) Separation MeOH NaOH aq. (16) J = COOH (17) J = acylating portion (D In this way, an ester of haloaryl acid (heteroaryl) carboxylic substituted appropriately, preferably a bromine (or iodo) methyl ester of formula (11) is coupled with a dialkylamino propyne, preferably 1-dimethylamino propino, in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) chloride and copper (I) iodide in an organic base such as triethylamine as the solvent and a fluctuating temperature of room temperature 80 ° essentially according to the procedure of Alami et al., Tetrahedron Lett., 34, 6403 (1993), and from Sanogashira et al., Tetrahedron Lett., 4467 (1975) to provide the substituted acetylene intermediate of general formula (12). The intermediate (12) is subsequently converted to its N-oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A., Synthesis, íéí Éiák? k- ,, 263 (1993) or with dioxirane reagents (Murray, RW, Chem. Rev., 1187 (1989), in an aprotic organic solvent such as dichloromethane at temperatures below ambient.) The intermediate N-oxide is not isolated but arranged in itself. You to an enone of general formula (13) by treatment with, preferably with heating, a hydroxylic solvent, including any solvent or combination of solvents composed of or containing water, any straight chain alkyl alcohol or branched chain of Ci-Cβ , ethylene glycol, polyethylene glycol, 1,2-propylene diol, propylene glycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, benzyl alcohol, phenol or any equivalent solvent containing one or more hydroxyl substituents (-OH) free that is known to those skilled in the art.Solvent systems containing one or more cosolvents, together with one or more solvents may also be used for this purpose of a adjust the N-oxide to the desired enaminone. The cosolvents referred to herein may be referred to as a diluent of the major solvents and may be selected from: hydrocarbons such as pentane, hexane or heptane; aromatic hydrocarbon such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxy ethane; chlorinated hydrocarbons such as dichloromethane, chloroform, dichloroethane or tetrachloroethane; or other common solvents such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, acetone or the like. The conversion of the amine N-oxide to an enaminone can be achieved by introducing the amine N-oxide into a suitable hydroxylic solvent, preferably with stirring, at or between about the normal or ambient temperature and about the reflux temperature of the solvent . In other cases the introduction of the amine N-oxide to a hydroxylic solvent, preferably with stirring, can be carried out in the presence of an acceptable catalyst, such as a palladium (II) catalyst or a copper (I) catalyst or the ambient temperature and the ambient temperature of the solvent. This process provides a novel synthesis of enaminone compounds from propargyl amines or their N-oxides in hydroxyl solvents, which influence the final result of the reaction. This new enaminone synthesis method provides a convenient alternative to existing methods and further extends the range of initial materials that can be converted into enaminone products.

Although the precise mechanism by which a propargyl amine N-oxide is converted to an enaminone product has not been rigorously determined, it is likely to resemble known processes; the rearrangement [2, 3] -sigmatropic thermal of the propargyl amine N-oxides (Craig, et al., Tetrahedron Lett., 4025, 1979; Hallstrom, et al., Tetrahedron Lett., 667, 1980; Khuthier, AH, et al., J. Chem. Soc. Chem. Commun., 9, 1979) and the conversion of certain isoxazoles to enaminones (Liguori, et al., Tetrahedron, 44, 1255, 1988). The treatment of (13) with a substituted hydrazine (6) in acetic acid at temperatures ranging from room temperature to reflux leads to a mixture of regioisomeric compounds of general formulas (14) and (15) in a variable ratio. The major isomer of formula (14) separated by means of chromatography and / or crystallization and subsequently is hydrolyzed to the desired carboxylic acid of formula (16). The intermediate (16) is then converted into an acylating species, preferably an acid chloride (bromide or iodide) or a mixture of anhydride of formula (17) by procedures analogous to those described herein above. The oscillating agent (17) is then used us.,, to acylate a tricyclic benzodiazepine of formula (1) by any of the methods described hereinbefore to produce the desired compound of formula (I), wherein A, B are CH and D, E, G, X, Y and R4 are as defined above, R2 is hydrogen and R1 is a heterocyclic portion selected from the group (g) of heterocycles illustrated below. (g) Likewise, the treatment of (13) with an unsubstituted hydrazine (6, R4 is H) in acetic acid at temperatures ranging from room temperature to that of reflux of the solvent yields the intermediate pyrazole ester of formula (18) . In this case the heterocyclic nitrogen can be alkylated or acylated as shown in Reaction Scheme VI to provide compounds of formula (I) wherein R 2 is hydrogen, and R 1 is a heterocyclic portion selected from the group (f) of heterocycles of sounds above . lÁÁ? kÁ. Ato ... Jttb? T? J &i.- _. . - - ^ fe ^ -Afaa ».

REACTION SCHEME VI OOCH. ft (15) J = COOCH3 (14) J = COOCH3 (major) (minor) Separation MeOH NaOH aq.

R R (19) J = COOH (20) J = acylating portion Thus, the intermediate ester of formula (18) is alkylated by treatment with a strong base such as sodium or potassium hydride and an alkylating agent such as an alkyl halide, preferably chloride (bromide or iodide) of alkyl, in an aprotic solvent "such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0 ° C to 80 ° C to produce a mixture of regioisomers of formulas (14) and (15) in a variable ratio.The major regioisomers of formula (15) are separated by chromatography and / or crystallization and subsequently hydrolyzed to the desired carboxylic acid of formula (19) which is then converted into an acylating agent, preferably an acyl chloride or an anhydride mixed by procedures analogous to those described here previously. The acylating species of formula (20) are then used to acylate the tricyclic benzodiazepine of formula (1) to produce the desired compound of formula (I), wherein A, B, D, E, G, X, Y and R4 are as they were defined above, R2 is hydrogen, and R is a heterocyclic portion selected from the group (f) of the heterocycles defined above.

The compounds of general formula (I) wherein R 1 is a heterocyclic portion selected from the group (h) of heterocycles R 1 defined above, can be prepared as set forth in Reaction Scheme VII.

REACTION SCHEME VII (23) J = acylated porcine A suitably substituted malondialdehyde of formula (21) first treated with a hydrazine in acetic acid at temperatures ranging from room temperature to reflux of the solvent and the intermediate pyrazole is then oxidized with potassium permanganate in a basic aqueous solution at temperatures which they fluctuate from the ambient temperature to that of the reflux of the solvent to produce an intermediate carboxylic acid of formula (22). The acid (22) is converted into an acylating agent, preferably a chloride (bromide or iodide) of acid or an anhydride mixed by analogous processes to those described here above. The acylating agent of formula (23) is finally reacted with a tricyclic benzodiazepine of formula (1) to produce compounds of the general formula (1) wherein A, B, D, E, G, X, Y and R4 are as defined above, and R1 is a heterocyclic portion selected from the group (h) of heterocycles defined above. 10 (h) In the case where R 4 in Reaction Scheme VII is hydrogen, the heterocyclic nitrogen can be alkylated or acylated according to the procedures set forth hereinbefore. The preferred malonaldehydes of formula (21) are the hydrazines of Reaction Scheme VII found Commercially available, or are known in the art, or can be readily prepared by procedures analogous to those of the literature for known compounds, such as those of Knorr et al., J. Org. Chem., 49, 1288, (1984) and Coppola et al., J. Het. Che., 11, 51 (1974). An alternative preparation of the intermediate carboxylic acids of formula (22) of Reaction Scheme VII where Y is as defined above and R4 is other than hydrogen, Reaction Scheme VIII is set forth. REACTION SCHEME VIII OCH. OCH, (26) J = COOCH. (22) J = COOH The organotin reagent of formula (25) is reacted in a Stille coupling reaction with an appropriately substituted aryl halide (heteroaryl), preferably a bromide or iodide of formula (28) in the presence of a catalyst such as tetra (triphenylphosphine) palladium (0) and copper iodide (I) in an organic aprotic solvent such as dimethylformamide at temperatures that fluctuate from room temperature to 150 ° C, essentially according to procedures analogous to those found in Fariña et al. , J. Orq. Che., 59, 5905 (1994). Basic hydrolysis of the resulting ester of formula (26) with sodium or lithium hydroxide in aqueous alcohol or tetrahydrofuran at temperatures ranging from room temperature to reflux of the solvent yields the carboxylic acids of formula (22). In turn, the organotin reagent of formula (25) where the R groups are preferably alkyl groups, are conveniently prepared by metalation of 4-bromo N-alkylpyrazole of formula (24) with a trialkyltin halide, preferably a tributyltin chloride (or bromide) in the presence of a metalating agent such as an alkyl lithium such as n-butyl lithium, sec-butyl lithium, or tert-butyl lithium in an aprotic organic solvent such as diethyl ether at temperatures ranging from -40 ° C to ambient temperature according to analogous procedures to those found in Martina et al.Synthesis , 8, 613 (1991). The preferred N-alkyl substituted 4-bromo pyrazoles of formula (24) are conveniently prepared from 4-bromo pyrazole by alkylation with an alkyl halide, preferably an alkyl chloride (bromide or iodide) in the presence of an strong base such as lithium, sodium or potassium hydride in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0 ° C to 80 ° C. Alternatively, the alkylation of 4-bromopyrazole can be carried out with an alkylating agent mentioned above, and a strong alkaline base such as lithium, sodium or potassium hydroxide in the presence of a phase transfer catalyst (Jones, RA Aldrichimica ACTA , 9 (3), 35, 1976) such as benzyldimethyltetradecylammonium chloride, or benzyltrimethylammonium chloride. Preferred aryl (heteroaryl) iodides of formula (28) are conveniently prepared by diazotization of the corresponding substituted anilines of formula (27) followed by the reaction of the corresponding diazonium salt with potassium iodide and iodine in aqueous acid medium essentially according to the procedures of Street et al., J. Med. Chem., 36, 1529 (1993) and Coffen et al., CL_ Org. Chem., 49, 296 (1984). An alternative preparation of the compounds of formula (I) are set forth in Reaction Scheme IX.

REACTION SCHEME IX regiois mere The tricyclic benzodiazepine of formula (1) is treated with a haloaroyl halide (heteroaroyl), suitably substituted, preferably an aroyl fluoride or a fluoro (or chloro) heteroaroyl chloride of formula (29), in the presence of such a base such as triethylamine or diisopropylethylamine in an aprotic organic solvent such as dichloromethane or tetrahydrofuran a temperatures of -40 ° C to the reflux temperature of the solvent to produce the acylated derivative (30). Alternatively, the acylating species may be a mixed anhydride of the carboxylic acid described above, such as that prepared by the reaction of 2,4,6-triclobenzoyl chloride in a solvent such as dichloromethane according to the procedure of Inanaga et al. ., Bull. Chem. Soc. Jpn, 52, 1989 (1979). The treatment of the mixed anhydride of general formula (29) with the tricyclic benzodiazepine of formula (1) in a solvent such as dichloromethane and in the presence of an organic base such as 4-dimethylaminopyridine at temperatures ranging from 0 ° C to reflux temperature of the solvent, produces the intermediate acylated derivative (30) of Reaction Scheme IX. A compound of formula (30) is then treated with the lithium, sodium or potassium salt of an appropriately substituted heterocycle of formula (31) in a polar aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from room temperature to the reflux temperature of the solvent to produce a compound of general formula (I), wherein A, B, D, E, G, X, Y, RR, R3 and R5 are as defined above, and R1 is a heterocyclic portion selected of the group consisting of (a), (b), (c), (d), (1), (n) (o) defined above. (a) (b) (c) (d) (I) (n) (o) The condensation of the intermediate of formula (30) with the intermediate salt of formula (31) leads to a variable ratio of regioisomers of general formula (1) which are separated by means of chromatography and / or crystallization. Preferred substituted aroyl and fluorine (or chloro) heteroaroyl fluorides of formula (29) are commercially available, or are known in the art, or can be readily prepared by analogous procedures to those in the literature for known compounds. .... .t__t.J ___? M_ < t ^ _Jt_a_ .. ^ ¡^ ^ The lithium, sodium or potassium salts of the heterocycles of formula (31) are prepared by treating the heterocycle with a strong base such as lithium hydride, sodium hydride, potassium hydride or a metal alkoxide which fluctuate from - 40 ° C at room temperature in an aprotic organic solvent such as ddimethylformamide or tetrahydrofuran. Alternatively, the compounds of general formula (I) described in Reaction Scheme IX can be prepared according to the process set forth in Reaction Scheme X.

X REACTION SCHEME (34) J = COOCH: (35) J = COOH (36) J = acylating portion Thus, fluoroaryl acid or fluoro (or chloro) heteroaryl carboxylic appropriately substituted formula (32) is esterified using methods known in the art such as treatment with oxalyl chloride (or thionyl chloride) in an alcoholic solvent such as methanol, in the presence of a catalytic amount of dimethylformamide; or by condensation with methanol in the presence of an acid catalyst such as paratoluensulfonic acid at temperatures ranging from ambient to reflux. The resulting ether of formula (33) is reacted with the lithium salt, sodium or potassium heterocycle appropriately substituted formula (31) in a polar aprotic organic solvent such as dimethylformamide at temperatures ranging from ambient to 150 ° C, to produce an intermediate ester of formula (34). The condensation (33) with (31) leads to a variable ratio of ~ * ±? *. ^^^ ú í ^? í regioisomers of formula (34) which are separated by chromatography and / or crystallization measurements. Subsequent hydrolysis of the intermediate ester of formula (34) with an aqueous base such as lithium, sodium or lithium hydroxide in methanol or tetrahydrofuran gives the carboxylic acid of formula (35). The intermediate carboxylic acid (35) is then converted into an acylating agent preferably into an acid chloride or a mixed anhydride of the general formula (36) using any of the methods described hereinabove. Subsequent reaction of the tricyclic benzodiazepine of formula (1) with intermediate acylating agent of formula (36) according to any of the procedures described hereinabove produces the desired compounds of formula (I) of Reaction Scheme IX. Alternatively, the substituted carboxylic acids of formula (35) described in Reaction Scheme X can be prepared according to the process set forth in Reaction Scheme XI. 1 ? * aj ^ jg ^ l XI REACTION SCHEME Thus, a fluoro aryl or fluoro (chloro) heteroaryl nitrile of formula (37) is reacted with the lithium, sodium or potassium salt of a substituted heterocycle of formula (31) in an apolar aprotic solvent such as dimethylformamide a temperatures in which they fluctuate from the environment to 150 ° C, to produce an intermediate of general formula (38). The reaction of (37) with (31) leads to a variable ratio of regioisomers of formula (38) which are separated by means of chromatography and / or crystallization. The hydrolysis of the intermediate nitriles of formula (38, Y? CF3) is preferably carried out with an organic acid such as sulfuric acid at temperatures that fluctuate from the ambient to 60 ° C. Alternatively, hydrolysis of the nitrile (38) can be carried out by heating the ethanol in the presence of a strong alkaline base such as sodium hydroxide with or without a phase transfer catalyst (Jones, R.A. Aldrichimica Acta, 9 (3), 35, 1976) such as benzyldimethyltetradecyl ammonium chloride. The resulting carboxylic acids of formula (35) are then converted to the desired compounds of formula (I) of Scheme IX, 1 by procedures analogous to those described herein above. Alternatively, the substituted carboxylic acids of formula (35) of Reaction Scheme X can be prepared according to the process set forth in Reaction Scheme XII by the sequential treatment of a nitrile of formula (38) wherein A and B are CH and wherein R 1 is not alkanoyl of 2 to 7 carbons, alkynyl, (b) or (d), with basic hydrogen peroxide in dimethyl sulfoxide essentially according to the procedure of Katritzky et al., Synthesis, 949 (1989), followed by the hydrolysis of the resulting amide of formula (38), preferably by treatment with dilute sulfuric acid and sodium nitrite according to Hanes et al., Tetrahedron, 51.7403 (1995).

REACTION SCHEME XII ÍÁ.ri li- iliilMiitrilitirilirtiliiÉiiii • n ii -iiairrt -'- ittri ??? Item Where R1 is not (b) or (d). A preferred process for the preparation of intermediate substituted carboxylic acids of formula (35) of Reaction Scheme X wherein R 1 is a heterocyclic portion selected from the group (a) of heterocycles R 1 defined above, as set forth in Reaction Scheme XIII.

SCHEME XIII SnCU 2, > HCl (40) J = COOCH 3 (41) J = COOCH, 2. Crystallization (42) J = C00CH. (34) J = C00CH ^^^ ^ ^ Mr 56 (36) J = acylating portion Diazotization of an appropriately substituted aniline of formula (40) followed by reduction of the diazonium salt of the resulting salt of formula (41) with tin (II) chloride in concentrated hydrochloric acid according to the procedure of Street et al. , J. Med. Chem., 36, 1529 (1993) provides the intermediate hydrazine hydrochloride salt of formula (42). After the condensation of (42) with an aldehyde derivative of formula (47) where R2 is as defined above, R3 and R5 is H, and P is dialkylacetal) such as acetylacetaldehyde dimethyl acetal, or a ketone of formula (47), wherein R2, R3 and R5 are as defined above, and P is = 0 or (O-alkyl) ) 2 in a solvent such as aqueous methanol at temperatures that fluctuate from the environment at 100 ° C provides after crystallization, the desired intermediate ether of formula (34) R1 is (a) and R5 is H), which is then converted to and ^^^^ and X compound of formula (I) as set forth in Reaction Scheme X above. (to) when Y is 0CH3, the compounds of general formula (I) of Reaction Scheme I can conveniently be demethylated as set forth in Reaction Scheme XIV.

XIV REACTION SCHEME (I) Y = OCH: (I) Y = OH In this way, the reaction of the compound (I) where Y is OCH3 with Iffro tribromide in an organic solvent, such as dichloromethane, produces the corresponding phenol of formula (I) wherein Y is OH, A, B, D , E, G, X, R2 and R3 are as defined above and R1 is a heterocyclic portion selected from group (a) of heterocycles defined above and illustrated below.

The compounds in which R contains three heteroatoms are prepared according to Reaction Scheme XV. l i.iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii XV REACTION SCHEME 2) H2S04 (44) Thus, a tricyclic benzodiazepine of formula (1) is treated with a halofodium cyano aroyl (suitably substituted heteroaroyl, preferably an aroyl chloride (heteroaroyl) of formula (43) in the presence of a base in an aprotic organic solvent such such as dichloromethane or tetrahydrofuran at temperatures ranging from 40 ° C to 80 ° C to produce an intermediate nitrile of formula (46, Reaction Scheme XVI) which in turn is hydrolyzed to an intermediate amide of general formula (44) with an organic acid such as sulfuric acid at room temperature up to 50 ° C. Treatment of the amide (44) with an acetal dialkyl amide of formula (4) in an appropriate organic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from 0 ° C to 80 ° C produces the intermediate of formula (45). Treatment of (45) with hydroxylamine or a hydrazine of formula (6) in acetic acid at temperatures ranging from ambient to reflux produces the desired target compounds of formula (I) wherein A, B, D, E, G , X, Y, R2 and R4 are as defined above, and R1 is a heterocyclic portion selected from group (e), (i) and (k) of heterocycles defined above. (e) (¡) (k) Another preferred process for the preparation of the intermediate amide of formula (44), see Scheme Reaction XV, where A and B are CH and D is not CH are exposed in the Reaction Scheme XVI and consists of the treatment of a nitrile of formula (46) with basic hydrogen peroxide dimethyl sulfoxide essentially according to the procedure of Katritzky et al., Synthesis, 949, (1989). REACTION SCHEME XVI J = acylating portion (43) (46) The preferred process for preparing the compounds of general formula (I) in which R1 contains four --- * - *** »- tttofrA. ^. 1 ... W .t __ ^ * jjßítr. het fdátomos and R4 is hydrogen is exposed in Reaction Scheme XVII.

REACTION SCHEME XVII The treatment of the nitrile intermediate of formula (46) of Reaction Scheme XVI with sodium azide and sodium chloride in an aprotic organic solvent such as dimethylformamide at temperatures ranging from room temperature to the reflux temperature of the solvent produces the desired compounds of formula (I) wherein A, B, D, E, G, X, and Y are as defined above, R4 is hydrogen, and R1 is a heterocyclic portion selected from the group (m) of heterocycles defined above.

JJÉk M ..., ... to £ ¿. .. i.

The compounds of general formula (I) wherein D is CW and W is hydrogen, can undergo Mannich condensation as shown in Reaction Scheme XVIII.

REACTION SCHEME XVIII Thus, the reaction of the compounds of formula (I, D is CH) with aqueous formaldehyde or paraformalddehyde, a substituted amine of formula (47), and glacial acetic acid and an alcohol solvent such as methanol at fluctuating temperatures of the ambient temperature to the reflux temperature produces the corresponding Mannich bases of general formula (I), wherein A, B, E, G, X, Y, R 2, R 3, R 5, R 6 and R are as defined above; D is CW; W is a dialkylaminoalkyl residue preferably a dimethylaminomethyl residue, and R1 is a heterocyclic portion selected from group (a), (c), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n) and (o) of heterocycles defined above. Likewise, compounds of general formula (I) wherein D is Ch can undergo halogenation as shown in Reaction Scheme XIX.

REACTION SCHEME XIX Thus, the reaction of (I, D is CH) with N-halosuccinimide such as N-chloro (bromo or iodo) succinimide in a polar aprotic organic solvent such as dichloromethane at temperatures ranging from -80 ° C to the room temperature produces the corresponding halogenated derivatives of formula (I), wherein A, B, E, G, X, R2, R3 and R5 are as defined above, D is CW, W is a halogen such as chlorine (bromine or iodine) and R1 is a heterocyclic portion selected from group (a), (c), (e), (f), ( g), (h), (i), (j), (k), (1), (m), (n) and (o) of heterocycles defined above. The compounds object of the present invention were tested for their biological activity according to the following procedures.

Effects of the Vasopressin V2 Agonist of the Test Compounds in Normal Conscious Water-Charged Rats: Female or male normotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Kingston, NY) of 350-500 g of body weight were supplied with standard rodent diet (Purina Rodent Lab Chow 5001) and water ad libi tum. On the day of the test, the rats were placed individually in metabolic cages equipped with devices to separate the faeces from the urine and containers for the collection of urine. The test compound of the reference agent was given at an oral dose of 10 mg / kg in a volume of 10 ml / kg. The vehicle used was 20% dimethylsulfoxide (DMSO) in 2.5% preheated corn starch. Thirty minutes after dosing the test compound, the rats were given water at 30 ml / kg in the stomach using a feeding needle. During the test, the rats were not provided with water or feed. The urine was collected four hours after the dosing of the test compound. At the end of four hours, the volume of urine was measured. The urinary osmolality was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, MA, 02062) and an Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, MA). Na +, K + and Cl "ion determinations were carried out using specific electrodes for the ions in a Beckman SYNCHRON EL-ISE Electrolyte System analyzer.The urine osmolarity had to be proportionally increased.In the separation test, two rats were used for each compound If the difference in urine volume in the two rats was greater than 50%, a third rat was used.

Effects of Vasopressin V2 Agonist on Test Compounds on Normal Consensitive Homozygous Brattelboro Rats with Central Insipid Diabetes Homozygous male or female Brattleboro rats (Harran Sprague Dawley, Inc., Indianapolis, IN) of 250-350 g of body weight were supplied with rodent diet ^ j ^ Ma.iAttj. ^^ ....?.,. ".», __ "_. «Aault ^ m, j standard (Purina Rodent Lab. Chow 5001) and water ad libi tum. On the day of the test, the rats were placed individually in metabolic cages equipped with devices to separate the faeces from the urine and containers for the collection of urine. The reference compound or agent was given at an oral dose of 1 to 10 mg / kg in a volume of 10 ml / kg. The vehicle used was 20% dimethyl sulfoxide (DMSO) in 2.5% pre-harvested corn starch. During the test, the rats were given water ad libi tum. Urine was collected for six hours after dosing the test compound. At the end of the six hours, the volume of urine was measured. Urinary osmolarity was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, MA, 02062) or an Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instrument-s, Norwood, MA). Na +, K + and Cl "ion determinations were carried out using specific electrodes for the ions in a Beckman SYNCHRON EL-ISE Electrolyte System analyzer.This animal model was used mainly for the evaluation of the power and direction of the action of the active compounds The results of this study are shown in Table I. _ = ¿^? S¿ ^ ^^^^^^^^^^^ AÜ Example # Osmolarity Volume (% Ratac Urine Type (% decrease) Increase) 1 osmolarity 2 80% (1 mg / kg) 306% (1 mg / kg) CD 3 58% 240% CD 4 57% 225% CD 5 56% 231% CD 6 58% 270% CD 7 13% 137% CD 9A 70% 325% CD 9B 21% 168% CD 11 70% 285% CD 12 69% 330% CD 13 50% 229% CD 14 86% 406% CD 15 47% 38% CD 16 88% 400% CD 18 52% 214% CD 20 25% 152% CD 21 49% 181% CD 22 80% 322% CD 24 47% 159% CD 5 87% 979% CD Example # Osmolarity Volume (% Ratac Urine Type (% decrease) 3 Increase) osmolarity 26 54% 279% CD 27 76% 183% CD 28 75% 37% CD 29 66% 305% CD 30 81% 334% BB 31 72% 298% CD 32 77% 373% CD 33 68% 362% CD 34 76% 407% BB 35 63% 308% CD 36 66% 164% BB 37 71% 370% CD 38 66% 256% BB 39 69% 253% CD 40 46% 183% CD 41 69% 240% CD 49 74% 221% BB 0 53% 223% CD 1 72% CD «» Í.iS¡ -JS Example # Volume of Osmolarity (% Ratac Urine Type (% decrease) to Increase) 'osmolarity 52 66% 261% CD 55 80% 164% CD 57 77% 288% CD 58 49% 324% CD 59 80% 607 % CD 60 54% 165% CD 61 59% 245% CD 62 22% 150% CD 63 27% 214% CD 64 79% p 349% CD 71 84% 264% CD 77 13% 90% CD 78 21% 115% CD 79 38% 123% CD 81 82% 490% CD 83 85% 442% CD 84 56% 291% CD 85 76% 436% CD 86 5% 86% CD Example # Osmolarity Volume (% Ratac Urine Type (% decrease) a Increase) osmolarity 87 71% 214% CD 88 68% 226% CD 90 61% 413% CD 91 22% 69% CD 92 69% 454% CD 95 68% 300% CD 97 3% 106% CD 99 43% 205% CD 100 24% 248% CD 101 76% '376% CD 107 31% 125% CD 108 30% 145% CD 109 21% 95% CD 115 66% 229% CD 116 66% 256% CD 117 68% 311% CD 120A 66% 269% CD 120B 67% 272% CD 121 22% 155% CD Example # Osmolarity Volume (% Ratac Urine Type (% decrease) to Increase) b osmolarity 123 88% 663% CD a Percent decrease in the volume of urine against the control at 10 mg per kg, unless otherwise stated. a Change in osmolarity as percent of control to 10 mg / kg, unless otherwise stated. c Rat model used: Spreague-Dawley (CD) or Brattleboro (BB). The following examples are presented to illustrate beyond the scope limit of the invention.

EXAMPLE 1 (4-Fluoro-2-trifluoromethyl-phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone Oxalyl chloride (2.0 g) was added to a suspension of 4-fluoro-2-trifluoromethylbenzoic acid (2.0 g) in dichloromethane (25 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resulting solution was evaporated to dryness to give the crude acid chloride. This was redissolved in dichloromethane and filtered. Evaporation of this material gave a liquid which was then dissolved in hexane, filtered, and evaporated to yield the acid chloride as a pale yellow viscous liquid, which was used without further purification. The acid chloride (2.26 g) in dichloromethane (25 ml) was added in portions to a mixture of 10,11-dihydro-5H, pyrrolo [2, 1-c] 1,4] benzodiazepine (1.66 g), dichloromethanol ( 10 ml), and diisopropylethylamine (1.30 g), cooled in an ice bath. After remaining at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further diluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration with 2.57 g of the title compound, m.p. 154-1155 ° C.

EXAMPLE 2 [4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl] (5H, HH-pyrrolo [2, 1-c].]. [1,4] benzodiazepin-10-yl) -metanone 60% sodium hydride in oil (0.15 g) was washed with hexane and dry dimethylformamide (25 ml) was added., followed by 3-methylpyrazole (0.25 g). After the evolution of hydrogen was used, (4-fluoro-2-trifluoromethyl-phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) - methanone (1.0 g). The reaction mixture was heated in a sand bath at 110 ° C for 15 hours. The reaction mixture was poured onto ice and saturated saline was added. The precipitate was collected by filtration. The pure reaction product was dissolved in dichloromethane and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several additional volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane. After cooling, the crystals were collected by filtration to yield 0.77 g of a crude product. Additional purification by additional filtration through a short column of anhydrous sodium magnesium silicate, ^ ¿^ Jjat ^ íU ^^. followed by the addition of hexane, afforded the title compound as a crystalline solid (0.66 g), m.p. 194-195 ° C.

EXAMPLE 3 [4- (4-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-yl) -methanone In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) -methanone (0.8 g), 60% sodium hydride in oil (0.15 g), 4-methylpyridol (0.20 g) and dimethylformamide (25 ml), the product (0.47 g) was obtained as a colorless amorphous solid, MS, m / z : 437.3 (M + H) +, 873.2 (2M + H) +.

EXAMPLE 4 (4-Pyrazol-1-yl-2-trifluoromethyl-phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone In the manner of the example, employing (4-fluoro-2-trifluoromethyl-phenyl) - (5H, 11H-pyrrolo [2, lc] [1,4] benzo-diazepin-10-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.20 g), pyrazole (0.25 g) and dimethylformamide (35 ml). the product (0.62 g) was obtained as an amorphous solid . . - - ~ i; -.? ~ Aá¡ a¡. jjtwatéj colorless, MS, m / z: 423.2 (M + H) 445.2 (M + Na) 845.3 (2M + H) +.

EXAMPLE 5 [4- (3-Cyclopropyl-poirazol-1-yl) -2-trifluoromethyl-phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (1.42) g), 60% sodium hydride in oil (0.20 g), 3-cyclopropylpyrazole (0.43 g) and dimethylformamide (50 ml), the product (1.22 g) was obtained as a crystalline solid, mp. 163-164 ° C.

EXAMPLE 6 [4- (4-Methyl-imidazol-1-yl) -2-trifluoromethyl-phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.20 g), 4-methylimidazole (0.25 g) and dimethylformamide (25 ml), the title compound (0.66 g) was obtained as an amorphous solid. MS, m / z: 437.2 (M + H) +, 873.2 (2M + H) +.

EXAMPLE 7 (5H, lIH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - (4- [1,2,4] triazol-1-yl-2-trifluoromethyl-phenyl) -metanone In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.20 g), 1, 2, 4-triazole (0.20 g), and dimethylformamide (25 ml), gave the title compound (0.36 g) (as an amorphous solid). colorless, MS m / z: 424.2 (M + H) +, 847.3 (2M + H) +.

EXAMPLE 8 (2-Chloro-4-fluorophenyl) -5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethanol (50 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resulting solution was evaporated . ,? -, ¿Ífa Afri .. »...,« tAail to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g). The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added in portions to a stirred, ice-cooled solution of 10,11-dihydro-5H-pyrrolo [2, 1-c. ] [1,4] benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate.The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of the hydrous magnesium sodium silicate and eluted further with several volumes of dichloromethane The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred.After cooling, the crystals were collected by filtration to yield the title compound (3.85 g) , mp 110-112 ° C.

EXAMPLE 9 [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) - pyrrolo [2, 1-c] (1,4] benzodiazepin-10-yl) -methanone (Isomer A) and [2-Chloro-4- (5-methyl-pyrazol-1-yl) -phenyl) ] - (5H, IIH) -pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (Isomer B) Method 1: A 60% sodium hydride in oil (0.3 g, degassed with hexane) in dimethylformamide (25 ml) was added to 3-methylpyrazole (0.55 g). When the evolution of hydrogen ended, (2-chloro-4-fluorophenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (1.70 g) was added. The reaction mixture was heated for 18 hours in a sand bath (internal temperature of 125 ° C). The reaction mixture was then poured onto ice and further diluted with a saturated saline solution. The precipitated solid was recovered by filtration. The crude product was dissolved in dichloromethane, dried over anhydrous sodium sulfate, and then filtered through a short column of hydrous sodium magnesium silicate and further diluted with several volumes of dichloromethane. The combined eluate was refluxed on a hot plate with the gradual addition of hexane until an opaque solution was observed. After cooling, an amorphous solid was obtained. After submitting this material to a second column of sodium silicate and i. ^ &S ^ -Á * j £ ¿* ^^: z &miit \ t¡¡i lffsi? Éi * k} Anhydrous magnesium and evaporation of the solvent in vacuo gave a mixture of regioisomers 9A and 9B in a ratio of approximately 9: 1 as an amorphous glass (1.11 g), MS, m / z: 403.2 (M + H) +. Method 2: To a pre-cooled suspension, with stirring of 60% sodium hydride washed with hexane (3.00 g) in dry dimethylformamide (250 ml), 3-methylpyrazole (5.50 g) was added dropwise at 0 ° C under hydrogen. The mixture was heated to room temperature. After gas evolution ceased, 2-chloro-fluorophenyl) - (5H, '< - HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (17.0 g) as a solid, and the mixture was heated at 103 ° C for one hour. The reaction mixture was poured into ice water, the filtered precipitate collected by filtration and air dried. The precipitate was dissolved in chloromethane, dried over anhydrous sodium sulfate, and filtered through a short column of silica gel, eluting with ethyl acetate. The combined filtrate was evaporated in vacuo to a residual foam (18.5 g). Purification and separation of the regioisomers by low pressure column chromatography on silica gel eluting with a gradient mixture of ethyl acetate-hexane (10:90 to 25:75), produced two purified regioisomers: Isomer A, [2 -chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -r ~ & .rí " methanone (13.5 g), as a colorless amorphous solid; MS (El), m / z: 402 (M) +. A sample (0.5 g) of diethyl ether was crystallized, followed by crystallization of ethanol to give regioisomer A (0.275 g) as a colorless, crystalline solid, m.p. 141-143 ° C; Isomer B; [2-chloro-4- (5-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone ( 1.93 g) as a colorless amorphous solid. A sample of diethyl ether was crystallized, followed by recrystallization of methanol for regioisomer B as colorless needles (1.4 g) m.p. 160-163 ° C; MS (El), m / z: 402 (M) +, Em (+ BAR), m / z: 403 (M + H) +.

EXAMPLE 10 [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo [2, 1-c] [1,4] benzodiazepin-10, il) - methanone Step a) 2-Chloro-4- (3-methylpyrazol-1-yl) benzonitrile: To a cold (0 ° C) suspension of sodium hydride (60% in oil, 2.0 g) in dimethylformamide (50 ml) was added 3-methylpyrazole (3.39 g) in portions. After the evolution of hydrogen gas ceased, 2-chloro-4-fluorobenzonitrile (5.17 g) was added and the mixture was stirred at room temperature for 18 hours. The mixture was poured ftJtfe ^^ a? ^ __ tinÍ ^^ ^ A "?? i 1; ¿^ tt &. < i on ice, it was diluted with brine and the resulting precipitate was collected by filtration. The crude product was dissolved in dichloromethane, filtered through a column of anhydrous sodium magnesium silicate, and crystallized by the addition of hexane. Recrystallization from ethanol gave 4.42 g of product, m.p. 148-150 ° C.

Step b) 2-Chloro-4- (3-methylpyrazol-1-yl) benzamide: A suspension of 2-chloro-4- (3-methylpyrazol-1-yl) benzonitrile (4.35 g) from step a in dimethyl sulfoxide ( 20 ml) containing potassium carbonate (0.40 g) was cooled in an ice bath. Hydrogen peroxide (30%, 2.4 ml) was added and the mixture was heated at room temperature for one hour. The resulting precipitate was recovered by filtration and recrystallized from ethanol to yield 2.44 g of product as fine needles, m.p. 159-160 ° C; Em, m / z: 235.9 (M + H) +. Step c) 2-Chloro-4- (3-methylpyrazol-1-yl) benzoic acid: A solution of 2-chloro-4- (3-methylpyrazol-1-yl) benzamide (1.09 g) from step b in sulfuric acid Aqueous 75% (25 ml) was cooled in an ice bath and sodium nitrite (1.73 g) was added. The mixture was heated at room temperature for 1 hour and poured on ice. The precipitate was collected by filtration and used directly in the next reaction. ^ £ g¡ ^ Step d) [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H-10, 11-dihydro-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone: A trifunction of 2-chloro-4- (3-methylpyrazol-1-yl) benzoic acid (0.69 g ), dichloromethane (25 ml) from step c, oxalyl chloride (1.0 g), and one drop of dimethylformamide was stirred at room temperature for 18 hours, the mixture was concentrated, extracted into dichloromethane (25 ml), and added to a mixture of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (0.51 g) in dichloromethane (25 ml) containing diisopropylethylamine (0.76 g). The mixture was stirred at room temperature for 18 h and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated and the resulting material was crystallized from diethyl ether to give 0.67 g of product, m.p. 137-138 ° C; MS, m / z: 403.2 (M + H) +, 805.8 (2M + H) +.

EXAMPLE 11 [2-Chloro-4- (4-methyl-pyrazol-11) -phenyl- (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone In the manner of Method 1 of Example 9, employing (2-chloro-4-fluorophenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (1.0 g), sodium hydride 60% in oil (0.3 g, defatted with hexane), 4-methylpyrazole (0.48 g) and dimethylformamide (25 ml), the title compound (0.74 g) was obtained as an amorphous solid, MS, m / z: 403.2 (M + H) +, 425.2 (M + Na) +, 805.3 ( 2M + H) +.

EXAMPLE 12 [2-Chloro-4- (4-methyl-imidazol-1-yl) -phenyl] - (5H, 11H, pyrrolo [2, 1-c] [1,4] benzodiazepin-yl) -metanone In the manner of Method 1 of Example 9, employing (2-chloro-4-fluorophenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) -methanone (1.0 g), 60% sodium hydride in oil (0.3 g, defatted with hexane), 4-methylimidazole (0.48 g) and dimethylformamide (25 ml), the title compound (0.38 g) was obtained as an amorphous solid, MS, m / z: 403.3 (M + H ) + EXAMPLE 13 [2-Chloro-4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone In the manner of Method 1 of Example 9, employing (2-chloro-4-fluorophenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) -methanone (0.8 g), 60% sodium hydride in Oil (0.25 g, defatted with hexane), 3- trifluoromethylpyrazole (0.61 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m / z: 457.2 (M + H) +.

EXAMPLE 14 (2-Chloro-4- (1,2,4-triazol-1-yl) -phenyl] - (5H, 1H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone In the manner of Method 1 of Example 9, employing (2-chloro-4-fluorophenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) -methanone (1.7 g), 60% sodium hydride in Oil (0.5 g, defatted with hexane), 1, 2, 4-triazole (0.70 g) and dimethylformamide (50 ml), gave the title compound (0.51 g) as an amorphous solid, MS, m / z, 390.3 (M + H) +, 779.3 (2M + H) +.

EXAMPLE 15 (2-Chloro-4-pyrrol-1-yl-phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone In the manner of Method 1 of Example 9, employing (2-chloro-4-fluorophenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) -methanone (1.7 g), 60% sodium hydride in ? ^^ ßjS ^ Sfefe * ^ oil (0.3 g, defatted with hexane), pyrrole (0.42 g) and dimethylformamide (25 ml), the title compound (0.60 g) was obtained as an amorphous solid, MS, m / z: 388.2 (M + H) + .

EXAMPLE 16 (2-Chloro-4-pyrazol-1-yl-phenyl) (5H, HH-Pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl-methanone In the manner of Method 1 of Example 9, employing (2-chloro-4-fluorophenyl) - (5H, 11H-pyrrolo [2, lc] [1,4] benzo-diazepin-10-yl) -methanone (1.0 g ), 60% sodium hydride in oil (0.2 g, defatted with hexane), pyrazole (0.20 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m / z: 389.2 ( M + H) +, 777.1 (2M + H) +.

EXAMPLE 17 [2-Chloro-4- (lH-imidazol-1-yl) -phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone In the manner of Method 1 of Example 9, employing (2-chloro-4-fluorophenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (2.0 g), sodium hydride 60% in oil (0.50 g, defatted with hexane), imidazole (0.50 g) and dimethylformamide (25 ml), the compound of title (0.57 g) as a pale yellow amorphous solid, MS, m / z: 389 (M + H) +.

EXAMPLE 18 [2-Chloro-4- (3-methylpyrazol-1-yl) -phenyl] - (3-methyl-5H, IIH-pyrrole [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone Step a) 1- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -2,2,2-trifluoro-ethanone: To an ice-cooled solution of 10, 11 -dihydro-5H-pyrrolo [2, 1-c] [1,) -benzodiazepine (5.62 g) and diisopropylethylamine (4.0 g) in dichloromethane (75 ml) was added dropwise trifluoroacetic anhydride (7.0 g) in dichloromethane. The mixture was stirred for 18 hours, and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to produce 7.70 g of product as fine needles, m.p. 134-135 ° C, MS, m / z: 281 (M + H) +. Step b) 1- (3-Dimethylaminomethyl-5H, HH-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-yl) -2,2,2-trifluoroethanone. A mixture of 1- (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -2,2,2-trifluoroethanone (2.80 g), from step a), bis-dimethylaminomethane ( 2.04 g), paraformaldehyde (2.70 g) and acetic acid (1.20 g) in a mixture of tetrahydrofuran (50 ml) and methanol (50 ml) and stirring at room temperature for 18 hours. The mixture was concentrated in vacuo, water was added and the aqueous mixture was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfates and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue was crystallized from hexane to yield 2.05 g of the product as a colorless solid m.p. 109-110 ° C, MS m / z: 338.3 (M + H) +. Step c) Trimethyl- (10-trifluoroacetyl-10,11-dihydro-5H-pyrrolo [2, 1-c) (1,4] benzodiazepin-3-yl-methyl) -ammonium iodide: A mixture of 1- ( 3-dimethylaminomethyl-5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -2,2,2-trifluoroethanone (1.83 g) from step b) and iodomethane (1.0 g) in trichloromethane (20 ml) was stirred at room temperature for 18 hours. Diethyl ether was added and the resulting precipitate was collected by filtration to give 2.54 g of product as a colorless solid, m.p. 140-155 ° C (dec). Step d) 10, 11-Dihydro-3-methyl-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine: Sodium borohydride (2.6 g) was added in two portions to a reflux mixture of trimethyl- (10- trifluoroacetyl-l, l-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepin-3-yl-methyl) -ammonium iodide (2.60 g) from step c) in ethanol. Four hours later, the mixture was concentrated in vacuo. Water was added to the residue and the mixture was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue was crystallized from hexane to yield 1.14 g of product, m.p. 150-151 ° C, MS, m / z: 199.1 (M + H) +. Step e) [2-Chloro-4- (3-methylpyrazol-1-yl) -phenyl] - (3-methyl-5H, HH-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10- il) -metanone: A mixture of 2-chloro-4- (3-methylpyrazol-1-yl) -benzoic acid (0.18 g) from step d), oxalyl chloride (0.18 g) and one drop of dimethylformamide in dichloromethane (10 ml), was stirred at room temperature for 18 hours, the mixture was concentrated in vacuo, and the residue was redissolved in dichloromethane and reconcentrated in vacuo to yield 2-chloro-4- (3-methyl-pyrazole-1) chloride. -yl) -benzoyl. A suspension of acid chloride in dichloromethane (25 ml) was added dropwise to a solution of 10,11-dihydro-3-methyl-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (0.12 g) and diisopropylethylamine (0.10 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 18 h, and washed with water and saturated aqueous sodium bicarbonate. The rf1il | ln, l_a ^ Ufei ^ ttfta_iá_¿l __ & _ ^ ___ ^ _ fc, ra. ^. . -r ^? iU &rr.r ^ *? St * k * * & amp; amp; amp; amp; amp; The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to yield 0.115 g of product as colorless crystals, m.p. 178-180 ° C, MS, m / z: 417.3 (M + H) +, 833.3 (2M + H) +.

EXAMPLE, 19 (2-Chloro-4-trifluoromethyl-pyrimidin-5-yl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) methanone 2-Chloro-4- (trifluoromethyl) pyrimidine-5-carbonyl chloride (2.57 g) was gradually added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1, 4]. ] -benzodiazepine, (1.8 g) and diisopropylethylamine (1.37 g) in dichloromethane (50 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The trichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with gradual vision of hexane until recrystallization occurred. After cooling, ßS? ).'Mr the crystals were collected by filtration to yield the title compound (3.22 g), m.p. 221-223 ° C.

EXAMPLE 20 [2- (3-Methyl-pyrazol-1-yl) -4-trifluoromethyl-pyrimidin-5-yl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10- il) -metanone Sodium hydride at 60% in oil, (0.15 g defatted with hexane) in dimethylformamide (25 ml) was added 3-methylpyrazole (0.25 g). When the evolution of hydrogen ceased, (2-chloro-4-trifluoromethyl-pyrimidin-5-yl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - methanone (0.98 g). The reaction mixture was heated for 18 hours in a sand bath (internal temperature 110 ° C). The mixture was then poured onto ice and further diluted with a saturated saline solution. The precipitate was filtered, redissolved in dichloromethane and dried over anhydrous sodium sulfate. The purification was aided by filtration through a short column of anhydrous sodium magnesium silicate and further elution with several volumes of dichloromethane. The combined eluate was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. Í? itri i ?! : After cooling, the solid was collected by filtration to yield the title compound (0.54 g) as colorless crystals, m.p. 202-204 ° C.

EXAMPLE 21 [2- (4-Methyl-pyrazol-1-yl) -4-trifluoromethyl-pyrimidin-5-yl] - (5H, 11H-pyrrolo [2, lc] [1,4] benzodiazepine-10-yl) ) - methanone In the manner of Method 1 of Example 9, employing (2-chloro-4-trifluorophenyl-pyrimidin-5-yl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (0.98 g), sodium hydride at 60% in oil (0.15 g), 4-methylpyrazole (0.42 g) and dimethylformamide (25 ml), the title compound (0.73 g) was obtained as a crystalline solid, mp 214-217 ° C.

EXAMPLE 22 1- [4- (5H, 11H, Pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -ethanone 4-Acetylbenzoic acid (5.0 g) and thionyl chloride (10 ml) were heated in a steam bath under argon for 0.75 hour, and the volatile material was removed under reduced pressure. Toluene and compounds were added The volatiles were removed again to give the crude acid chloride as a red-orange oil. This compound tended to solidify and was used as such for further transformations. The acid chloride (4.56 g) in dichloromethane (25 ml) was added in portions to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (3.68). g) and diisopropylethylamine (3.25 g) in dichloromethane (100 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate with several volumes of dichloromethane. • The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1.75 g), m.p. 135-137 ° C.

EXAMPLE 23 3-Dimethylamino-l- [4- (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-propen-l-one A reaction mixture of 1- [4- (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -ethanone (1.40 g), t-butoxy-bis-dimethylaminomethane (5.0 ml) and dichloromethane (10 ml) was stirred for 18 hours. The red-orange precipitate was precipitated to yield the title compound (1.22 g), m.p. 203-205 ° C. The additional product (0.18 g) was isolated from the reaction mixture by concentration.

EXAMPLE 24 [4- (lH-Pirázol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone A reaction mixture of 3-dimethylamino-l- [4- (5H, HH-pyrrolo [2, 1-c) [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-prop-1-one ( 1.0 g), anhydrous hydrazine (0.20 g), and acetic acid (20 ml) was refluxed for 7 hours and evaporated to dryness. The crude residue was dissolved in dichloromethane, washed with a saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. in ^^ te * ^., .. - * ...,. . Jafchl anhydrous. The solution was filtered through a short column of anhydrous sodium magnesium silicate, eluting with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration. The procedure of the column was repeated to yield the title compound (0.65 g), m.p. 219-221 ° C.

EXAMPLE 25 [4- (l-Methyl-lH-pyrazolyl-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -metanone To a mixture of 60% sodium hydride in oil (0.35 g, defatted with hexane) and dimethylformamide (20 ml) was added [4- (lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,] benzodiazepin-10-yl) -methanone (0.98 g) followed in a few minutes by iodomethane (0.50 g). The reaction mixture was stirred for 18 hours at room temperature and then poured into water and extracted with dichloromethane. After drying, the organic layer was filtered through a short column of anhydrous sodium magnesium silicate, eluting with several volumes of dichloromethane. The combined organic phase was concentrated - »•« '»» *' "irimüf ' on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.70 g), m.p. 194-195 ° C.

EXAMPLE 26 [4- (l-Ethyl-lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone In the manner of Example 25, employing [4- (lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4) benzodiace-pin-10-ill- methanone (1.0 g), 60% sodium hydride in oil (0.27 g), dimethylformamide (25 ml), and ethyl iodide (0.87 g), gave the title compound (0.69 g) as a crystalline solid, !F. 180-183 ° C.

EXAMPLE 27 [4- (l-Propyl-lH-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -metanone In the manner of Example 25, employing [4- (lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4) benzodiace-pin-10-yl- methanone (0.98 g), 60% sodium hydride in oil (0.30 g), dimethylformamide (25 ml), and 1-iodopropane (0.60 g), the title compound (0.32 g) was obtained as a crystalline solid, m.p. 159-161 ° C.

EXAMPLE 28 [4- (l-Butyl-lH-pyrazol-3-yl) -phenyl] - (5H, IIH-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone In the manner of Example 25, employing [4- (lH-pyrazol-3? L) -phenyl] - (5H, HH -pyrrolo [2, 1-c] [1,4) benzodiace-pin-10-ill-methanone (0.98 g), 60% sodium hydride in oil (0.30 g), dimethylformamide (25 ml), and 1- iodobutane (0.60 g), the title compound (0.32 g) was obtained as a crystalline solid, mp 122-123 ° C.

EXAMPLE 29 [4- (1-methoxymethyl-1H-pyrazol-3-yl) -phenyl] - (5H, 1IH-pyrrolo [2, 1-c) [1,4] -benzodiazepin-10-yl) -methanone In the manner of Example 25, employing [4- (lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4) benzodiace-pin-10-yl- methanone (1.0 g), 60% sodium hydride in oil (0.15 g), dimethylformamide (25 ml), and iodomethyl methyl ether (0.50 g), the title compound (0.26 g) was obtained as an amorphous solid, MS, m / z: 399.2 (M + H) +, 797.2 (2M + H) +. or EXAMPLE 30 l-. { 3- [4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-carbonyl) -phenyl] -pyrazol-1-yl} -etanone To a solution of [4- (1H-pyrazol-3-yl) -phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (0.50 g) in dry pyridine (10 ml) was added acetic anhydride (0.20 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column of anhydrous sodium magnesium silicate, eluted with several volumes of dichloromethane. The eluent was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.46 g), m.p. 192-194 X EXAMPLE 31 l-. { 3- [4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-carbonyl) -phenyl] pyrazol-1-yl} -propan-l-one By way of Example 30, employing [4- (lH-pyrazol-3-i]) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (0.16 g) in dry pyridine (10 ml) and propionic anhydride (0.10 g), the title compound (0.17 g) was obtained as a crystalline solid, mp. 150-152 ° C.

EXAMPLE 32 [4- (1-Cyclopropanecarbonyl-1H-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone To a solution of [4- (lH-pyrazol-3-yl) -phenyl) - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone (0.10 g) in dry pyridine (10 ml) was added cyclopropanecarbonyl chloride (0.44 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column of anhydrous sodium magnesium silicate, eluted with several volumes of 'i dichloromethane. The eluent was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.88 g) which was obtained as a crystalline solid, m.p. 197-199 ° C.

EXAMPLE 33 1-. { 3- [4- (5H, 11H-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-carbonyl) -phenyl] -pyrazol-1-yl} butan-l-ona By way of Example 32, employing [4- (lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone ( 0.71 g) in dry pyridine (10 ml) and butyl chloride (0.32 g), the title compound (0.54 g) was obtained as a solid, mp. 105-110 ° C; MS, m / z: 424 (M) +.

EXAMPLE 34 (5H, llH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -. { 4- [1- (thiophene-2-carbonyl) -lH-pyrazol-3-yl] phenyl} -metanone By way of Example 32, employing [4- (lH-pyrazol-3-yl) -phen?] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - methanone (0.5 g) in dry pyridine (10 ml) and ^ mMÁltt tr thiophen-2-carbonyl (0.25 g), the title compound (0.41 g) was obtained as a crystalline solid, m.p. 195-197 ° C; MS, m / z: 464 (M) +.

EXAMPLE 35 { 4- [1- (5-Fluoro-2-methyl-benzoyl) -lH-pyrazol-3-yl] -phenyl} - (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone By way of Example 32, using [4- (1H-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,) benzodiazepin-10-yl) -methanone (0.35) g) in dry pyridine (10 ml) and 2-methyl-5-fluorobenzoyl chloride (0.22 g), the title compound (0.11 g) was obtained as a pale yellow amorphous solid, MS, m / z: 490 (M ) + EXAMPLE 36 { 4- [1- (2-Methyl-benzoyl) -lH-pyrazol-3-yl] -phenyl} - (511, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone By way of Example 32, employing [4- (lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone ( 0.71 g) in dry pipdin (20 ml) and o-chloride Ate¿a.fc »« f- - - tmJ? K .._. > ^ ^ ^? toluyl (0.39 g), the title compound (0.59 g) was obtained as a crystalline solid, m.p. 170-173 ° C; MS, m / z: 472 (M) +.

EXAMPLE 37 { 4- [1- (2-Chloro-4-fluoro-benzoyl) -IH-pyrazol-3-yl] -phenyl} - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl.} - methanone 2-Chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4- (lH-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1 , 4] benzodiazepin-10-yl) -methanone (1.0 g) in portions and diisopropylamine (0.55 g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was concentrated by stirring overnight at room temperature. The reaction mixture was washed with water and saturated with sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of anhydrous sodium magnesium silicate, eluted with several volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157 ° C; MS, m / z: 510 (M) +. .dtA * ** V &kÍi »? b. ^ ^ ¡*? m EXAMPLE 38 { 4- [1- (2,4-Dichloro-benzoyl) -lH-pyrazol-3-yl] -phenyl} - (5H, llH-pyrrolo [2, 1-c) [1,4] benzodiazepin-10-yl) -metanone By way of Example 32, employing [4- (lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone ( 0.71 g) in dry pyridine (20 ml) and 2,4-dichlorobenzoyl chloride (0.52 g), the title compound (0.66 g) was obtained as a crystalline solid, mp. 180-182 ° C; MS, m / z: 528 (M) +.

EXAMPLE 39 2- (2,4-Dicyoro-phenyl) -l-. { 3- [4- (5H, 11H-pyrrolo [2, l-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -pyrazol-1-yl} -etanone By way of Example 32, employing [4- (1H-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone ( 0.71 g) in dry pyridine (20 ml) and 2,4-dichlorophenylacetyl chloride (0.56 g), the title compound (0.20 g) was obtained as a crystalline solid, mp. 130-140 ° C, resolidified, p. f .180-182 ° C. a * k EXAMPLE 40 { 4- [1- (Biphenyl-2-carbonyl) -lH-pyrazol-3-yl) -phenyl} - (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone By way of Example 32, employing [4- (1H-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone ( 0.71 g) in dry pyridine (20 ml) and 2-biphenylcarbonyl chloride (0.65 g), the title compound (0.49 g) was obtained as an amorphous solid, MS, m / z: 534 (M) +.

EXAMPLE 41 { 4- (1- (4'-Trifluoromethyl-biphenyl-2-carbonyl) -1H-pyrazol-3-yl] -phenyl) - (5H, 11H-pyrrolo [2, 1-c] (1,4) -benzodia - cepin-10-yl) -metanone By way of Example 32, employing [4- (1H-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone ( 0.71 g) in dry pyridine (20 ml) and 4'-trifluoromethyl-2-biphenylcarbonyl chloride (0.71 g), the title compound (0.59 g) was obtained as an amorphous solid, MS, m / z: 602 (M ) + EXAMPLE 42 3-Dimethylamino-1- [4- (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -phenyl] -2-buten-1-one A mixture of 1- [4- (5H, HH-pyrrolo (2, lC] [1,4] benzocyccepin f-10-carbonyl) -phenyl] -ethanone (2.0 g) and dimethylacetal dimethylacetamide (15 ml) was subjected to at reflux in an inert atmosphere for 15 hours and the volatiles were removed under reduced pressure.The crude solid was dissolved in dichloromethane and filtered through a short column of anhydrous sodium magnesium silicate followed by several volumes of dichloromethane. The combined solution was added gradually until recrystallization occurred.The cooled solution was filtered to collect the title compound (1.03 g) as a crystalline solid, mp 183-185 ° C.

EXAMPLE 43 [4- (5-Methyl-lH-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4) -benzodiazepin-10-yl) -methanone Anhydrous hydrazine (0.10 g) was added to a solution of 3-Dimethylamino-1- [4- (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazole- cepin-10-carbonyl) -phenyl] -2-buten-l-one (0.50 g) in glacial acetic acid (25 ml). The reaction mixture was refluxed for 18 hours and then concentrated in vacuo. The solid was extracted with dichloromethane and washed with aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated in a steam bath with gradual addition of hexane to give an opaque solution. After cooling the amorphous solid was collected by filtration to produce the product (0.33 g), MS, m / z: 368 (M) +.

EXAMPLE 44 • 4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -benzonitrile 4-Cyanobenzoic acid (5.0 g) and thionyl chloride (5.0 ml) were heated in a steam bath for one hour, and all volatiles were removed under reduced pressure. Hexane was added and the crude crystalline acid chloride (5.30 g) was collected by filtration, and used without further purification.

To the reaction mixture of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (3.68 g), dichloromethane (100 ml), and diisopropylethylamine (2.80 g) was added 4-cyanobenzoyl (2.97 g). After remaining at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate, eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (5.05) g, m.p. 184- 186 ° C.

EXAMPLE 45 4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepine-10-car-bonyl) -benzamide 4- (5H, 11H-Pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -benzonitrile (0.5 g) from Example 44 was added to the concentrated sulfuric acid (5 ml) and the mixture was stirred for 18 hours at room temperature to produce a bright yellow solution. The solution was poured on ice and made basic with the addition of concentrated ammonium hydroxide. The resulting solid was filtered, dissolved in dichloromethane and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (5.05 g), m.p. 226-228 ° C.

EXAMPLE 46 N- (Dimethylaminomethylene) -4- (5H, IIH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide A mixture of 4- (5H, 11H-pyrrolo [2, 1-c] [1,4), enzodiacepin-10-carbonyl) -benzamide (1.25 g) of Example 45 and dimethylacetal dimethylformamide (20 ml) was refluxed during refluxing. 4 hours and the volatiles were removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated in a steam bath with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1.40 g), m.p. 232-234 ° C.

EXAMPLE 47 N- (1-Dimethylammoninoethylene) -4- (5H, 11H-pyrrolo [2, 1-cj [1,4] benzodiazepine-10-carbonyl) -benzamide A mixture of 4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide (1.24 g) from Example 45 and dimethylacetal dimethylacetamide (5.0 ml) was heated in a bath of steam for 4 hours. Upon cooling for 18 hours a crystalline solid precipitated which was collected by filtration. The solid was washed with hexane to yield the product (1.54 g), m.p. 210-212 ° C; MS, m / z: 400 (M) +.

EXAMPLE 48 (5H, llH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - [4- (2H- [1,2,4] triazol-3-yl) -phenyl] -metanone A mixture of N- (dimethylaminomethylene) -4- (5H, HH-pyrrolo [2, 1-c] [1,4] -benzodiazole was refluxed. í k ki cepin-10-carbonyl) -benzamide (1.0 g) of example 46, glacial acetic acid (15 ml), and anhydrous hydrazine (0.16 g) for 15 hours and the volatiles were removed in vacuo. A saturated aqueous solution of sodium bicarbonate was added and the resulting solid was collected by filtration. The solid was refluxed for 4 hours and the volatiles removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated in a steam bath with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.39) g, p.f-. 225-227 ° C; MS, m / z: 355 (M) +.

EXAMPLE 49 [4- (2-Methyl-2H- [1, 2,4] triazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine- 10-il) -metanone In the same manner as in Example 48, using N- (dimethylaminomethylene) - (5H, IIH-pyrrolo [2, 1-c) [1,] benzodiazepine-10-carboml) -benzamide (1.56 g) of Example 46 in glacial acetic acid (75 ml) and methylhydrazine (0.32 g), the title compound (0.10 g) was obtained as a solid, m.p. 155-158 ° C; MS, m / z: 369 (M) +.

EXAMPLE 50 4- (2-Methyl-2H- [1,2,4] triazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10 -il) -metanone In the same manner as in Example 48, using N- (dimethylaminomethylene) 4- (5H, llH-pyrrolo [2, 1-c) [1,4] benzo-diazepin-10-carbonyl) -benzamide (1.00 g) of Example 47 in glacial acetic acid (75 ml) and anhydrous hydrazine (0.25 g), the title compound (0.20 g) was obtained as an amorphous solid, MS, m / z: 369 (M) +.

EXAMPLE 51 '4- (2-Methyl-2H- [1,2,4] triazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, lc] [1,4] -benzodiazepine-10- il) -metanone In the same manner as in Example 48, using N- (dimethylaminomethylene) 4- (5H, IIH-pyrrolo [2, 1-c) [1,4] benzo-diazepin-10-carbonyl) -benzamide (1.18 g) of Example 47 in glacial acetic acid (75 ml) and methylhydrazine (0.30 g), the title compound (0.33 g) was obtained as a solid, mp. 193-195 ° C; MS, m / z: 383 (M) +.

; Mfci tlj ifcikrii Jaia fcjéÉ EXAMPLE 52 [4- (3-Methyl [1,2,4] oxadiazol-5-yl) -phenyl] - (5H, 11H-pyrrolo- [2, 1-c] [1,4] -benzodiazepin-10- il) -metanone A solution of N- (1-dimethylaminoethylene) -4- (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiaceppin-10-carbonyl) -benzamide (1.15 g) was refluxed. ) of Example 47 in glacial acetic acid (50 ml) containing hydroxylamine hydrochloride (0.40 g) and potassium acetate (1.0 g) for 2 hours. All volatile compounds were removed under reduced pressure and a saturated aqueous solution of sodium bicarbonate was added. The mixture was extracted with dichloromethane and the extracts were dried over anhydrous sodium sulfate. The solution was filtered through a short column of sodium magnesium anhydrous silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated in a steam bath with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.38 g), m.p. 177-179 ° C; MS, m / z: 371.3 (M) +, 741.3 (2M) +.

EXAMPLE 53 l-Methyl-4- (4-methylphenyl) -lH-pyrazole A mixture of 2- (4-methylphenyl) -malondialdehyde (3.05 g) and methylhydrazine (1.09 g) was stirred at room temperature for 18 hours and the volatiles removed at room temperature. Water was added and the mixture was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solution was filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated in a steam bath with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (2.91 g), m.p. 107-108 ° C.

EXAMPLE 54 4- (l-Methyl-lH-pyrazol-4-yl) -benzoic acid A mixture of 1-methyl-4- (4-methylphenyl) -lH-pyrazole (1.70 g), potassium permanganate was refluxed. (9.70 g) and 1 N sodium hydroxide (100 ml) for 18 hours.

The suspension was filtered through diatomaceous earth chilled The aqueous solution was extracted with dichloromethane and discarded. The aqueous solution was acidified to pH 5.5. The resulting precipitate was difficult to filter and was therefore extracted with dichloromethane. After evaporation of the solvent, the resulting solid was recrystallized from acetone to yield the title compound (0.60 g), m.p. 274-275 ° C; MS m / z: 202 (M) +.

EXAMPLE 55 [4- (l-Methyl-lH-pyrazol-4-yl) -phenyl] - (5H, llH-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -metanone Oxalyl chloride (0.30 g) was added to a suspension of 4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid (0.46 g) in dichloromethane (25 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resulting solution was evaporated to dryness to give the crude acid chloride product (0.57 g), which was used without further purification. The acid chloride was added to the solution 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (0.37 g) and diisopropylethylamine (0.58 g) in dichloromethane (50 ml). after 18 hours at room temperature, the reaction mixture was washed with water and saturated sodium bicarbonate aqueous. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated in a steam bath with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.38 g), m.p. 200- 201 ° C; MS m / z; 368 (M) +.

EXAMPLE 56 6- (l-Methyl-lH-pyrazol-4-yl) -pyridine-3-carboxylic acid A suspension of 6- (l-formyl-2-hydroxyvinyl) pyridine-3-carboxylic acid (1.93 g) (Eastman Chemicals) was stirred in total ethanol (50 ml) and methylhydrazine (0.50 g) for 18 hours at room temperature. The reaction mixture was filtered to give a product (1.30 g). The filtrate was evaporated to give a solid which was recrystallized from ethyl acetate to give an analytical sample of the title compound (0.55 g), m.p. 262-264 ° C.

EXAMPLE 57 [6- (l-Methyl-lH-pyrazol-4-yl) -pyridin-3-yl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl -metanone A suspension of 6- (1-methyl-1H-pyrazol-4-yl) pyridine-3-carboxylic acid (0.48 g) in thionyl chloride (5.0 ml) was stirred at room temperature for 2 hours. The volatile material was removed under reduced pressure to produce 6- (l-methyl-lH-pyrazol-4-yl) pyridine-3-carbonyl chloride as a solid, which was used without further purification. A solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (0.37 g) and diisopropylethylamine (0.61 g) in dichloromethane (25 ml) was cooled to 0 ° C and added a solution of 6- (1-methyl-lH-pyrazol-4-yl) pyridine-3-carbonyl chloride in dichloromethane (25 ml) in portions. After 18 hours at room temperature, the reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.31 g), m.p. 173-175 ° C; MS m / z: 370.3 (M + H) +.

EXAMPLE 58 [4- (Pyrazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone To a suspension of 4- (pyrazol-1-yl) benzoic acid (1.56 g) in dichloromethane (25 ml) was added oxalyl chloride (1.04 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours to produce a clear solution. The volatile material was removed under reduced pressure to produce 4- (pyrazol-1-yl) benzoyl chloride as a pale yellow solid (1.58 g), which was used without further purification. 4- (Pyrazol-1-yl) benzoyl chloride (0.75 g) was added to a solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (0.61 g) and diisopropylethylamine (0.47 g) in dichloromethane (25 ml). After 18 hours at room temperature, the reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and eluted further with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.90 g), m.p. 179-181 ° C.

EXAMPLE 59 [4- (3-Methyl-pyrazol-1-yl) -phenyl] - (5H, HH-pyrrolo- [2, 1-c] [1,4] -benzodiazepin-10-yl) -metanone To a suspension of 4- (3-pyrazol-1-yl) benzoic acid (1.84 g) in dichloromethane (25 ml) was added oxalyl chloride (1.16 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. Dichloromethane, the filtered solution, and the solvent evaporated under reduced pressure were added to produce 4- (3-methylpyrazol-1-yl) benzoyl chloride as a yellow solid (1.76 g), which was used without further purification. 4- (Pyrazol-1-yl) benzoyl chloride was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (0.55 g) and diisopropylethylamine ( 0.44 g) ... Zr * klíÍ.k? Ítk-í,? SX, Írk.rM £ ¿Í, .. in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.90 g), MS, m / z: 369 (M + H) +.

EXAMPLE 60 [4- (4-Methyl-pyrazol-1-yl) -phenyl] - (5H, 11H-pyrrolo- [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone To a suspension of 4- (4-methylpyrazol-1-yl) benzoic acid (0.754 g) in dichloromethane (15 ml) was added oxalyl chloride (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and volatile material was removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo produced 4- (4-methylpyrazol-1-yl) benzoyl chloride (0.77 g), which was used without further purification. 4- (4-Methylpyrazol-1-yl) benzoyl chloride (0.72 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine ( 0.60 g) and diisopropylethylamine (0.48 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.75 g), m.p. 179-181 ° C; MS m / z: 369 (M + H) +.

EXAMPLE 61 [4- (3,5-Dimethyl-pyrazol-1-yl) -phenyl] - (5H, HH-pyrrole [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone It was added to a suspension of 4- (3,5-dimethylpyrazol-1-yl) benzoic acid (1.34 g) in dichloromethane (25 g). ml) oxalyl chloride (1.0 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo yielded 4- (3,5-dimethylpyrazol-1-yl) benzoyl chloride (0.80 g), which was used without further purification. 4- (3,5-Dimethylpyrazol-1-yl) benzoyl chloride was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,] benzodiazepine (0.55 g) and diisopropylethylamine (0.42 g) in dichloromethane (25 ml).

After stirring at room temperature for 18 hours, the reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the title compound (0.79 g) was obtained as an amorphous solid, MS, m / z: 383 (M + H) +.

EXAMPLE 62 (5H-IIH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - [4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] methanone A suspension of 4- (3-trifluoromethyl-pyrazolyl-1-yl) benzoic acid (1.45 g) in thionyl chloride (5.0 ml) was heated to reflux for 3 hours. The volatile material was removed under reduced pressure, the residue was dissolved in dichloromethane, and filtered through diatomaceous earth. Evaporation of the in va solvent gave 4- (3-trifluoromethylpyrazol-1-yl) benzoyl chloride (1.45 g), which was used without further purification. A solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,) -benzodiazepine (0.88 g) and diisopropylethylamine (0.66 g) in dichloromethane (50 ml) was added. After stirring at room temperature for 18 hours, the reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1.70 g) m.p. 166-167 ° C; MS, m / z: 423.3 (M + H) +, 845.4 (2M + H) +.

EXAMPLE 63 [4- (Imidazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] - [1,4] benzodiazepin-10-yl) -metanone A suspension of 4- (imidazol-1-yl) benzoic acid (0.90 g) in thionyl chloride (2.0 ml) was heated in a steam bath under argon for one hour. Evaporation of the volatile material under reduced pressure produced a residue which crystallized after the addition of hexane to yield 4- (imidazol-1-yl) benzoyl chloride as the hydrochloride salt (1.17"g), mp 242- 247 ° C to a solution of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (0.75), dilsopropylethylamine (1.20 g), and 4-dimethylaminopyridine (0.1 g) in dichloromethane (50 ml) was added 4- (imidazoT-1-yl) benzoyl chloride hydrochloride (1.12 g). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of sodium silicate and «» I »ft» ft? M «ÍÉiMfrri" r r -v, ~ v, - "if, M á anhydrous magnesium and was further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.57 g) m.p. 171-172 ° C; MS, m / z: 354 (M + H) +.

EXAMPLE 64 [4- (4-Methyl-imidazol-1-yl) -phenyl] - (5H, HH-pyrrolo- [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone To a suspension of 4- (4-methylimidazol-1-yl) benzoic acid (0.80 g) in dichloromethane (25 ml) was added oxalyl chloride (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure to yield 4- (4-methylimidazol-1-yl) benzoyl chloride (1.02 g), which was used without further purification. 4- (4-Methylimidazol-1-yl) benzoyl chloride (0.99 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine ( 0.64 g) and diisopropylethylamine (0.60 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the .J.AJAA.1 ^ The reaction mixture was washed with water and a saturated aqueous solution of sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of anhydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until recrystallization occurred. After cooling, the title compound (0.52 g) was obtained as a solid, m.p. 140-145 ° C; MS, m / z: 369 (M + H) +.

EXAMPLE 65 Methyl ester of 4-Bromo-2-chloro-benzoic acid Thionyl chloride (1.64 ml) was added dropwise to a suspension of 4-bromo-2-chlorobenzoic acid (6.92 g) in methanol, and heated at 60 ° C for 2 hours. The solvent was removed in vacuo, the residue redissolved in ethyl acetate, and washed sequentially with 0.5N sodium hydroxide (2x), water, and brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to yield the title compound (7.8 g). X H NMR (300 MHz), (DMSO-d 6) d: 3.87 (s, 3 H), 7.68-7.9 (m, 3 H).

EXAMPLE 66 2-Chloro-4- (3-dimethylamino-propin-1-yl) benzoic acid methyl ester To a solution of 4-bromo-2-chlorobenzoic acid methyl ester (18.69 g) in triethylamine (110 ml), l-dimethylamino-2-propin (12.1 ml), bis (triphenylphosphine) palladium (II) chloride (1.26 g), and copper (I) iodide (0.136 g) were added with stirring. The reaction mixture was heated slowly to 60 ° C, and the temperature was maintained for one hour. The reaction was cooled to room temperature, filtered through diatomaceous earth, and the collected solid was washed with ethyl acetate. The solvent was removed in vacuo, the resulting residue was redissolved in ethyl acetate, and washed with water (3x). The combined organic extract was dried over anhydrous sodium sulfate, and the solvent removed in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel (225 g), eluted with 40% ethyl acetate / hexane. After removing the solvent in vacuo, the title compound was obtained as a viscous oil (17.7 g), MS (+ BAF), m / z: 252 (M + H) +. tvfíi? • I! EXAMPLE 67 2-Chloro-4- (3-dimethylamino-2-propen-1-on-1-yl) -benzoic acid methyl ester Gradually, 3-chloroperoxybenzoic acid (10.76 g) was added to a solution of 2-chloro-4- (3-dimethylamine-propynyl) -benzoic methyl ester, (15.07 g in dichloromethane (40 ml), at a high speed to maintain the reaction temperature at -20 ° C. The mixture was stirred for 10-15 minutes.The resulting N-oxide was purified by chromatography on basic alumina of Degree of Activity I (215 g), eluted with 10% methanol The solvent was evaporated in vacuo, between 12 to 18 ° C. The resulting residue was dissolved (100 ml) and 60-65 ° C. with stirring for 18 hours, after removing the solvent in vacuo, and the product was purified by column chromatography on silica gel (190 g), eluted with 70% ethyl acetate / hexane, trituration with diethyl ether containing some hexane afforded the title compound as a solid (5.68 g), mp 92 -96 ° C.

EXAMPLE 68 2-Chloro-4- (lH-pyrazol-3-yl) -benzoic acid methyl ester To a suspension of 2-chloro-4- (3-dimethylamino-2-propenyl-1-yl) -benzoic acid methyl ester, (13.67 g) in Ethanol (53 ml) was added hydrazine monohydrochloride (7.0 g). The mixture was heated in an oil bath at 75-80 ° C for one hour. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield the title compound as a crude solid (12 g). A purified sample had a melting point of 130-131 ° C.

EXAMPLE 69 2-Chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid methyl ester To a suspension of hexane washed with sodium hydride (3.05 g, 60% dispersion) in dimethylphomamide (6 ml) under nitrogen was added a solution of 2-chloro- (1H-pyrazol-3-yl) -benzoic acid methyl ester ( 12.0 g) in dimethylformamide (30 ml) above a period of 15 minutes.

The mixture was stirred at room temperature for 30 minutes. Iodomethane (9.5 ml) was added dropwise over 15 minutes. The mixture was kept under stirring at room temperature for 45 minutes. Additional iodomethane was added (5.16 ml), and the reaction was stirred another 75 minutes. The reaction was diluted with a small amount in water, and concentrated in vacuo. The residue was diluted with water (500 ml) and extracted with a small amount of ethyl acetate (5x). The combined organic phase was evaporated in vacuo to yield a crude product (13.48 g). The crude product was purified by column chromatography on silica gel (195 g) eluted with; 15% ethyl acetate / hexane to produce the pure 1-methyl regioisomer (4.29 g), followed by a mixture of 1-methyl and 2-methyl regioisomers (4.6 g). The mixture of isomers was triturated with hexane three times to give an additional sample of the pure 1-methyl regioisomer (2.55 g), m.p. 66.5-67 ° C; MS (+ BAR), m / z 251 (M + H) +.

EXAMPLE 70 2-Chloro-4- (l-methyl-lH-pyrazol-3-yl) -benzoic acid To a solution of 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid methyl ester (6.85 g) in methanol (32 ml) was added 2.5 N sodium hydroxide solution (15.3 g). ml). The reaction was heated at 50 ° C for one hour. The solvent was removed in vacuo, and the residue was dissolved in water (250 ml), cooled in an ice bath, and acidified with 2N hydrochloric acid (24 ml). The resulting precipitate was filtered and dried to give a colorless solid (6.3 g) m.p. 232-233 ° C; MS (+ BAR) m / z: 236 (M + H) +.

EXAMPLE 71 [2-Chloro-4- (l-methyl-lH-pyrazol-3-yl) -phenyl) - (5H, IIH-pyrrolo [2, 1-s] - [1,4] benzodiazepin-10-yl -metanone Well-pulverized 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) -benzoic acid (6.3 g) and dimethylformamide were suspended. (2.16 ml) under nitrogen in a tetrahydrofuran mixture (70 ml) and dichloromethane (15 ml). It was added dropwise to a solution of oxalyl chloride (2.43 ml) in dichloromethane (5 ml), and the reaction was stirred for one hour. The resulting suspension I of 2-chloro-4- (1-methyl-1H-pyrazol-3-yl) benzoyl chloride was used in further purification. To a suspension of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (4.93 g) in dichloromethane (15 ml) was added diisopropylethylamine (7 ml). The freshly prepared acid chloride suspension was added gradually for 15 minutes under a positive flow of nitrogen. The warm reaction mixture was stirred under nitrogen for 50 minutes. After stirring for one hour, the mixture was concentrated in va cuo. The residue was dissolved in dichloromethane, washed with water, bicarbonate of sodium at 5%, and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give an - > »J«? Wa «*« ~ -A- • - raw product (10.95 g). The crude product was purified by column chromatography on silica gel (200 g), the column loaded with 25% ethyl acetate / hexane. The few polar impurities were eluted with 25-30% ethyl acetate / hexane. The product was eluted with 30-40% ethyl acetate / hexane to produce a pure sample (7.42 g); which, after settling as crystals, was ground with diethyl ether containing some hexane for 24 hours. Filtration afforded the title compound as a crystalline solid (6.88 g), m.p. 148.5-150 ° C; MS (El), m / s: 402 (M) +.

EXAMPLE 72 2-Chloro-4- (2-methyl-1H-pyrazol-3-yl) -benzoyl acid methyl ester The title compound was prepared in the same manner as described in Example 68, employing methyl-2-chloro-4- (3-dimethylamino-2-propenyl-ot) -benzoate (0.8 g) and methylhydrazine (0.319). ml). The major regioisomer of 2-methyl was isolated by column chromatography on silica gel, XH NMR (300 MHZ), (DMS0-d6) d: 3.87 (s, 3H), 3.89 (s, 3H), 6.58 (d, 1H), 7.5 (d, 1H) 7.62-7.93 (m, 3H).

EXAMPLE 73 2-Chloro-4- (2-methyl-lH-pyrazol-3-yl) -benzoic acid The title compound was prepared in the same manner as described in Example 68, using 2-chloro-4- (2-methyl-1H-pyrazol-3-yl) -benzoic acid methyl ester (0.464 g) and hydroxide of sodium 2.5 N (1.04 ml). X NMR (300 MHZ), (DMSO-d6) d: 3.89 (s, 3H), 6.56 (d, 1H), 7.49 (d, 1H), 7.59-7.90 (m, 3H) EXAMPLE 74 [2-Chloro-4- (2-methyl-lH-pyrazol-3-yl) -pheni] - (5H, 11H-pyrrolo [2, 1-c] [lH] benzodiazepin-10-yl) -metanone The title compound was prepared in the same manner as described in Example 71, using 2-chloro-4- (2-methyl-1H-pyrazol-3iL) -benzoic acid (3.98 g) to produce the corresponding acid chloride, acylation with 10,11-dihydro-5H-pyrrolo (2, 1-c) [1,4] benzodiazepine (0.293 g) afforded the title compound as a foam, mp. '• 8-79 ° C; MS (El), m / z: 402 (M) +.

«Jfc llflÉftf« fruit ».fr m & SY i a * ^ * EXAMPLE 75 2-Chloro-4-cyanobenzoic acid methyl ester 2-Chloro-4-aminobenzoic acid methyl ester (13.95 g) was suspended in a mixture of water (65 ml) and concentrated hydrochloric acid (15.7 ml). After stirring at room temperature for 10 minutes, the suspension was cooled to 0 ° C. A solution of sodium nitrite (5.71 g) in water (37 ml) was gradually added over 20 minutes, maintaining the reaction temperature at 0 ° C. After stirring at 0 ° C for 35 minutes, the reaction mixture was partially neutralized by the addition of solid sodium carbonate (3.16 g) to yield a cold solution of diazonium salt. A precooled solution of copper (I) cyanide (8.4 g) and sodium cyanide (9.19 g) in water (112 ml) was gradually added to the above diazonium salt solution over a period of 45-50 minutes. The diazonium salt solution was maintained at 0 ° C during the addition. The resulting mixture was stirred for 18 hours at room temperature. The precipitate was filtered, dried with air, dissolved in ethyl acetate (250 ml), and filtered to remove the insoluble matter. The organic phase was dried over anhydrous magnesium sulfate, and the solvent removed in vacuo to produce a raw product as a brown solid (13.2 g). the crude product was purified by column chromatography on silica gel (250 g), eluted with ethyl acetate / hexane to give the title compound (10.9 g) as a solid, m.p. 90-92 ° C; MS (El), m / z: 195 (M) +.

EXAMPLE 76 2-Chloro-4-cyanobenzoic acid To a solution of 2-chlorocyanobenzoic acid methyl ester (24.3 g) in methanol (150 ml) was added 2.5 N sodium hydroxide (54.5 ml) with stirring. After stirring at room temperature Durnate 45 minutes, the solvent was removed in va cuo. The residue was dissolved in water, cooled in an ice bath, and acidified with 2N hydrochloric acid (14 ml). The resulting precipitate was filtered and dried in vacuo to yield the title compound as a solid (22.55 g) m.p. 154-158 ° C.

EXAMPLE 77 3-Chloro-4- (5H, 11H-pyrrolo [2, 1- [1,4] benzodiazepine-10-carbonyl) benzonitrile To a suspension of 2-chloro-4-cyanobenzoic acid (9.1 g) in a mixture of dichloromethane (40 ml) and dimethylformamide (3.88 ml) was added dropwise a solution of oxalyl chloride (4.6 ml) in dichloromethane (10 ml) at 0 ° C. The reaction was concentrated with warm-room temperature agitation for a period of one hour. A cloudy solution of 2-chloro-4-cyanobenzoyl chloride was used without further purification. To a solution of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,] benzodiazepine (7.32 g) and diisopropylethylamine (13.6 ml) in dichloromethane (35 ml) was added with stirring, under nitrogen, the Turbid solution of 2-chloro-cyanobenzoyl chloride. After one hour at room temperature, the mixture was diluted with dichloromethane and washed sequentially with water, 5% sodium bicarbonate, and 50% saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to yield a crude product (18.0 g). Purification by column chromatography on silica gel (250 g), eluted with 20% ethyl acetate / hexane, followed by 25% ethyl acetate / hexane, afforded the title compound (13.56 g) as a yellow foam. , MS (El), m / z 347 (M) +. .. »- vUtS .AisA? .- EXAMPLE 78 3-Chloro-4- (5H, 11H-Pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -benzoic acid To a suspension of 3-chloro-4- (5H, 11H-pyrrolo- [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -benzonitrile (90.72 g) in ethanol was added 10 N sodium hydroxide ( 1.02 ml) and the mixture heated under reflux for two hours. The solvent was removed in vacuo, the residue dissolved in water, and acidified with 2N hydrochloric acid (4.7 ml). The resulting precipitate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After removing the solvent in vacuo, the foam was triturated with diethyl ether for 18 hours and filtered to give a crude product (0.69 g). the crude product was purified by treatment with activated carbon in ethanol. Crystallization of methanol / ether afforded the title compound as a pure solid (0.29 g), m.p. 198-199 ° C; MS (El), m / z: 366 (M) +.

. ".» * »M üMth? IÉ?; T? I "rt'i í? Ii a a ^^» ** aiáir¿ EXAMPLE 79 3-chloro-4- (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-carbonyl) -benzamide Concentrated sulfuric acid (70 ml) was added to 3-chloro-4- (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -benzonitrile (12.85 g). The mixture was stirred at 60 ° C for 3 hours, followed by stirring at room temperature for 18 hours. The reaction mixture was placed on ice and neutralized at 0 ° C, with 30% ammonium hydroxide (184 ml). The resulting suspension was filtered, and reextracted with ethyl acetate. The aqueous mixture was filtered and reextracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent removed in vacuo. The residue was triturated with a mixture of diethyl ether (50-60 ml) and a small amount of ethyl acetate. Filtration of the precipitate afforded the title compound as a crystalline solid (10.44 g), m.p. 211-212 ° C; MS (El), m / z: 365 (M) +.

EXAMPLE 80 N- (1-Dimethylaminoethylene) -3-chloro-4- (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -benzamide A suspension of 3- chloro-4- (5H, 11H-pyrrolo [2, 1-c] [1, 4] enzodiacep-n-10-carbon? l) -benzamide (5.4i) .afeAj &MÜiafÜ tfrrtütiáj g) and dimethylacetamido dimethyl acetal (10.97 ml) at 90 ° C for 20 minutes. The excess reagent was removed under reduced pressure, and the title compound used without further purification, MS (El), m (z: 434 (M) +.

EXAMPLE 81 [2-Chloro-4- (5-methyl-2H- [1, 2,] triazol-3-yl) phenyl- (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiacep n-10-carbonyl) - methanone To a solution of N- (1-dimethylaminoethylene) -3-chloro-4- (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -benzamide (3.01 g) in Acetic acid (4 ml) was added anhydrous hydrazine solution (0.435 ml) in acetic acid (4 ml). The reaction mixture was stirred at 85-90 ° C for 45 minutes. After removing the acetic acid in vacuo, the reaction mixture was diluted with water (35-40 ml), neutralized to pH 7.0 with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield a crude product. (2.68 g). Purification of the crude product by column chromatography on silica gel (45 g), eluted with 70% ethyl acetate / hexane, yielded a product purified (2.5 g), which, after trituration with diethyl ether, yielded the title compound as a solid (2 g), m.p. 211-212 ° C; MS (El), m / z: 403 (M) +.

EXAMPLE 82 N- (Dimethylaminomethylene) -3-cl-oro-4- (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide The compound of the title was! prepared in the same manner as described in Example 80, employing 3-chloro-4- (5H, llH-pyrrolo [2, 1-c) [1,4] benzodiazepine-10-carbonyl) -benzamide (1.83 g) and dimethylformamide dimethyl acetal (5.3 ml), MS (El), m / z: 420 (M) \ EXAMPLE 83 '[2-Chloro-4- (2H-1, 2,4-triazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10 -il) -metanone The title compound was prepared in the same manner as described in Example 81, employing N- (dimethylaminomethylene) -3-chloro-4- (5H, 11H-pyrrolo [2, 1-c [1,4] benzodiazepine- 10-carbonyl) -benzamide (2.53 g) and hydrazine (0.38 ml), mp 174-177 ° C; MS (El), m / z 389 (M) +. ki ». ,.

EXAMPLE 84 [2-Chloro-4- (2-methyl-2H- [1,2,4] triazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1, 4] ] benzodiazepine-19-carbonyl) -metanone The title compound was prepared in the same manner as described in Example 48, using N- (dimethylaminomethylene) -3-chloro-4- (5H, lHP-pyrrolo [2, lc [1,4] -benzodiazepine-10-carbonyl) -benzamide (0.572 g), and methylhydrazine (0.149 ml). p.f. 141-143 ° C. MS (El): 403 (M) +.

EXAMPLE 85 4- [(2, 5-Dimethyl-2H- [1,24] tri-azole-3-yl) -2-chloro-phenyl) - (5H, IIH-pyrrolo [2, lc] [1, 4 ] ben odiacepin-10-carbonyl) - methanone The title compound was prepared in the same manner as described in Example 48, using N- (1-dimethylaminoethylene) -3-chloro-4- (5H, 11H-pyrrolo [2, 1-c] [1.4 ] - benzodiaceptin-10-carbon? l) -benzamide (0.51 g) and methylhydrazine (0.125 ml). p.f. 197-199 ° C. MS (El): 417 (M) +.

EXAMPLE 86 [2-Chloro-4- (lH-tetrazol-5-yl) -phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone To a solution of 3-chloro-4- (5H, llH-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -benzonitrile (0.348 g) in dimethylphomamide (2 ml) was added sodium azide (0.078 g) and ammonium chloride (0.065 g). The mixture was heated at 100 ° C for 18 hours. The majority of the dimethylformamide was removed in vacuo. The residue dissolved in water (approximately 8 ml) and basified to pH 9.0 with 2.5 N sodium hydroxide (0.6 ml) and reextracted with ethyl acetate. The aqueous extract was acidified with 2N hydrochloric acid (1.1 ml), reextracted with ethyl acetyl, dried over anhydrous sodium sulfate and the solvent removed in vacuo to give a crude product (0.350 g) as an oil. The oily product was triturated with diethyl ether, filtered through acid treated silica gel and eluted with 40% ethyl acetate / hexane to give a pure sample. This was further triturated with diethyl ether, and filtered to give a sample (1.1 0.88 g) m.p. 218-220 ° C. Em (+ BAR) 391 (M + H) +.

EXAMPLE 87 [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl) - (3-dimethylaminomethyl-5H, IIH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10- il) -metanone To a solution of [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (1.61 g), N, N, N ', N', tetramethyldiamine-methane (0.82 g), and glacial acetic acid (0.48 g) in methanol (25 ml) was added with stirring an aqueous formaldehyde solution at 37 ° C. % (4 ml). The mixture was warmed at 40 ° C for 10 minutes. After stirring at room temperature for one hour, the reaction was concentrated in vacuo, redissolved in dichloromethane, and extracted sequentially with aqueous sodium bicarbonate (4x). The organic phase was dried over anhydrous sodium sulfate, and filtered through a plug of silica gel, eluted with ethyl acetate. Evaporation of the solvent in va cuo produced an oil, which upon trituration with hexane yielded 0.36 of the title compound as a colorless powder, m.p. 100-102 ° C, MS (BAR +), m / z: 482 (M + Na) +, 460 (M + H).

EXAMPLE 88 (3-Bromo-5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] -metanone To a pre-cooled solution of [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl) - (5H, IIH-pyrrolo [2, 1-c) [1,4] benzodiazepin-10 -yl) -metanone (1.61 g) in dichloromethane (25 ml) was added with stirring solid N-bromosuccinimide (0.712 g) for 10 minutes at -78 ° C. The reaction was concentrated at a warm temperature at -40 ° C for more than thirty minutes. The mixture was diluted in dichloromethane, and extracted sequentially with saturated aqueous sodium bicarbonate (2 X 100 ml) in water (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered over a plug of silica gel and evaporated in vacuo to give a residue. Crystallization of diethyl ether yielded 1.47 g of the title compound as a colorless solid, m.p. 148-149! C (dec); MS (El), m / z: 480 (M) +.

EXAMPLE 89 (4-Bromo-2-chlorophenyl) - (5H, 11H, -pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone Dimethylformamide (1 drop) was added to a solution of 4-bromo-2-chlorobenzoic acid (2.20 g) in anhydrous tetrahydrofuran (20 ml). Oxalyl chloride (1.46 g) was added and the g ^ ^^^^^ > J ^ J ^ * AMaa ¿'* * í ^ "' t« - '»-" - ^ *, jfa - * - - • • • f -JifTr-r rttií Mix It was heated to reflux. The resulting solution was cooled to room temperature after having evaporated to dryness to give crude 4-bromo-2-chlorobenzoyl chloride as a viscous solid, which was used without further purification. To a mixture of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,] -benzodiazepine (1.44 g) and triethylamine (0.95 g) in dichloromethane (40 ml), cooled in an ice bath, a solution of 4-bromo-2-chlorobenzoyl chloride (2.42 g) in dichloromethane (20 ml) was added dropwise. The cooling bath was removed and after stirring for 22 hours, the reaction mixture was washed sequentially in water saturated aqueous sodium bicarbonate, 0.5N hydrochloric acid and water. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, then evaporated in vacuo to dryness to produce a white foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (2: 1) resulted in a white foam (3.02 g), m.p. 77-80 ° C, MS m / z: 400 (M) +.

Do you know it?; EXAMPLE 90 [2-Bromo-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo- [2, 1-c] (1,4] benzodiazepin-10-yl) -metanone Step a): 4-Fluoro-2-bromobenzoyl chloride was added: Dimethylformamide (2 drops) was added to a solution of 4-fluoro-2-bromobenzoic acid (4.91 g) in anhydrous tetrahydrofuran (55 ml). Oxalyl chloride (3.41 g) was added and the mixture was heated to reflux. The resulting solution was cooled to room temperature, evaporated in vacuo to give a crude acid chloride as a golden viscous liquid, which was used without further purification. Step b) (4-Fluoro-2-bromophenyl) - (5H, 11H-pyrrolo (2, 1-c] [1,) benzodiazepin-10-yl) -methanone: To a solution of 4-fluoro-2-chloride -bromobenzoyl (5.32 g) from step a), in dichloromethane (35 ml), a solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (3.44) was added dropwise. g) and triethylamine (2.27 g) in dichloromethane (80 ml) and cooled in an ice bath. The ice bath was removed and after stirring for 16 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and evaporated to give a purple foam. pale. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) resulted in the intermediate (4-fluoro-2-bromophenyl) - (5H, 11H-pyrrolo [2, 1-c] (1 , 4] benzodiazepin-10-yl) -methanone as a dark foam (6.91 g), MS m / z: 384 (M) + This material was used without further purification in the next step Step c) [2-Bromo4 - (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone: A hydride dispersion was washed of sodium at 60% in oil (0.20 g) with hexane, and then suspended in dimethylformamide (15 ml). 3-Methylpyrazole (0.41 g) was added to this suspension.

When evolution of the hydrogen gas ceased, (4-fluoro-2-bromophenyl) - (5H, 11H-pyrrolo [2, 1-c] -benzodiazepin-10-yl) -methanone (1.74 g) from step b was added. ). The reaction mixture was heated at 130 ° C for 6 hours. After cooling the reaction mixture to room temperature, it was poured into 50% saturated aqueous sodium chloride and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to yield a brown oil. Purification by flash chromatography on silica gel eluting with ethyl acetate (1: 1) gave a colorless solid (0.75 g). Recrystallization of methanol gave a white crystalline solid (0.53 g), m.p. 141-142.5 ° C, MS m / z: 446 (M) +.

EXAMPLE 91 (2, 4-Difluoro-phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone Step a): 2,4-Difluorobenzoyl chloride: A suspension of 2,4-difluorobenzoic acid (3.6 g) containing a few drops of dimethylformamide in dichloromethane (40 ml) was treated by dripping under nitrogen with oxalyl chloride (2.4. ml). After the evolution of gas ceased, the reaction mixture was refluxed for a further 15 minutes. The solution was evaporated to dryness in vacuo and the residue was used without further purification. Step b) (2,4-Difluorophenyl) - (5H, llH-pyrrolo [2, lc] [1,4] benzodiazepin-10-yl) -methanone: To a solution of the crude 2,4-difluorobenzoyl hydrochloric acid of the Step a in dichloromethane under nitrogen was added the solid amine 10, 11-dihydro-5H-pyrrolo [2, lc] [1,4] benzodiazepine (2.0 g) and diisooroDyl ethylamine (3.4 ml). The reaction mixture turned yellow orange. After stirring at room temperature for 10 minutes the reaction mixture was washed in water, 1 N hydrochloric acid, IN sodium hydroxide and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give a solid Brown. The crude product was purified by column chromatography on silica gel (Merck-60) with 20% ethyl acetate-hexane to provide 2.9 g of the title compound as a white foam. MS (El, m / z): 324 (M) +.

EXAMPLE 92 [2-Fluoro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1 H] -benzodiazepin-10-yl-methanone A suspension of hexane washed with 60% sodium hydride (0.31 g) in dry dimethylformamide was treated by dripping with 3-methylpyrazole (0.62 ml) under nitrogen at room temperature. Stirring continued until gas evolution ceased (10 minutes). In a portion of '(2,4-difluorophenyl) - (511, llH-pyrrolo (2, 1-c] [1,4] benzod? Acceptin-10-yl) -methanone (2.5 g) from step b) of the Example 91 was added and stirred continuously until the clear solution was obtained. The mixture was heated in an oil bath preheated to 130 ° C for one hour. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (Merck-60) eluting with hexane-acetate.

. A. 20% ethyl to give 0.82 g of the title product as a foam which was crystallized by sonication of ethanol / hexane, m.p. 192-193 ° C. MS (El) m / z: 386 (M) +.

EXAMPLE 93 Methyl 4- (3-methyl-pyrazol-1-yl) -2-trifluoromethyl-benzoate Step a) Methyl 4-fluoro-2-trifluccsterilh = Petyl Nitrate: A suspension of 4-fluoro-2-trifluoromethylbenzoic acid (25.6 g) and a few drops of dimethylformamide in dichloromethane (250 ml) under nitrogen were treated by dropping. oxalyl chloride (11.3 ml). After the gas evolution ceased, the reaction mixture was refluxed for an additional 15 minutes. The reaction was cooled and methanol (50 ml) was added. After stirring for 2 hours, the reaction was concentrated in vacuo, and the residue partitioned between dichloromethane and water. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness to give 18.0 g of the title compound as a golden oil. EM; (El) m / z: 222 (M) +. The aqueous layer was acidified with 2N hydrochloric acid to give a colorless solid which was ^^ gggg ^ gfA ^ g ^^ collected by filtration to give 7.5 g of the initial benzoic acid. Step b) Methyl 4- (3-methyl-pyrazol-1-yl) -2-? trifluoromethyl-benzoate: A hexane hexane washed with 60% sodium hydride (3.85 g) in dimethylformamide (150 ml) was treated by further dropping a solution of 3-methylpyrazole (7.75 ml) in dimethylformamide (50 ml) under nitrogen at room temperature. The agitation continued until gas evolution ceased (10 minutes). The solution was added dropwise to a solution of methyl 4-fluoro-2-trifluoromethylbenzoate (17.8 g) from step a) in dimethylformamide (50 ml). After stirring for 30 minutes at room temperature the reaction was fixed with saturated ammonium chloride and extracted with ethyl acetate. The organic extracts (3x) were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (Merck 60) with a dichloromethane-hexane gradient (50% -75%) to give 13.6 of the title product as a colorless solid. P.f. 59-61 ° C EM (The, m / z): 284 (M) +. and ^ '^ ^^ EXAMPLE 94 4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethylbenzoic acid Methyl 4- (3-methyl-pyrazol-1-yl) -2-trifluoromethyl-benzoate (1.19 g) from Example 93, step b) was dissolved in methanol (10 ml) and a 2.5 sodium hydroxide solution was added. N (3.3 ml). The reaction was heated to reflux for 90 minutes, cooled to room temperature and concentrated in vacuo to dryness. The residue was partitioned between ethyl acetate and IN hydrochloric acid. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.14 g of the title compound as a colorless solid. MS (BAR) m / z: 271 (M + H) +.

EXAMPLE 95 [4- (3-Methylpyrazol-1-yl) -2-trifluoromethylphenyl] - (5H, HH-pyrazole [5, 1-c] - [1,4] benzodiazepin-10-yl) -methanone A solution of 4- (3-methyl-pyrazol-1-yl) -2-trifluoromethylbenzoic acid (0.26 g) of Example 94 in tetrahydrofuran (5 ml) was treated with dimethylformamide (0.020 ml) followed by oxalyl chloride (0.090 ml). . the solution was stirred at room temperature until it stopped the evolution of the gas and then the solution was warmed to reflux for 10 minutes. The sample was cooled to room temperature, concentrated to a solid and the solid was dissolved in tetrahydrofuran (25 mL). This solution was added to the solution (5H-10, 11-dihydropyrazole [5, 1-c) [1,] benzodiazepine (0.143 g) and triethylamine (0.150 ml) in tetrahydrofuran (20 ml). The solution was stirred at room temperature overnight. A precipitate formed. The sample was diluted with dichloromethane to dissolve the precipitate and then the sample was concentrated in vacuo at about 1/3 of the original volume. The sample was divided between dichloromethane and saturated aqueous ammonium chloride. The sample was extracted with dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in an oil. The oil was subjected to flash chromatography on silica gel using a gradient of ethyl acetate / hexanes at 40% to 100% ethyl acetate yielding the title compound as a foam (0.30 g). A portion of this material was recrystallized from acetone / hexanes to give heavy plates m.p. 100-102 ° C, MS m / z: 437 (M) +.

EXAMPLE 96 2-Chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid methyl ester and 2-chloro-4- (5-methyl-1H-pyrazol-1-yl) methyl ester ) -benzoic A washed suspension of hexane and potassium hydride (0.424 g) in dimethylformamide (5 ml) was treated in a 3-methyl pyrazole portion (0.85 ml), with stirring. After gas evolution ceased, the methyl ester of 2-chloro-4-fluorobenzoic acid (2.0 g, 10.6) was added to the clear solution and heated at 130 ° C for 15 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo yielded 2.2 g of a yellow oil. (Note: hydrolysis of the 20% ester was detected by analysis of the NMR spectrum of the crude product). The desired regioisomer of 2-chloro- (3-methyl-1H-pyrazol-1-yl) -benzoic acid methyl ester was isolated from the other isomer (described below) by flash column chromatography on silica gel (Merck 60) eluted with dichloromethane-hexane 2: 1) to give 1.55 g of the title compound as a colorless solid. MS (m / z: 250/252 (M) +.

The 5-regioisomer, namely 2-chloro-4- (5-methyl-1H-pyrazol-1-yl) -benzoic acid methyl ester was isolated from the previous flash column chromatography on silica gel (Merck 60) by further elution with dichloromethane-hexane 2: 1 to give 0.20 g of the product as a colorless solid. MS (El), m / z: 250/252 (M) +.

EXAMPLE 97 2-Chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid A solution of methyl ester of 2-chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid (1.42 g) from Example 96 and 6 ml of aqueous lithium hydroxide ÍM in tetrahydrofuran (20) was stirred. ml) for 18 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo yielded 1.05 g of the title compound as a colorless solid, m.p. 192-193 ° C. MS (El), m / z: 236/238 (M) +.

EXAMPLE 98 (2,6-Dichlorompyridin-3-yl) (5H, HH-Pyrrolo [2, 1- c] [1,4] benzodiazepin-10-yl) -metanone A solution of 2,6-dichloronicotinic acid (3.84 g), oxalyl chloride (2.0 g), and 1 drop of dimethylformamide in dichloromethane (25 ml) was stirred at room temperature for 18 hours. The solution was concentrated in vacuo to give 3.50 g of 2,6-dichloronicotinyl chloride which was added dropwise in dichloromethane (25 ml) to an ice-cold solution of 10,1-dihydro-5H-pyrrolo [2.1]. -c) [1,4] -benzodiazepine (2.15 g) and dilsopropylethylamylamine (2.03 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The combined organic phase was concentrated on a hot plate with gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield 2.65 g of the title as an amorphous solid. P.f. 115-130 ° C. MS m / z: 358.1 (M + H) +.

EXAMPLE 99 (2-Chloro-6-pyrazol-1-yl-pyridin-3-yl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added pyrazole drop (0.15 g). After gas evolution ceased, (2,6-dichloropyridin-3-yl) (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (0.67) was added. g) and the reaction mixture was heated in a sand bath at 110 ° C for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column and anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to give 0.18 g of the title compound as a colorless solid, m.p. 133-135 ° C. MS m / z 390.8 (M + H) +, 779.1 (2M + H) +.

EXAMPLE 100 [2-Chloro-6- (3-methylpyrazol-1-yl) -pyridin-3-yl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added by ,! í, Ath & -i 3-methylpyrazole drip (0.15 g). After gas evolution ceased, (2,6-dichloropyridin-3-yl) (5H, 1 lH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl was added. ) -metanone (0.67 g) and the reaction mixture was heated in a sand bath at 110 ° C for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column and anhydrous sodium magnesium silicate. The crude product was purified by preparative CLAP (Dynamax c60 silica cartridge) eluting with 40% ethyl acetate in hexane to give 0.21 g of colorless crystals, m.p. 171-172 ° C, MS, m / z: 404.2 (m + H) \ 807.1 (2M + H) +.

EXAMPLE 101 [2-Chloro-6- (4-methylpyrazol-1-yl) -pyridin-3-yl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added dropwise 3-methylpyrazole (0.45 g). After the - ~ ^ r r? 'É-k¿¡ *' k? ¿«, ...«? gas evolution, (2,6-dichloropyridin-3-yl) (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (1.79 g) was added and the mixture Reaction was heated in a sand bath at 110 ° C for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column and anhydrous sodium magnesium silicate. The crude product was purified by preparative CLAP (Dynamax c60 silica cartridge) eluting with 40% ethyl acetate in hexane to give 0.26 g of colorless crystals, m.p. 155-156 ° C, MS, m / z: 404.2 (m + H) +, 807.1 (2M + H) +.

EXAMPLE 102 [2-Chloro-4- (3-methyl-1,2,4-triazol-1-yl) -phenyl] - (511, HH-pyrrolo [2, 1-c] - [1, 4 ] benzodiazepin-10-yl) -metanone To a suspension of 60% sodium hydride in oil (0.3 g) in dimethylformamide (25 ml) was added pyrazole dropwise (0.45 g). After gas evolution ceased, 2-chloro-4-fluorophenyl- (5H, 11H-pyrrolo [2, 1-c] [1,4] benzocyccynin-10-yl) -methanone (1.70 g) was added and the reaction mixture was heated in a bath of sand at 110 ° C for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to give 1.25 g of the title compound as colorless solids, m.p. 191-193 ° C. MS m / z: 404.1 (M + H) +.

EXAMPLE 103 [4- (3-Methyl-1,2,4-triazol-lyl) -2-trifluoromethyl-phenyl] (5H, 11H-pyrrolo [2, lc] [1,4] benzodiazepin-10-yl) - methanone To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added pyrazole dropwise (0.45 g). After gas evolution ceased, 4-fluoro-2-trifluoromethyl-phenyl- (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone (1.76 g) was added. ) and the reaction mixture was heated in a sand bath at 110 ° C for 18 hours. The mixture was poured onto ice, diluted with brine and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of sodium and magnesium anhydrous silicate. The solution was concentrated in vacuo and the residue triturated with diethyl ether to give 0.81 g of the title compound as colorless solids, m.p. 148-150 ° C. MS m / z: 438.2 (M + H) +, 875.8 (2M + H) +.

EXAMPLE 104 4-Hydrazino-2-methoxybenzoic acid, methyl ester, hydrochloride (1: 1), hydrate (2: 1) A stirred suspension of 4-amino-2-methoxybenzoic acid, methyl ester (21.74 g) in concentrated hydrochloric acid (110 ml), which was cooled to -10 ° C, was treated with a pre-cooled sodium nitrite solution (8.5 g) in water (45 ml) at a rate required to maintain a reaction temperature less than 0 ° C. After the addition was complete, the reaction mixture was stirred at -2 ° C for 10 minutes. The turbid orange solution was added dropwise to a pre-cooled, vigorously stirred solution of tin (II) chloride dihydrate (101 g) in concentrated hydrochloric acid (67 ml) at -10 ° C. The rate of addition was controlled to maintain the reaction temperature at less than 5 ° C. After the addition was completed, the cream colored suspension was warmed to room temperature and a solid was filtered. The solid was -e.?Ííát tÁ? washed with diethyl ether and dried over anhydrous sodium sulfate to yield 52 g of crude product. The crude product (20 g) was divided between 2.5 N aqueous sodium hydroxide and dichloromethane. The organic phase was filtered through diatomaceous earth, washed with brine and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent in vacuo yielded a cream colored solid (7.1 g), which after treatment with one equivalent of anhydrous hydrogen chloride solution in diethyl ether afforded the title compound as a monohydrochloride salt, m.p. 76-79 ° C, MS, m / z: 197 (M + H) +.

EXAMPLE 105 2-Methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid, methyl ester To a solution of 4-hydrazino-2-methoxybenzoic acid, hydrochloric methyl ester (0.88 g) of Example 104, and a drop of hydrochloric acid in a 1: 1 water / methanol mixture (10 ml) was added with acetylacetaldehyde dimethylacetal stirring ( 0.53 g). The reaction was heated at 90 ° C for 5 minutes. The reaction was concentrated in vacuo and partitioned between IN sodium hydroxide (lOml) and ethyl acetate (50 ml). The organic phase was fcAsLJ -fc, stirred and washed with brine, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent in vacuo yielded a brown oil which was combined with a previous batch (0.54 g) and recrystallized three times from diisopropyl ether to give 2-methox-4- (3-methyl-p-razol-l) acid. - il) -benzoic acid, methyl ester (0.5 g). p.f. 167-169 ° C, MS, m / z: 246 (M) +.

EXAMPLE 106 2-Methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid A solution of 2-methoxy-4- (3-methyl-p-razol-1-yl) -benzoic acid methyl ester was treated. (0.5 g) of Example 105 in tetrahydrofuran (2.5 ml) with 1 N lithium hydroxide (2.13 ml) at room temperature. After 14 hours the solvent was removed in vacuo and the title compound precipitated by the addition of IN hydrochloric acid at 0 ° C. After drying under vacuum 0.42 g, the title compound was obtained as an MS solid, m / z: 232 (M) +.

EXAMPLE 107 [2-Methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl] (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzod? -en-10-yl) methanone Oxalyl chloride (0.17 ml) was added with stirring to a solution of 2-methoxy4- (3-methyl-pyrazol-1-yl) - benzoic acid (0.41 g) of Example 106 and dimethylformamide (0.004 ml) in anhydrous tetrahydrofuran (10 ml). The reaction was heated at 35 ° C for ten minutes. The resulting solution was evaporated in vacuo to yield the carbonyl chloride of crude 2-methoxy-4- (3-methyl-pyrazol-1-yl) -benzoic acid. After coevaporation with dichloromethane, the acid chloride dissolved in dichloromethane (10 ml) and 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (0.31 g) was added. Diisopropylethylamine (0.37 ml) was added and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water followed by IN hydrochloric acid. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness in vacuo. The solid residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (2/1) to give 0.35 g of the title compound as a colorless solid, m.p. 92-94 ° C.

EXAMPLE 108 (3-Dimethylaminomethyl-5H, llH-pyrrolo [2, lc] [1,4] -benzodiazepin-10-yl) [2-methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl] -methanone To a solution of [2-methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl) (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepine- 10- il) methanone from Example 107 (0.57 g) in warm methanol (10 ml) was added with stirring N,, N, N '-tetramethyldiaminomethane (0.392 ml) and acetic acid (0.164 ml). Followed by the addition of 37% aqueous formalin solution (2.9 ml) the reaction was stirred for fifteen minutes. The mixture was concentrated in vacuo and divided between dichloromethane and sodium acid carbonate. The organic phase was removed, washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed in va cuo. The residue was purified by flash column chromatography on silica eluting with chloroform / methanol (50/1) to yield a solid. Recrystallization of the acetone solid gave the title compound as a colorless solid, m.p. 196-198 ° C.

EXAMPLE 109 [2-Hydroxy-4- (3-methyl-? Irazol-1-yl] (5H, HH-pyrrolo- [2, 1-c] [1,4] -benzodiazepin-10-yl) -metanone (2-Methoxy-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) methanone ( 0.82 g) of Example 107 was dissolved in dichloromethane (20 ml) and cooled to -78 ° C. Boron tribromide (6.2 ml) was added and the reaction was stirred at 0 ° C. for five minutes Ammonium hydroxide (15 ml) was added. ) and extracted with ..? k.kkí ^ - ^ ikllL ?, dichloromethane. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solid was removed by filtration and the solvent removed in va cuo. The residue was purified by flash column chromatography of silica eluting with hexane / ethyl acetate (3/1 to 2/1) to yield 0.19 g of the title compound as a colorless solid, m.p. 134-136 ° C.

EXAMPLE 110 2-Chloro-4-iodo-benzoic acid methyl ester 4-Amino-2-methoxy-benzoic acid methyl ester (22.97 g) was cooled to an internal temperature of -10 ° C in concentrated hydrochloric acid (110 ml) and stirred as a suspension. A pre-cooled solution of sodium nitrite (98.71 g) in water (45 ml) was added to this mixture, at such a rate to maintain the reaction temperature of less than 0 ° C. After stirring the reaction for 25 minutes at 0 ° C it was treated with a solution of potassium iodide (24.44 g) and iodine (18.37 g) in water (50 ml) at a rate such that the reaction temperature was maintained at -4 ° C. Ethyl acetate (100 ml) was added during the addition and the dark mixture was stirred at 0 ° C for one hour. The organic layer was diluted with ethyl acetate and washed well with saturated sodium thiosulfate solution. The The resulting orange solution was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to yield an oil which was purified by suction filtration through silica gel eluting with hexane / ethyl acetate (50/1). The resulting purified oil was solidified on cooling to give 33.71 g of the title compound. MS, m / z: 296 (M) +.

EXAMPLE 111 4-Bromo-l-methyl-1H-pyrazole To a pre-washed solution of (tetrahydrofuran) 60% sodium hydride in oil (11.67 g) in tetrahydrofuran (200 ml) was added dropwise a solution of 4-bromopyrazole (39.77 g) in tetrahydrofuran (50 ml). The solution was stirred at room temperature for two hours. The excess iodomethane 33 ml) in tetrahydrofuran (50 ml) was added at such a rate to maintain the increase in temperature. The reaction was stirred for two more hours. The solvent was removed in vacuo and the residue stirred in diethyl ether. A precipitate was removed by filtration by suction and washing with diethyl ether. The combined organic phase was evaporated in vacuo to give 42.22 g of the title compound as an oil. MS, m / z 160 (M) +.

EXAMPLE 112 1-Methyl-4-tributylstannyl-1H-pyrazole To a pre-cooled solution (<-10 ° C internal temperature) of 1.6 M n-butyl lithium in hexane (100 ml) in anhydrous diethyl ether (100 ml) under argon was added a solution of 4-bromo-1-methyl- IH-pyrazole (23.42 g) of Example 111 in diethyl ether (50 ml) at such a rate to maintain the temperature. The reaction was concentrated with stirring for a further 20 minutes before adding tributyltin chloride (43.4 ml) in diethyl ether (50 ml). The reaction temperature was maintained at 20 ° C. The reaction was diluted with diethyl ether and the insoluble material was removed by suction filtration The evaporation of the in va solvent gave 56 g of the title compound as an oil MS: m / z: 373 [M + H] + The residual amounts of tin residues were removed from the oil by distillation using a kugeirohr apparatus under high vacuum at 170 ° C.

EXAMPLE 113 2-Chloro-4- (l-methyl-lH-pyrazol-4-yl) -benzoic acid, methyl ester A solution of degassed dimethylformamide of argon (70 ml) 2-chloro-4-iodo-benzoic acid methyl ester (25.4 g) pyrazole of Example 110, l-methyl-4-tributyltin-1H- (31.77 g), tetracis ( triphenylphosphine) palladium (0) (1.8 g) and catalytic copper iodide (1) was heated at 80 ° C for 7 hours. The solvent was removed in vacuo and the residue absorbed on silica gel. Purification by suction filtration through a pad of silica gel eluting sequentially with hexane and followed by hexane / ethyl acetate (2/1) produced, after evaporation of the solvent, a solid residue which was recrystallized from diisopropyl. ether to give 7.82 g of the title compound MS, m / z 250 (M) +.

EXAMPLE 114 2-Chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid To a solution of 2-chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid, methyl ester (6.25) of Example 113 in methanol (80 ml) was added IN sodium hydroxide (30 ml) . It was The volume of the solvent was reduced in vacuo to three quarts and the residue was treated with 2N hydrochloric acid at 0 ° C. A precipitate was filtered and dried in vacuo to yield 5.84 g of the title compound. MS m / z: 237 [M + H] +.

EXAMPLE 115 [2-Chloro-4- (l-methyl-lH, pyrazol-4-yl) phenyl) (5 H, 11 H -pyrrolo [2, 1-c] [1,4) -benzodiazepin-10-yl) - methanone Oxalyl chloride (0.49 ml) was added to a solution of 2-chloro-4- (1-methyl-) 1H-pyrazol-4-yl) -benzoic acid (0.41 g) of Example 114 and dimethylformamide (0.012 ml) in anhydrous tetrahydrofuran (20 ml). The reaction was heated at 35 ° C for ten minutes. The resulting solution was evaporated in vacuo to dryness to yield the carbonyl chloride of crude 2-chloro-4- (1-methyl-1H-pyrazol-4-yl) -benzoic acid. After coevaporation with anhydrous methylene chloride, the acid chloride was dissolved in dichloromethane (20 ml) followed by the addition of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] -benzodiazepine (0.888 g) and dipropylethylamine (1.06 ml). The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water followed by IN hydrochloric acid. The organic phase was washed with ", .l, .sa & amp;," h__A ____; _ »,,. - i ?? k» lrÍUA4 brine and dried over anhydrous magnesium sulfate. The dichloromethane was filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography on silica under pressure eluting with hexane / ethyl acetate (2/1) to yield 1.4 g of the title compound as a colorless solid m.p. 105-109 ° C.

EXAMPLE 116 (2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (4H, 10H-pyrazo [5,1-c] [1,4] -benzodiazepin-5-yl) - methanone To a solution of 2-chloro-4- (3-methyl-pyrazol-1-yl) -benzoyl chloride (0.214 g) from Example 18 Step e in dichloromethane (10 ml) was added 5H-10,11-dihydropyrazolo [ 5, 1-c] [1, 4) benzodiazepine (0.153 g) and diisopropylethylamine (0.173 ml). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water followed by IN hydrochloric acid. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The dichloromethane solution was filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography on silica pressure eluting with hexane / ethylene acetate (1/1) to yield 0.3 g of the title compound as a colorless solid, m.p. 187-188 ° C.

^ ¿¿¿? Fi ^? ^^; * » EXAMPLE 117 2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5, 10-di-hydro-4H-tetrazolo [5, 1-c] [1,4] benzodiazepine -5-il) -metanone To a solution of 2-chloro4- (3-methyl-pyrazol-1-yl) -benzoyl chloride (0.18 g) from Example 18 Step 2 in dichloromethane (10 ml) was added 10,11-dihydro-5H-tetrazole [5]. , 1- [1,) benzodiazepine (0.13 g) and diisopropylethylamine (0.145 ml). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water followed by IN hydrochloric acid. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The dichloromethane solution was filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography on silica under pressure eluting with hexane / ethylene acetate (1/1) to yield 0.14 g of the title compound as a colorless solid, e.g. f. 110- 114 ° C. Í? ' i rir? riiB ill ^^ '8 EXAMPLE 118 1- [4- (4H, lOH-pyrazole [5, 1-c] [1,4] benzodiazepine-5-carbonyl) phenyl] -ethanone A mixture of 5, 10-dihydro-4H-pyrazolo [5, 1-c] [1,4] benzodiazepine (0.555 g), 4-acetylbenzoyl chloride (0.657 g) and N, N-dilsopropyleethylamine (0.464 g) 'in dichloromethane (15 ml) was stirred at room temperature for 4 hours. The mixture was poured into water and extracted with dichloromethane. The dichloromethane extract was washed with saturated sodium hydrogen carbonate, water, and brine and dried over anhydrous sodium sulfate. The extract was filtered through a thin pad of anhydrous sodium silicate and the filter. in the form of pad washed with dichloromethane. The filtrate was concentrated in vacuo to give 1.53 g of yellow solid. Trituration of the solid with ethyl acetate gave 0.747 g of the solid compound as a glass, m.p. 201-210 ° C. The mother liquors from the trituration were evaporated and the residue (0.30 g) was subjected to chromatography on thin-film silica gel plates (200 microns) using hexane-ethyl acetate (1: 1) as solvent. The solid was triturated with ethyl acetate and combined with 0.747 g of initial isolated product. The combined solids were precipitated from the dichloromethane-hexane mixture to give 0.73 g of the product as a glass.

EXAMPLE 119 1- [4- (4H, 10H-pyrazolo [5, 1-c] [1,4] benzodiazepine-5-carbonyl) Phenyl] -3- (dimethylamino) -prop-2-en-1-one A mixture of 1- [4- (4H, lOH-pyrazolo [5, 1-c] was stirred. [1,) benzodiazepine-5-carbonyl) phenyl] ethanone (0.73 g), tert-butoxybis- [dimethylamino) methane (0.964 g) in dichloromethane (10 ml) at room temperature for 2 days. The mixture was concentrated in vacuo and the residue was recrystallized from dichloromethane-hexane to give 0.65 g of the title compound as yellow crystals, m.p. 225-230 ° C.

EXAMPLE 120 [4- (l-Methyl-lH-pyrazol-3-yl) phenyl] (4H, 10H-pyrazolo [5, lc] [1,4] benzodiazepin-5-yl methanone (Isomer A) and [4- (2-Methyl-lH-pyrazol-3-yl) phenyl] (4H, lOH-pyrazole [5, le] [1,4] -benzodiazepin-5-yl) methanone (Isomer B) A mixture of 1- [4- (4H, lOH-pyrazole [5, 1-c] [1,] benzodiazepine-5-carbonyl) phenyl] -3- (dimethylamino) -prop-2-en-l-one ( 0.83 g), hydracma (0.198 g) and acetic acid i - .- .j, .- r »a: a, au« jl * ÍaÍMfcHfi - »t, > • ______, _________tn. Ikkk tui? -. «i ** ¿& fe-i. aAtfc. "... < kkk? jM Jk.?á (0.336 g) in 10 ml of ethanol was refluxed for 4 hours. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. The solution was washed in water, sodium hydrogen carbonate, water and brine and dried over anhydrous sodium sulfate. The solution was filtered through a thin pad of anhydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated in vacuo to give 0.56 g of light yellow solid. The solid was subjected to chromatography on a thin layer of silica gel plates (200 microns) with ethyl acetate as solvent to give 0.35 g of white solid as a mixture of A and B (1: 4). Multiple fractional crystallizations of ethyl acetate gave 89 mg of crystals, m.p. 155-156 ° C as a mixture of A and B (9: 1) and 65 mg of a glass as a mixture of A and B (1: 6).

EXAMPLE 121 l- [4- (5H, HH-pyrrolo [2, l-c] [1,4] benzodiazepine-10-carbonyl) -3-chlorophenyl] -ethanone Step a) Triethylamine (8.80 ml) was added to a solution of (4-bromo-2-chlorophenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone (2.37 g) in pyridine (1.80 ml), in a 20 ml Carrius tube. The resulting solution was purged with nitrogen for 25 minutes, then (trimethylsilyl) acetylene (1.67 ml), bis (triphenylphosph) palladium (II) chloride (0.08 g) and copper iodide (I) (0.01 g) were added. The tube was filled with triethylamine purged with nitrogen, sealed and heated in an oil bath at 90 ° C for 80 hours. The solution was cooled to room temperature, the solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The dichloromethane extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a brown foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) resulted in the intermediate acetylene as a white foam (2.11 g), MS m / z: 418 (M) +. This material was used without further purification in the next step. Step b) A solution of 1% sulfuric acid in tetrahydrofuran was saturated with mercury (II) sulfate. The intermediate acetylene (1.00 g) in tetrahydrofuran (5 ml) was stirred for 50 hours with 30 ml of the mercury (II) sulfate-tetrahydrofuran solution mentioned above. An additional amount of mercury (II) sulfate (0.01 g) and 0.3 ml water was added. After stirring for 120 hours, the reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane solution was washed sequentially with saturated aqueous sodium bicarbonate and water. The dichloromethane solution was dried •• ^ ---- ^^ f ^ f ^ yi »- * ' on anhydrous magnesium sulfate, evaporated to dryness to give a brown solid. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) gave a white solid (0.30 g), proliferation 98-100 ° C, MS m / z 364 (M) +.

EXAMPLE 122 l- [4- (5H, 11IH-pyrrolo [2, l-c] [1,4] benzodiazepine-10-carbonyl) -3-chlorophenyl] -ethanone Tributyl (ethoxyvinyl) tin (1.17 g) was added to a solution of (4-bromo-2-chlorophenyl) - (5H, llH-pyrrolo [2, 1-c] [1-4] benzodiazepin-10-yl) ) -metanone (1.24 g) in toluene (10 ml). The resulting solution was purged with nitrogen for 10 minutes, then bis (triphenylphosphine) palladium (II) chloride (0.11 g) was added. The reaction mixture was heated to reflux for 24 hours. The solution was cooled to room temperature and 5% aqueous hydrochloric acid was added. After stirring for one hour, the mixture was filtered through a diatomaceous earth pad. Diethyl ether (5 ml) was added to the filtrate, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to produce a glass Brown. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) resulted in a white solid (0.30 g), MS, m / z: 364 (M) +.

EXAMPLE 123 [2-Chloro-4- (3-methyl-4-ethynyl-phenyl) (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone Treatment of the intermediate acetylene of Example 121 step A with tetrabutylammonium fluoride solution IN in tetrahydrofuran at a temperature provided with removal of the solvent and afforded 84% of the title compound as a yellow-orange solid, m.p. 84-86 ° C, MS m / z: 346 (M) + Process for Preparing Pharmaceutical Formulations This invention also includes methods for producing the formulations described herein. A process of this invention comprises the steps of: a) combining, preferably with mixing or stirring, the PEG and surfactant components to create a first carrier mixture; tkatoné.M.?. r? -rrrr-.t. ^ r b) raising the temperature of the first carrier mixture to a range of about 75 ° C to about 95 ° C, preferably about 80 ° C to about 90 ° C; c) adding the active ingredient to create a first mixture of pharmaceutical composition; d) shaking the first pharmaceutical composition mixture, preferably with heating, until the first pharmaceutical composition mixture is transparent, preferably at a temperature of about 115 ° C to about 170 ° C, preferably at a temperature from about 130 ° C to about 150 ° C, more preferably at a temperature from about 135 ° C to about 145 ° C; e) cooling the first pharmaceutical composition, if necessary, at a temperature from about 75 ° C to about 95 ° C, preferably from about 80 ° C to about 90 ° C; g) adding the amount of sucrose fatty acid ester and / or povidone to create a final pharmaceutical composition mixture, preferably with stirring until the final pharmaceutical composition mixture is clear or transparent.

In cases where optional antioxidants or preservatives are used, such as BHA, NHT, etc., the following steps may be employed: a) combining, preferably with mixing or stirring, the PEG component (such as a mixture of Peg) 400 and PEG 1000) and a surfactant component (such as Polysorbate 80) to create a first carrier mixture; b) raising the temperature of the first carrier mixture to a range of about 75 ° C to about 95 ° C, preferably about 80 ° C to about 90 ° C; c) adding to the first carrier mixture optional antioxidant or preservative components to create a second carrier mixture, which is then stirred or otherwise mixed until the second carrier mixture is a clear or transparent solution; d) adding the active ingredient to create a first mixture of pharmaceutical composition; e) stirring the first pharmaceutical composition mixture, preferably with heating, until the first pharmaceutical composition mixture is clear or transparent, preferably at a temperature of about 130 ° C to about 150 ° C, preferably at a temperature of about 135 ° C to about 145 ° C; e) optionally cooling the first pharmaceutical composition, at a temperature of from about 75 ° C to about 95 ° C, preferably from about 80 ° C to about 90 ° C; g) adding the amount of fatty acid esters of sucrose and / or povidone to create a final pharmaceutical composition mixture, preferably with stirring until the final pharmaceutical composition mixture is clear or transparent. One skilled in the art will understand that the viscosity and shape of the final formulation can be manipulated with component within the scope of this invention and temperature ranges during processing. For example, a fluid-or semi-solid composition with the most fluid PEG, surfactant and PVP species can be produced within the scope of this invention. Viscous or semi-solid compositions more gene-like can be produced with combinations of higher molecular weight PEG components and PVP components having higher K values. In addition, the components can be cooled below their melting point if they are moved or processed differently to the desired final composition. To create a more granular initial composition, a composition of this invention can be sprayed onto a surface coated with Teflon® to form small ? iM n ^ rk ^^^^^^^^ tí ^ kr ^ rr. solid spheres, which can be individually coated or reconnected for further processing. Specific non-limiting examples of the formulations within the scope of this invention are provided below.

Example 1 50 mg / capsule: Oral formulation at a 10% loading of Drug Instead of the polysorbate 80 in this formulation of Example 1, another series of polysorbates such as Tween 20, 40 and 60 may also be used, alone or in combination with each other and / polysorbate 80. (% in Per capsule (mg) Lot of weight / weight) 20,000 capsules (g) Active ingredient 10.42 50.00 1000.00 Inactive ingredients PEG 1000, NF 30.96 148.61 2,972.16 Povidona USP K-17 10.00 48.00 960.00 Polisorbato 80, NF 10.00 48.00 960.00 BHT, NF 0.09 0.42 8.32 afc-- fefe faith (% in Per capsule (mg) Lot of weight / weight) 20,000 capsules (g) BHA, NF 0.87 4.16 83.2 PEG 400, NF2 Q.S. to 100 Q.S. to 480.00 Q.S. to 9,600 1. Weight of Polysorbate 80, PEG 400, and PEG 1000 in a suitable mixing vessel, stir using a mixer mounted on top, and heat to 85 ° C. 2. Add BHT and BHA to the mixing vessel, very slowly to prevent the formation of lumps. Continue stirring at 85 + 5 ° C, until a clear or transparent solution forms. 3. Add the active ingredient to the container at 85 + 5 ° C, very slowly to prevent the formation of lumps, slowly raise the temperature to 125 + 5 ° C, and shake until the active ingredient dissolves completely. the solution in Step 4 at 60 + 5 ° C. 5. Add povidone, USP, K-17 (Plasdone C-15, ISP) slowly to step 5, to prevent the formation of lumps. 85 + 5 ° C. Stir until the solution becomes clear 6. Encapsulate 480 mg of finished solution (in step 10) in capsules of size 1 to 38 + 5 ° C using the encapsulating machine of Hoflmger and Karg (H &K) 800L. During the encapsulation, cool the body of the capsule by cooling liquid nitrogen, which was passed through dry ice. 7. Seal the capsules with a gelatin solution with a band.

Example 2 50 mg / capsule: Oral Formulation at a Drug Charge of 10% In place of the surfactant used in this formulation (poloxamer 188), other polymers in the series such as Pluronic L44, Pluronic LlOl may also be used. (% in Per capsule (mg) Lot of weight / weight) 20,000 capsules (g) Active ingredient 10.42 50.00 1000.00 Inactive ingredients Povidone USP K-17 10.00 48.00 960.00 (Plasdone C-15, ISP) Poloxamer 188, NF 12.00 57.60 1152.00 BHT, NF 0.09 0.42 8.32 BHA, NF 0.87 4.16 83.20 PEG 400, NF-1 Q.S. to 100 Q.S. to 480.00 Q.S. to 9600 g This formulation is manufactured in the same manner as the formula of Example 1 (50 mg / capsule) with the exception that 12% poloxamer was used in place of the polysorbate 80 of this formulation. The weight of encapsulation is 480 mg.

Example 3 50 mg / capsule Example 3 provides a formulation with a combination of two or more surfactants. (% in Per capsule (mg) Lot of weight / weight) 20,000 capsules (g) Active ingredient 10. 64 51. 07 1, 021 44 Inactive ingredients PEG 1000, NF 28.60 137.28 2,725.60 Povidona USP K-17 10.00 48.00 960.00 (Plasdona C-15, ISP) Polysorbate 40, NF 5.00 24.00 480.00 Poloxamer 188, NF 10.00 48.00 BHT, NF 0.09 0.43 8.64 BHA, NF 0.87 4.18 83.52 PEG 400, NF Q.S. to 100 Q.S. to 480. .00 Q.S. to 9, 600. 00 L-rí- ík -? , kr? MSkk. -irfillWfite Ú¡k ~ kr- ?? The formulation of Example 3 was manufactured in the same manner as that of Example 1 (50 mg / capsule) with the exception that two surfactants, polysorbate 40 and poloxamer 188 were added in step 1 together with PEG 400 and PEG 1000. The weight of encapsulation is 480 mg.

Example 4 25 mg / capsule: Oral Formulation at a Drug Load of 5% (% in Per capsule (mg) Lot of weight / weight) 20,000 capsules (g) Active ingredient 5.49 25.00 500.00 Inactive ingredients. PEG 1000, NF 32.66 148.61 2,972.16 Povidona USP K-17 10.55 48.00 960.00 (Plasdona C-15, ISP) Polysorbate 80, NF 10.55 48.00 960.00 BHT, NF 0.09 0.42 8.32 BHA, NF 0.91 4.16 83.2 PEG 400, NF2 Q., S. to 100 Q., S. to 455. .00 Q., S. at 9,100 g The formulation of Example 4 was produced in the same manner as that of 50 mg / capsule, above, with the exception that the solubilization temperature to solubilize the active ingredient in step 3 is 115 + 5 ° C, instead of 120 + 5 ° C. The weight of encapsulation is 455 mg.

Example 5 100 mg / capsule: Oral Formulation at a 15% Drug Load (% in Per capsule (mg) Lot of weight / weight) 20,000 capsules (g) Active ingredient 15.38 100.00 2,000.00 Ingredients inactive PEG 1000, NF 28.98 188.35 3,767.05 Povidone USP K-17 10.00 65.00 1,300.00 (Plasdone C-15, ISP) 3 Polysorbate 80, NF 9.45 61.39 1,227.91 BHT, NF 0.08 0.53 10.64 BHA, NF 0.82 5.32 106.42 PEG 400, NF Q., S. to 100 Q., S. to 650,, 00 Q.S. to 13,000.00 This formulation was produced with the same steps as the 50 mg / previous capsule, with the exception that the heating temperature to solubilize the active ingredient in step 3 is 145 + 5 ° C, instead of 120 + 5 ° C. The weight of encapsulation is 650 mg in hard gelatin capsules of size 0.

Example 6 150 mg of Active Ingredient in capsules Size 00 (% in Per capsule (mg) Lot of weight / weight) 20,000 capsules (g) Active ingredient 16. 48 149. 97 2, 999. 36 Inactive ingredients PEG 1000, NF 26.3 239.33 4,786.60 Povidona USP K-17 15 136.50 2,730.00 (Plasdona C-15, ISP) Polysorbate 80, NF 9.32 84.81 1,696.24 BHT, NF 0.08 0.73 14.56 BHA, NF 0.81 7.37 147.42 PEG 400, NF Q., S. to 1100 Q., S. to 910., 00 Q.S. to 18,200.00 . . k fdftf *! ..... - -. í! This formulation of Example 6 was produced with the same steps as that of 50 mg / capsule with the exception that the heating temperature to solubilize the active ingredient in step 3 is 150 + 5 ° C, instead of 145 + 5 ° C. The encapsulation weight is 910 mg in size 00 hard gelatin capsules. The following specific Examples 7 to 11 shown in Table 1 below, can be formulated as described above to create 10% active ingredient formulations with several formulations of PEg 400, PEG000, two components of PVP with respective K values of 15 and 90, and a combination of BHA and BHT as an adjuvant component.

Table I No. of PEG 400 PEG PVP K15 PVP BHT BHA NATC Ingredient Zj emplo (%) 1000 (%) K990 active (%) (%) (%) 7 55.40 20.00 10.00 0.00 0.20 2.00 2.40 10.00 8 40, .40 35.00 10.00 0.00 0.20 2.00 2.40 10.00 9 75, .40 0.00 5.00 5.00 0.20 2.00 2.40 10.00 10 65. .40 10.00 0.00 10.00 0.20 2.00 2.40 10.00 11 40., 40 35.00 5.00 5.00 0.20 2.00 2.40 10.00 Similarly, the following Examples 12 through 23 can be formulated by the methods herein using PEG 400, PEG 1000, PVP with a K value of 17, active ingredient, NHA and BHT as antioxidants or preservatives and the additional components listed like others" .

Table 2 No. PEG PEG PVP IngreBHA BHT Other Other 400 400 K-17 tooth E] active 12 40.40 35.00 10.00 10.00 2.00 0.20 Sodium taurocholate 2.40 13 75.40 5.00 10.21 2.00 0.20 Taurocholate Sodium PVP K-90 2.40 5.00 14 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 Poloxamer 188 15.00 16 42.59 20.00 10.00 10.21 2.00 0.20 Poloxamer 188 15.00 17 37.10 30.49 10.00 10.21 2.00 0.20 Poloxamer 188 10.00 Table 2 (continued) or. PEG PEG PVP IngreBHA BHT Other Other 400 400 K-17 tooth Active 18 35.72 29.36 10.00 10.21 2.00 0.20 Poloxamer 188 12.50 19 34.35 28.23 10.00 10.21 2.00 0.20 Poloxamer 188 15.00 20 37.10 30.49 10.00 10.21 2.00 0.20 Poloxamer 188 10.00 1 34.35 28.23 10.00 10.21 2.00 0.20 Poloxamer 188 15.00 2 35.72 29.36 10.00 10.21 2.00 0.20 Poloxamer 188 12.50 3 36.86 30.30 10.00 10.64 2.00 0.20 Pluronic L44 10.00 4 36.86 30.30 10.00 10.64 2.00 0.20 Pluronic LlOl 10.00 5 39.61 32.55 10.00 10.64 2.00 0.20 Tween 40 5.00 6 41.25 33.91 10.00 10.64 2.00 0.20 Tween 40 2.00 7 39.61 32.55 10.00 10.64 2.00 0.20 Tween 20 5.00 Table 2 (continued) Sio. PEG PEG RRP IngreBHA BHT Other Other 400 400 K-17 tooth Active 28 41.25 33.91 10.00 10.64 2.00 0.20 Tween 20 2.00 29 34.12 28.04 10.00 10.64 2.00 0.20 Tween 40 Poloxᬠ5. 00 mere 188 10.00 30 36.86 30.30 10.00 10.64 2.00 0.20 Tween 40 10.00 31 36.86 30.30 10.00 10.64 2.00 0.20 Tween 80 10.00 32 34.12 28.04 10.00 10.64 2.00 0.20 Tween 80 Poloxá5.00 mero 188 10.00 It is noted that in relation to this date, a better method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. ai tajOM **** 11 **. **** * - ^ *? «.. ^ Aq ^ fcJH

Claims (22)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. A pharmaceutical composition characterized in that it comprises (% by weight / weight): a) from about 1% to about 20% active ingredient, or a pharmaceutically acceptable salt thereof, having the structure: where: A, B, E, G are, independently CH or nitrogen; D is independently, C-W or nitrogen; R1 is alkanoyl of 2 to 7 carbon atoms, a group selected from C0NH2, | A H, R 9, or a selected portion of the group (a) (b) (c) (d) (¡) 0) (k) (I) (m) (n) (o) R2, R3 and R5 are, independently hydrogen, straight-chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 atoms of carbon; R 4 is hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, or a substituent of acyl selected from the group consisting of alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, cycloalkanoyl of 3 to 7 carbon atoms, aroyl or arylalkanoyl; X and Y are independently hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, halogen (including chlorine, bromide, fluorine and iodine), alkoxy of 1 to 6 carbon atoms, hydroxy, CF3 or perfluoroalkyl of 2 to 6 carbon atoms; W is hydrogen, halogen (preferably chlorine, bromine or iodine), alkyl, alkoxyalkyl of 2 to 7 carbons, hydroxyalkyl of 1 to 6 carbons, or CH2NR6R7; ?. ^. vy < 1 i, a .. < ... r. ..... - -iMÉÉftWil iffrffl, _j ^ ?. j,. »J? *. m *. go. - ^ f - .ll »^» * »* ...,. R5 and R7 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms; or, taken together with the nitrogen atom of CH2NR6R7, R6 and R7 form a five or six member ring optionally containing one or more additional heteroatoms such as, but not limited to, those of the group: R is a straight chain alkyl of 1 to 6 carbon atoms R9 is independently hydrogen, trimethylsilyl or a straight chain alkyl of 1 to 6 carbon atoms; b) from about 1% to about 18% of a surfactant component; c) from about 50% to about 80% of a component of one or more polyethylene glycols; and d) from about 1% to about 20% of a component of; i) one or more sucrose fatty acid esters; or ii) a polyvinyl pyrrolidone with a K value between about 15 and 90; or iii) a combination of one or more fatty acid esters of sucrose and a polyvinylpyrrolidine. 2. The pharmaceutical composition according to claim 1, characterized in that the active ingredient has the structure: where: A and B are, independently CH or nitrogen D is C-W or nitrogen; R1 is alkanoyl of 2 to 7 carbon atoms or a group selected from twenty (a) (b) (e) (O R2, R3 and R5 are, independently, hydrogen, straight-chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6. carbon atoms; R4, X, Y, W, R6, R7 and R8 are as defined in Claim 1; or a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition according to claim 1, characterized in that the active ingredient is selected from: (4-Fluoro-2-trifluoromethyl-phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,] benzodiazepin-10-yl) -metanone, [4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl] (5H, HH-pyrrolo [2, 1-c] - [1,4) benzodiace [epsilon] -l-yl) -metanone] , [4- (4-Methyl-pyrazol-1-yl) -2-trifluoromethyl-phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, (4-Pyrazol-l-yl-2-trifluoromethyl-phenyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, [4- (3-Cyclopropyl -pyrazol-l-yl) -2-trifluoromethyl-phenyl] - (5H, HH-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, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - (4- [1,2,4] triazol-l-yl-2-trifluoromethylphenyl) -methanone, (2-Chloro-4-fluorophenyl) - ( 5H, 11H-? Irrolo [2, lc] [1-4] benzodiazepin-10-yl) -methanone, [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone [2-Chloro-4- (5-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) ) -pyrrolo (2, 1-c] [1, 4] benzodiacep in-10-yl) -metanone [2-chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H, 11H) -pyrrolo [2, 1-c) [1,4] benzodiazepine -10-yl) -metanone, [2-Chloro-4- (4-methyl-pyrazol-1-yl) -phenyl- (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10 -il) -metanone, i n ÉÉÉif i r! • i i iiiirtflii h [2-Chloro4- (4-methyl-imidazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-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] benzodiazepin-10-yl) -methanone, (2-Chloro) 4-pyrrol-1-yl-phenyl) - (5H, 11H-pyrrolo [2,1-c] [1,4) benzodiazepin-10-yl) -methanone, (2-Chloro-4-pyrazole-1 il-phenyl) (5H, HH-Pyrrolo [2, 1- c] [1,4) benzodiazepin-10-yl) -methanone, [2-Chloro-4- (lH-imidazol-1-yl) -phenyl) - (5H, 11H- pyrrolo [2, 1-c] [1,4) benzodiazepin-10-yl) -methanone, [2-Chloro-4- (3-methylpyrazol-1-yl) -phenyl] - (3 -methyl- 5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, (2-Chloro-4-trifluoromethyl-pyrimidin-5-yl) - (5H, 1IH- pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, [2- (3-Methyl-pyrazol-1-yl) -4-trifluoromethyl-pyrimidin-5-yl] - (5H , llH-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) -metanone, 1- [4- (5H, HH-Pyrrolo [2, lc] [1,4] benzodiazepine-10-carbonyl) -phenyl] -ethanone 3-Dimethylamino-l- [4- (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-propen-l-one, [4- (lH -Pirazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, [4- (l-Methyl-lH-pyrazolyl- 3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, [4- (l-Ethyl-lH-pyrazole-3- il) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, [4- (l-Propyl-lH-pyrazol-3-yl) -phenyl] - (5H, 11H- pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, [4- (l-Butyl-lH-pyrazol-3-yl) -phenyl) ) - (5H, 11H- pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, [4- (l-methoxymethyl-lH-pyrazol-3-yl) -phenyl] - (5H, 11H- pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, 1-. { 3- [4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepine- '10-carbonyl) -phenyl] -pyrazol-1-yl} -etanona, l-. { 3- [4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepine > -10-carbonyl) -phenyl] -pyrazol-1-yl} -propan-l-one, [4- (l-Cyclopropanecarbonyl-lH-pyrazol-3-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiace [epsilon] in-10 -il) -metanone, l-. { 3- [4- (5H, 11H-Pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -pyrazol-1-yl} -butan-1-one, (5H, llH-Pyrrolo [2, 1-c] [1,4] Enzydiacepin-10-yl) -. { 4- [1- (t? Ofen-2-carbonyl) -lH-pyrazol-3-yl] phenyl Jmetanone, - > ** < "ulhA- l * J A? kí . { 4- [1- (5-Fluoro-2-methyl-benzoyl) -lH-pyrazol-3-yl] -phenyl} - (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone,. { 4- [1- (2-Methyl-benzoyl) -lH-pyrazol-3-yl] -phenyl} - (5H, HH-pyrrolo [2, 1-c] (1,4] benzodiazepin-10-yl) -methanone,. { 4- [1 - (2-Chloro-4-fluoro-benzoyl) -lH-pyrazol-3-yl] -phenyl} - (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl.} Methanone,. {4- [1- (2,4-Dichloro-benzoyl) -lH-pyrazole -3-yl] -phenyl.} - (5H, 11H-pyrrolo (2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, 2- (2,4-Dichloro-phenyl) - l- { 3- [4- (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -pyrazol-1-yl.} - ethanone,. {4- [1- (Biphenyl-2-carbonyl) -lH-pyrazol-3-yl] -phenyl} - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10 -yl) -metanone,., 4- (1- (4'-Trifluoromethyl-biphenyl-2-carbonyl) -1H-pyrazol-3-yl] -phenyl.} - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone, 3-Dimethylamino-1- [4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10 -carbonyl) -phenyl] -2-buten-l-one, [4- (5-Methyl-lH-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1 , 4] -benzodiazepin-10-yl) -methanone, 4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -benzonitrile, 4- (5H, HH-Pyrrolo [2, lc] [1,4] benzodiazepine-10-carbonyl) -benzamide, N- (Dimethylaminomethylene) 4- (5H, llH-pyrrolo [2, 1- c] [1, 4] benzodiazepine-10-carbonyl) -benzamide, N- (1-dimethylaminoethylene) -4- (5H, llH-pyrrolo [2, 1-c) [1,4] benzodiazepine-10-carbonyl) -benzamide, (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - [4- (2H- [1, 2, 4] triazol-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,] 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, llH-pyrrolo [2, 1-c] [1,] benzodiazepin-10-yl) -methanone, (4- (3-Methyl [1,2,2] oxadiazol-5-yl) -phenyl] - (5H, 11H-pyrrolo- [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, l-Methyl-4- (4-methylphenyl) -lH-pyrazole, 4- ( l-Methyl-lH-pyrazol-4-yl) -benzoic acid, [4- (l-Methyl-lH-pyrazol-4-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1 , 4] -benzodiazepin-10-yl) -methanone, 6- (l-Methyl-lH-pyrazol-4-yl) -pyridine-3-carboxylic acid, [6- (l-Methyl-lH-pyrazole-4- il) -pyridin-3-yl] - (5H, 11H-pyrrol [2, 1-c] [1,] -benzodiazepin-10-yl) -methanone, [4- (Pyrazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-yl) -methanone, [4- (3-Methyl-pyrazole -l-yl) -phenyl] - (5H, HH-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, [4- (4-Methyl-pyrazol-1-yl) ) -phenyl] - (5H, llH-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) -methanone, [4- (3, 5-Dimethyl-pyrazol-1-yl) -phenyl) - (5H, 11H-pyrrolo [2 , 1-c] [1,4] -benzodiazepin-10-yl) -methanone, (5H, HH-Pyrrolo (2, 1-c) [1,4] benzodiazepin-10-yl) - [4- (3 -trifluoromethyl-pyrazol-1-yl) -phenyl] -methanone, [4- (Imidazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepine-10 -yl) -metanone, [4- (4-Methyl-imidazol-1-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepin-10-yl) - methanone, 4-bromo-2-chloro-benzoic acid methyl ester, 2-chloro4- (3-dimethylamino-propin-1-yl) benzoic acid methyl ester, 2-chloro-4- (3-methyl-2-methyl ester) dimethylamino-2-propen-1-on-l-yl) -benzoic acid, 2-chloro-4- (lH-pyrazol-3-yl) -benzoic acid methyl ester, 2-chloro-4- ( 1-methyl-lH-pyrazol-3-yl) -benzoic acid, 2-chloro-4- (l-methyl-lH-pyrazol-3-yl) -benzoic acid, i? kt fíigftí .¿AH? »? k..SK *? lfM * f. ! «K? ^? KS? [2-Chloro-4- (1-methyl-1H-pyrazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -metanone , 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) -pheni] - (5H, 11H-pyrrolo [2, 1-c] [1,4) benzodiazepin-10-yl) -metanone , Methyl ester of 2-chloro-4-cyanobenzoic acid, 2-chloro-4-cyanobenzoic acid, 3-chloro-4- (5H, llH-pyrrolo (2, lc] [1,4] benzo diazepin-10-carbonyl) -benzonitrile, 3-chloro-4- (5H, HH-Pyrrolo [2, 1-c] [1,4] benzo-diazepine-10-carbonyl) -benzoic acid, 3-chloro-4- (5H, llH- pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -benzamide, N- (1-Dimethylaminoethylene) -3-chloro-4- (5H, 11H-pyrrolo [2, 1-c] [ 1,4] -benzodiazepine-10-carbonyl) -benzamide, [2-chloro-4- (5-methyl-2H- [1, 2, 4) triazol-3-yl) phenyl] - (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -metanone, N- (Dimethylaminomethylene) -3-chloro-4- (5H, llH-pyrrolo [2, 1-c] [1,4 benzodiazepine-10-carbonyl) -benzamide, [2-Chloro-4- (2H-1, 2,4-triazol-3-yl) -phenyl] - (5H, 11H-pyrrolo [2, lc] [1, 4] -benzodiazepin-10-yl) -metanone, [2-Chloro-4- (2-methyl-2H- [1, 2,4] triazol-3-yl) -phenyl] (5H, 11H-pyrrolo [2, 1-c) [1,4] benzodiazepine- 10-carbonyl) -metanone, 4- [(2, 5-Dimethyl-2H- [1, 2,4] triazol-3-yl) -2-chloro-phenyl] - (5H, 11H-pyrrolo [2, 1 -c] [1,4] benzodiazepine-10-carbonyl) methanone, [2-chloro-4- (lH-tetrazol-5-yl) -phenyl] - (5H, 11H-pyrrolo [2, 1-c] ( 1,4] benzodiazepin-10-yl) -methanone, [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl] - (3-dimethylaminomethyl-5H-HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, (3-Bromo-5H, llH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) - [2 -chloro-4- (3-methyl-pyrazol-1-yl) -phenyl) -methanone, (4-Bromo-2-chlorophenyl) - (5H, 11H-pyrrolo [2, 1-c] [1, 4] ben? odiacepin-10-yl) -metanone, [2-Bromo-4- (3-methyl-pyrazol-1-yl) -phenyl] - (5H-11H) -pyrrolo [2, 1-c] [1, 4] benzodiazepin-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] -benzodiazepin-10-yl) -methanone, Methyl 4 - (3-methyl-pyrazol-1-yl) -2-trifluoromethylbenzoate, 4- (3-Methyl-pyrazol-1-yl) -2-trifluoromethyl-benzoic acid, [4- (3-Methylpyrazol-1-yl) -2-trifluoromethylphenyl] - (5H, 11H-pyrazolo [5, 1-c] [1,4] benzodiazepin-10-yl) -methanone, 2-methyl ester -chloro-4- (3-methyl-1H-pyrazol-1-yl) -benzoic acid and methyl ester of 2-chloro-4- (5-methyl-1H-pyrazol-1-yl) -benzoic acid, 2- Chloro-4- (3-methyl-lH-pyrazol-1-yl) -benzoic acid, (2,6-dichloropyridin-3-yl) (5H, HH-Pyrrolo [2, 1-c] [1,4] benzodiazepine -10-yl) -methanone, (2-Chloro-6-pyrazol-1-yl-pyridin-3-yl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepine-10- il) -metanone, [2-chloro-6- (3-methylpyrazol-1-yl) -pyridin-3-yl] - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10 -yl) -metanone, [2-chloro-6- (4-methylpyrazol-1-yl) -pyridin-3-yl] (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10 -yl) -metanone, [2-Chloro-4- (3-methyl-l, 2,4-triazol-1-yl.} - phenyl] (5H, HH-pyrrolo [2, 1-c] - [1,4] benzodiazepin-10-yl) -methanone, [4- (3-Methyl-1,2,4-triazo] -lyl) -2-trifluoromethyl-phenyl ] (5H, llH-pyrrolo [2, lc] [1,4] benzodiazepin-10-yl) -methanone, 4-Hydrazino-2-methoxybenzoic acid, methyl ester, 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, llH-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] -benzodiazepin-10-yl) -methanone, 2-Chloro acid -4-iodo-benzoic acid, methyl ester, 4-Bromo-l-methyl-lH-pyrazole, l-Methyl-4-tributylstanyl-lH-pyrazole, 2-chloro-4- (l-methyl-lH-pyrazole- 4-yl) -benzoic acid, methyl ester, 2-Chloro-4- (l-methyl-lH-pyrazol-4-yl) -benzoic acid, [2-Chloro-4- (l-methyl-lH-pyrazole-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] -benzodiazepin-5-yl) -methanone, 2-Chloro-4- (3-methyl-pyrazol-1-yl) phenyl] - (5, 10-dihydro-4H-tetrazole [5,1-c] [1,4] benzodiazepin-5-yl) -methanone, 1- [4- (4H, 10H-pyrazolo [5,1] -c] [1,4] benzodiazepine-5-carbonyl) f enyl] -ethanone, 1- [4- (4H, 10H-pyrazolo [5, 1-c] [1,4) benzodiazepine-5-carbonyl) phenyl) -3- (dimethylamino) -prop-2-en-1 -one, [4- (l-Methyl-lH-pyrazol-3-yl) phenyl] (4H, lOH-pyrazolo [5,1c] [1,4] -benzodiazepin-5? l) methanone [4- (2-Methyl-lH-pyrazol-3-yl) phenyl) (4H, 10H-pyrazolo [5, le] [1,4] -benzodiazepin-5-yl) methanone l- [4- (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -3-chlorophenyl] -ethanone, 1- [4- (5H, HH-pyrrolo [2, lc] [1,4] benzodi ^ cepin-10-carbonyl) -3-chlorophenyl] -ethanone, [2-chloro-4- (3-methyl-4-ethynyl-phenyl) (5H, 11H-pyrrolo [2, 1-c] [1, 4] -benzodiazepin-10-yl) -metanone, 4. The pharmaceutical composition according to claim 1, characterized in that the active ingredient is [2-Chloro-4- (3-methyl-pyrazol-1-yl) -phenyl) - (5H, 11H) - pyrrolo [2, 1-c] [1,4] benzodiazepin-10-yl) -methanone, or a pharmaceutically salt thereof. 5. The pharmaceutical composition according to claim 1 characterized in that it comprises (% by weight / weight): a) from about 5% to about 16% active ingredient, or a pharmaceutically acceptable salt thereof; b) from about 5% to about 15% of a surfactant component; c) from about 55% to about 70% of a component of one or more polyethylene glycols; and d) from about 1% to about 20% of a component of; i) one or more sucrose fatty acid esters; or ii) a polyvinylpyrrolidone K with a value between about 15 and 90; or iii) a combination of one or more fatty acid esters of sucrose and polyvinylpyrrolidine, as defined above. 6. The pharmaceutical composition according to claim 1, characterized in that the surfactant component comprises polysorbate., polysorbate 60, polysorbate 40, polysorbate 80, Sorbitan oleate of Span 80, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholates, sodium deoxytaurocholates, chenodeoxycholic acid and ursodeoxycholic acid, and pluronic or poloxamers or combinations thereof. The pharmaceutical composition according to claim 1, characterized in that the component of one or more polyethylene glycols comprises one or more polyethylene glycols have an average molecular weight of from about 190 to about 3450. 8. The pharmaceutical composition according to claim 5, characterized in that the component of one or more polyethylene glycols comprises one or more polyethylene glycols have an average molecular weight between about 400 and 1540. 9. The pharmaceutical composition according to claim 5, characterized in that the component of one or more polyethylene glycols comprises a mixture of PEG 400 and PEG 1000 in a ratio between about 2.5: 1 to about 1: 2.5. 10. A pharmaceutical composition according to claim 1, characterized in that the polyvinylpyrrolidone component has a K value of about 17. 11. A pharmaceutical composition characterized in that it comprises (% by weight / weight): a) from about 1% to about 20% active ingredient of claim 1, or a pharmaceutically acceptable salt thereof; b) from about 1% to about 18% of a surfactant component; c) from about 50% to about 80% of a component of one or more polyethylene glycols; d) from about 1% to about 20% of one or more sucrose esters of fatty acids or polyvinylpyrrolidone with a K value between about 15 and 90; and e) from about 0.1% to about 4% of one or more antioxidants or preservatives. 12. A pharmaceutical composition according to claim 11, characterized in that: a) a surfactant component comprises polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, Sorbitan oleate of Span 80, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocolates, sodium deoxytaurocholates, chenodeoxycholic acid and ursodeoxycholic acid, and pluronic or poloxamers or combinations thereof; b) the component of one or more polyethylene glycols comprises one or more polyethylene glycols having an average molecular weight of between about 400 to about 1540; and c) one or more antioxidants or preservatives are selected from ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole or butylated hydroxytoluene, or combinations thereof. 13. A pharmaceutical composition according to Claim 11, characterized in that it comprises (% w / w): a) from about 5% to about 16% active ingredient of claim 1, or a pharmaceutically acceptable salt thereof; b) from about 5% to about 15% of a surfactant component; c) from about 55% to about 70% of a component of one or more polyethylene glycols; . j »^ ^« ttr ^? ^ | íeyn ^ - > . »4: .j ^^? | ^: d) from about 1% to about 20% of one or more sucrose esters of fatty acids or polyvinylpyrrolidone with a K value between about 15 and 90; e) from approximately 0.3% to approximately 2. 5% (% by weight / weight) of BHA and / or from about 0.005% to about 0.15% (% by weight / weight /) of BHT. 14. The pharmaceutical composition according to claim 11, characterized in that it comprises (% by weight / weight): a) from about 5% to about 16% of an active ingredient, or a pharmaceutically acceptable salt thereof; b) from about 5% to about 15% of a surfactant component comprising polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, Sorbitan Span 80 oleate, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholates, sodium deoxytaurocholates, chenodeoxycholic acid, ursodeoxycholic acid, pluronic acid or poloxamers, or combinations thereof; c) a component of about 55% to about 70% of one or more polyethylene glycols having an average molecular weight of between about 400 and 1540; d) from about 1% to about 20% polyvinylpyrrolidone (PVP) with a K value of between about 15 and 90; and e) from about 0.3% to about 2.5% (% by weight / weight) of BHA, and from about 0.005% to about 0.15% (% by weight / weight) of BHT. 15. The pharmaceutical composition according to claim 1, characterized in that it is contained within a hard or soft gelatin capsule. 16. A process for formulating a pharmaceutical composition, which comprises (% by weight / weight) from about 1% to about 20% active ingredient, or a pharmaceutically acceptable salt thereof; 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; and from about 1% to about 20% of a component of one or more fatty acid esters of sucrose or polyvinylpyrrolidone with a K value of between about 15 and 90; or a combination of one or more fatty acid esters of sucrose and polyvinylpyrrolidone; the process is characterized in that it comprises the steps of: a) combining the surfactant component and the component of one or more polyethylene glycols to create a first carrier mixture; b) raising the temperature of the first carrier mixture to a range of about 75 ° C to about 95 ° C; c) adding the active ingredient, or a pharmaceutically acceptable salt thereof, to create a pharmaceutical composition mixture; d) stir until the first mixture of the pharmaceutical composition is clear; e) cooling the first pharmaceutical composition if necessary at a temperature of about 75 ° C to about 95 ° C; g) adding the amount of one or more fatty acid esters of sucrose and / or povidone to create a final pharmaceutical composition mixture. The process according to claim 13, characterized in that it comprises the steps of: a) combining the surfactant component and the component of one or more polyethylene glycols to create a first carrier mixture; b) raising the temperature of the first carrier mixture to a range of about 80 ° C to about 90 ° C; r.Z ~ rr, i¡r * itrkí? My. ü & d c) adding the active ingredient, or a pharmaceutically acceptable salt thereof, to create a first mixture of pharmaceutical composition; d) raising the temperature of the first pharmaceutical composition to a temperature of about 135 ° C to about 145 ° C and mix or stir until the first pharmaceutical composition mixture is clear or transparent; e) cooling the first pharmaceutical composition, if necessary at a temperature of about 80 ° C to about 90 ° C; g) adding the amount of one or more fatty acid esters of sucrose and / or povidone to create a final pharmaceutical composition mixture. 18. A process for formulating a pharmaceutical composition comprising (% by weight / weight) from about 1% to about 20% of an active ingredient according to claim 1, or a pharmaceutically acceptable salt thereof; from about 5% to about 18% of a surfactant component; from about 50% to about 80% of a component of one or more polyethylene glycols; a component of about 1% to about 20% of one or more sucrose fatty acid esters or polyvinylpyrrolidone with a K value of between approximately 15 and 90; and from about 0.1% to about 3% of one or more adjuvants; the process is characterized in that it comprises the steps of: a) combining the component of one or more polyethylene glycols and the surfactant component to create a first carrier mixture; b) raising the temperature of the first carrier mixture to a range of about 75 ° C to about 95 ° C; c) adding to the first carrier mixture one or more antioxidants or preservatives to create a second carrier mixture; d) adding the active ingredient, or a pharmaceutically acceptable salt thereof, to create a first mixture of pharmaceutical composition; e) shake until the first pharmaceutical composition mixture is clear or transparent; f) cooling the first pharmaceutical composition if necessary at a temperature of about 75 ° C to about 95 ° C; g) adding the component from about 1% to about 20% of one or more fatty acid esters of sucrose or polyvinylpyrrolidone with a K value of between about 15 and 90 to create a final pharmaceutical composition mixture. 19. The process according to claim 18, characterized in that: a) the surfactant component comprises polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, Sorbitan Span 80 oleate, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholates, deoxytaurocholates sodium, chenodeoxycholic acid, ursodeoxycholic acid, pluronic acid or poloxamers, or combinations thereof; b) a component of one or more polyethylene glycols comprises one or more glycols having an average molecular weight of between about 400 and 1540; and c) one or more oxidants or preservatives are selected from ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole or butylated hydroxytoluene, or combinations thereof. A process for formulating a pharmaceutical composition, comprising (% by weight / weight) from about 1% to about 20% of an active ingredient according to claim 1, or a pharmaceutically acceptable salt thereof; from about 5% to about 18% of a surfactant component; from about 50% to about 80% of a component of one or more polyethylene glycols; a component from about 1% to about 20% of polyvinyl pyrrolidone with a K value of between about 15 and 90; and a preservative antioxidant component of from about 0.3% to about 2.5% by weight of butylated hydroxyanisole and from about 0.005% to about 0.15% of butylated hydroxytoluene; the process is characterized in that it comprises the steps of: a) combining, preferably with mixing or stirring, the component of one or more polyethylene glycols and the surfactant component to create a first carrier mixture; b) raising the temperature of the first carrier mixture to a range of about 75 ° C to about 95 ° C; c) adding the antioxidant component or preservative to the first carrier mixture to create a second carrier mixture; d) adding the active ingredient, or a pharmaceutically acceptable salt thereof, to create a first mixture of pharmaceutical composition; e) raising the temperature of the first pharmaceutical composition mixture to a temperature of about 130 ° C to about 150 ° C; f) shaking or mixing the first pharmaceutical composition mixture until the first pharmaceutical composition mixture is clear or transparent; g) bringing the first pharmaceutical composition to a temperature of about 75 ° C to about 95 ° C; h) adding the component from about 1% to about 20% povidone to create a final pharmaceutical composition mixture. The process according to claim 18, characterized in that: a) the surfactant component comprises polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80, Sorbitan Span 80 oleate, polysorbate 81, polysorbate 85, polysorbate-120, taurocholates of sodium, sodium deoxytaurocholates, chenodeoxycholic acid, ursodeoxycholic acid, pluronic acid or poloxamers, or combinations thereof; and b) the component of one or more polyethylene glycols comprises one or more polyethylene glycols having an average molecular weight of between about 400 and 1540. 22. A process for formulating a pharmaceutical composition, comprising (% by weight / weight) of about 5% up to about 16% of an active ingredient according to claim 1, or - ~ * «- atatoí a pharmaceutically acceptable salt thereof; from about 5% to about 15% of a surfactant component; from about 55% to about 70% of a component of one or more polyethylene glycols; a component of about 5% to about 15% polyvinylpyrrolidone with a K value of between about 15 and 90; and a preservative antioxidant component of from about 0.3% to about 2.5% by weight of butylated hydroxyanisole and from about 0.005% to about 0.15% of butylated hydroxytoluene; the process is characterized in that it comprises the steps of: a) combining, preferably with mixing or stirring, the component of one or more polyethylene glycols and the surfactant component to create a first carrier mixture; b) raising the temperature of the first carrier mixture to a range of about 80 ° C to about 90 ° C; c) adding the antioxidant component or preservative to the first carrier mixture to create a second carrier mixture; d) adding the active ingredient, or a pharmaceutically acceptable salt thereof, to create a first mixture of pharmaceutical composition; e) raising the temperature of the first pharmaceutical composition mixture to a temperature of about 135 ° C to about 145 ° C; f) shaking or mixing the first pharmaceutical composition mixture until the first pharmaceutical composition mixture is clear or transparent; g) bringing the first pharmaceutical composition to a temperature of about 80 ° C to about 90 ° C; h) adding the component from about 5% to about 15% povidone to create a final pharmaceutical composition mixture.