Title of Invention

BENZODIAZEPINE DERIVATIVES AS GABA A RECEPTOR MODULATORS

Abstract

The present invention relates to a compound of the general formula wherein R1 is hydrogen, halogen, C<sub>1</sub>-<sub>7</sub>-alkyl, C<sub>1</sub-<sub>7</sub>-alkOXY, hydroxy, cyano, trifluoromethyl, trifluoromethoxy or C<sub>1</sub>.ralkyithio; R<sub>1</sub> is -C(O)O- C<sub>1</sub>-<sub>7</sub>-alkyl, isoxazol, 1,2,4-oX3Ai~7.n1-3-yl or 1,2,4-oxadiazol-S-yl, .which rings may be substituted by C<sub>1</sub>-:-a]kyl, trifluoTometbyi or C<sub>3</sub>-<sub>7</sub>- cycloalkyl; R<sub>3</sub> is hydrogen, C<sub>1</sub>-<sub>7</sub>-alkyl, -(CHvn- C<sub>3</sub>-,cycloalkyl, -(CH<sub>2</sub>)n-halogen, -( CHvn-pyridin-4-yl, or -( CHvn-phC1yl, wherein the phenyl ring may be substituted by one or two substituents selected from the group consisting of C<sub>1</sub>-<sub>7</sub>- alkoxy, halogen, -SOiCH<sub>3</sub>, phenyl, OCF-~ nitro, CF<sub>3</sub>, -NRz, or is -(CHVn- indl?lyl, optionally substituted by C<sub>1</sub>-,a}kyl or C<sub>1</sub>-,alkoxy. or is . pyrrolidinyl-5-oxo, -C(O)-NRh -(CHVn-OH, -(CHVn-NR<sub>2</sub> or -( CH<sub>2</sub>)n-benzo[ 1,3 ]dioxole; R is hydrogen or C<sub>1</sub> -<sub>7</sub>-alkyl; and n is 0, 1,2 or 3; and their pharmaceutically acceptab1e acid addition salts, with the exception of the following compounds: Ethy19H-imidazo[ 1,S-a] [1,2,4]triazolo[3,4-d] {1,4]benzodiazepine-10-carboxylate, 10-(3-cyclopropyl-1,2,4-oxadiazol-S-yl)-9H -imidazo [l,S-a] [1,2,4] triazolo[ 4,3- d] [1,4 ]benzodiazepine, ethy13-fluoro-9H-imidazorl,S-a] [1,2,4]triazolo[ 4.3-d] [1,4]benzodiazepine-1O- ' c'1rboxylate, 10-(3-cyclopropyl-l ,2.4-oxadiazol-S-yl)-3-fluoro-9H-imidazo[ 1 ,S-a] [1,2,4]triazolo (4,3- d][1,4]benzodiazepine, ". ethy13-chl.oro-9H-imidazo( 1,S-a] [1 ,2,4]triazolo [ 4,3-d] [l,4]benzodiazepine-lO- carboxylate, 3-chlo~o-lO-(3-cyclopropyl-l,2,4-oxadia'/'ol-S-yl)-9H-imidazo( 1,S-a] (1,2.4]triazolo[ 4,3- d] [1,4 ]benzodiazepine and ethy13-methyl-9H-imidazo[ 1,S-a] [1,2,4] triazolo[3,4-d] [1,4]benzodiazepine-lO- carboxylate. These compounds have a good affinity to the GABA cl 5 receptor and therefore useful for the treatment of diseases, related to this receptor.

Full Text

Benzodiazepine derivatives as GABA A receptor modulators The present invention is concerned with substituted imidazo[l,5-a] [1,2,4] triazolo[4,3-d] [l,4]benzodiazepine derivatives of the following formula wherein Rl is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, trifluoromethyl, trifluoromethoxy or lower alkylthio; R2 is -C{0)0-lower alkyl, isoxazol, l,2,4-oxadiazol-3-yl or Ii2,4-oxadiazol-5-yl, whose rings maybe substituted by lower aikyl, trifluoromethyl or cycloalkyl; R3 is hydrogen, lower alkyl, -(CHzVcycloalkyl, -(CH2)n-halogen, -(CH2)r.-pyridin-4-yl, or -(CH2)n-phenyl, wherein the phenyl ring may be substituted by one of two substituents selected from the group consisting of lower alkoxy, halogen, -SO2CH3, phenyl, OCF3, nitro, CF3, -NR2, or is -(CH2)r-indolyl, optionally substituted by lower alkyl or lower alkoxy, or is pyrrolidinyl-5-oxo, -C(0)-NR2, -(CH2)n-OH, -(CH2)n-NR: or -(CH2)n-benzo[l,3]dioxole; R is hydrogen or lower alkyl; and n is 0,1, 2 or 3; and with their pharmaceutical^ acceptable acid addition salts with the exception of the following compounds: Ethyl 9H-imidazo[l)5-n][l,2,4]triazolo[3,4-rf}[l,4jbenzodiazepine-10-carboxylate, 10-(3-cyclopropyM,2,4-oxadiazol-5-yl)-9H-imidazo[l)5-n][],2,4]triazolo[4,3- d] 11 ,4] benzodiazepine, ethyl 3-fluoro-9H-imidazo[l,5-fl][l,2,4]triazoIo[4,3-rf][lJ4]benzodiazepine-10- carboxylate, 10-C3-cyclopropyl-l,214-oxadiazol-5-yl)-3-fluoro-9/f-imidazo[l,5-a][lI2,4]triazolo[4,3- d] [ 1,4] benzodiazepine, ethyl 3-chloro-9H-imidazo[l,5-a][lJ2,4]triazolo[4,3-{i][l,4]benzodiazepine-10- carboxylate, 3-chioro-10-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-9H-imidazo[lJ5-a][l,2,4]triazoIo[4,3- d] [l,4]benzodiazepine and ethyl 3-methy!-9H-imidazo[l,5-a][l,2,4]triazolo[3,4-d][lJ4]benzodiazepine-10- carboxylate. The above mentioned specific imidazo[l,5-a] [l,2,4]triazolo-[4,3-d][l,4]benzodiazepine derivatives have already been described {Heterocydes, Vol 39, No. 2,1994), however, in this document it is mentioned that these"conrpounds unexpectedly show low affinities for BzR (benzodiazepine receptor) and therefore are devoid of anxiolytic activity. Surprisingly, it has now been found thatlKrcTass of compounds show high affinity and selectivity for GABA A a5 receptor binding sites and might b^usefufarcognitrre enhancer OT ~ Alzheimer's disease. Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA A receptors, which are members of the ligand-gated ion channel superfamily arid (2) GABA B receptors, which are members of the G-protein linked receptor family. The GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of a, Q and y sub units. Presendy a total number of 2L subunits of the GABA A receptor have been cloned and sequenced. Three types of subunits (a, p and y) are required for the construction of recombinant GABA A receptors which most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA A receptors obtained from mammalian brain cells. There is strong evidence that the benzodiazepine binding site lies between the a and y subunits. Among the recombinant GABA A receptors, aip2y2 mimics many effects of the classical type-I BzR subtypes, whereas ct2p2y2, ct3B2y2 and a5P2y2 ion channels are termed type-II BzR. It has been shown by McNamara and Skelton in Psychobiohgy, 21:101-108 that the benzodiazepine receptor inverse agonist p-CCM enhance spatial learning in the Morris watermaze. However, ji-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans. In addition, these compounds are non-selective within the GABA A receptor subunits, whereas a GABA A a.5 receptor partial or full inverse agonist which is relatively free of activity at GABA A al and/or ct2 and/or ct3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity. It is also possible to use GABA A a5 inverse agonists which arenot free of activity at GABA A al and/or a2 and/or ct3 receptor binding sites but which are functionally selective for a5 containing subunits. However, inverse agonists which are selective for GABA A a5 subunits and are relatively free of activity at GABA A al, a2 and ct3 receptor binding sites are preferred. Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments. The most preferred indication in accordance with the present invention is Alzheimer's disease. The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term "lower alkyl" denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. The term "lower alkoxy" denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom. The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "cycloalkyl" denotes a cyclic alkyl ring, having from 3 to 7 carbon ring atoms, for example, cyclopropyl, cyclopentyl or cyclohexyl. The term "lower alkylthio" means the group -S-Ci.7-alkyl. The term "pharmaceutical^ acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like. Exemplary preferred are compounds, which have a binding activity (Ki) of lower 15 nM and are selective for GABA A cc5 subunits and are relatively free of activity at GABA A al, ct2 and a3 receptor binding sites. Preferred compounds of formula I for use in the above mentioned disease are those, in which R2 is the group -C(0)0-lower alkyl. Exemplary preferred are compounds of this group, wherein R3 is hydrogen and R1 is hydrogen, methoxy, methyl, -SCH3 or halogen, for example the following compounds: Ethyl 3-methoxy-9H-imidazo[l,5-fi][l,2)4]triazolo[4,3-ri][l)4]-benzodiazepine-10- carboxylate, ethyl 3-methyI-9#-imidazo[l,5-fl] [l,2,4]triazolo[3,4-rf] [l,4]benzodiazepine-10- carboxylate, ethyl 3-bromo-9H-imidazo[ 1,5-a] [ 1,2,4]triazolo[4,3-rf] [1,4]-benzodiazepine-10- carboxylate, ethyl 9H-imidazo[l,5-fi][l,2,4]triazolo[3,4-(i][l,4]benzodiazepine-10-carboxylate, ethyl 3-fluoro-9H-imidazo[l15-fl][l,2,4]triazolo[4,3-H][l,4]benzodiazepine-lO-carboxylate or ethyl 3-chloro-9H-imidazo[l,5-n][l,2,4]triazoIo[4,3-rf] [l,4]benzodiazepine-10- carboxylate. Further preferred compounds of this group are those, wherein R3 is -CH2OH, -(CH2)2-methylenedioxyphenyl, methyl, -CH2-indolyl, optionally substituted by methoxy, or is CH2-phenyl, substituted by -S02CH3, phenyl, -OCE3. -N(CH2)2, N02 or methoxy, and RL is methoxy, chloro or bromo, for example the following compounds: Ethyl 3-methoxy-7-methyl-9H-imidazo[ 1,5-n] [ 1,2,4] triazolo [4,3-rf] [ l,4]-benzodiazepine- 10-carboxylate, ethyl 3-methoxy-7-{lH-indol-3-ylmethyl)-9H-imidazo[l,5-(i] [1,2,4] triazolo [4,3-rf] [1,4]- benzodiazepine-10-carboxylate, ethyl 7-hydroxymethyl-3-methoxy-9H-imidazo[l,5-fl][l,2,4]triazolo[4,3-rf] [1,4]- benzodiazepine- 10-carboxylate, ethyl 3-methoxy-7-(3-methoxybenzyl)-9H-imidazo[l,5-(i][l,2,4]triazolo[4,3-rf] [1,4]- Upn7ndia7pnirip-10-carboXylate, ethyl 3-methoxy-7-[(7-methoxy-lfJ-uidol-3-yl)methyl]-9H-imidazo[l,5-n][1^4]triazolo[4>3-^[l»4]-benzodi2zepine-10-caib(scylate, ethyl-3-bromo-7-(lH-indol-3-ylmethyl)-9H-imidazo[l,5-a][lJ2,4]triazolo[4,3-fJ][lJ4]-benzodiazepine-10-carboxylate, ethyl-3-bromo-7-(3-methoxy-benzyl)-9H-imida2o[l,5-fl](l,2)4]triazolo[4)3-d][l,4]-benzodiazepine-1O-carboxylate, ethyl 7-[2-benzo[l,3]dioxol-5-yl)-ethyl]-3-chloro-9H-imidazo[l,5-fl][ 1,2,4] triazolo [4,3-£i][l,4]-benzodiazepine-10-carboxylate, ethyl 7-(4-methanesulfonyl-benzyl)-3-methoxy-9H-imidazo[l,5-n][l,2,4]triazolo[4,3- d] [1,4] -benzodiazepine- 10-carboxyIate, ethyl S-methoxy^-Ifbiphenyl^-ylJmethyll-gH-imidazotUS-d] [1,2,4] triazolo [4,3-^] [1,4]- benzodiazepine-10-carboxylate, ethyl 3-methoxy-7-(4-trifiuoromethoxy-benzyl)-9H-imidazo[l,5-fl][l>2J4]triazo]o[4J3- (f)[l,4]-benzodiazepine-10-carboxylate, ethyl 3-chloro-7-(4-nitro-benzyl)-9H-imidazo[l,5-rt][l)2,4]triazolo[4J3-rf][l,4]- benzodiazepine-10-carboxylate, ethyl 7-(4-dimethylamino-benzyl) -3-methoxy-9H-imidazo [ 1,5-n] [1,2,4] triazolo [4,3 - d] [l,4]-benzodiazepine-10-carboxylate or ethyl 3-bromo-7-(4-dimethylamino-benzyl)-9H-imidazo[l,5-n][l,2)4]triazolo[4,3- d][l,4]-benzodiazepine-10-carboxylate. Further preferred compounds for use in the above mentioned disease are those, in which R2 is the group 3-cyclopropyl-[l,2,4]oxadiazol-5-yl. Exemplary preferred are compounds of this group, wherein R' is hydrogen and R1 is hydrogen! methoxy, methyl, -SCH3 or halogen, for example the following compounds: 10-(3-Cyclopropyl-l,2,4-oxadiazoI-5-y])-3-methoxy- 9H-imidazo[l,5-rt](l,2,43triazolo[4,3-£i)[l,4]benzodiazepine, 10-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methyl-9H-imidazo[l,5-fl][l,2,4]triazolo[4,3-d] [l,4]benzodiazepine, 10-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-3-bromo-9H-imidazo[l,5-a] [1,2,4] triazolo[4,3-d][l,4]benzodiazepine, 10-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methylsulfanyl-9H-imidazo[l,5-a][ 1,2,4] triazolo[4,3-d][l,4]benzodiazepine, 10-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-9H'-imidazo[l,5-n][l,2,4]triazolo[4,3-d] [ 1,4]benzodiazepine, 10-{3-cyclopropyl-l,2,4-oxadiazol-5-yl)-3-fluoro-9H-imidazo[l,5-n][l,2,4]triazolo[4,3- /i\ M A 1V»anTrvliadenine. 3-chloro-10-(3-cyclopropyl-l,2>4-oxadiazol-5-yl)-9H-imidazo[l15-n][l,2,4]triazolo[4,3-d] [l,4]benzodiazepine or 3-chloro-10-(5-cydopropyl-l)2,4-oxadiazol-3-yl)-9H-imidazo[l,5-n][lJ2J4]triazolo[4,3-d] [l,4]benzodiazepine. Further preferred are compounds from this group, wherein R3 is -CHi-indolyl or -CH2-phenyl, optionally substituted by -N(CH3)2 and R1 is chloro or bromo, for example the following compounds: 10-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-7-(4-dimethylamino-benzyl)-3-bromo-PH-imidazo[l,5-fl][ 1,2,4] triazolo[4,3-d][l,4jbenzodiazepine, 3-Chloro-10-(5-cyclopropyI-l,2,4-oxadiazol-3-yl)-7-(lH-indol-3-ylmethyl)-9H-imidazo[l,5-n][l,2,4]triazolo[4,3-d][l,4]benzodiazepineor 7-Benzyl-3-chloro-10-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-9H-imidazo[l,5-fl][l,2J4]triazolo[4,3-d][l,4]benzodiazepine. The present compounds of formula I and their pharmaceutical^ acceptable salts may be prepared by methods known in the art, for example, by processes described below, which process comprises wherein R'-R3 have the significances given above, or :) modifying one or more substituents R'-R3 within the definitions given above, and f desired, converting the compounds obtained into a pharmaceutically acceptable acid iddition salt. The compounds of formula I in accordance with reaction variant a) may be prepared is follows: A compound of formula II, for example 6-chloro-8-methoxy-4H-2,5)10Z>-triaza-?enzo[e]azulene-3-carboxylic acid ethyl ester or 6-chloro-8-methyl-4H-2,5,10&-triaza-)enzo[e]azulene-3-carboxy]ic acid ethyl ester or 6-chloro-S-bromo-4H-2,5,10&-triaza-3enzo[e]azulene-3-carboxyhc acid ethyl ester is treated with a compound of formula III, :or example with formylhydrazine, acethydrazine, indole-3-acetic acid hydrazide, iimethylaminoacetyldrazide or the like. The reaction is carried out in the presence of N,N-iimethyl-p-toluidine, or N-ethyldiisopropylarnine or even without a base and is heated mder reflux in chlorobenzene or p-xylene for some hours. In accordance with process variant b) compounds of formula I maybe prepared in :he following way: A compound of formula IV, for example 6,8-dibromo-4H-2,5,10&-:riaza-benzo[e]azulene-3-carboxyUc acid ethyl ester or 6-bromo-3-(3-cyclopropyl-[l,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4H-2,5)10i'-triaza-benzo[e]azulene is treated with an anhydrous solution of hydrazine. A suitable solvent is THF. The resulting mixture is heated for some hours. After cooling and evaporation the solid may directly used in the next step. The obtained solid is then treated with a corresponding compound of formula VI, for example with triefhyl orthoformate in an alcohol, such as ethanol. The mixture is heated under reflux for several hours. The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids are possible. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like are examples of such salts. The following scheme 1 describes the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds.or may be prepared according to methods known in the^rjjjbxfixample in accordance with schemes 2,3 and crystallization occurred. The obtained compound of formula IX is solved in toluene in the presence of N,N-dimethyl-p-toluidine. Then phosphorous oxide chloride is added and the solution is heated and after completion of the reaction toluene is evaporated. The obtained compound of formula X is then dissolved in THF and added to a mixture of a cooled solution of lithium diisopropylamide in THF and of (E)-(dimethylamino-methyIeneamino)-acetic acid ethyl ester or of (E/ZJ-N'fS-cyclopropyl-f 1,2,4] oxadia2ol-5-yl-methyl-dimethyl-formamidine. In a further step the obtained compound of formula XII is dissolved in a mixture of CH2GI2 and trichloroacetic acid and then treated with trifluoromethanesulfonic acid. The obtained compound of formula XIII is purified in conventional manner. A mixture of this compound and N,N-dimethyl-p-toluidine is dissolved in chlorobenzene under argon and phosphorous oxide chloride or bromide is then added at room temperature and the mixture is heated at reflux. The obtained compound of formula XTV is purified by known methods. If "hal" in formula XIV is chlorine, a compound of formula I may be obtained by reaction of a compound of formula XIV, for example the compound 6-chloro-S-methoxy-4H-2,510b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester, with a corresponding formylhydrazine of formula III. The reaction is carried out in the presence of N,N-dimethyl-p-toluidine, or N-ethyldiisopropylamine or even without a base and is heated in chlorobenzene or p-xylene under reflux. If "hal" in formula XIV is bromine, a compound of this formula, for example 6,S-dibromo-4H-2,510b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester, is treated with an anhydrous solution of hydrazine and the obtained solid compound of formula V may directly used in the last reaction step. Finally, a compound of formula I is obtained by heating under reflux a mixture of a compound of formula V in ethanol, containing triethylorthoformate. The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form oftablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenteraliy, e.g. in the form of injection solutions. The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production oftablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients P a fnr taHWs Hragees and hard gelatine capsules. Suitable excipients for soft gelatine :apsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc. Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc. Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, fiavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary. The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius. Intermediate A (2,4-Dimethoxy-benzylamino)-aceticacid This intermediate is known1 and may be prepared by methods, known in the art, for example in the following way: Glycine {100 g, 1.33 mol) was dissolved in 1 N NaOH (1.6 L) and treated with a solution of 2,4-dimethoxybenzaldehyde (200 g, 1.20 mol) in MeOH (S00 mL). The resulting solution was hydrogenated over 10%Pd/C(40g) at 1.1 bar H2 for 2 h at rt. The catalyst was filtered off and washed with MeOH (500 mL). The filtrate was concentrated to ca. 2 L by distilling off all the MeOH. The resulting basic aqueous solution was cooled in ice, and acidified to pH 4 with 3 N HC1 (ca. 500 mL), causing the product to precipitate. The white solid was filtered off, and washed with ice water (200 mL). The wet crystals were dried at 60 DC, first at 25 mbar overnight, then at 0.1 mbar for 8 h. One obtained 232 g (85 %), which was contaminated with 3 % NaCl, but was used without further purification, mp 115 °C. m/z 225 (M). Intermediate B (E)-(Dimethylamino-merhyleneamino) -acetic acid ethyl ester This intennediate is known2 and maybe_grepared by methods, known in the art, for example in the following ways: Method A A mixture of glycine (69.8 mL, O.S mol) and N,N-dimethylformamide diethylacetal (69.8 mL, 4.0 mol) was heated under reflux and the ethanol formed was removed by means of a Dean-Stark trap. Distillation. Yield: 10S.4 g (86 %): bp 120-122 °C / 28 mbar. Method B Gycine ethyl ester HC1 was dissolved in portions in 10 % aqueous Na2C03- The resulting solution was saturated with NaCl, filtered, and the filtrate extracted twice with CH2Q2 (400 mL). The organic layer was dried, filtered and carefully evaporated. The residue was distilled at 45 °C/18 mbar. One obtained glycine ethyl ester (32 g, 43 %) as a colorless liquid. Glycine ethyl ester (35 g, 339 mmol) was dissolved in N,N-dimethylformamide diethyl acetal (64 mL, 373 mL) and heated to 130 °C. Ethanol (ca. 20 mL) was distilled off by means of a Dean-Stark trap. The residue was distilled at 110aC/18 mbar. One obtained a yellowish liquid (52 g, 97 %). m/z 159 (M+H). Intermediate C (£/Z)-N,-(3-Cyclopropyl-[l,2,4]oxadiazol-5-ylmethyl)-N,N-dimethyl-formamidine Stepl N-[(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)methyl]phthalimide N-Phthaloylglycine (90.7 g, 442 mmol) was dissolved in portions (because of clumping) in DMF (500 mL). l,r-Carbonyldiimidazole (78.9 g, 486 mmol) was added in portions (attention CO evolution). The resulting suspension was heated at 80 °C for 20 min. and then cooled to rt, then cyclopropanecarboxamidoxime * added and then heated at 110DC for 2 h. The solution was cooled to rt, then poured into water (4 L), stirred for 15 min, filtered, washed with water (400 mL) and dried. Yield: 104 g (87 %). Mp 115 °C. m/z 269 (M). Step 2 4-(Ammomethyl)-3-cyclopropyl-I,2,4-oxadiazole N-[(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)methyl]phthalimide (104 g, 387 mmol) was dissolved in 1,2-dichloroethane (500 mL), N-methylhydrazine (22.4 mL, 426 mmol) was added and the solution was refluxed for 5 h. The suspension was cooled in ice, the nreciDitate f2-methyl-2J3-dihydra-phthalazine-l,4-dione) was filtered off and washed with ,2-dichloroethane (100 mL). The filtrate was evaporated and the residue distilled at 0 °C/0.4 mbar (bath-T 100-150 °C). Yield: 39.3 g (73 %). m/z 139 (M). tep3 E/2)-N'-(3-Cyclopropyl-[l,24]oxadiazol-5-ylmethyl)-N,N-dimethyl-formaraidine -(Aminomethyl)-3-cyclopropyl-l,2,4-oxadiazole (39.3 g, 282 mmol) was dissolved in [.N-dimethylformaldehyde diethyl acetal (77 mL, 451 mmol) and heated at 130 °C until [1 liberated EtOH had distilled off (Hickmann condenser). Vacuum was then applied to smove first the excess reagent and then the product was distilled at 140-150 °C bath-T / .1 mbar. Yield: 49.3 g (90 %). m/z 195 (MH+). Example 1 ;thyl3-methoxy-9H-irnidazo[l,5-fl][l,2,4]triazolo[4,3-d][l,4]-benzodia2epine-10-arboxylate tepl -Methoxy-2H-3,l-ben2oxazine-2,4(lH)-dione 'his intermediate is known3 and may be prepared by methods, known in the art, for xample in the following way: :-Amino-5-methoxybenzoic acid (19.3 g, 115 mmol) was dissolved in dioxane (200 mL), reatedwith bis(trichloromethyl)carbonate(11.3g, 38 mmol) and refluxed for 1 h.The uspension was cooled to rt, the crystals filtered off and washed with dioxane (20 inL). The nother liquor was evaporated and the residue crystallized from ethyl acetate. Yield: 20.9 g 94 %). mp 244 °C (dec), m/z 193 (M). itep2 l-(2,4-Dimethoxy-benzyl)-7-methoxy-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione 5-Methoxy-2H-3,l-benzoxazine-2,4(lH)-dione (23 g, 119 mmol) and (2,4-dimethoxy-jenzylamino)-acetic acid 1 (27 g, 120 mmol) were suspended in p-xylene (500 mL) and seated under argon at reflux {140 °C) for2h. The hot solution was allowed to cool tort, while spontaneous crystallization occurred. The crystals were filtered off and washed with p-xylene (50 mL). Yield: 39 g (92 %). mp 196 DC. m/z 356 (M). Step 3 2-Chloro-4-(2,4-dimethoxy-benzyl)-7-methoxy-3,4-dihydro-benzo[e][lJ4]diazepin-5-one 4-(2,4-Dimethoxy-benzyl)-7-methoxy-3,4-dihydro-lH-benzo[e][l,4]diazepme-2,5-dione (23.7 g, 67 mmol) and N,N-dimethyl-p-toluidine (19.2 mL, 133 mmol) were mixed in toluene (200 mL) and heated to 100 °C. Then phosphorous oxide chloride (6.7 mL, 73 mmol) was added dropwise and heating at 100 °C was continued for 2.5 h. The resulting dark red solution was evaporated to dryness and the residue redissolved in THF (150 mL) and used directly in the subsequent step. Step 4 5- (2,4-Dimethoxy-benzyl)-8-methoxy-6- oxo-5,6-dihydro-4H-2,5,10 fc-triaza- benzo[e]azulene-3-carboxylic acid ethyl ester Hexamethyldisilazane (48.5 mL, 66 mmol) was dissolved in THF (150 mL), cooled under argon to -70 "C, and treated slowly with a 1.6 M solution of n-butyllithium in hexane (145 mL, 233 mmol). After stirring for 1 h at -70 °C, a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (21 g, 133 mmol) in THF (50 mL) was added, and stirring continued for 1 h at -70 °C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-methoxy-3,4-dihydro-benzo[e] [l,4]diazepin-5-one (24.9 g, 66 mmol) in THF (150 mL) was added at-70 °C, and subsequendy allowed to warm to 10 "Cover ca.lh, then cooled again to -30 °C. Neat acetic acid (38 mL, 664 mmol) was added slowly at -30 °C with cooling, the muddy suspension was allowed to warm to 0 °C, water (40 mL) added, and the resulting solution was refluxed for 1 h, leading to the formation of a thick precipitate. The hot suspension was diluted with water (450 mL), cooled to 30 DC, filtered, and the white crystals washed with THF/water 1:1 (400 mL), and dried at 25 mbar/60 °C. Yield: 16.7 g (56 %). mp 204 °C. m/z 451 (M). Step 5 8-Methoxy-6-oxo-5,6-dihydro-4iyr-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester 5-(2,4-Dimethoxy-ben2yl)-8-methoxy-6-oxo-5,6-dihydro-4H-2>5,10&-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (9.8 g, 22 mmol) was suspended in CH2CI2 (50 mL), cooled in ice, and diluted sowly with trifluoroacetic acid (50 mL). The resulting clear solution was treated at 5 °C with trifluoromethanesulfonic acid (3.8 mL, 44 mmol). The now red solution was stirred at rt for 2 h, evaporated to dryness, and the residue extracted with CH2Cl2 (500 mL), and 2 x 10 % NaHC03 (500 mL). The crude product (ca. 10 g) was digested with hot ethyl acetate (100 mL), allowed to cool, and the white crystals (5.6 g, 85 %) were filtered off. mp 240 °C. m/z 301 (M). Step 6 6-Ch\oro-8-methoxy-4H'2,5,10b-tnaza-benzo[e]azulene-3-carboxy}ic acid ethyl ester 8-Methoxy-6-oxo-5l6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (7.5 g, 25 mmol) and N,N-dimethyI-p-toluidine (10.8 mL, 75 mmol) were mixed in chlorobenzene (80 mL) under argon. Phosphorous oxide chloride (3.4 mL, 37 mmol) was added at rt, and the mixture heated at reflux for 3.5 h. The resulting solution was cooled to rt, diluted with CH^CVaceton 100:15 (300 mL), and directly purified by flash chromatography on silica gel in CHjCIi/acetone 100:15. The white product was recrystallized by dissolution in hot ethyl acetate (300 mL), concentrated until precipitation started (ca. 100 mL). Yield: 7 g (88 %). mplS6°C.m/z 301 (M). Step 7 Ethyl 3-methoxy-9H-imidazo[lJ5-fl][l,214]rria2olo[4,3-^]Jl,4]-benzodiazepine-10- carboxylate 6-Chloro-8-methoxy-4H-2,5,10&-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (0.1 g, 0.31 mmol), formylhydrazine (41 mg, 0.69 mmol), and N-ethyldiisopropylamine 0.054 mL, 0.31 mmol) were refluxed in chlorobenzene (1 mL) for 4 h. The reaction mixture was extracted with CH2Cl;;/water, the organic layer was dried and evaporated. The residue was purified by chromatography on silica gel in CH2Cl2/MeOH 30:1. mp 197 °C. m/z 325 (M). Example 2 Ethyl 3-methyl-9H-imidazo[l,5-a][l,2,4]triazolo[3,4-d][l,4]benzodiazepine-10-carboxylate Stepl 6-Methyl-2H-3,l-benzoxazine-2,4(lH)-dione This intermediate is known and may be prepared by methods, known in the art, for example in the following way: A mixture of 2-amino-5-methylbenzok: acid (45.2 g, 0.30 mol) and ethyl chloroformate (31.4 mL, 0.33 mol) in dioxane (250 mL) was heated under reflux for 4.5 h. After cooling, acetyl chloride (50 mL) was added and heating under reflux continued for another 4 h. After cooling, the mixture was evaporated and the resulting solid digested with tert-butyl methyl ether : heptane (1:1, 400 mL) by heating under reflux for 1 h. Thesoildwas then filtered offand washed with tert-butyl methyl ether: heptane (1:3, SO mL). Yield: 47.7 g (90 %). m/z 177 (M). Step 2 4-(2,4-Dimethoxy-benzyl)-7-methyl-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione A suspension of 6-methyl-2H-3,l-bezoxazine-2,4(lH)-dione (18.3 g, 103 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (25.6 g, 114 mmol) in p-xylene (125 mL) was heated under reflux (150 °C) for 2.5 h. After cooling to room temperature the precipitate was filtered offand washed with p-xylene (2x20 ml). Yield: 34.1 g (97 %). m/z 341 (MH+). Step 3 2-Chloro-4-(2)4-dimethoxy-benzyl)-7-methyl-3,4-dihydro-benzo[e][l,4]diazepin-5-one 4-(2,4-Dimethoxy-benzyl)-7-methyl-3,4-dihydro-lH-benzo[eHl.4]diazepine-2,5-dione (34.0 g, 100 mmol) and N,N-dimethyI-p-toluidine (28.9 mL, 200 mmol) were mixed in toluene (100 mL) and heated to 100 °C. Then phosphorus oxychloride (10.1 mL, 110 mmol) was added dropwise and heating at 100 °C was continued for 2.5 h. The resulting dark red solution was used directiy in the subsequent step. Step 4 5- (214-Dimethoxy-benzyl}-8-methyI-6-oxo-5,6-dihydr o-4H-215,l 0 &-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester Hexamethyldisilazane (68.7 mL, 330 mmol) was dissolved in THF (350 mL), cooled under Argon to -70 °C, and treated slowly with a 1.6 M solution of n-BuLi in hexane (206 mL, 330 mmol). After stirring for 1 h at -70 °C, a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (31.6 g, 200 mmol) in THF (30 mL) was added, and stirring continued for 1 hat-70 °C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-methyl-3,4-dihydro-benzo[e] [l,4]diazepin-5-one (35.9 g, 100 mmol) (prepared as described above) was added at -70 °C, and subsequently allowed to warm up to at 10 °C over 1 h, then cooled again to -30 °C. After 30 min, acetic acid (57 mL) was added at-30 °C and the suspension was allowed to warm up to room temperature and water (57 mL) added and the resulting mixture heated under reflux for 14 h. After cooling, the mixture was evaporated and then dissolved in DCM (300 mL). This solution was then washed with HCl (1 M, 2 x 100 mL) and 10% sodium hydrogen carbonate (100 ml), dried (Na2S04) and evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 17.6 g (41 %). m/z 436 (MH+). Step 5 8-Methyl-6-oxo-5)6-dihydro-4H-2,5,10&-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester 5-(2,4-Dimethoxy-benzyl)-8-methyl-6-oxo-5,6-dihydro-4H-2,5)10b-triaza-benzo[e]azulene-3-carboxylk acid ethyl ester (9.8 g, 23 mmol) was suspended in CH2CI2 (100 mL), cooled in ice, and diluted slowly with trifluroacetic acid (30 mL). The resulting solution was treated at 5 °C with trifmoromethanesulfonic acid (3.0 mL, 34 mmol). The red solution was stirred at room temperature for 2 h. The mixture was then evaporated and dissolved in CH2C12 (20 mL), washed with 10 % sodium hydrogen carbonate (2x5 *iL) and the organic layer was dried (Na2S04) and evaporated. Trituration with EtOAc. field: 9.55 g (92 %). m/z 283 (M-H"). Step 6 and Step 7 (without isolation of 6-chloro-8-methyl-4H-2,5,10Mriaza-:>enzo[e]azulene-3-carboxyIic acid ethyl ester) 5-Chloro-8-methyl-4H-2,5I10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester and Ethyl 3-methyi-9H-imidazo[I,5-fl][I,2,4]tria2oIo[3^^[l,4lbenzodia^be-10-carboxylate 8-MethyI-6-oxo-5,6-dihydro-4ff-2,5,10&-triaza-benzo[c]azulene-3-carboxylic acid ethyl ester (9.5 g, 33 mmol) and N,N-dimethyl-p-toluidine (14.4 ml, 99 mmol) were mixed in chlorobenzene (100 mL) under argon. Phosphorous oxychloride (4.6 mL, 50 mmol) was added at room temperature and the resulting mixture heated under reflux for 1.5 h. After cooling, the mixture was evaporated and used in the subsequent step. The mixture was dissolved in chlorobenzene (100 mL) and then N,N-ethyldiisopropylamine (5.7 mL, 33 mmol) and formylhydrazine (4.4 g, 66 mmol) added and the resulting mixture heated under reflux for 4 h. After cooling, the mixture was evaporated and dissolved in CH2Q2 (50 mL) and water (20 mL). The organic layer was separated, dried (Na2S04) and evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 2.85 g (28 %). m/z 310 (MH+).mp 236-238 °C. Example 3 Ethyl-3-isopropyl-9H-imidazo[l,5-fl][l,2)4]triazolo[4,3-rf][lJ4]-benzodiazepine-10- carboxylate Stepl 6-IsopropyMH-benzo[(£][l,3]oxazine-2,4-dione A mixture of 2-amino-5-isopropylbenzoic acid (30. g, 16.7 mmol) and ethyl chloroformate (1.75 mL, 18.4 mmol) in dioxane (20 mL) was heated under reflux for 2 h. After cooling, acetyl chloride (1.4 mL) was added and heating under reflux continued for another 3 h. After cooling, the mixture was evaporated and the resulting solid digested with tert-butyl methyl ether : heptane (1:1,20 mL) by heating under reflux for 1 h. The soOd was then filtered off and washed with tert-butyl methyl ether : heptane (1:1,10 mL). Yield 3.1 g (89 %). m/z 204 (M-H"). Step 2 4-(2,4-Dimethoxy-benzyl)-7-isopropyl-3,4-dihydro-lH-benzo[e][l>4]diazepine-2,5-dione A suspension of 6-isopropyMH-benzo[d][l,3]oxazine-2,4-dione (3.0 g, 15 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (3.7 g, 16 mmol) in p-xylene (40 mL) was heated under reflux (150 °C) for 2.5 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (2 x 20 ml). Yield: 4.9 g (90 %). m/z 367 (M-H'). Step 3 2-Chloro-4-(2,4-dimethoxy-benzyl)-7-isopropyl-3,4-dihydro-benzo[e][l,4]diazepin-5-one 4-(2,4-Dimethoxy-benzyl)-7-isopropyl-3,4-dihydro-lH-benzo[e][l>4]diazepine-2,5-dione (1.5 g, 4.1 mmol) and N,N-dimethyI-p-toIuidine (1.76 mL, 12.2 mmol) were mixed in toluene (8 mL) and heated to 100 °C. Then phosphorus oxychloride (559 uL, 6.1 mmol) was added dropwise and heating at 100 °C was continued for 2.5 h. After cooling, the mixture was evaporated and dissolved in THF (10 mL) and was used directly in the subsequent step. Step 4 5-(2,4-Dimethoxy-benzyl)-8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10&-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester Hexamethyldisilazane (2.8 mL, 13.4 mmol) was dissolved in THF (25 mL), cooled under Argon to -70 °C, and treated slowly with a 1.6 M solution of n-BuLi in hexane (8.4 mL, 13.4 mmol). After stirring for 1 h at -70 °C, a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (1.28 g, 8.1 mmol) in THF (5 mL) was added, and stirring continued for 1 h at -70 °C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-isopropyl-3,4-dihydro-benzo[e][l,4]diazepin-5-one (1.59 g, 4.1 mmol) (prepared as described above) was added at -70 °C, and subsequently allowed to warm up to at 10 °C over 1 h, then cooled again to -30 °C. After 30 min, acetic acid (3.0 mL) was added at -30 °C and the suspension was allowed to warm up to room temperature and water (3.0 mL) added and the resulting mixture heated under reflux for 14 h. After cooling, the mixture was evaporated and then dissolved in DCM (30 mL). This solution was then washed with HCl (1 M, 2 x 15 mL) and sodium hydrogen carbonate (sat., 10 ml), dried (Na2SC>4) and evaporated. Chromatography on silica gel eluting with EtOAc: Hexane (19:1). Yield: 1.9 g (99 %). m/z 464 (MH+). Step 5 8-Isopropyl-6-oxo-5,6-dihydro-4H-2,5,10&-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester 5-(2,4-Dimethoxy-benzyl)-8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10ib-tria2a-benzo[e]azulene-3-carboxylic acid ethyl ester (410 mg, 0.9 mmol) was suspended in CH2CI2 (3.0 mL), cooled in ice, and diluted slowly with trifluoroacetic acid (2.0 mL). The suiting solution was treated at 5 °C with trifluoromethanesulfonic acid (1.0 mL, 1.3 mo\). The red solution was stirred at room temperature for 2 h. The mixture was then 'aporated and dissolved in CH1CI2 (20 mL), washed with sodium hydrogen carbonate (10 ', 2 x 5 mL) and the organic layer was dried (Na2S04) and evaporated. Trituration with :OAc. Yield: 250 mg (90 %). m/z 313 (MH). :ep6 ■Chloro-8-isopropyl-4H-2,5-10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester ■Isopropyl-6-oxo-5,6-dihydro-4/f-2,5,10&-triaza-benzo[f]azulene-3-carboxyIic acid ethyl ;ter (1.8 g, 5.6 mmol) and N.N-dimethyl-p-toluidine (2.4 mL, 16.9 mmol) were mixed in nlorobenzene (10 mL) under argon. Phosphorus oxychloride (771 uL, 8.4 mmol) was dded at room temperature and the resulting mixture heated under reflux for 2 h. After ooling, the mixture was evaporated. Chromatography on silica gel eluting with EtOAc. ield: 1.3 g (68%). tep7 ithyl-S-isopropyl-SH-imidazojljS-fl] [1,2,4] triazolo[4,3-d][l,4]-benzodiazepine-10- arboxylate i-Chloro-8-isopropyl-4H-2,5,10&-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (50 ng, 0.15 mmol), formylhydrazine (10 mg, 0.17 mmol), and N,N-dimethyl-p-toluidine (24 tL, 0.17 mmol) were heated under reflux in chlorobenzene (2 mL) for 10 h. The reaction nixture was then evaporated. Chromatography by preparative HPLC. Yield 8.7 mg (17 %) Tti/2 338 (M)mp 160-163 °C. Example 4 (Method A) Ethyl 3-bromo-9H-imidazo[l,5-fl][l,2,4]triazolo[4,3-d] [l,4]-benzodiazepine-10-carboxylate Step I 4-(2,4-Dimethoxy-benzyl)-7-bromo-3)4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione A suspension of 6-bromo-2H-3,l-bezoxazine-2,4(lH)-dione (22.0 g, 91 mmol) containing (2,4-dimethoxy-benzyIamino)-acetit acid (22.5 g, 100 mmol) in p-xylene (200 mL) was heated under reflux (150 °C) for 1 h. After cooling to room temperature die precipitate was filtered off and washed with p-xylene (100 ml). Yield: 33.5 g (91 %) m/z 403/405 (M). Step 2 2-Chloro-4-(2,4-dimethoxy-benzyl)-7-bromo-3,4-dihydro-benzo[e][l,4]dia2epin-5-one 4-(2,4-Dimethoxy-benzyl)-7-bromo-3,4-dihydro-lH-benzo[e][l)4]diazepine-2J5-dione (3.0 g, 7.4 mmol) and N,N-dimethyl-p-toluidine (2.1 mL, 14.8 mmol) were mixed in oluene (30 mL) and heated to 100 °C. Then phosphorus oxychloride (745 uL, 8.1 mmol) vas added dropwise and heating at 100 "C was continued for 2.5 h. The resulting dark red ;olution was evaporated and the residue dissolved in THF (10 mL) and used directly in the subsequent step. Step 3 5-(2,4-Dimethoxy-benzyl)-8-bromo-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-Denzo[e]azulene-3-carboxylic acid ethyl ester Hexamethyldisilazane (5.1 mL, 24.4 mmol) was dissolved in THF (30 mL), cooled under Argon to -70 °C, and treated slowly with a 1.6 M solution of n-BuLi in hexane (14.5 mL, 23.2 mmol). After stirring for 1 hat -70 °C, a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (2.34 g, 14,8 mmol) in THF (10 mL) was added, and stirring continued for 1 hat-70 °C. Then a solution of2-chloro-4-(2,4-dimethoxy-benzyl)-7-bromo-3,4-dihydro-benzo[e][l,4]diazepin-5-one (3.1 g, 7.4 mmol) in THF (10 mL) (prepared as described above) was added at -70 °C, and subsequently allowed to warm up to at 10 "C over 1 h, then cooled again to -30 °C. After 30 min, acetic acid (8 mL) was added at —30 °C and the suspension was allowed to warm up to room temperature and water (8 mL) added and the resulting mixture heated under reflux for 2 h. After cooling, the mixture was evaporated and then dissolved in DCM (30 mL). This solution was then washedwithHCl(l M, 2x 15 mL) and sodium hydrogen carbonate (sat., 10 ml), dried (NaiSCt) and evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 0.9 g (24 %). m/z 500/502 (M). Step 4 8-Bromo-6-oxo-5,6-dihydro-4H-2,5,10fc-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester 5-(2,4-Dimethoxy-benzyl)-8-bromo-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azuIene-3-carboxylic acid ethyl ester (2.6 g, 5.2 mmol) was suspended in CH2CI2 (15 mL), cooled in ice, and diluted slowly with trifiuoroacetic acid (11.9 mL). The resulting solution was treated at 5 °C with trifluoromethanesulfonic acid (680 uL, 7.8 mmol). The red solution was stirred at room temperature for 1.5 h. The mixture was then evaporated and dissolved in CH2CL (50 mL), washed with sodium hydrogen carbonate (10 %, 2 x 25 mL) and the organic layer was dried (Na2SC>4) and evaporated. Trituration with EtOAc. Yield: 1.8 g (100 %). m/z 350/352 (M). Steps 5 and 6 6,8-Dibromo-4H-2,5-10Mriaza-benzo[e]azulene-3-carboxylic acid ethyl ester and 8- bromo-6-hydrazino-4H-2J5,10b-triaza-benzo[g]azulene-3-carbDxyiic acid ethyl ester 8-Bromo-6-oxo-5,6-dihydro-4H-2,5,10i7-triaza-benzo[e]a2ulene-3-carboxylic acid ethyl ester (0.2 g, 0.6 mmol) and N,N-dimethyl-p-toiuidine (165 \, 1.1 mmol) were mixed in toluene (5 mL), treated with phosphoryl bromide (180 mg, 0.6 mmol) and refluxed for 5 h. After cooling, the mixture was evaporated and the residue was extracted with CH2CI2 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SCu) and then evaporated. The residue was dissolved in THF (10 mL) and treated with an anhydrous solution of hydrazine (1 M, in THF, 2.0 mL, 0.2 mmol) and the resulting mixture heated under reflux for 12 h. After cooling the mixture was evaporated and the solid was used directly in the subsequent step, m/z 364/366 (M). Step 7 Ethyl 3-bromo-9H-imidazo[l)5-fl]{l,2,4]triazolo[4,3-d][l,4]-benzodiazepine-10-carboxylate A mixture of 8-bromo-6-hydrazino-4H-2,5,10&-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (0.4 g, 0. 6 mmol) in ethanol (16 mL) containing triethyl orthoformate (285 ul, 1.7 mmol) was heated under reflux for 18 h. After cooling the mixture was evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 4.6 mg (5 %). m/z 374/376 (M). mp 198-200 qC. Example 4 (Method B) 6-Chloro-S-bromo-4H-2,5-10&-triaza-benzo[^]azulene-3-carboxylic acid ethyl ester 8-Bromo-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (2.3 g, 6.4 mmol) and N,N-dimethyl-p-toiuidine (2.8 mL, 19.3 mmol) were mixed in chlorobenzene {25 mL) under argon. Phosphorus oxychloride (882 uL, 0.96 mmol) was added at room temperature and the resulting mixture heated under reflux for 2 h. After cooling, the mixture was evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 1.4 g (59 %). m/z 368/370 (M). Example 5 10-(3-Cyclopropyl-l,2J4-oxadiazol-5-yl)-3-methoxy-9H-imidazo[l,5-a] [1,2,4] triazolo[4,3-^[l,4]benzodiazepine StepJ 3-(3-Cyclopropyl-[l,2J4]oxadiazol-5-yl)-S-(2,4-dimethoxy-benzyl)-8-methoxy-4,5-dihydro-2,5,10fc-triaza-benzo[e]azulen-6-one Hexamethyldisilazane (29 mL, 139 mmol) was dissolved in THF (250 mL), cooled to -70 °C, and treated slowly with a 1.6 M solution of n-BuLi in hexane (88 mL). After stirring for 15 min. at -70 CC, a solution of (£/2)-N'-(3-cyclopropyl-[l,2,4]oxadiazoI-5-ylmethyI)-N.N-dimethyl-formamidine (16.4 g, 840 mmol) in THF (50 mL) was added over 15 min. The resulting orange solution was stirred for 30 min. at -70 °C, then the crude toluene solution of the 2-chIoro-4-(2)4-dimethoxy-benzyl)-7-methoxy-3)4-dihydro-benzo[e][l,4]diazepin-5-one (13.5 g, 42 mmol) was added over 15 min. and stirring at -70 °C continued for 30 min. The reaction mixture was quenched at -70 °C with acetic acid (30 mL) and allowed to warm up to rt. Water (30 mL) was added and the deep red solution was heated at reflux for 2 h, and then evaporated. The residue was dissolved in CH2Cl2 (200 mL) and extracted with 1 N HCI and 10% NaHC03. The product crystallized directly from CH2CI2 upon concentration. Yield; 11 g (53 %). mp >240 °C. m/z 487 (M). Step 2 3-(3-Cyclopropyl-[l)2,4]oxadiazol-5-yl)-S-methoxy-4>5-dihydro-2,5,10&-tria2a-benzo[e]azulen-6-one 3-(3-Cyclopropyl-[l,2)4]oxadiazol-5-yl)-5-(2J4-dimethoxy-benzyl)-8-methoxy-4,5-dihydro-2,5J10Mriaza-benzo[e]azulen-6-one (5 g, 10.3 mmol) were dissolved in CH2CI2 (30 mL), cooled to 0 °C, then TFA (30 mL) was added, followed by trifluoromethanesulfbnic acid (2 mL, 22.9 mmol). The mixture was stirred for 4 h at rt, evaporated, the residue dissolved in CH2CI2 (100 mL), and extracted with 10 % NaHC03. The product precipitated upon evaporation of CH2C12. Yield: 3 g (§6 %); mp 245CC. m/z 337 (M). Step 3 [3-(3-Cyclopropyl-[l,2,4]oxadiazol-5-yl)-8-methoxy-4H-2,5,10fc-triaza-benzo[e]azulen-6-yl]-hydrazine 3-(3-Cyclopropyl-[l,2)4]oxadiazol-5-yl)-8-methoxy-4,5-dihydro-2,5,10fc-triaza-benzo[e]azulen-6-one (1 g, 3 mmol) and N.N-dimethyl-p-toIuidine (0.856 mL, 5.9 mmol) were mixed in toluene (25 mL), treated with phosphoryl bromide (0.935 g, 3.3 mmol), and refluxed for 15 h. Toluene was evaporated and the residue extracted with CH2CI2 (50 mL) and water (50 mL). The organic layer was dried, evaporated, redissolved in THF (50 mL), and treated with a 1 M solution of anhydrous hydrazine in THF (10 mL, 10 mmol) at reflux overnight. The mixture was evaporated and directly chromatographed on silica gel in CH2Cl2/MeOH 10:1. One obtained a light brow solid (0.4 g, 3S %). m/z 352 (MH+). Step 4 10-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methoxy-9H-imidazo[l,5- a][l,2,4]triazolo[4(3-d][l,4lbenzodiazepine [3-(3-Cyclopropyl-[lJ2)4]oxadia2oI-5-yl)-8-methoxy-4H-2,5l10b-triaza-benzo[e]azuIen-6-^IJ-hydrazine (0.1 g, 2.S mmol) and triethyl orthoformate (0.142 mL, 0.85 mmol) were refluxed in ethanol (8 mL) for 14 h. The resulting solution was cooled in ice and the white crystals filtered off. Yield: SO mg (78 %). mp 252 °C. m/z 361 (M). Example 6 10-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methyI-9H-iinidazo[l,5-fl][l)2,4]triazolo[4,3-d] [l,4]benzodiazepine Stepl 3-(3-CycIopropyI-[l,24Joxadiazo^5-yI)-5-(2,4-dimetfloxy-faenzyI}-8-methyI-4,5-dihydro-2,5,10&-triaza-benzo[e]azulene-6-one 4-(2,4-Dimethoxy-benzyl)-7-methyI-3)4-dihydro-lH-benzofe][l,4jdiazepine-2)5-dione (5.0 g, 14.7 mmol) and N,N-dimethyl-p-toluidine (6.4 mL, 44.0 mrnol) were mixed in toluene (50 mL) and heated to 100 °C. Then phosphorus oxychloride (4.0 mL, 44.0 mmol) was added dropwise and heating at 100 °C was continued for 2 h. After cooling the mixture was evaporated and dissolved in THF (2.0 mL) and used directly in the subsequent step. Hexamethyldisilazane (10.1 mL, 48.5 mmol) wcs dissolved in THF (60 mL), cooled under Argon to -70 °C, and treated slowly with a 1.6 M solution of n-BuLi in hexane (30.3 mL, 48.5 mmol). After stirring for 1 h at -70 °C, a solution of (£/Z)-N'-{3-cyclopropyl-[l,2,4]oxadiazol-5-ylmethyl)-N,N-dimethyl-formamidine (5.7 g, 29.4 mmol) in THF (2 mL) was added, and stirring continued for 1 hat-70 °C. Then a solution of 2-chJoro-4-(2,4-dimethoxy-ben2yl)-7-methyl-3,4-dihydro-benzo[e][l,4]diazepin-5-one(5.28 g, 14.7 mmol) (prepared as described above) was added at -70 CC, and subsequently allowed to warm up to 10 °C over 1 h, then cooled again to -30 °C. After 30 min, acetic acid (17 mL) was added at -30 °C and the suspension was allowed to warm up to room temperature and water (17 mL) added and the resulting mixture stirred at room temperature for 12 h. The mixture was evaporated and then redissolved in EtOAc (100 mL). This solution was then washed with HC1 {1 M, 2 x 50 mL) and sodium hydrogen carbonate (sat, 10 ml), dried (Na2S04) and evaporated. Filtration on silica gel eluting with EtOAc : Hexane (9:1). Yield: 4.8 g (69%). m/z 471 (M). Step 2 3(-3-Cyclopropyl-[l,2,4]oxadia2ol-5-yl)-S-methyl-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one 3-{3-Cyclopropyl-[l,2,4]oxadia2ol-5-yI)-5-(2,4-dimethoxy-benzyl)-8-methyl-4)5-dihydro-2,5,10k-triaza-benzo[e]azulene-6-one (17.5 g, 37.1 mmol) was suspended in CH2CI2 (100 mL), cooled in ice, and diluted slowly with trifluoroacetic acid (85.2 mL). The resulting solution was treated at 5 °C with trifluoromethanesulfonic acid (4.9 mL, 55.7 mmol). The red solution was stirred at room temperature for 4 h. The mixture was then evaporated and dissolved in CH2CI2 (100 mL), washed with sodium hydrogen carbonate (10 %, 2 x 50 mL) and the organic layer was dried (NaiSOi) and evaporated. Digestion in EtOAc (100 mL) followed by the slow addition of hexane (100 mL). The solid obtained was washed twice with EtOAc: Hexane (1:1,2 x 20 mL). Yield: 9.3 g (78 %) m/z 321 (M). Step 3 6-Chloro-3-(3-cydopropyl-[l)2,4]oxadiazol-5-yl)-S-thiomethyl-4flr-2,5,10&-triaza-bezo[e]azulene 3(-3-Cyclopropyl-[l)2,4]oxadiazol-5-yl)-8-methyl-4,5-dihydro-2,5110&-triaza-benzo[c]a2ulene-6-one (9.3 g, 28.8 mmol) and N,N-dimethyl-p-toluidine (12.5 mL, 86.5 mmol) were mixed in chlorobenzene (100 mL) under argon. Phosphorus oxychloride (4.0 mL, 43.2 mmol) was then added at room temperature and the resulting mixture heated under reflux for 2 h. After cooling, the mixture was evaporated and then extracted with CH^CIT (100 mL) and water (50 mL). The organic layer was separated, dried (Na2S04) and evaporated. Chromatography on silica gel eluting with CH2G2 : Acetone (30:1). Yield: 3.8 g(39%).m/z340(MH+). Step 4 10-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methyl-9H-imidazo[l,5-a][l,2,4]triazolo[4,3-(i][l,4]benzodiazepine A mixture of 6-chloro-3-(3-cyclopropyl-[l,2,4]oxadiazol-5-yl)-8-thiomethyl-4H-2,5,10b-triaza-bezo[e]azulene (3.0 g, 8.8 mmol), formylhydrazine (1.1 g, 17.7 mmol) and N,N-ethyldiisopropylamine (1.5 mL, S.8 mmol) in chlorobenzene (30 mL) was heated under reflux for 2.5 h. After cooling, the mixture was evaporated and then extracted with CH2Q2 (100 mL) and water (50 mL). The organic layer was separated, dried (Na2SC>4) and evaporated. Chromatography on silica gel eluting with CH2CI2: Acetone (30:1). Yield: 2.4 g (80%). m/z 346 Example 7 10-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-3-bromo-9H-irnidazo[l,5-a][l,2,4]triazolo[4,3-d) {l,4]benzodiazepine Steps 1 and 2 ' 3-(3-Cyclopropyl-[I,2,4]oxadiazol-5-yl)-5-(2,4-dimethox>r-benzyl)-S-bromo-4,5-dihydro- 2,5,10£>-triaza-benzo[eJazulene-6-one 4-(2,4-Dimethoxy-benzyl)-7-bromo-3,4- toluene (20 mL) and heated to 100 °C. Then phosphorus oxychloride (3.4 mL, 37.0 mmol) was added dropwise and heating at 100 °C was continued for 2 h. After cooling the mixture was evaporated and dissolved in THF (20 mL) and used directly in the subsequent step. Hexamethyldisilazane (8.5 mL, 40.7 mmol) was dissolved in THF (60 mL), cooled under Argon to -70 °C, and treated slowly with a 1.6 M solution of n-BuLi in hexane (25.5 mL, 40.7 mmol). After stirring for 1 h at -70 °C, a solution of {£/Z)-N'-(3-cyclopropyi-[lJ2,4]oxadiazol-5-ylmethyl)-N,N-dimethyl-formamidine (4.8 g, 24.7 mmol) in THF (2 mL) was added, and stirring continued for 1 h at -70 °C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-bromo-3)4-dihydro-benzo[e][l,4]diazepin-5-one (5,26 g, 12.4 mmol) (prepared as described above) was added at -70 °C, and subsequently allowed to warm up to 10 °C over 1 h, then cooled again to-30 °C. After 30 min, acetic acid (14 mL) was added at -30 °C and the suspension was allowed to warm up to room temperature and water (14 mL) added and the resulting mixture stirred at room temperature for 1.5 h. The mixture was evaporated and then redissolved in EtOAc (100 mL). This solution was then washed with HCI (1 M, 2x50mL) and sodium hydrogen carbonate (sat., 10 ml), dried (NaiSCi) and evaporated. Filtration on silica gel eluting with EtOAc: Hexane (9:1). Yield: 2.0 g (31 %). m/z 536/538 (M). Step 3 3(-3-Cyclopropyl-[l,2,4]oxadiazol-5-yl)-8-bromo-4,5-dihydro-2,5,10&-triaza-benzo [e] azulene-6-one 3-(3-Cyclopropyl-[l,2,4]oxadia2ol-5-yl)-5-(2,4-dimethoxy-benzyl)-8-bromo-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one {1.1 g, 2.0 mmol) was suspended in CH2C12 (6 mL), cooled in ice, and diluted slowly with trifluroacetic acid (4.7 mL). The resulting solution was treated at 5 °C with trifiuoromethanesulfonic acid (266 j.tL, 3.0 mmol). The red solution was stirred at room temperature for 1.5 h. The mixture was then evaporated and dissolved in CH2CI2 (10 mL), washed with sodium hydrogen carbonate (sat., 10 mL) and the organic layer was dried (Na^SC^) and evaporated. Trituration with EtOAc. Yield: 772 mg (100 0/0). m/z 3S5/387 (M-H"). itep4 )-Chloro-3-(3-cyclopropyl-[l,2,4]oxadiazol-5-yl)-8-bromo-4H-2,5,10b-tria2a- >enzo[e]azulene i(-3-Cyclopropyl-[l,2,4]oxadiazol-5-yl)-S-bromo-4,5-dihydro-2,5f10&-triaza-3enzo[e)azu\ene-6-one (1.1 g, 20.3 mmol) and N,N-dimethyl-p-to3uidine (881 uL, 6.1 nmol) were mixed in chlorobenzene (8 mL) under Argon. Phosphorus oxychloride (279 it, 3.1 mmol) was then added at room temperature and the resulting mixture heated -mder reflux for 2.5 h. After cooling, the mixture was evaporated and then extracted with CH2CI2 (50 mL) and water (25 mL). The organic layer was separated, dried (Na2S04) and evaporated. Chromatography on silica gel eluting with CH1CI2: Acetone (30:1). Yield: 550 mg (67 %). m/z 403/405 (M-H'). Step 5 10-(3-Cyclopropyl-l,24-oxadiazol-5-yl)-3-bromo-9H-imidazo[l,5-i3][l^J4]triazolo[4,3-d] [ 1,4] benzodiazepine A mixture of S-chloro-S-tS-cyclopropyHl^^oxadiazol-S-y^-S-bromo-iH-2,5,10b-triaza-bezo[e]azulene (150.0 mg, 0.37 mmol), formylhydrazine (245.0 mg, 0.41 mmol) and N,N-dimethyl-p-toluidine (59 uL, 0.41 mmol) in chlorobenzene (6 mL) was heated under reflux for 3 h. After cooling, the mixture was evaporated. Chromatography on silica gel eluting with CH2CH3: acetone (30 :1). Yield: 94 mg (62 %). m/z 410/412 (M). mp 259-261 °C Example 8 10-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methylsulfanyl-9H-imidazo[l,5-fl][l,2,4]triazolo[4,3-(J][l14]benzodiazepine Stepl 6-MemylsulfanyI-lH-benzo[tf|[l,3]oxazine-2,4-dione This intermediate is known and may be prepared by methods, known in the art, for example in the following way: A mixture of 2-amino-5-methylbenzoic acid (4.9 g, 26.7 mmol) and ethyl chloroformate (2.9 mL, 30.0 mmol) in dioxane (25 mL) was heated under reflux for 2 h. After cooling, acetyl chloride (2.3 mL) was added and heating under reflux continued for another 3 h. After cooling, the mixture was evaporated and the resulting solid digested with tert-butyl methyl ether : heptane (1:1,20 mL) by heating under reflux for 1 h. The soild was then filtered off and washed with tert-butyl methyl ether : heptane (1:1,10 mL). Yield 4,8 g (85 %). m/z 208 (M-H-)- Step 2 4-(2,4-Dimethoxy-benzyl)-7-methylsulfanyl-3,4-dihydro-lH-benzo[c][l,4]diazepine--2,5- dione A suspension of 6-memylsuIfanyl-lH-benzo[rf][l,3]oxazine-2,4-dione (4.8 g, 23 mmol) containing (2,4-dimemoxy-benzyIamino)-acetic acid (5.6 g, 25 mmol) in p-xylene (50 ml) was heated under reflux {150 °C) for 3 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (2 x 20 ml). Yield: 7.5 g (89 %). m/z 373 (MH+). Step 3 2-Chloro-4-(2J4-dimethoxy-benzyl)-7-rnediylsulfanyi-3J4-dihydro-benzo[e][l,4]diazepin-5-one 4-{2J4-Dimethoxy-benzyl)-7-methylsulfanyl-3J4-dihydro-lJi'-benzo[£]ll,4]diazepine-2,5-dione (630 mg, 1.7 mmol) and N,N-dimethyl-p-toluidine (489 uL, 3.4 mmol) were mixed in toluene (5 mL) and heated to 100 °C. Then phosphorus oxychloride (170 ul, 1.9 mmol) was added dropwise and heating at 100 °C was continued for 1 h. The resulting dark red solution was used directly in the subsequent step. Step 4 3-(3-Cyclopropyl-[l,2,4]oxadiazol-5-yl)-5-(2>4-dimethoxy-benzyl)-8-methylsulfanyl-4)5- dihydro-2,5,10fc-triaza-benzo[e]azulen-6-one Hexamethyldisilazane (1.2 mL, 5.6 mmol) was dissolved in THF (10 mL), cooled under argon to -70 °C, and treated slowly with a 1.6 M solution of n-BuLi in hexane (3.5 mL, 5.6 mmol). After stirring for 1 h at -70 °C, a solution of (E/Z)-N'-(3-cycIopropyl- | l^^Joxadiazol-S-ylmethylJ-N.N-dimethyl-formamidine (0.66 g, 3.3 mmol) in THF (30 mL) was added, and stirring continued for 1 h at -70 °C. Then a solution of 2-chloro-4- (2,4-dJmethoxy-ben2yl)-7-methylsulfanyl-3,4-dihydro-benzo[e][l,4]diazepm-5-one(0.67 g, 1.7 mmol) (prepared as described above) was added at-70 °C, and subsequently allowed to warm up to at 10 °C over 1 h, then cooled again to —30 °C. After 30 min, acetic acid (4 mL) was added at -30 "C and the suspension was allowed to warm up to room temperature and water (4 mL) added and the resulting mixture heated under reflux for 6 h. After cooling, the mixture was evaporated and then redissolved in CHjCHi (20 mL). This solution was then washed with HC1 (1 M, 2 x 30 mL) and sodium hydrogen carbonate (sat., 30 ml), dried (NaiSCi) and evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 0.29 g (34 %). m/z 504 (MH*). Step 5 a i*.r*rA——«"i-ri,2)4]oxadiazol-5-yl)-S-methylsulfanyl-4,5-dihydro-2)5,10b-triaza- benzo [e] azulen-6-one 3-(3-Cyclopropy,I-[l,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxy-benzy'])-S-methy'lsulranj'l-4)5-dihydro-2,5,10i'-triaza-ben2o[e]azulen-6-one (280 mg, 0.6 mmol) was suspended in CH3Q2 (5 mL), cooled in ice, and diluted slowly with trifluroacetic acid (1.3 ml). The resulting solution was treated at 5 °Cwith trifluoromethanesulfonic acid (74 uL, 0.8 mmol). The red solution was stirred at room temperature for 1.5 h. The mixture was then evaporated and dissolved in CH2CI2 (10 mL), washed with sodium hydrogen carbonate (sat, 10 mL) and the organic layer was dried (Na2S04) and evaporated. Trituration with EtOAc. Yield: 160 mg (81 %). m/z 354 (MH+). Step 6 and 7 6-Bromo-3-(3-cycIopropyl-[l,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4H-2,5,10fo-triaza-bezo[e]azulene and [3-(3-Cyclopropyl-[l,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4H-2,5,10&-triaza-benzo[e]azulen-6-yl]-hydrazine 3-(3-CycIopropyl-[l>2)4]oxadiazol-5-yl)-8-methylsuEfanyI-4,5-dihydro-2,5,106-triaza-benzo [e]azulen-6-one (160 mg, 0.45 mmol) and N,N-dimethyl-p-toluidine (131 uL, 0.9 mmol) were mixed in toluene (5 mL), treated with phosphoryl bromide (143 mg, 0.5 mmol) and refluxed for 5 h. After cooling, the mixture was evaporated and the residue was extracted with CH2CI; (10 mL) and water (10 mL). The organic layer was separated, dried (Na2S04) and then evaporated. The residue was redissolved in THF (10 mL) and treated with an anhydrous solution of hydrazine (1 M, in THF, 1.6 mL, 0.16 mmol) and the resulting mixture heated under reflux for 12 h. After cooling the mixture was evaporated and the solid used directly in the next step, m/z 368 (MH-1"). Step 8 10-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methylsulfanyl-9H-imidazo[l,5- a] [l,2,4]triazolo[4,3-d] [l,4]benzodiazepine A mixture containing [3-(3-cyclopropyl-[lJ24]oxadiazol-5-yl)-8-methylsulfanyl-4H-2f5,10b-triaza-benzo[e]azulen-6-yl]-hydrazine (210 mg, 0.57 mmol) and triethyl orthoformate (2S5 ul, 1.7 mmol) in ethanol (8 mL) was heated under reflux for 3 h. After cooling, the mixture was evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 43 mg (20 %) m/z 377 (M). mp 164-166 QC yellow solution was evaporated and the residue purified by chromatography on silica gel in CH2Cl2/acetone 20:1. One obtained a white foam (3.5 g, 61 %). m/z 408 (MH+) Step 3 8-Chloro-5-(2,4-dimethoxy-benzylJ-N-hydroxy-6-oxo-5,6-dihydro-4H-2,5,10&-triaza-benzo[e]azulene-3-carboxamidine 8-Chloro-5-(2,4-dimethoxy-benzyl)-6-oxo-5,6-dihydro-4H-2,5,10&-triaza-benzo[e]azulene-3-carbonitrile (2g, 4.9 mmol) and hydroxylamine HC1 (1 g, 14.6 mmol) were suspended in DMF (10 mL) and treated slowly with a 5.4 M solution of sodium methylate in methanol (2.7 mL, 14.6 mmol). The yellow suspension was stirred overnight. The suspension was cooled in ice and diluted with water (20 mL) and stirred for 1 h in ice. The crystals were filtered off and washed with cold water (5 mL). One obtained white crystals (1.9 g, 89 %). m/z 442 (MH+). Step 4 8-Chloro-3-(5-cyclopropyl-[l,2)4]oxadiazol-3-yl)-5-(2,4-dimethoxy-benzyl)-4,5-dihydro-2,5,10b- triaza-benzo[e]azulen-6-one 8-Chloro-5-(2)4-dimethoxy-benzyl)-N-hydroxy-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxamidine (1.9 g, 4.3 mmol), magnesiumoxide (0.156 g, 3.9 mmol), and cyclopropanecarbonyl chloride (0.5 mL, 5.3 mmol) were refluxed in dioxane overnight. Dioxane was evaporated and the residue dissolved in DMF (20 mL) and refluxed for 1 h. DMF was evaporated and the residue extracted with CH2CI2 and water. The product crystallized upon concentration of the organic layer and dilution with ethyl acetate. One obtained a white solid (0.8 g, 39 %). mp 198-205 °C. m/z 492 (MH+). Step 5 S-Chloro-3-(5-cyclopropyl-[l,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,30b-triaza-benzo [ e] azulen-6-one 8-Chloro-3-(5-cyclopropyl-[l,2,4]oxadiazol-3-yl)-5-(2,4-dimethoxy-benzyl)-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (2 g, 4 mmol) was dissolved in CH2CI2 (S mL) and trifluoroacetic acid (8 mL), cooled in ice and treated slowly with trifluorometanesulfonic acid (0.7 mL, 8 mmol) and then stirred for 2 h without cooling. The solvents were evaporated and the residue extracted with CH2CI2 and water. From the organic layer one obtained a white foam (0.S4 g, 62 %). m/z 342(MH+). Step 6 6,8-Dichloro-3-(5-cyclopropyl-[l12)4]oxadia2ol-3-yl)-4H-2,5,10b-triaza-benzo[e]azulene 8-Chloro-3-(5-cyclopropyl-[l,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-triaza- ' :me (0.S4 g, 2.5 mmol) was suspended in chlorobenzene {8 mL), N,N- dimethyl-p-toluidine (1.1 mL, 7.4 mmol) and phosphorus oxychloride (0.34 mL, 3.7 mmol) were added and the mixture was refluxed overnight. The resulting solution was evaporated and the residue was purified by chromatography on silica gel in CH2Cl2/acetone 10:1. One obtained a white solid (0.56 g, 63 %). mp 200 °C. m/z 359(M). Step 7 3-Chloro-10- (5-cyclopropyl-1,2,4-oxadiazol-3-yl)-9H-imidazo [ 1,5-a] [ 1,2,4] triazolo [4,3-d] [l,4]benzodiazepine 6,8-Dichloro-3-(5-cyclopropyl-[l,2,4joxadiazol-3-yl)-4H-2,5,10&-triaza-benzo[e]azulene (70 mg, 0.194 mmol), formylhydrazine (23 mg, 0.39 mmol) and N-ethyldiisopropylamine (0.066 mL, 0.39 mmol) were mixed in chlorobenzene and refluxed for 3.5 h. The solvent was evaporated, the residue extracted with Cr^Cli/water and then purified by chromatography on silica gel in CEbCk^-propanol 20:1. One obtained a white solid (36 mg, 50 %). mp >230 °C. m/z 365(M). Example 61 3-Chloro-10- (5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7- (lH-indol-3-ylmethyl)-9H- imidazo [ 1,5-a] [ 1,2,4] triazolo [4,3-d] [ 1,4] benzodiazepine Analogously to example 60 using indole-3-acetic acid hydrazide, white foam, m/z 499(MH+). Example 62 3-Chloro-10-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-7-(4-dimethylamino-benzyl)-9H-imidazo[l,5-a] [l,2,4]triazolo[4,3-d] [1,4] benzodiazepine Analogously to example 60 using using (4-dimethylamino-phenyl)-acetic acid hydrazide, white solid, m/z 495(MH+) Example 63 7-Benzyl-3-chloro-10-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-9H-imidazo[l,5- a] [ 1,2,4] triazolo [4,3-d] [l,4]benzodiazepine Analogously to example 60 using phenylacetic acid hydrazide, white solid, m/z 456(MH+) Example 64 3-Chloro-7-cyclopropylmethyl-10-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-9H-imidazo[l,5- a] [l,2,4]triazolo[4,3-d] [1,4] benzodiazepine Analogously to example 60 using cyclopropyl-acetic acid hydrazide, white solid, m/z 420 (M) Example 64 3-Chloro-10- (5-cyclopropyl-l ,2,4-oxadiazol- 3-yl)-7- (3,4-dimethoxy-benzyl)-9H-imidazo[l,5-a] [ 1,2,4] triazolo[4,3-d] ^^benzodiazepine Analogously to example 60 using 3,4-dimethoxy-phenyIacetic acid hydrazide, colorless gum, m/z 515 (M). Example 65 3-Chloro-10-(5-cyclopropyl--lI2,4-oxadiazol-3-yI)-7-(5-methyl-lH-indol-3-ylmethyl)-9H-imidazo[l ,5-a] [ 1,2,4] triazolo [4,3-d] [ 1,4] benzodiazepine Analogously to example 60 using (5-methyl-lH-indol-3-yl)-acetic acid hydrazide, brown solid, m/z 509 (M). Example 66 3-Chloro-10-(5-cycIopropyl-l,2,4-oxadiazol-3-yl)-7^3-methox7-berizyl)-9H-irrudazo[l,5-a] [ l?2,4]triazoIo[4,3-d] [l,4]benzodiazepine Analogously to example 60 using 3-methoxy-phenylacetic acid hydrazide, white foam, m/z 485 (M). Example 67 Ethyl 3-hydroxy-9H-imidazo[l,5-*i][l)2,4]triazolo[4,3-^[l>4]-benzodiazepine-10-carboxylate Step 1 6-Hydroxy-lH-benzo[d][l,3]oxazine-2,4-dione 5-Hydroxyanthranilic acid (9.5 g, 62 mmol) was suspended in dioxane (50 mL), bis (trichloromethyl) carbonate (6 g, 20 mmol) was added (slightly exothermic), the suspension was refluxed for lh, allowed to cool to rt, the solid was filtered off and washed with dioxane, affording brown crystals {10.1 g, 90 %), mp. 236 °C (dec). Step 2 6-((ert-Butyl-diphenyl-silanyloxy)-lH-benzo[d][l,3]oxazine-2,4-dione 6-Hydroxy-lH-benzo[d][l13]oxazine-2,4-dione (9.7 g, 54 mmol), tert-butyldiphenylchlorosilane (15.2 mL, 59 mmol) and imidazole (4 g, 59 mmol) were stirred inDMF (100 mL) for 24 h at rt. The reaction mixture was extracted with ethyl acetate (400 mL) and water 300 mL). The product in the organic layer was purified by chromatography on silica gel in hexane/ethyl acetate 2:1 and then crystallized from hot ethyl acetate/hexane, affording white crystals (13 g, 58 %), mp. 185 °C. step 3 7- (t ert-Butyl-diphenyl-siIanyloxy)-4-(2,4-diroethoxy-ben2yl)-3,4-dihydro- 1H- benzo [e] [1,4] diazepine-2,5-dione Analogously to example 1 (step 2), the crude product was purified by chromatography on silica gel in hexane/ethyl acetate 1:1, affording a white foam in SO % yield. 5S0 (M). Step 4 8- (tert-Butyl-diphenyl-silanyloxy) - 5- (2,4-dimethoxy-benzyl) -6-oxo-5,6-dihydro-4H- 2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester Analogously to example 1 (step 3 and 4), the crude product was purified by chromatography on silica gel in hexane/ethyl acetate 1:2, affording a yellow foam in 54 % yield. 675 (M). Step 5 8-(tert-Bu1yl-diphenyl-silanyloxy)-6-oxo-5,6-dihydro-4H-2,5,10b-triaza- benzo[e]azulene-3-carboxylic acid ethyl ester Analogously to example 1 (step 5), limiting the reaction time to 1 h, the crude product was purified by chromatography on silica gel in dichloromethane/2-propanol 30:1, affording a white foam in 65 % yield. 526 (MH+). Step 6 8-(£erf-Butyl-diphenyl-silanyloxy)-6-chloro-4H-2,5,10fc-triaza-benzo[c]azulene-3- carboxylic acid ethyl ester Analogously to example 1 (step 6), the crude product was purified by chromatography on silica gel in hexane/ethyl acetate 1:1, affording a white foam in 10% yield. 543 (M). Step 7 Ethyl 3-(rert-butyl-diphenyl-silanyloxy)-9H-imidazo[l)5-a][l,2,4]triazolo[4,3-d][l,4]- benzodiazepine-10-carboxylate Analogously to example 1 (step 7), the crude product was purified by chromatography on silica gel in ethyl acetate, affording white crystals in 46 % yield, mp 233 °C. Step 8 Ethyl 3-hydroxy-9H-imidazo[l,5-fl][l,2,4]triazolo[4,3-rf][l,4]-benzodiazepine-10- carboxylate Ethyl 3-(ferf-butyl-diphenyl-silanyloxy)-9H-imidazo[lJ5-n][l,2,4]triazolo[4,3-d] [1,4]- benzodiazepine-10-carboxylate (155 mg, 0.28 mmol) was stirred in an 1 M solution of tetrabutylammonium fluoride (1 mL) for 30 min. The mixture was extracted with Hiz-KinrrtmotVioriB and water. The crude product was purified by chromatography on silica gel in DCM/MeOH 40:3. One obtained white crystals (55 mg, 62 %), mp >250 °C, 310 (M-H)Example 69 Ethyl 3-chloro-7-(pyridin-4-ylmethyl)-9H-imidazo[l,5-a] [l,2,4]triazolo[4,3-i] [1,4]- benzodiazepine-10-carboxylate Analogously to example 4 (Method B) using 4-pyridine-acetic acid hydrazide dihydrochloride, light brown solid, mp 213 °C, m/z 421(MH+). References C) Hunkeler, W.; Kyburz, E;. EP 150040 (2) Rogers-Evans, M.; Spurr, P.; EP 787729 (3) Zhang, P.; Zhang, W.; Liu, R.; Harris, B.; Skolnick, P.; Cook, J. M. /. Med. Chem. 1995, 3S, 1679-88. (4) Gerecke, M.,; Kyburz, E.; Borer, R..; Gassner, W.; Heterocycles, 1994, 39, 693-721. Example C Suppositories of the following composition are manufactured: mg/supp. Active substance 15 5 Suppository mass 1285 Total 1300 The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of 10 suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil. WE CLAIM: 1. A compound of the general formula wherein R1 is hydrogen, halogen, C1.7-alkyl, C1-7-alkoxy, hydroxy, cyano, trifluoromethyl, trifluoromethoxy or C1-7 alkylthioc; R2 is -C(O)O- C1-7-alkyl, tsoxazol, l,2,4-oxadiazol-3-yl oc l,2,4-oxadiazol-5-yl, which rings may be substituted by C1-alkyi, trifluoromethyl or C3-7- cycloalkyl; R1 is hydrogen, C1-7-alkyl, -(CH2)„- C1-7cydoalky!, -(CH2)n-halogen, -(CH2)n-pyridin-4-yl, or -(CH3)„-phenyl, wherein the phenyl ring may be substituted by one or two substituents selected from the group consisting of C1.7-alkoxy, halogen, -SOjCH3, phenyl, OCFs, nitxo, CF3, -NR3, or is -(CHa)a-indolyl, optionally substituted by Ci-T-alkyi or Q.r-alkoxy, or is pyrrolidinyl-5-oxo, -C(0)-NR2> -(CH0n-OH, -(CH2)n-NRi or -(CH2)n-benzo[l,3]dioxole; R is hydrogen or Ci-7-alky!; and n is 0, 1, 2 or 3; and their pharmaceutical!/ acceptable acid addition salts, with the exception of the following compounds: Ethyl 9H-imidazo[l,5-a][l,2,4]triatolo[3,4-(f][l,4]benzodiazepine-10-carboxylate, 10-(3-cyclopropyM,2,4-oxadiazol-5-yl)-9H-imidazo[l,5-a][l,2,4]triazolo[4,3- 4} [ 1 ^benzodiazepine, n is independently from each other 0, 1,2 or 3; and their pharmaceutical^ acceptable acid addition salts, with the exception of the following compounds: ethyl 7-hydroxymethyl-3-methoxy-9H-imidazo[l,5-a] [l,2,4]triazolo[4,3-d][i,4]-benzodiazepine- 10-carboxylate, ethyl 3-methoxy-7-(3-methoxyfaenzyl)-9H-imidazo[l)5-fl][l,2,4]triazolo[413-d][l,4]- benzodiazepine-10-carboxylate, ethyl 3-methoxy-7-[(7-methoxy- lH-indoI-3-yl) methyl] -9H-imidazo[l,5- a][ 1,2,4] triazolo[4,3-£J3 [1,4] -benzodiazep in e-10-carboxylate, ethyl-3-bromo-7-(lH-indol-3-ylmethyl)-9H-imidazo[l,5-fl][l)2,4]triazolo[4,3-d][l14]-benzodiazepine-LO-carboxylate, ethyl-3-bromo-7-(3-methoxy-benzyl)-9H-imidazo[lJ5-fl][l,2)4]triazolo[4,3-d][l,4]-benzodiazepine-10-carboxylate, ethyl 7-t2-benzo[l,3]dioxol-5-yl)-ethyl]-3-chloro-9H-imidazo[l,5-a][l12,4]tria2olo[4,3-fJ][l,4}-benzodiazepine-10-carboxylate, ethyl 7-f4-methanesulfonyl-benz)d)-3-methoxy-9H-imidazo[l,5-a][l^J4]triazolo[4,3- tf][l,4]-benzodiazepine-10-carboxylate, ethyl 3-methoxy-?-Kbiphenyl-4-y3)meth^]-9W-imida2o[l,5-flKi.2,4]triazolo[4,3-^ [1,4]- benzodiazepine-10-carboxylate, ethy! 3-methoxy-7-(4-trifluoromethoiy-benzyJ)-9H-imidazo[l,5-fl][I^,4]triazolo[4,3- d] [ 1,4] -benzodiazepine- 10-carboxyiate, ethyi3-chJoro-7-C4-nitro-benzyl)-9fi-iinida2o[lI5-a][l,2,4ltriazoIo[4,3-£/IU)4]- benzodiazepine-10-carboxylate, ethyl 7-(4-dimethylamino-benzyl)-3-methoxy-9H-imidazo[l,5-a}[ 1,2,4]triazolo[4,3- d)[l,4]-benzodia2epine-10-carboxyiateor ethyl 3-bromo-7-(4-dimethylamino-benzyi)-9H-imidazo[l,5-fl] [1,2,4]triazolo[4,3- d] [ 1,43-benzodiazepine-lO-carboxjdate. 8- The compound as claimed in claim 1, wherein R2 is the group 3-cyclopropyl-[l,2,4]oxadiazol-5-yl. 9- The compound as claimed in claim 8, wherein R3 is hydrogen and R1 is hydrogen, methoxy, methyl, -SCH3 or halogen. 10- The compound as claimed in claim 9, which is 10-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methoxy-9H-jmidazo[l15- a] [ 1,2,4]triazolo [4,3-d] [ 1,4]benzodiazepine, 10-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-3-methyl-9H-imidazo[l,5-a][l)2)4]triazolo[413-dl I ^benzodiazepine.

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