DD292914A5 - PROCESS FOR PREPARING DIAZEPINE DERIVATIVES - Google Patents

Abstract

Prepared are PAF antagonists of formula * (II) or (III) wherein A is optionally substituted benzene, pyridine, naphthalene, quinoline, thiophene, benzothiophene, pyrazole or isothiazole, {diazepine derivatives; PAF antagonists; orally active; antiallergic; entzuendungshemmend}

Description

Field of application of the invention

This invention relates to diazepine derivatives which are potent, orally active antagonists of platelet activating factor and, as such, have clinical utility for the treatment of allergic and inflammatory conditions, such as asthma and arthritis, respectively.

Background of the invention

The platelet activating factor (PAF, 10-Alkvl-Z-acetyl-sn-glyceryl-S-phosphorylcholine) is an ethorphospholipid whose structure was first elucidated in 1979. It is derived from pro-inflammatory cells, platelets, and the kidney In addition to potent platelet-aggregating activity, PAF exhibits a broad spectrum of biological activities, either directly or through the release of other potent mediators, such as thromboxane A ₂ or the leukotrienes, stimulated in vitro PAF the movement and aggregation of neutrophils and the release of tissue damaging enzymes and oxygen radicals from them.These activities contribute in vivo to PAF effects that correspond to its significant role in inflammatory and allergic responses, thus, it has been demonstrated that intradermal PAF induces inflammation that with pain, the accumulation of v on inflammatory cells and increased vascular permeability, which is comparable to an allergic skin reaction after exposure to an allergen. Similarly, both acute bronchoconstriction caused by allergens in asthma and chronic inflammatory reactions may be mimicked by intratracheal administration of PAF. Therefore, agents that antagonize the effects of PAF and thus also prevent mediator release by PAF have clinical utility in the treatment of many different allergic and inflammatory conditions, such as asthma and arthritis, respectively.

In addition to the above, it has been suggested that PAF is involved in many other medical conditions. Thus, in circulatory shock characterized by systemic hypotension, pulmonary hypertension, and increased vascular permeability of the lung, the symptoms may be mimicked by PAF infusion. This, together with evidence that circulating PAF levels are increased by endotoxin infusion, indicates that PAF is a major mediator in certain forms of shock. Intravenous infusion of PAF at doses of 20 to 20 ooMol kg "'min' ¹ leads to the formation of extensive haemorrhagic erosions of the gastric mucosa in rats, and thus PAF is the most potent gastric ulcerogen so far described whose endogenous release is due to various forms of gastric ulceration Psoriasis is an inflammatory and proliferative lesion characterized by skin lesions PAF is pro-inflammatory and has been isolated from lesioned dandruff of psoriatic patients, indicating that PAF plays a role in psoriatic disease Increased evidence of the potential pathophysiological role of PAF in cardiovascular disease: Recent studies in angina pactoris patients indicate that PAF is released during arterial rhythm formation, and in pigs, intracoronary PAF injection induces a long-lasting decrease in coronary flow, while si e induces regional shunt formation and ischemia in guinea pig hearts. PAF also has been shown to induce thrombus formation in an artery preparation of the mesentery, both in exogenous administration and in endogenous release. More recently, PAF has been shown to play a role in brain ischemia induced in animal models of stroke.

Object of the invention

Therefore, because of their ability to antagonize the effects of PAF, the compounds of this invention may well be of value in the treatment of any of the above conditions

 According to the invention, compounds of the formula (I), (II) or (III)

He c

(D

(II)

or

Hec

(III)

A is a fused benzene, pyridine, naphthalene, quinoline, thiophene, benzothiophene, pyrazole or isothiazole ring which may optionally be substituted by 1 or 2 substituents independently selected from C ₁ -C ₄ -alkyl, C ₄ -C ₇ cycloalkyl, Haiogen, perfluoro (C, -C ₄₎ alkyl, cyano, (Ci-C ₄ alkoxy) carbonyl, nitro, amino, amino substituted by (C | -C ₄ alkyl) sulfonyl, amino substituted by (C, -C ₄ alkyl) oxalyf, CHVAIkoxy ICT C ^ alkyDimino, hydroxy (C, -C ₄ alkyl), (C, -C ₄ - Alkoxy) -C, -C ₄ alkyl, (C 1 -C ₄ alkoxy) - (C ₂ -C ₄ alkoxy) -C, C ₄ alkyl, -CONR ⁶ R ⁶ , wherein R ⁶ and R ^e each independently is H or C ₁ -C ₆ alkyl, or Rs is H or C ₁ -C ₄ -Alkyl and R ₆ is C ₃ -C ₇ -Alkyl or 2-pyridyl, or R ⁶ and R ⁶ are joined to form a morpholino, pyrrolidino or piperidino group with the nitrogen atom to which they are attached, and phenyl, thienyl or pyridyl, optionally substituted by halogen, cyano, Trifluoromethyl, (C, -C ₄ alkoxy) carbonyl or carbamoyl;

X is O, S or NH;

Y is 1,4-phenylene or a group of formula / \ __;

Π 'is either H or C 1 -C ₄ -alkyl, optionally substituted by a substituent selected from phenyl, halophenyl,

Pyridyl, (C 1 -C ₄ alkoxy) carbonyl and di-C ₁ -C ₄ alkylamino, or C ₂ -C ₄ -alkyl substituted by hydroxyl or by an or

two C 1-4 alkoxy groups, or (CH ₂ JnCONR ⁷ R ⁸ wherein η = 1 to 4 and R ⁷ and R ^{8 are} each independently H or C 1 -C ₄ alkyl

mean;

R ^{2 is} H or C ₁ -C ₄ -alkyl; R ^{3 is} H or C 1 -C ₄ alkyl; B is a condensed 5-membered heterocyclic ring containing 1 to 4 nitrogen atoms or a condensed one

6-membered heterocyclic ring containing 2 nitrogen atoms means, wherein the fused 5 or 6 membered ring optionally substituted by 1 or 2 substituents independently selected from C, -C ₄ alkyl, C, -C ₄ haloalkyl,

Halogen and oxo;

and "Het" is either a 5-membered aromatic heterocyclic ring having 2 or 3 nitrogen atoms or a pyridine ring which may be optionally fused to a benzene or pyridine ring or to another 5-membered aromatic heterocyclic ring, at least one of these heterocyclic rings optionally containing a sulfur or Oxygen atom and at least one of these rings is optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₄ alkyl,

C ₁ -C ₄ alkoxy, halogen, CF ₃ , CN and formyl are selected;

and wherein the dashed line represents an optional bond and their pharmaceutically acceptable salts are provided.

Explanation of the essence of the invention

As used herein, the term "halogen" means fluoro, chloro, bromo or iodo.Alkyl and alkoxy groups having 3 or more carbon atoms may be straight or branched chain, and examples of the fused ring represented by A include benzene, dimethylbenzene, dichlorobenzene, nitrobenzene , Aniline, fluorobenzene, chlorobenzene, pyridine, quinoline, methylpyridine, dimethylpyridine, ethoxycarbonylpyridine, pyrid-2-yl-carbamoylpyridine, morpholinocarbonylpyridine, diethylcarbamoylpyridine, t-butylcarbamoylpyridine, thiophane, 2-methoxycarbonyl-5-methylthiophene, 1-methyl-C-phenylpyiazole , i-phenyl-3-methylpyrazole, i-methyl-3-t-butylpyrazole, 1,2-dimethylpyrazole, 1,3-dimethylpyrazole, 1-pyrid-2-yl-3-methylpyrazole, 1-t-butyl-3 -methylpyrazole, 1- (2-hydroxyethyl) -3-methylpyrazole, 1-methyl-3-pyrid-3-ylpyrazole, 1-methyl-3-pyrid-4-ylpyrazole, 1-methyl-3-pyrid-2-ol ylpyrazole, 1- (2-hydroxyethyl) -3-phenylpyrazole, 1- {2-methoxyethoxy) methyl-1-methylpyrazole, 1-methyl-3-cyclohexylpyrazole, 1-methyl-3- (t-butylhydroxymethyl) pyrazole, 1-methyl-3-hydroxymethylpyrazole, 3-cyclohexylpyrazole, 1-methyl-3- (3-isobutoxymethyl) pyrazole, 1-methyl-3- (4-chlorophenyl ) pyrazole, 1-methyl-3-isopropylpyrazole, 1-pyridyl-S-phenylpyrazole, 1-methyl-3- (2-chlorophenyl) pyrazole, 1-methyl-3- (3-trifluoromethylphenylpyrazole, 1 Methyl-3-thienylpyrazole, bromopyridine, 1-ethoxyethyliminobenzene, N-ethylsulfoxyaniline, 3-methylisothiazole and ethoxycarbonylcarbamidobenzene.

Examples of R 'are H, methyl, ethyl, benzyl, 4-chlorobenzene, -CH ₂ CO ₂ Et, -CH ₂ CH ₂ N (CH ₃ ) ₂ and CH ₂ CON (CH ₃ J ₂ , CH ₂ CH ₂ CH . (OCH ₃ I ₂ and 4-hydroxybutyl Examples of the condensed represented by B ring are imidazole, methyl imidazole, triazole, methyltriazole, Trifluormethyltriazol, triazolone, tetrazole, pyrimidone, imidazoline and tetrahydropyrimidine. ^D: is preferably hydrogen or methyl, R ³ is preferably Hydrogen or methyl.

Examples of "Het" are dimethyl pyridyl, 1,2,4-triazolyl optionally substituted with 1 or 2 C, C ₄ alkyl groups, and imidazolyl optionally substituted with up to 3 groups selected from C ₁ -C ₄ -A yl, halo and formyl, or optionally substituted with a C ₍ -C ₄ alkyl or CF ₃ group and fused to a benzene, thiazole or pyridine ring. "Het" is preferably 2-methylimidazo [4,5- c] pyrid-1-yl, 2,4,6-trimethylimidazo [4,5-c] pyrid-1-yl, 3, S-dimethyl-1,2,4-triazol-4-yl, 1,6- Dimethylpyrid-3-yl, 6-chloro-Z-methylimidazol-1-yl, 5-chloro-4-formyl-2-methylimidazol-1-yl or 4-methylimidazo [1,2-d] thiazol-5-yl.

Particularly preferred compounds are 8,9-dichloro-5- [4- (2-methyl-1H-imidazo [4,5-c] pyrid-1-yl) phenyl] -4H-imidazo [1,2-a] - (1,5) benzodiazepine, 8,9-dichloro-1-methyl-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -4 H -imidazo [1, 2-a) [1,5] benzodiazepine, 3,5-dihydro-2- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -5,7,9-trimethyl- 1 H -pyrido [2,3-b] [1,4-diazepin-4-one, 8-bromo-3,5-dihydro-1-methyl-2- [4- (2-methyl-imidazo [4,5-cl-pyrid-1] yl) phenyl-4H-pyridol2,3-b] (1,4) diazepin-4-one, 1,3-dihydro-1,8-dimethyl-6-methoxycarbonyl-4- (4- (2-methylimidazo [4 , 5-c] pyrid-1-yl) phenyl] -2H-thieno [3,4-b] [1,4-diazepin-2-one, 5- [4- (2-methylimidazo [4,5-clipyridine] 1-yl) phenylJ-1,6,7,8-tetrahydro-1,3,8-trimethyl-pyrazolo [3,4-bl [1,4] diazepin-7-one, 3-cyclohexyl-1,8- dimethyl-5- [4- (2-methylimidazo (4,5-c] pyrid-1-yl) phenyl-1,6,7,8-tetrahydropyrazolol3,4-b] [1,4] diazepin-7-one , 1,8-Dimethyl-5- [4- (2-methyl-imidazoKB-c-pyrid-i-y-phenyl-S-pyrid-S-yl-ihe-e-tetrahydro-pyrazoloO ^ -bJII-1-diazepine ^ -undundi.e) e tetrahydro-1,8-dimethyl-5- [4- (2-meth yl-1H-imidazo [4,5-clpyrid-1-yl) -phenyll-7-oxo-3- (3-pyridyl) pyrazolo [3,4-b) [1,4) diazepine. Of course, for the compound of formula (I), when R ^{2 is} H and the dotted line is a bond as shown in formula (I a), this formula may alternatively be written as formula (I b), these forms of the compound are tautomeric. Similarly, formula (Ha) may be written as formula (Nb) and formula (IIIa) as (HIb).

κ Υ.

Hel

I Ib)

Has

111 '.)

K γ

here

(Lib)

He c

(IIIb)

When R ^{1 is} H and X is NH, the compound of formula (Ic) can also be written as an alternative tautomeric form (I d):

Ke c

(Id)

(Ic)

Such compounds and their salts may be present as a tautomer or as a mixture of tautomeric forms, which are characterized by

physical measures, such as fractional crystallization or chromatography, can be separated. The invention includes all-separated or non-separated tautomers.

Compounds of formula (I b), (II b) and (ill b), wherein R ^{3 has} a meaning other than H, and compounds of formula (I), (II) and

(III) in which the dashed line is absent (ie, in the ring between R ³ and Y there is a single bond rather than a double bond) are chiral and therefore exist as pairs of isomers which can be separated by conventional means. The

Invention includes all of these - separate or non-separate - enantiomers. The pharmaceutically acceptable acid addition salts of the compounds of formula (I), (II) and (III) are selected from acids

formed, which form non-toxic addition salts, such as. As the hydrochloride, hydrobromide, sulfate or bisuifate, phosphate or

Acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulfonate and dimethanesulfonate, Benzenesulfonate and p-toluenesulfonate. A particularly preferred sol is the dimethanesulfonate of 8,9-dichloro-5- [4- (2-methyl-

1H-imidazo [4,5-c] pyrid-1-yl) phenyl] -6H-irnidazo (1,2-a] (1,5] benzodiazepine.

When the bond represented by the dotted line is in formula (I), X is O, R ^{1 is} H or alkyl and R ² and R ³ are H,

Compounds of formula (I) can be prepared according to the following synthesis:

4

Hey t

(IV)

(V)

(I)

wherein A, Y and Het are as defined above and Q is a separating group such as C, -C ₄ alkoxy. In a typical

Operation, the diamine (IV) and the compound (V) in a suitable anhydrous solvent, such as toluene, under

an inert atmosphere, such as nitrogen, for the duration necessary to complete the reaction, typically 5 hours, below

Refluxed, and after cooling, the resulting mixture is filtered and to form the product of formula (I) with

washed the solvent.

In the above synthesis, since the diamine (IV) has two identical amino groups, those having the corresponding carbonyl groups

of compound (V), two regio-isomers of compound (I) are generally formed; these isomers are only identical when the diamine (IV) is symmetrical about the attachment of ring A, which connects the amine-bearing carbon atoms. The different isomers are usually separated by chromatography.

Alternatively, where A is a substituted pyrazolo ring, the diamine (IV) and the compound (V) are first prepared in a suitable manner

anhydrous solvents such as toluene, optionally in the presence of a dehydrating agent such as silica gel, or in

Ethanol containing a catalytic amount of zinc chloride for a suitable duration, typically 20 to 24 hours, under reflux

heated, and then the solvent is removed under vacuum. The residue is then in an alcoholic

Solvent, such as ethanol containing a suitable sodium alkoxide dissolved and to stop the reaction at Room temperature stirred, whereupon the products are isolated and separated by conventional methods. In this synthesis, one of the amine groups of the substituted pyrazole (IV) having the keto group of compound (V) in the

The first step condenses, and in the second step the ring closure occurs to form the diazepine, as shown in the following scheme:

(IVi

4

! V, »iec

ZnCL / EtOH

He c

(I)

If desired, the intermediate compound (IV) can be isolated and purified before the second stage. When ring A in the compound of formula (I) carries an amino group as a substituent, the above synthesis can be carried out by using the corresponding nitro-substituted diamine of formula (IV), and the nitro group in the obtained compound (I) can then be purified by conventional methods be reduced to form the corresponding amine compound.

When ring A in the compound of formula (I) bears a carbamoyl group as a substituent, the compound may be prepared from the corresponding halo-substituent, such as bromo, bearing compound of formula (I) by reacting the halogen compound with the appropriate amine in a carbon monoxide atmosphere in the presence of a catalyst, such as tetrakis-triphenylphosphine-palladium, to convert the halo group to a carbamoyl group. When "Het" in formula (I) includes a formyl derivative of a heterocyclic group, the above synthesis can be carried out by using a compound (V) in which "Het" is the corresponding dloxolane derivative. The formyl derivative is obtained from the reaction of the compound (IV) and the dioxolane compound (V), followed by hydrolysis of the crude product. The compounds of formula (I) or (III) wherein X is O and R ^{1 is} other than hydrogen may be prepared from the corresponding compound in which R ^{1 is} H by treatment of the compound with the appropriate alkyl halide, phenyl-substituted alkyl halide, Esters of a halogen-substituted carboxylic acid or halogen-substituted amine or amide can be obtained. The halogen compound used is suitably the bromide or iodide. In a typical procedure, the compound of formula (I) or (III) in which R ^{1 is} H is dispersed in a suspension of sodium hydride in a dry solvent such as dimethylformamide under nitrogen, followed by addition of the halogen compound and continued Stir until completion of the reaction (typically 3 hours). Then, the reaction mixture with aqueous acid, for. Hydrochloric acid, and treating the product by washing with an organic solvent, neutralizing the organic layer, e.g. B. with aqueous sodium carbonate, and extracting the product with a solvent such as dichloromethane, are separated. The resulting extract may then be dried and concentrated, and the desired compound purified by flash chromatography.

The compounds of formula (I) wherein X is S may be prepared from the corresponding compounds in which X is O by treating the latter with phosphorous pentasulfide, typically by heating the oxo compound of formula (I) with P ₂ S ₅ in a dry solvent. such as pyridine, in an inert atmosphere, pouring the cooled solution into water and isolating the desired thioamide by filtering off the solid product, drying it by azeotropic distillation, dissolving the residue in dichloromethane, and eluting the solution through silica gel.

The compounds of formula (II) may be prepared from the compounds of formula (Ib) in which R ¹ and R ^{3 are} H, X is S and the dotted line represents a bond (formula Ie). In one operation, the compound of formula (Ie) is first allowed to react with hydrazine to form an intermediate compound of formula (VI):

NH.

+ · HK, .NH

Hey t

(Ie) (VP

This reaction can be carried out by heating the thioamide of formula (Ie) with hydrazine hydrate and either an acid such as p-toluenesulfonic acid or red mercuric oxide in a suitable solvent such as n-butanol, and the compound of formula (VI), if necessary, isolated by filtration and the filtrate concentrated under reduced pressure. The compound (VI) can be converted into a compound (II) according to the identity of the substituent (B) by various methods. When B oi is a condensed tetrazole ring, compound (II) can be obtained by diazotizing compound (VI), usually by treating with sodium nitrite in aqueous hydrochloric acid at low temperature, followed by neutralizing the solution, extracting compound (II) in an organic solvent such as ethyl acetate / butanol, drying and concentrating the extract, and purification by flash chromatography, followed by recrystallization:

NH.NH.

(VI)

When B is a fused 1,2,4-triazole ring which may be substituted by an alkyl or haloalkyl group, the compound (Vl) may be reacted with a trialkyl orthoformate and formic acid (to give the unsubstituted triazole) or the appropriate trialkyl orthocarboxylate and the corresponding carboxylic acid (to obtain a substituted triazole) are treated:

.NH. NH

R ¹¹ C (OAlk)

R ⁴ CO, H

uet

He c

(VI)

wherein R ^{4 is} H, C ₁ -C ₄ -alkyl or haloalkyl. In a typical procedure, the reactants combine to form

Refluxed, and the resulting mixture is dissolved in an aqueous acid, followed by extraction with a

organic solvents, such as ethyl acetate. The desired compound can be isolated by conventional methods on the extract.

When R ^{4 is} a trifluoromethyl group, the hydrazino diazepine compound (VI) can be reacted with trifluoroacetic acid to form the trifluoromethyl group

desired compound of formula (II) are reacted.

When B is a fused 3-oxo-i, 2,4-triazole ring, compound (II) can be prepared by treating a compound of formol (lo) with an alkyl carbazate such as ethyl carbazate to form an intermediate-stage carbazato (VII):

N.NH.CO jU

'Vl f)

Then, the compound (VII) can be cyclized in the presence of sodium hydride to the desired compound of the formula (IIc): O

This preparation is carried out by refluxing compound (Ie) with ethyl carbazate in the presence of p-toluenesulfonic acid in a solvent such as n-butanol, removing the solvent under reduced pressure, and purifying the residue by flash chromatography to obtain the intermediate-stage carbazate , This can then be dissolved in a dry solvent, such as tetrahydrofuran, followed by the addition of sodium hydride and stirring at room temperature to cyclize the interstage carbazate. The desired compound can then be extracted and purified by conventional methods.

When B is an unsubstituted imidazole ring, the compound (II) may be prepared from the corresponding compound of formula (Ie) by reacting the compound (Ie) with an acetal of aminoacetaldehyde such as aminoacetaldehyde dimethyl acetal in the presence of either p-toluenesulfonic acid or red Mercury II oxide in a suitable solvent, followed by ring closure, e.g. B. by treatment with conc. Sulfuric acid or formic acid, are prepared:

(Le)

₂ ClI (CCH ₃ J ₃

Hec

In one operation, the compound (Ie) is heated to reflux with aminoacaldehyde dimethyl acetal and either p-toluenesulfonic acid or red mercuric oxide in n-butanol in an inert atmosphere, and the mixture is cooled, diluted with methanol and, if necessary , filtered; the solvent is removed under vacuum and, if necessary, the intermediate is purified by flash chromatography. Then the intermediate stage in conc. Dissolved sulfuric acid and heated to 10O ⁰ C. The solution is then poured onto ice, neutralized and extracted with an organic solvent. The desired compound is recovered by concentrating the solvent and purifying by flash chromatography. The conc. Sulfuric acid can be replaced by formic acid.

Certain compounds in which B is a substituted imidazole ring can be prepared in a similar manner using the corresponding homologue of the aminoacetaldehyde acetal, e.g. 2-amino-1,1-diethoxypropane, to produce a methyl-substituted imidazole ring.

Other compounds (II) in which B is an imidazole ring substituted by a methyl group can be prepared from compound (Ie) by treating it with propargylamine in the presence of red mercuric L-oxide.

+ HC

Ϊ - Het

Y - Kec

In one procedure, compound (Ie) is refluxed with propargylamine and red mercuric oxide in n-butanol, the resulting mixture is diluted with methanol and filtered and concentrated to give the crude compound, which is purified by flash chromatography. Corresponding compounds in which the substituent on the imidazole ring is other than methyl can be prepared using the appropriate homologue of propargylamine. In a method of preparing compounds of formula (II) in which B is an imidazoline ring, a compound of formula (Ie) is reacted with ethanolamine to give a compound of formula (VIII) which can then be cyclized to the dihydroimidazole compound :

.OH

(VIII)

In one operation, the compound (Ie) is refluxed with red mercuric oxide and ethanolamine in a suitable solvent to give the compound (VIII), which is then separated and treated with triphenylphosphine and diethylazodicarboxylate in a nonaqueous solvent to close the compound Imidazoline ringes is treated. Substituted imidazoline rings can be formed in a similar manner using an appropriately substituted ethanolamine.

The same method can be used to prepare compounds of formula (II) in which B is a substituted or unsubstituted tetrahydropyrimidine ring using 3-amino-i-propanol or a substituted derivative thereof instead of ethanolamine.

When B is a pyrimidone ring, the compound (II) may be obtained by reacting a compound of the formula (Ie) with ammonia

Formation of the corresponding 2-amino compound of formula (IX) and reacting the latter prepared with methyl propiolate

become:

(IX)

Hcc

The compound of formula (I) may be heated with red mercuric oxide in an ammonia-saturated solvent and the resulting 2-amino compound is isolated and refluxed with methyl propiolate to form compound (II), which is then purified by conventional methods Methods is isolated.

The syntheses described above refer to compounds of formula (I), (II) or (III) in which the dotted line represents a bond. The corresponding compounds lacking this linkage, d. H. Compounds having a simple instead of a double bond at this point can be prepared by reducing the compound with a double bond. This reduction can z. B. by treatment of the double-bonded compound with Natriurncyanoborhydrid.

The above methods of preparation refer to compounds of formula (I), (II) or (III) in which R * = R ³ = H. These compounds can be converted to the corresponding compounds in which R ² or R ^{3 is} a C 1 -C ₄ alkyl group by reaction with the appropriate alkyl halide in the presence of sodium hydride in a non-aqueous solvent. Of course, for compounds of formula (I) or (II) wherein the dotted line represents a bond, proton removal gives R ² = H and X is O, an ambident anion attached to either the nitrogen and / or the carbon atom and / or the Oxygen atom, which depends on the compound in question, the reaction conditions and the alkyl halide used.

The activity of the compounds of the invention is demonstrated by their ability to inhibit the platelet aggregating activity of PAF in vitro. Testing is done as follows:

Blood samples are taken from the rabbit or human in 0.1 volume of disodium ethylenediamine tetraacetic acid buffer, and the samples are centrifuged for 15 minutes to obtain a platelet-rich plasma. The plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 mM KH ₁ PO ₄ , 6 mM Na ₂ HPO ₄ , 10 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) and then resuspended in buffer solution to a concentration of 2 x 10 * platelets / ml. A sample (0.5 ml) is preincubated for 2 min at 37 ° C. in a Paton Aggregometer with stirring, either with the vehicle alone or with a vehicle containing the particular test compound. PAF is added in sufficient concentration to give in the absence of the test compound a maximum aggregation response

(10 ~ ⁸ to 10 ~ ⁸ molar), and platelet aggregation is measured by monitoring the increase in light transmittance of the solution. The experiment is repeated in the presence of the test compound at a range of concentrations and the concentration of compound necessary to reduce the response to 50% of its maximum value is recorded as the IC _M value:.

The activity of the compounds of formula (I), (II) or (III) is also demonstrated in vivo by their ability to protect mice from the lethal effect of PAF injection. A mixture of PAF (5 (tyg / kg) and DL-propranolol (5 mg / kg) in 0.9% w / v sodium chloride is injected into mice via the tail vein (0.2 ml) The test compounds are either immediately before injection of PAF / propranolol injection into the tail vein or administered orally 2 hours earlier by gavage The compounds are tested at several doses in groups of 5 mice and the dose reducing mortality to 50% is recorded as the PD _M value ,

Furthermore, the compounds are tested for their ability to reduce PAF-induced bronchoconstriction in anesthetized guinea pigs. In this test, airway resistance and dynamic lung compliance are calculated from recordings of airflow and transpleural pressure and calculation of tidal volume. The bronchoconstriction induced by PAF (100ng / kg) is determined. One hour after the PAF start dose, the test compound is administered and the test is repeated. The ability of the compound to reduce the bronchoconstrictor effect of PAF is recorded as a ratio.

For therapeutic use, the compounds of formula (I), (II) or (III) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. The compounds may, for. B. orally in the form of tablets containing diluents such as starch or lactose, or in capsules or dragees, alone or in admixture with diluents, or in the form of elixirs or suspensions containing flavoring or coloring agents. You can parenteral, z. As intravenous, intramuscular or subcutaneous injected. For parenteral administration, they are best used in the form of a sterile aqueous solution containing other substances, e.g. For example, it may contain sufficient salts or glucose to make it blood isotonic. For administration to humans in the curative or prophylactic treatment of allergic bronchial conditions and arthritis, the oral doses of the compounds are usually in the range of 1 to 1000 mg daily for an average adult patient (70 kg). Thus, for a typical adult patient, single tablets or capsules contain from 1 to 500 mg of active compound in a suitable pharmaceutically acceptable vehicle or carrier. Doses for intravenous administration were typically in the range of 1 to 10 mg per single dose as needed. For the treatment of allergic and bronchial overreaction conditions, inhalation by nebulizer or aerosol may be the preferred route of administration of the drug. Dosages for this route, as needed, are usually in the range of 0.1 to 50 mg per single dose. The physician's experience will determine the actual dose most appropriate for an individual patient, and this will vary with the age, weight, and response of the particular patient. The above doses are examples of the average case, but of course there may be isolated cases where higher or lower dose ranges are favorable, and these are within the scope of this invention.

In a further aspect, therefore, the invention provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.

Further, the invention also includes a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof for use in medicine, in particular in the treatment of allergic and inflammatory conditions in a human.

embodiments

The preparation of the compounds of the invention is further illustrated by the following examples.

Example 1 2,3-Dlhydro-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1H- [1,5] benzodiazepin-2-one

A mixture of 1,2-diaminobenzene (1.389 g, 17.03 mmol) and ethyl 4 '- (2-methylimidazo [4,5 H: pyrid-1-yl) benzoylacetate (5.00 g, 15.48 mmol) in dry toluene (50ml) was heated to reflux for 5h under nitrogen. The mixture was cooled and the product was filtered off and washed with toluene to give a buff solid; 4,097g (72%), mp. 292 ⁰ C. Analysis for C ₂₂ H ₁₇ N ₆ CVJ H ₂ O calc .: C 70.19 H 4.82 N 18.61 Found .: C 70.31 H 4, 73 N 18.88

The following compounds (shown in Table 1) were similarly prepared from the appropriate 1,2-diaminobenzene and 4-heterocyclic substituted benzoylacetic acid ester.

TABLE 1

Ute

Be'.spiel Wet R ¹ R ² η ?. Analysis% (theory in parentheses) CHN 2 _, A » CH ₃ CH ₃ 238-239 ° C 70.51 5.56 16.56 (70.41 5.82 16.56) * 3 A ³ -Λ ö ^ - N C) Cl 22 2 -4 ⁰ C 59.23 3.59 15.38 (59.10 3.96 15.20) //.

NJ (O IS)

example llnC R ¹ R ² FP. Analysis% in brackets) N (Theory H C 16:31 CH- 5.89 4 A CH ₃ CH ₃ 279-281 ° C 73.65 16:54) -H IJ 5.95 \ / (73.73 ρ- "· 11:14 6.Π 11:37) 5 CH ₃ CH ₃ 253-5 * C 77.96 6.27 (78.02 18:15 CH A. 18 6 JL ' F 234-236 ^e C 68.81 18:17) -On '..18 W Il (68.56 <D \ - '> -M H ι ·· mixture receive

example IU: t CH ₃ "1 I i i Ch ₃ Mp. ^e C Analysis% in brackets) N 73 H Cl (Theory H 16th 05) ^f Cl H CH ₃ C 4.21 17th 7 mixture 203-205 64.47 4.17 receive * C (64.31 52 η Q CH ₃ 12th 55) ⁰ C .S. 3 3 12th 61 -On CH ₃ 240-242 70.97 5:42  i .. 76) (71.27 4.96 9 125-128 66.09 5:03 (66.49

example Hec . ' κ ² η ?. Analysis%. (Theory in brackets) CHN 10 Λ -NN Cl Cl 26O-262 ° C 56.83 3.89 16.73 A * (56.51) 4.Cl 17.04) 11 A '-A »W CH ₃ CII ₃ C ₃ 26O-262 ° C fto. /, 7 ή. on ly.SH AAHi (69.30 5.95 19.24)

# calculated for 0.3 StCH.0.5 H ₃ O solvate

I calcd for 0.5 H ₂ O solvate P calculates for 0.5 toluene

* "calculated for 0.4 EtCH.0.5 H ₃ O solvate

** calculated for 0.3 MeCH

*** calculated for 0.25 H-O

Example 12 2,3-Dihydro-4- [2- (2-methylimidazo [4,5-c] pyrid-1-yl) pyrld-5-ylJ-1H- [1,5] at) zodiazepine-2-one

CH.

The procedure of Example 1 was repeated using 1,2-diaminobenzene (86 mg, 0.76 mmol) and ethyl 2- (2-methylimidazo4,5-c] pyrid-1-yl) pyrid-5-oylacetate (260 mg, 0.8 oM mol). The crude product was purified by flash chromatography (eluting with ethyl acetate / methanol = 6: 1), followed by recrystallization from acetone to afford the title compound (40mg, 14%) as a buff solid, m.p. 208-210 ⁰ C. Analysis for C ₂₁ H. ₁₆ NeOVzH ₂ OO ^ eMe ₂ CO calc .: C 66.70 H 4.68 N 21.71% Found: C 66.90 H 4.45 N 21.62%

Example 13 2,3-Dihydro-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -6-nltro-1H- [1,5] benzodiazepine-2 -one

A mixture of 3-nitro-1,2-phenylenediamine (5 g, 33 mmol) and ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetate (9.7 g, 30 mmol) in 100 ml Toluene was heated at reflux for 16 h. After cooling, the red / orange

Precipitate (12g) filtered and washed with ether.

This material was used directly without further purification in Example 14 below; Mp. 200 ⁰ C 2.52 (3H, 2), 4.30 (2H, s) ((broad) ¹ H-NMR (300MHz, DMSO-d6), 6.68 (1H, m), 7.27 1H, d, J 5Hz), 7.82 and 8.29 (each 2H, d, J 8Hz), 8.33

(1H, d, J 5Hz), 8.92 (1H, s) and 9.70 (1H, brs).

Example 14 6-Amino-2,3-dlhydro-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) -phenylMH [1,5] benzodiazepine-2-one

NB

A solution of the product of Example 13 (10.3 g, 25 mmol) and stannous chloride dihydrate (28 g, 125 mmol) in 2m HCI (20 ml), ethanol (40 ml) and water (75 ml) was refluxed for 20 min, then stand at ambient temperature overnight (16h). The precipitated solids were filtered off, then the filtrate was adjusted to pH 6 by addition of saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried

(Magnesium sulfate) and concentrated to a solid (3 g).

Two crude batches were obtained as above was chromatographed on silica gel, eluting with a gradient of 2 to 10% diethylamine in ethyl acetate and gave the title compound as a yellow solid (3.7 g, 20%), mp. 259-263 ⁰ C.

Analysis for C ₂₂ H | _B Ne0.1 / 2 H ₂ O calc .: C 67.51 H 4.89 N 21.47% Found: C 67.63 H 4.86 N 21.56%

Example 15 2,3-Dlhydro-6- (1-ethoxyethyl-1-methyl) -4- [4- (2-methylimidazo [4,5-c] -pyrald-1-yl) -phenyl] -1H- [1,5] benzodiazepine 2-one

CH

A solution of the aniline of Example 14 (0.38 g, 1 mmol) and glacial acetic acid (0.5ml) in triethyl orthoacetate (5ml) WUR The 72 h at ⁰ C 2 S

touched. The product was filtered and recrystallized from toluene (60 mg, 13%). Mp 214-217 ⁰ C.

Analysis for C ₂₆ H ₂₄ N ₆ O ₂

calc .: C, 69.01; H, 5.35; N, 18.57; F: C, 60.78, H, 5.39, N, 18.34.

Example 16 2,3-Dlhydro-6-ethyloxalamldo-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1H- [1,5] benzodiazine-2-one

CH.

Oxalyl chloride (87 μL, 1 mmol) was added with stirring to a suspension of the aniline of Example 14 (0.19 g, 0.5 mmol) in chloroform (2 mL, containing 2% w / w ethanol). After 2 h, pyridine (0.3 g) was added and stirred again for 1 h. The mixture was partitioned between chloroform and sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (eluting with 5% methanol in chloroform) to give a white solid (75 mg, 31%), m.p. 269-273 ° C. Analysis for C ₂₆ H ₂₂ N ₆ O ₄ · '/ 2H ₂ O calc .: C 63.53 H 4.72 N 17.10% Found: C 63.57 H 4.48 N 17.19%.

Example 17 2,3-Dlhydro-6-ethanesulfonylamino-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1H- [1,5] benzodiazepl n-2 -one

CH.

A suspension of the aniline of Example 14 (0.5 g, 1.3 mmol) in dry pyridine (3 mL) was treated with ethanesulfonyl chloride (0.133 mL, 1.4 mmol). After 1 h, the mixture was concentrated to dryness, then between dichloromethane and

diluted aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated to a yellow solid which was recrystallised from ethyl acetate (0.37 g, 69%); Mp 258-260 ⁰ C.

Analysis for C ₂₄ H ₂₂ N ₆ O ₃ S · O ₂ ViH

bee: C 57.41 H4.43 N 16.04 S 6.13%

Found: C 57.58 H 4.86 N 15.75 S 6.63%.

Example 18 2,3-DIhydro-7,8-dlmethylo-4- [4- (5-chloro-4-formyl-2-methv-imidazole-1-vl) ρhenvll. 1H.x1.5] bθnzodlazepln.times.2on

CH.

A solution of 4- [5-chloro-4- (1,3-dioxolan-2-yl) -2-methylimidazol-1-yl) benzoylacetate from Preparation 5 (155 mg, 0.38 mmol) and 4,5-dimethyl 1,2-diaminobenzene (55 mg, 0.4 mmol) in toluene (4 mL) was heated to reflux for 4.5 h, then concentrated to dryness and purified by flash chromatography (eluting with ethyl acetate) to a pale yellow gum. 1 m HCI (2 ml) was added to the solution of the residue in THF (2 ml), and the mixture was 1 h at 7O ⁰ C heated. The THH was evaporated and the residue partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over magnesium sulfate and evaporated.

Flash chromatography (eluting with 2% methanol in ethyl acetate) gave a pale yellow solid (0.048 g, 31%). ¹ H-NMR (300 MHz, CDCl ₃ ): 2.34 (6H, brs), 2.40 (3H, s), 3.63 (2H, s), 6.90 (1H, s), 7, 33 (1H, s), 7.41 (2H, d, J8Hz), 8.14 (1H, br s), 8.33 (2H, d, J 8Hz), 9.97 (1H, s).

Example 19 2,3-Dihydro-7,8-dimethyl-4- [4- (2-methylimidazo [4,5-c] pyrld-1-yl) -phenyl] -1H- [1,5] benzodiazepine-2 -thlon

CH.CH.

CH,

Phosphorus pentasulfide (2.31 g, 5.19 mmol) was added to a suspension of 2,3-dihydro-7,8-dimethyl-4- [4- (2-methyl-imidazo [4,5-

c] pyrid-1-yl) phenyl] -1 H- [1,5] benzodiazepin-2-one (Example 2) in dry pyridine (21 ml) under nitrogen. The mixture was heated to reflux for 45 min, then cooled and poured onto ice-water (200 mL). The solid material was filtered off, dried by azeotropic distillation with toluene, then dissolved in dichloromethane and adsorbed onto silica gel (200 mesh). This material was placed on a column of flash silica gel and the product was eluted with

Dichloromethane! Methanol = 9: 1 won. The solvent was removed under reduced pressure, giving a

orange solid gave (2.1 g, 73%), mp 233-235 ° C.

¹ H-NMR (300MHz, CDCl ₃ ): 2.38 (6H, s), 2.64 (3H, s), 4.05 (2H, s), 7.00 (1H, s), 7.18 (1H, d, J 4Hz), 7.38 (1H, s), 7.58 (2H, d, J 6Hz), 8.50 (1H, d, J 4Hz), 8.56 (2H, d, J 6Hz), 9.14 (1H, s), 9.62 (1H, s).

The following compounds (shown in Table 2) were similarly prepared from the corresponding benzodiazepinones

(see Examples 1 to 11).

χ: ζ

N.M.R. (300 MHz); (Solvent) (DMSO-d) 2.54 (3H.s), A.00 (2H, br.s). 6.91 (IH, br.s), 7.28 (IH, d, J 6Hz), 7. 3A (3H, m). 7.50 (IH, ie J 7Hz). ? .77 (2H, ie J 8Hz). 8.31 (IH, d, J 6 Hz), 8.46 (2H, d, J 8Uz), 8.93 (IH, s). ft Ct ₄ O O r-4 I CN CC X l-t cc X Het X jb ~ "^ Y ^^ Z example O fs)

example Het n ¹ K ² Mp. N.M.R. (300 MHz) (solvent) 21 ™, -An Cl Cl 195-198 ^e C (CDCl.) 2.63 (3H.s), ".12 (2H, s), 7.15 (IH, br.s), 7.17 (IH. D, J AIIz). 7.40 (IH.s), 7.57 (2H, ie J 6Hz) ₁ 7.72 (IH, s). 8.43 (IH, d, J «Hz), 8.55 (2H, d, J 6Hz). 9.10 (IH, s). 22 - _t r \ c / ₃ CH ₃ CH ₃ 245-248 ° C (CDCl.) 2.35 (6H, s). 2.57 (3H, s), 2f6O (3H, s). 2.93 (3H, s), 4.08 (2H, s). 6.86 (IH, s), 7.00 (IH, s), 7.34. (IH, s), 7.50 (2H, d, J 6Hz). 8.53 (2H, d, J 6Hz), 9.96 (IH, s).

CD IS)

example dec κ ¹ κ ² Mp. N.M.R. (300 ΜΉζ) 23 -N N C] Cl 26O-262 ° C (DMSO-d) 2.16 (6H, s), U. 08 (2H, br, s). 7.13 (lH.br.s), 7.58 (lH, s) 7.65 (2H.dJ 8.5 Hz) 7.77 (IH, s) and 8.37 (2H, d, J 8.5Hz) 24 -Λν ö It received F 11 F as a solution 173-18O ⁰ C

Example 25

2,3-Dihydro-4- [4- (2-methylimidazo [4,5-cipyridyl) phenyl] -1 H- [1,5 l -benzodiazepin-2-one (367 mg, 1.0 mmol) became a Suspension of sodium hydride (60% dispersion in oil, 48 mg, 1.2 mmol) in dry tetrahydrofuran (3.5 ml) was added and the mixture was stirred at room temperature for 1 h under nitrogen. Methyl iodide (142mg, 1, OmMoI) was added and the mixture stirred for a further 3h. The reaction mixture was treated with 2N hydrochloric acid (15 ml) and washed with toluene (15 ml). The organic layer was neutralized with saturated aqueous sodium bicarbonate and the product extracted into dichloromethane (2x50ml). The combined extracts were dried (MgSO4), concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with ethyl acetate: methanol = 3: 1) to give the title compound as an off-white solid, 107mg, (28%), m.p. 147 ⁰ C. Analysis for C ₂₃ H ₁₉ N ₆ O. 0.25H ₂ O calc .: C 71.58 H 5.09 N 18.15% Found: C 71.30 H 4.91 N 18, 04%.

The compounds of Examples 26 and 27 shown in Table 3 below were similarly prepared using benzyl bromide and ethyl bromoacetate instead of methyl iodide.

Table 3

example R Mp. C Analysis% (theory in parentheses) H N 26 CH ₂ Ph 125-128 ⁰ C 75.40 (75.38 5.01 5.13 14,99 15,16) · 27 CH ₂ CO ₂ Et 105-110 ⁰ C 68.46 (68.86 5.14 5.11 15:28, 15:44)

calculated for 0.7.5 H ₂ O

Example 28 1,2-Dihydro-8,9-dimethyl-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -6H- [1,2,4] triazole [ 4,3-a] [1,5] benzodlazepln-1-one

A solution of 2,3-dihydro-7,8-dimethyl-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1H-l1,5-benzodiazepine-2-thione ( 411 mg, 1, OmMoI), ethyl carbazate (210 mg, 2 mmol) and p-toluenesulfonic acid (10 mg) in n-butanol (5 ml) was stirred at reflux overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluting with dichloromethane / methanol = 9: 1). The interstage carbazate was then dissolved in dry tetrahydrofuran (5 ml) and cyclized by addition of sodium hydride (60% dispersion in oil, 40 mg, 1 mmol) and stirring at room temperature for 3 hours. The mixture was partitioned between 2N hydrochloric acid (5 ml) and ethyl acetate (20 ml). The aqueous phase was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate: tetrahydrofuran = 1: 1 (2 x 30 ml). The extracts were combined, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: methanol - 10: 1). The product was further purified by recrystallization from methanol / dichloromethane to give a white solid (85 mg, 20%), mp> 325 ° C

Analysis for C ₂₆ H ₂₁ N ₇ O calc .: C 68.94 H 4.86 N 22.52% Found: C 68.98 H 4.99 N 22.31%.

Example 29 8,9-D, methyl 5- [4- (2-methylimidazo [4,5-c] pyrld-1-yl) phenyl] -6H- [1,2,3,4] tetrazolo [1, 5-a] [1,5] benzodiazepln

CH.

The corresponding hydrazinobenzodiazepine (from the corresponding benzodiazepinethione, 411 mg as described in Preparation 6) was dissolved in 2N hydrochloric acid and cooled to -5 ° C. Aqueous sodium nitrite (72 mg in 11 ml of water) was added over 2 minutes with stirring. The mixture was further held for 5 minutes at -5 ⁰ C, then neutralized with 2 η aqueous sodium hydroxide. The solution was extracted with ethyl acetate: butanol = 2: 1 (2x50ml) and the combined extracts were dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (eluting with dichloromethane: methanol = 9: 1) followed by recrystallisation from isopropanol gave the title compound as a brown solid (68mg, 16%), mp 315 ⁰ C.

Analysis for C ₂₄ H ₂₀ N ₈ 0.25H ₂ O calc .: C 67.82 H 4.86 N 26.36% Found: C 67.63 H 5.15 N 26.63%.

Example 30 8,9-Dimethyl-5- [4- (2-methylimidazo [4 _< 5-4:] pyrid-1-yl) phenyl] -6H- [U, 4] trfazolo [4,3-a] [ 1,5] benzodiazepine

The corresponding hydrazinobenzodiazepine (from the corresponding benzodiazepinethione, 411 mg as described in Preparation 6) was treated with triethyl orthoformate (9 ml) and formic acid (2 ml) at reflux for 10 min. The reaction mixture was cooled, concentrated under reduced pressure and dissolved in 1N hydrochloric acid (10 ml). This solution was washed with ethyl acotate (20 ml), neutralized with dilute aqueous ammonia and extracted with ethyl acetate: tetrahydrofuran = 1: 1 (3x 50 ml). The extracts were combined, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with EthylacetatiMethanol = 9: 1) to give a white solid (95mg, 23%), mp 302-304 ⁰ C (acetone).. Analysis for C ₂₆ H ₂ iN ₇ calc .: C 71.58 H 5.05 N 23.37% Found: C 71.42 H 5.14 N 23.25%.

Example 31

5- [4- (2-Methylimldazo [4,5-c] pyrid-1-yl) ph8nyl] -1,8,9-trimethyl-6H [1,2,4Jtriazolo [4,3-a] [1 , 5] benzodiazepine CH.

CH.

CH

The procedure of Example 30 was repeated using triethyl orthoformate and formic acid, respectively. The Product was purified by flash chromatography (eluting with dichloromethane: methanol = 9: 1) followed by sonication Ethyl acetate: ether = 1: 2 and drying to afford a brown solid (48mg, 11%), mp 294-296 ⁰ C. under vacuum. Analysis for C ₂₆ H ₂₃ N ₇ · V2H 2 O

Calc .: C 70.56 H 5.46 N 22.16% Found: C 70.95 H 5.45 N 22.39%.

Example 32 8,9-Dichloro-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1-trifluoromethyl-6H- [1,2,4] triazolo [4,3 -a] [1,5] benzodiazepine

CL

A solution of 7,8-dichloro-2-hydrazino-4- [4- (2-methylimidazo (4,5-c] pyrid-1-yl) phenyl] -3H- [1,5] benzodiazepine (from the corresponding Benzodiazepinethione, 452 mg, as described in Preparation 7) in trifluoroacetic acid (3 ml) was refluxed under nitrogen for 30 min, cooled and poured onto ice The solution was basified by addition of 2N aqueous sodium hydroxide and the mixture was treated with ethyl acetate: n-butanol The extracts were washed with saturated aqueous sodium chloride (30 ml), dried (MgSO ₄ ) and concentrated under reduced pressure The residue was purified by flash chromatography (eluting with ethyl acetate: methanol = 5: 1 ) to give a buff solid which was triturated with ethyl acetate and dried in vacuo to give the title compound (60mg, 11%), mp. 145-15O ⁰ C.

¹ H-NMR _(CDCl3): 2.55 (3H, s), 6.19 (1 H, s), 6.41 (1 H, br s.), 6.84 (1 H, s), 7.10 (1 H, d, J 6Hz), 7.38 (2H, d, J 8Hz), 7.50 (1H, s), 7.91 (2H, d, J 8Hz), 8.35 (1H, d, J 6Hz), 9.00 (1H, s).

Example 33 8,9-Dimethyl-5- [4- (2-methylimile8zo [4,5-c] pyrld-1-yl) phenyl] -6H-imidazo [1,2-a] [1,5] benzodiazepine

CH

A mixture of 2,3-dihydro-7,8-dimethyl-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1H- [1,5] benzodiazepine-2 -thione (575 mg, 1.4 mmol), aminoacetaldehyde dimethyl acetal (294 mg, 2.8 mmol) and p-toluenesulfonic acid (14 mg) in n-butanol (7 ml) was refluxed under nitrogen for 8 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluting with ethyl acetate / methanol = 6: 1). The intermediate thus obtained was concentrated in conc. Dissolved sulfuric acid (5ml) and heated to 100 ° C for 20min. The mixture was cooled and poured onto ice and then neutralized with saturated aqueous sodium bicarbonate. The product was extracted into dichloromethane (2 x 150 ml) and the combined extracts were dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (eluting with ethyl acetate: methanol = 6: 1) gave the title compound as a tan solid (180mg, 31%); Mp 193-195 ⁰ C after dissolving in methanol and precipitating with acetone. Analysis for C ₂₆ H ₂₂ N ₆ · H ₂ O · acetone ger .: C 70.41 H 6.11 N 16.99% Found .: C 70.70 H 5.80 N 16.62%.

Example 34

(a) 7,8-Dhlchloro-2- (2'-1-methoxyethylamino) -4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -3 H [1,5] benzodiazepine

OCH,

Cl

A mixture of 7,8-dichloro-2,3-dihydro-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) -phenyl-1HH, 5] benzodiazepine-2-thione ( 1.36g, 3, OmMoI), aminoacetaldehyde dimethyl acetal (630mg, 6, OmMoI), and red mercuric ll-oxide (650mg, 3, OmMoI) in n-butanol (15ml) was heated to reflux for 2.5h. The mixture was cooled, diluted with methanol (50 ml) and filtered through a Hyflo filter aid. The solvents were removed under reduced pressure to give a foam which was dissolved in

Pentane was suspended and sonicated for 5min. The pentane was removed in vacuo to give the title compound, 1.0g

¹ H-NMR (300MHz, CDCl ₃ ), 2.61 (3H, s), 3.36 (2H, brs), 3.42 (6H, s), 3.60 (2H, t, J = 5Hz) , 4.53 (1H, t, J = 5Hz), 5.38 (1H, t, J = 5Hz), 7.15 (1H, d, J = 5Hz), 7.46 (1H, s ), 7.51 (2H, d, J = 8Hz), 7.64 (1H, s), 8.23 (2H, d, J = 8Hz), 8.42 (1H, d, J = 5Hz), 9.13 (1H, s).

(b) 8,9-Dichloro-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -6H-imidazo [4,5-c] [1,5] benzodiazepine

Cl

7,8-Dichloro-2- (2,2-dimethoxyethylamino) -4- [4- (2-methylimidazol4,5-c] pyrid-1-yl) phenyl] -3H- [1,5-benzodiazepine (1.10g, 2,1OmMoI) was written in conc. Dissolved sulfuric acid (10ml) and the mixture was heated to 100 ⁰ C for 30 min, cooled to Eisgegossen. The solution was neutralized with 4N aqueous sodium hydroxide and extracted with dichloromethane (3x 100ml). The

Extracts were combined, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (under Eluting with ethyl acetate / methanol = 3: 1). The product was dissolved by dissolving in 100 ml of boiling methanol, filtering Solution, concentrate to 10ml and filter off the product and dry in vacuo further purified. The title connection

was obtained as a buff-colored solid (340 mg, 25%), mp. 241-243 ⁰ C.

Analysis for C ₂₄ H ₁₈ Cl ₂ N ₈ · '/ 2H ₂ O

Calc .: C61.54 H3.66 N 17.95% Found: C 61.58 H 3.56 N 18.07%.

The above procedure was repeated using an equivalent amount of formic acid instead of sulfuric acid. An identical product was obtained in 50% yield. The following compounds shown in Table 4 were prepared by the method of Example 34 using the

prepared suitable thioamide.

Table 4

CH.

example R ¹ R ² Mp ₁ ⁰ C Analysis% (theory in parentheses) CHN 4,48 4,84 20,78 20,88) · 35 H H 193-195 71.44 (71.61 4,13 4,30 19,97 20,28) »» 36 F H H F mixture obtained 203-207 69.68 (69.55

• calculated for VjH ₂ O ·· calculated for VaH ₂ O

Example 37 8,9-Dimethyl-5- [4- (2,4,6-tri-methyl-imidazo [4,5-c] pyr! D-1-yl) -phenyl] -4H-imidazo [1-a] [1 , 5] benzodiazeptn

CH.

CH,

CH.

The procedure of Example 34 was repeated using the corresponding thioamide of Example 22 to form the title compound (yield 14%).

¹ H-NMR (300MHz, CDCl ₃ ): 2.40 (6H, s), 2.56 (3H, s), 2.60 (3H, s), 2.91 (3H, s), 4.05 (2H , brs), 6.80 (1H, s), 7.15 (1H, s), 7.36 (1H, s), 7.40 (2H, s), 7.45 (2H , d, J 8 Hz), 8.34 (2 H, d, J 8 Hz).

Example 38 8,9-Dichloro-1-methyl-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -4 H -imidazo [1,2-a] [1, 5] benzodia2epin

CL

A mixture of 7,8-dichloro-2,3-dihydro-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1H- [1,5] benzodiazepine-2 -thione (452mg, 1, OmMoI), propargylamine (110mg, 2, OmMoI) and red mercuric ll-oxide (216mg, 1, OmMoI) in n-butanol (5ml) was heated to reflux for 10h. The mixture was cooled, diluted with methanol (50 ml) and filtered through an Arbocel filter aid. The filtrate was concentrated under reduced pressure and purified by flash chromatography (eluting with ethyl acetate: methanol = 3: 1). The product was further purified by trituration with ether to give the title compound as a buff solid (170mg, 38%), mp. 242-246 ⁰ C. Analysis for C ₂₆ H ₁₈ Cl ₂ N ₆ · H ₂ O Calcd .: C61. 11 H4.10 N 17.10% Found: C 61.10 H 3.66 N 16.99%.

Example 39 8,9-D-chloro-1-methyl-5- (4- (3,5-dimethym, 2,4-triazol-4-yl) phenyl] -4 H -imidazo [1.2-a] [1.5] benzodiazepine

CH.

Cl

The procedure of Example 38 was repeated using the corresponding thioamide of Table 2 to give the title compound (12% yield), m.p. 165 ° C.

7.57 (1H, s), 7.72 (1H, s), 8.30 (2H, d, J 8Hz).

Example 40

Following the method of Example 38, the thioamide of Example 20 (383 mg, 1, OmMoI) was converted into 1-methyl-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -4H -lmldazo [1,2-a] [1,5] benzodiazep! n (110mg, 27%), m.p. 213-215 ° C.

CH.

CH.

Analysis for C ₂₆ Hj ₀ N ₈ Va H ₂ O

Calc .: C 72.09 H 5.16 N 20.18% gof .: C 72.02 H 5.07 N 20.13%

Example 41 8,9-Dichloro-2-ynethyl-5- [4- (2-methyl! Imazo [4,5-c] pyrid-1-yl) -pienyl] -4 H -imidazo [1,2-a] [ 1,5] benzodIazepln

CH.

CH.

Cl

The procedure of Example 34 was repeated using 2-amino-1,1-diethoxypropane instead of aminoacetaldehyde diethyl acetal and formic acid at reflux instead of the conc. Sulfuric acid repeated. The crude product was purified by flash chromatography eluting with ethyl acetate: methanol = 6: 1. The product was made by precipitation

-33- 292 914 from hot ethyl acetate by adding pentane further purified. The resulting yellow solid (16% yield) was as

was detected as a mixture of imine and enamine tautomers (ratio 85:15).

Analysis for C ₂₆ H, _e CI ₂ N _e H ₂ O

Calc .: C 61.10 H 4.10 N 17.10% Found: C 60.83 H 3.90 N 16.59%.

¹ H NMR (300MHz, CDCl ₃ ) (malt autautomeric only) 2.32 (3H, s), 2.62 (3H, s), 4.03 (2H, br. S), 7.13 (2 H, br. S), 7.53 (2H, d, J 8Hz), 7.67 (1H,

s), 7.75 (1H, s), 8.37 (2H, d, J 8Hz), 8.57 (1H, d, J 5Hz), 9.10 (1H, s).

Example 42

CL

(a) A mixture of 7,8-dichloro-2,3-dihydro-4- | 4- (2-methylimidazo (4,5-c] pyrid-1-yl) -phenyl-1H- [1,5] benzodiazepine 2-thione (453mg, 1, OmMoI), ethanolamine (122mg, 2, OmMoI) and red mercuric ll-oxide (216mg, 1, OmMoI) was heated at reflux in n-butanol (5ml) for 1h The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate-ethanol = 4: 1. Product-containing fractions were concentrated to give 7,8-dichloro-4-chloro-2-propanol. 2- [2-hydroxyethylamino] -4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -3H- [1,5] benzodiazepine as a yellow foam (345 mg, 72%) ¹ H-NMR (300 MHz, CDCl ₃ ): 2.60 (3H, s), 3.40 (2H, br s), 3.60 (2H, br s), 3.88 (2H, m), 6.38 (1H, br s), 7.14 (1H, d, J 4Hz), 7.38 (2H, d, J6Hz), 7.46 (1H, s), 7.60 (1H, s) , 8.18 (2H, d, J 6 Hz), 8.35 (1H, d, J 4Hz), 9.17 (1H, s).

(b) The above product of (a) (340 mg) and triphenylphosphine (242 mg, 0.92 mmol) were dissolved in dry tetrahydrofuran at room temperature. Diethyl azodicarboxylate (160 mg, 0.92 mmol) was added and the mixture was stirred for 20 minutes. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate: methanol: diethylamine = 85: 15: 1. The product was further purified by precipitation from the solution in hot ethyl acetate by addition of pentane. The product precipitated as a yellow solid is obtained (95mg, 29%), mp. 159-162 ⁰ C. Analysis for C ₂₄ Hi ₈ Cl ₂ N ₈ '/ 2H ₂ O

calc .: C61.28 H4.07 N 17.87% Found: C 60.94 H 3.93 N 17.52%.

Example 43 9,10-Dl-chloro-6- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) -phenyl] -1,3,5-tetrahydro-5H-pyrimido [1,2-e ] [1,5] benzodlazepin

Cl

CH.

(a) Using the method of Example 42 (a), using 3-amino-1-propanol instead of ethanolamine 7.8-

Dlchloro-2- (3-hydroxypropylamino) -4- [4- (2-methylimidazo [4,5-c] pyrld-1-yl) phenyl] -3H- [1,5] benzodiazepine as a yellow solid

manufactured.

¹ H NMR (300MHz, CDCl ₃ ) 1.80 (2H, m), 2.58 (3H, s), 3.42 (2H, br s), 3.60 (2H, m), 3.77 (2H, t, J 3Hz), 5.05 (1H, br s), 6.63 (1H, t, J5Hz), 7.12 (1H, d, J4Hz), 7.34 (2H, d, J6Hz ), 7.46 (1H, s), 7.80 (1H, s), 8.18 (2H, d, J 6 Hz), 8.32 (1H, d, J 4Hz), 9.07 (1H, s) ,

(b) The product from (a) was converted to the title compound as in Example 42 (b), giving a cream solid (62%), m.p. 157-158 ° C.

calc .: C 61.98 H 4.37 N 17.35% Found: C 62.05 H 4.06 N 17.41%

Example 44

CH

A mixture of the thioamide (from Example 19) (2.98 g, 7.24 mmol) and red mercury 11 oxide (1.57 g, 7.24 mmol) in n-butanol (40 mL) was saturated with ammonia gas at room temperature and then Stirred at 120 ° C for 3h. After cooling, the mixture was diluted with methanol (150 ml) and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with ethyl acetate: methanol: diethylamine = 100: 10: 5). The product-containing fractions were evaporated to give the title compound as a bright yellow solid (1,085g, 33%), mp. 299-302 ⁰ C.

Analysis for C ₂₄ H ₂₂ H ₈ · VaH ₂ O Calcd .: C 71.98 H 5.71 N 20.99% Found .: C 72.25 H 5.65 N 20.88%

Example 45 2-Amino-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -3H- [1,5] benzodiazepine

CH.

The title compound was prepared by the method described in Example 44 with the thioamide of Example 20 replacing the thioamide of Example 19. The product was obtained as a yellow solid (21% yield), mp. 201-203 ⁰ C. 'H-NMR (300MHz, CDCI _3), 1.70 (2 H, br s), 2.62 (3 H, s), 3.42 (2H, brs), 7.16 (1H, d, J 5Hz), 7.29 (3H, m), 7.52 (2H, d, J8Hz), 7.55 ( 1 H, d, J8Hz), 8.29 (2H, d, J8Hz), 8.43 (1H, d, J5Hz), 9.10 (1H, s).

Belsp! El46

A solution of 2-amino-7,8-dimethyl-l4- (2-methylimidazo [4,5-clpyrid-1-yl) phenyl] -3H- [1,5] benzodiazepine (Example 44) (395 mg, 1 , OmMoI) and methyl propiolate (168 mg, 2, OmMoI) in n-butanol (4 ml) was refluxed under nitrogen for 16 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluting with ethyl acetate: methanol: diethylamine = 100: 10: 5). Product containing fractions were concentrated and the residue was treated with dichloromethane leaving slightly insoluble tarry material. The dichloromethane solution was decanted, concentrated, and the brown solid was verrioben with hexane to give the title compound (46 mg, 10%), mp. 192-194 ⁰ C.

Analysis for C ₂₇ H ₂₂ N ₆ O · ¹ A hexane Vi H ₂ O Calcd .: C 71.08 M 5.65 N 17.45% GAF .: C 71.01 H 5.41 N 17.13%.

Example 47 4,5-Dihydro-8,9-dimethyl-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) -phenyl] -eH-imidazo [1,2-a] [1,5] benzodlazeptn

CH.

A solution of e ^ -dimethyl-S-H-ia-methylimidazoKS-clpyrid-i-y-d-phenyl) H-imidazolyl-ali-benzodiazepine (100 mg,

0.24 mmol) in dichloromethane was stirred with excess ethereal hydrogen chloride until precipitation ceased.

The solid was filtered and added in dry methanol (5 ml), the sodium cyanoborohydride (20 mg, 0.32 mmol)

was, solved. After stirring for 16 hours, the solution was acidified with dilute hydrochloric acid, then the pH was checked

Addition of sodium bicarbonate solution adjusted to 8. The mixture was extracted with ethyl acetate over Magnesium sulfate was dried. Evaporation left a colorless resin. The residue was purified by flash chromatography (eluting with ethyl acetate: methanol = 3: 1) to give a

white solid (30 mg, 30%), mp 223-227 ⁰ C.

Analysis for C ₂₆ H ₂₄ N ₆ H ₂ O

Calc .: C71.21 H 5.98 N 19.16% Found: C71.12 H 5.87 N 18.80%.

Example 48

1,3-dihydro-7,9-dimethvl-4- [4- (2-methyllmldazo [4,5-c] pyrld-1-yl) -phenyl] do [2,3-b] -2H-pyr! [1,4] diazepln-2-one (compound A)

iiiiion (compound B)

CH

A mixture of 2,3-diamino-4,6-dimethylpyrin (6.85g, 50mMoI), ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetate (19.40g, 6OmMoI), silica gel (Merck Kieselgel 60.40-63μ, 25g) and toluene (500 ml) was added under nitrogen for 6 h

Reflux heated. Was.ser was removed from the reaction mixture by means of a Dean-Stark apparatus. Then the Concentrated to dryness and the residue by column chromatography on silica, eluting with Dichloromethane: methanol = 19: 1. Evaporation of the faster migrating isomer and recrystallization from Ethyl acetate gave Compound (B) (3,20g, 16%), mp. 256-259 ⁰ C.

analysis

Calc .: C 68.2 H 5.2 N 20.7% F: C 68.5 H 5.2 N 20.7%.

Evaporation of the slower moving isomer and recrystallization from ethyl acetate: methanol gave the compound (A)

(8.40 g, 42%), mp. 244-248 ⁰ C. Analysis for C ₂₃ H ₂₀ N ₀ O · '/ 2H ₂ O Calcd .: C 68.2 H 5.2 N 20.7% Found. : C 68.5 H 5.1 N 20.8%.

Example 49

3,5-dihydro-2- [4- (2-methyl! Mldazo [4,5-c] pyrld-1-yl) phenyl] -5,7,9-trlmethyl-4H-pyrldo [2,3-b ] [1,4] diazepln-4-one (a) Method A

CH,

CH

3,5-dihydro-7,9-dimethyl-2- [4- (2-methylimidazo | 4,5-clpyrid-1-yl) phenyU-4H-pyrido | 2,3-bl (1,4ldiazepin-4- (3.19g, 8 mmol) (Example 48B) was stirred in dry dimethylformamide under nitrogen, sodium hydride (60% dispersion in oil, 0.40 g, 10 mmol) was added and the mixture stirred at room temperature for 1 h. 28g, 9 mmol) was added, and after stirring for a further 2 hours, the mixture was poured into water (100 ml), which was then extracted with dichloromethane (1 x 100 ml, 2 x 50 ml) and the combined extracts were dried over sodium sulfate, filtered and evaporated

The solution gave the crude product, which was purified by column chromatography on silica eluting with

Dichloromethane: methanol = 96: 4. The product was recrystallized from ethyl acetate / methanol (2.99 g, 91%), m.p.

272-276 ⁰ C.

Analysis'

Calc .: C 70.2 H 5.4 N 20.5% Found: C 69.9 H 5.5 N 20.2%.

(b) Method B

A solution of 3-amino-4,6-dimethyl-2-methylaminopyridine (0.52 g, 3.4 mmol) and ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetate (1.2g, 3.7mmol) in toluene (25ml) was heated to reflux, removing water with a Dean-Stark apparatus. After 12 h, the solution was allowed to cool and the solvent removed under vacuum. The residue was purified by column chromatography on silica eluting with dichloromethane: methanol = 9: 1 and the product recrystallised from ethyl acetate / methanol to give the title compound (1.0g, 75%), which was prepared in all respects by Method A. Product was identical.

Examples 50 to 70

The compounds shown in Tables 5 and 6 below were prepared according to the procedures of Examples 48 and 49 (a) using the appropriate 2,3-diaminopyridine instead of 2,3-diamino-4,6-dimethylpyridine. The melting points and analyzes of the compounds obtained are given in the tables.

Table 5

example R R ' R " R ' " Mp. C Analysis% (theory in parentheses) H N 22.0 22.1) 50 H H CH ₃ H 303-305 ⁰ C 69.1 (69.0 4.7 4.7 20,6 20,6) » 51 H H CH ₃ CH ₃ 239-241 ⁰ C 68.9 (69.0 5.1 5.1 20.3 20.1) » 52 H CH ₃ CH ₃ CH ₃ 230-233 ⁰ C 69.5 (69.4 5.5 5.5 21.5 21.5) · 53 H CH ₃ H H 253-256 "C 67.5 (67.6 4,9 4,8 20,9 20,8) # 54 H CH ₃ H CH ₃ 234-236 ⁰ C 68.7 (68.5 5.1 4.9 18.2 18.4) · 55 br H H H 250-252 ⁰ C 55.1 (55.3) 3.2 3.5) 18.0 18.2) 56 br H H CH ₃ 249-251 ⁰ C 57.2 (57.3 3.7 3.7 22,39 22,27) · 57 H H H H 228-23O ⁰ C 67.06 (66.83 4.37 4.54

Continuation of Table 5

example R R ' R " R ' " Mp. C Analysis% (theory in parentheses) H N 20,93 20,99) 58 H H H CH ₃ 155-156 ⁰ C 66.16 (65.96 4,65 5,03 18.55 18.89) · 59 CO ₂ Et H H H 246-248 ⁰ C 64.73 (64.79 4.59 4.61 18.51 18.50) 60 CO ₂ Et H H CH ₃ 201-204X 65.98 (66.08 4,84 4,85

• calculated for O, 25HjO

# calculated for Vi H] O ·· Röckfluß for 16 h

Table β

example R R ' R " R ' " Mp. C Analysis% (theory in parentheses) H N 22.0 21.7) 61 H H CH ₃ H 292-294 ⁰ C 69.1 (68.7 4,7 4,8 21.0 20.8) » 62 H H CH ₃ CH ₃ 252-255 ⁰ C 68.9 (68.7 CM O in m 19.8 19.9) ⁺ 63 H CH ₃ H H 252-255 ⁰ C 63.5 (03.4 4.5 4.4 20.3 20.5) # 64 H CH ₃ H CH ₃ 251-253 ⁰ C 66.7 (66.9 5.3 5.1 18.6 18.4) * 65 br H H H 258-26O ⁰ C 55.4 (55.3) 3,3 3,5 18,2 18,2) 66 br H H CH, 252-254 "C 57.3 (57.3 3.8 3.7 21.92 22.27) * 67 H H H H 252-253 ⁰ C 66.49 (66.83 4,27 4,54 22.06 21.98) 68 H H H CH ₃ 252-255 ⁰ C 69.19 (69,10 4,81 4,74 18, 44, 18, 83) P 69 CO ₂ Et H H H 243-245 ⁰ C 64.85 (64.57 4,81 4,78 18,23 18,50) 70 CO ₂ Et H H CH ₃ 211-213 ⁰ C 66.00 (66.08 4.90 4.85

• calculated for 0.25 H ₂ O + calculated for 0.5 CH ₂ Cl ₂

# calculated for 1.0 H ₂ O

* calculated for 0.5 H ₂ OP calculated for P, 33 H ₂ O

Examples 71 to 73 The compounds in the following Table 7 were prepared from 3-amino-4,6-dimethyl-2-methylaminopyridine and the appropriate B-ketoester prepared by the method of Example 49 (b). TABLE 7

Hefc

example Hey C 27O-289 ° C Analysis X / H NMR (theory in Klemnern) CHN 71 -ίγ ~ \ N 66.16 6.09 21.15 ) N 248-252 ° C (66.43 6.16 20.81) * 72 B ! 89-192 ⁰ C (CDCl.) 2.50, 2.56 and 2.63 (each 3H, s), 3.00br (IH.s), 3.53 (3H, s), 4.32br (IH, a), 6.84 (IH, dJ - 4.4Hz) , 7.02 (III ε), 7.55 (IH, d J - 4.4 Hr). 7.60 and 8.31 (each 2H, dJ- 8.3 Hz). 73 CH ₃ 75.07 6.38 14.91 ^ ** ^^ * ^ C M .. j (74.97 6.29 14.57)

* calculated for 1/3 ethyl acetate

N) (O N)

(0

Examples 74 to 82

The compounds in Table 8 were prepared according to the procedures of Examples 48.49 (a) and 49 (b) using

suitable heterocyclic diamine prepared in place of 2,3-diamino-4,6-dimethylpyridine.

Table 8

CH.

I. example A Δ R * · Analysis% (Theory in Klantnern) OHN ' TC H 240-2 * 0 66.33 5.06 20.11 (66.65 5.35 20.27) /. ' 75 H : 62-3 ° C 67.00 5.20 20.15 (66.65 5.35 20.21) 4

example A 3 CO ₂ CH ₃ S CH, R Mp. Analysis % in clamps) H N 19.72 Cl (Theory C 20:03) 0 CH ₃ » ct 5:36 18.76 76 / if Ar * f6Y ^N Y CH ₃ 24O-l ^e C 68.76 ' 5:52 18:34) S (68.69 4:05 15.72 77 H 293-5 ⁰ C 64.32 3.93 (64.03 4.24 15.72) 78 H 268-9 ° C 61.92 4.30 17.90 (62.00 α.52 18:08) 79 CH. 217-9 ⁰ C 64.86 Iu. 76 4:42 15.2 ") (65.09 4.72 80 CH. 218- 62.41 ά.61 15.73 220-C (62.73 3.19) + t.Sl 81 CK 278-282 "C 71.17 α. 79 (70.73

ι example A R Mp. NMR analysis 82 H ¹ H NMR (300 MHz) ₁ CDCl.) 2.39 (3H, s), 2.63 (3H, sT, 3.77 (2H, brs), 3.93 (3H, s) 7.14 (lH, d, J »5Hz), 7.49. (2H, d, J-8Hz), 8.42 (3H, m), 9.08 (lH, s).

^ - Compound exists as a 1: 1 mixture of amide tautomers

¹ compound exists only as the enamine tautomer

+ Analysis for hemihydrate

# Analysis for hydrate

Example 83 5-Methyl-2- [4- (2-methyl) -imidazo [4,5-c] pyrld-1-yl) -phenyl] 8-pyrid-2-yl-aminocarboxy) -5H-pyrido [2 , 3-b] [1,4] dlazepln-4-one

me

me

8-bromo-5-methyl-2- (4- (2-methyl-imidazo [4,5-c) pyridin-1-yl) -phenyl] -5H-pyrido (2,3-bl (1.4) diazepin-4-one (435 mg, 0.94 mmol), 2-aminopyridine (132 mg, 1.4 mmol), tetrabistriphenylphosphine-palladium (O) (50 mg, 0.04 mmol) and dimethylacetamide (10 ml) were mixed and placed under a carbon monoxide atmosphere ( Balloon) for 8 h at 120 ° C. The cooled solution was poured into saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3x50 mL) The combined extracts were dried over MgSO ₄ , filtered and evaporated to dryness CN column chromatography (SiO ₂ Merck Kieselgel 60) eluting with dichloromethane: 3 further purified productive The term thai fractions were concentrated to dryness and recrystallized from ethyl acetate: methanol = 97..

Yield 222mg (47%), mp 276-228 ° C.

Analysis for C ₂₈ H ₂₂ N ₈ O ₂ .5H ₂ O

calc .: C65 / 74 H4.53 N 21.90%

Found: C 65.59 H 4.59 N 21.71%.

Examples 84 to 88 The compounds of Table 9 were replaced by the method of Example 83 using the appropriate amine

made of 2-aminopyridine.

Table 9

R ₂ NCO

example R ₂ N fp • i · C Analysis% C H O ₂ -H ₂ O 18 N (Theory in parentheses) .39 5.U ₂ 18 ., 3 .36 5:40 C α .76) C 64 25 ^N 7 O ₃ 0.5H ₇ O 0.25 19 "10 ° 8α O N 167-173 ⁰ C Zen (64 .02 5.70 19 ., 0 C 27 ^H .25 5.95 .01) 67 2 ^N 7 ° 2 ° x ^{25 c} , ^H 10 ^u 19 19 85 Ec ₂ N 195-198 ⁰ C (67 .69 .92 5.68 5.85 .33 .63) 27 ^H 27 ^N 7 86 Tl CH ₃ -Y-MH- 307-309 ⁰ C 6 ". (64 CH ₃ 27 ^H

Examples 87 and

The compounds shown in Table 10 were prepared by the method of Example 19 from the appropriate pyridodiazepinone.

Table 10

CH.

example t br -ν. A Mp. ⁰ C Analysis% (theory in parentheses) CHN 3.5 16.0 87 cn N 316-8 53.2 3.9 16.3) * JQL (53.5 ⁰ C 5.0 5.0 19.8 19.9) rf 38 Ö 257-9 65.9 (65.6

> calculated for 0.5 ethylacelate # calculated for O, 5H _a O

Examples 89 and 90 The compounds of Table 11 were prepared according to the method of Example 34 using the thiones of Examples 86 and 34, respectively

87 produced. Table 11

CH.

example I A Mp. Analysis% (theory in Kiemnern) C K 3.4 20 N 89 J Br 258- 57.6 3.6 20 .5 ^αί3 Ί 261 ⁰ O (57.6 5.0 23 .5) * 90 I 2 ^ 2 72.0 5.0 23 _# 2 2 <i. ° C ι '7 1.6 • A) ^CH 3

* calculated for Vj H ₂ O

The following Examples 91 to 96 illustrate three methods of preparation referred to as Methods I to III

Substituted pyrazoiodiazepines according to the invention.

Example 91

(Compound C)

1.3 x Dlmethyl x 7 x [4 · (2-methvllmldazo [4,5 · c] pγrid-1 · yl) phenvll · 1Λ5,6-tetrahvdropyrazolo [3,4-b] [1,4] diazep! N · 5-on (connection D)

Method I

CH

CH.

A mixture of 4,5-diamino-1,3-dimethylpyrazole (8.98 g, 71.2 mmol), ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetate (23, 0g, 71.2 mmol), silica gel (Merck Kieselgel 60.40-63μ, 14 g) and toluene (330 ml) was refluxed under nitrogen for 21 h After cooling, the silica was filtered off and washed with methanol and a mixture of methanol and dichloromethane The filtrate was concentrated under reduced pressure, the residue was dissolved in ethanol (300 ml), and sodium hydride (2.6 g, 60% oil dispersion, 66 mmol) was added in portions at room temperature and the mixture became The solution was concentrated under reduced pressure and the residue was absorbed on silica gel (60-200μ) and then purified by flash chromatography (gradient elution with ethyl acetate / diethylamine / methanol) First, compound (D) was eluted by recrystallization from methanol to a bright g The same powder was purified (600 mg, 2%), m.p. 237-238 ° C.

Analysis for C ₂₁ H ₁₉ N ₇ O.V ₄ H ₂ O calc .: C 63.22 H 5.18 N 24.58% Found: C 63.27 H 5.18 N 24.49% The second eluted isomer (compound [C]) was further to a pale yellow powder was purified by Umkristailisation of methanol (10g, 38%), mp. 313-315 ⁰ C.

Analysis for C ₂₁ Hi ₉ N ₇ O · 3AH ₂ O calc .: C63.22 H 5.18 N 24.58% Found: C 63.40 H 5.02 N 24.66%

Example 92

1,8-Dimβthyl-3 · (2 · mθthoxyθthoxy) methyl · 5 [4 · (2 · mθthvlimldazo [4,5-c] pyrld-1 · yl) phθnγl] · 1,6,7,8-tβtrahydropyrazolo [3 , 4 × b] [1,4] diazepln-7-one

Method!!

Ethyl-3- [3- (2-methoxyethoxymethyl-1-methyl-5-methylaminopyrazole-4-yl] amino-3- [4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl ) propenoate (0.72 g, 1.4 mmol) (see Preparation 69) was dissolved in ethanol (7 ml) and sodium hydride (60% dispersion in oil, 0.6 g, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 18h under nitrogen. The ethanol was removed under reduced pressure. The resulting foam was dissolved in dichloromethane (50 ml) and washed with saturated aqueous sodium chloride (20 ml). The dichloromethane solution was dried over magnesium sulfate. And the solvent removed under reduced pressure. The crude product was chromatographed on silica eluting with 20% methanol in ethyl acetate. Product containing fractions were evaporated. The yellow foam obtained was sonicated in ether for 20 min, the white solid was filtered and dried in vacuo to give the title compound (0.29 g, 44%), mp. 142-144 ⁰ C.

Analysis for C ₂₆ H ₂ SN ₇ O ₃ calc .: C 63.68 H 5.34 N 20.79% Found: C 63.30 H 5.76 N 20.98%.

Examples 93 to 95

The compounds of Table 12 were prepared by the method of Example 92 using the appropriately substituted aminopyrazole.

Table 12

12

example

Mp.

189-191 ⁰ C

Analysis%

Found

 C

68.13 6.05 20.A0

calc.

C H

C ₂₇ H ₂₉ N ₇ O-0.5 H ₂ O requires 68.05 6.34 20.57

CH ..

CH

65.53 6.24 20.47

^C ? 6 ^H 29 ^N 7 ° 2 ' ⁰ * ²⁵

65.59 6.24 20.59

HuCH ₂ -

299-30O ⁰ C

02.28 5.10 23.57

C ₂₂ H ₂₁ N ₇ O ₂ -0.5H ₂ O requires 62.25 5.22 23.10

Example 96 S-M-ia-Met Method III

CH.

M '

A suspension of 1,3-dimethyl-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1,6,7,8-tetrahydropyrazolo [3,4-b] [1,4] diazepin-7-one (Example 91) in dry dimethylformamide (11 ml) was treated with sodium hydride (56 mg, 60% dispersion in oil, 1.4 mmol) under nitrogen at room temperature and stirred for 30 minutes to give a red solution , Methyl iodide (182 mg, 1.27 mmol) was added and the mixture stirred at room temperature for a further 16 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate: diethylamine = 20: 1. Dio title compound was obtained as a white solid (220mg, 48%), mp 248-25O ⁰ C (from methanol). Analysis for C ₂₂ H ₂ IN ₇ O calc .: C 66.15 H 5.30 N 24.55% Found: C 65.83 H 5.26 N 24.24%

Examples 97 to The compounds shown in Tables 13 and 14 were prepared by the procedures of Examples 90 to 96 (Methods I to III) using the appropriate diaminopyrazoles and halides. The melting points and analyzes of the compounds obtained are given in the tables.

TABLE 13 example

method

IFJ

Cl! ..

l'h

CH ..

CH.,

C-Bu

l'h

CH.,

CH.

CH.

Mp.

315-32O ⁰ C

> 300 ^e C

245-2AS ⁰ C

183,185 ⁰ C

179-181 ⁰ C

* calculated for 0.25 H ₃ O + calculated for 0.5 H ₃ O # calculated for H_o

Analysis% (theory in parentheses) C H N 6:02 22.72 I 67.S3 5.89 22.94) O I (67.42 4.70 21.69 ro (C 69.29 , 4.70 21.69) * (0 _ι *. (69.29 4.81 21:48 68.35 4.85 21:45) + (68.40 6.12 24.13 64.51 6.28 24.07) + (64.49 5.69 22.96 61.23 5.77 22.94) # (61.46

example method R ¹ R ² . R ³ * - ⁰ C Analysis% (theory in parentheses) CHN 5.37 5.28 22. 22. 88 85) 1 102 ι CH ₃ CM -OH H 238-240 "C. 61.56 (61.58 4.90 5.08 19. 19. 53 78) 11 103 ί Ph CH ₂ -CH., 0H H 185-190 65.29 (65. '»2

calculated for 0.75 H-O

II calculates for -H., 0

ID έ vO cv » υ No C O H I υ I X ο £ S-S 1 * 4 <r 0 G «· OO * · F-I <- ( X CN I ο o 1 CN CM O in Ό O -4 CN C-) I ST O CN ΙΛ <Τ O O X vO vO J * * νθ νθ CN rh C O in VO OO CN Cl X • · αο oo O 00 00 vO vO CN νθ vC X X υ υ 0 {Ν σ \ at υ 0 X γΗ ι C σ " method Cl αο example Cl ι * » 3 χ O Cl X * 0 0 • -4 O "-4

'H • m co ι η ι te ^ < * rf ·· * N A M • 0 • W • - ^, 3! ^ -. N .Τ X cw £ CN ^ J " ? <- r. 01 X Α ro l-i ε χ CN χ / \ CN JZ I • OO J X • co Φ fix CN • Wii ^ l X> 1Λ X Il P. P S? Ί U CO · CN -1 Anal; in : ί) - » ** s « • X - ^ / r; Z XO X O TJ - -t -R- < O - • Η + V CN · ^ o * N ·   ^ SJ σν • X «^ CSl V Q • \ T * VO CO CN CN Σ JC ιη OC O « ^^ O · in. -V (D · • CN ρ • • X X CN · ^ - ^ ^^^ ι cn ro -4 m ~ 3 " r * Ξ · p ^ · · E cc , co ES "" * X • (Ό • o ro i-i X · Γ " C * CN ν 00 - ^ νθ _t 's · in N - O O X X * I-- N * ** 2C • 00 'in · (J ^ 00 JD ο X ^ • Il ι-ι "-. IM 3 • in in ν Ο) j " σ »χ CN · / -ν Τ3 • in • ^^ Q • · £ · CN Il - .-1 ρ * 9 "* -ι • X I - X χ -ι r -i * · _ - X CN «-» T) ^^ --T I X - ^ CD - (*> · CJ C · ZL °° • X ι- * Γ- » O • QO X f-i "J 00 co ^ v P ^ C - I ^ -v > ^ CN • J / ^ CT> N oo <r • N » I CN X m · N ~ • ir « • 00 X./^ ο - · Il CN II CO CN O ~. lT. · W "1 Z <r **** t O X ^ ^ _- ?

example method κ ¹ Xi I. ² κ ³ 232 ° C Analysis% (theory in parentheses) CHN 1! I CH ₃ 255 ° C 69.93 5.07 20.83 (70.26 5.02 21.23) ι: ü I H 233-235 ° C 66.94 4.53 24.78 (66.95 4.49 24.99 111 ii C ₃ CH ₃ J86-188 ° C 67.49 4.80 24.19 (67.52 4.79 24.22) 1 12 i i H > 300 ° C 69.17 4.36 21.19 (69.34 4.46 21.56) + 1 13 I H > 325 ° C 64.81 4.25 20.06 (64.79 4.18 20.35) 1} / ₍ 1 C ₃ H 218-22O ° C 64.96 4.20 20.34 (64.79 4.18 20.35) 115 IiI CH ₃ CH ₃ 65.60 4.51 19.94 (65.39 4.47 19.77)

+ calculated for hydrate

e cjv CN vO ' ^J "^ O CN ON CN σι 03 O ι I vO , -I (-i O O) H (O V! C CT> QO I s CN i-H O CN Z Analy! Le in 1 > - * r-i 00 CN CN CN cn O r-4 r-t V0 00 ΙΛ o _r Oi 1-4 u i cn O CNI -J ! H CN CN cn CN cn σ * C r ^ CN cn cn nT v £> CN cn i O\ CN NT VO vO vO CN vO vc 0 'J V I 'J CN 0 ) W CN i vO - O O cn QO I - I CN 00 u i I , -ι 1-) Z) co cn cn 26 S = CN - ^ X'J m 0) r cn K  8th A V) r J meth iel isp - ^ ~ 00 - - rh

example method κ ¹ H ² k ³ η ?. Analysis% (theory in parentheses) CHN 120 ii ClI, H 305-31O ⁰ C 63.37 A.71 23.28 (63.15 A.87 23.56 12 1 1 11 CH ₃ 272 ° C 67.41 A.73 23.86 (67.52 A.79 2A.23) I2:> 1 CH ₃ Il 322-324 ° O

° calculated for 0.25 H-O

+ calculated for hemihydrate / a calculated for 1.5 H ₃ O

¹ I-NMK (JOOMIIz, CDCl). 2.62 (JH, β). 3.87 (2H.br s),. 4.03 (3H, s), 7 .16 (IH, d, Jf = 7Hz), 7 .44 (IH, dd, J-5 and 7Hz)

 7. 53 (211, d.J-BIIz), 8. 37 (2H .d, .J-8Hz). 8.45 (2H, d, J-7Hz), 8.66 (111, J-SHz), 9.H (IH, s), 9.43 (lH, s) ppm.

cn α> I

example method κ ¹ κ ² R ¹ 240-242 ⁰ C. Analysis% (theory in klanrmern) CHN 12J U or III 0- CH, CH ₃ 226-227 ° C 67.65 4.84 23.85 (67.52 4.79 24.23) 12 /, (I 1 CH, CH ₂ CH ₃ 326-328 ° C 66.84 4.95 22.75 (66.79 5.19 23.08) 12S Il H 200 ⁰ C 63.98 4.98 22.99 (64.07 4.95 23.44) 4 126 1 l ο- CH ₃ CH ₃ 66.30 4.84 23.50 (66.23 4.92 23.76) * r

Δ calculated for 1/2 MeCH. 3/4 H ₃ O + calculated for hemihydrate $ this reaction also yielded the following product:

Mp 198-200 ⁰ C

Analysis for C ₂₇ H ₂₄ NgO. 1/2 H ₃ O

Calculated: C 66.79 H 5.19 N 23.08% Found: C 66.98 H 5.08 N 23.10%

TABLE III 14

CH,

example Method * κ ¹ κ ² R ¹ , Ft). Analysis% (Theory in brackets) ι: H N 5.74 22nd 70 127 1 CH ₃ CH ₃ CH ₃ 258-26O ° C 63.95 5.84 22nd 73) * (64.03 5.83 23rd OO 128 L t-Bu Ci ₃ H 265-27O ° C 66.81 5.95 22nd 70) + (66.72 A.75 21st 56 129 ι CU, Ph H > 300 ° C 69.55 4.73 21st 91) (69.78

* calculated for 1.0 CH ₃ OH + calculated for 0.25 H ₂ O

CJl CO

IS} (O M

In game method R ¹ R ² R ³ Mp. Analysis% (theory in parentheses) CHN no ι i: h., ch .oh in., H 29 /.-? 97 ° C 62.01 5.49 22.53 (62.24 5.22 23.09) 5- 131 I CH ₇ -CH ₉ OH Ph H 285-2 <> O ° C 67.78 4.93 20.33 (67.91 4.85 20.53) 132 I CH ₃ H 32O ° C 67.1? 4.5C 24.97 (66.95 4.49 24.98) 13 y 1 1 ί t-Bu CH ₃ CH ₃ 270-272 ⁰ C 67.99 6.37 21.95 (68.01 6.16 22.21) 134 ι ^CH -J H 2O5-2O8 ° C 63.78 4.07 20.07 (63.60 4.31 19.97) *

J calculates for 0.5 H-O

Examples 135-137

The compounds shown in Table 15 were prepared by the method of Example 19 from the appropriate pyrazodiazepinone

manufactured. Table 15

example R η ?. From booty ¹ H NMROOOMHz, CDCl ₃ ZCD ₃ OD) ^ = 2.38 (3H, s), 2.55 (3H, s), 3.80 (3H, s), 4.07 (2.1, s), 7.13 (lH, d, J) 5Hz), 7.45 (2H, d, J = 6Hz), 8.31 (lH, d, J = SHz), 8.44 (2H ₁ (I ₁ J-OHz), 8.95 (lH, s). 135 CH ₃ 52Ζ ¹ H NMR (300MHz, CDCl 2) 2.62 (3H, s) 4.OK3H.S), 4.25 (2H, s), 7.18 (1H, d, J-5Hz), 7.51 (ftH, m), 8.10 (lH , d, J = 9Hz), 8.L5 (lH, d, J = SHz), 3. ^ (lH, d, J = 5Hz), 3.15 (2H, m,), 9.H (IH, s) , 13 6 2O3-2O5 ° C 7IZ Analysis for C ₂₅ H ₂₀ NgS.1.75 H ₃ O calc .: C 60.53 H 4.77 N 22.59 Found: C 60.67 H 4.61 N 22.25 13 7 270-275 Ό 6 Π

Example 138

1,6-Dil ^ ydro · 1,9-dlmθthyl x 5 x [4 · (2 · methyllmίdazo [4,5-cIpyrld-1 · vl) prιθnyll · 3 · (3 · pyr! Dyl) triazolo [3,4- -g] pyrazolo [3 _l 4-b] [1,4] dlazepln

The thione from Example 139 (464 mg, 1 mmol), hydrazine hydrate (100 mg, 2 mmol), red mercuric ll oxide (216 mg, 1 mmol) and n-butanol were refluxed under nitrogen for 15 min and at room temps for 1 h. touched. The mixture was filtered through Arbocel filter aid and the filter cake washed with methanol. The filtrate was concentrated under reduced pressure and the residue was suspended in triethyl orthoacetate (9 ml) at reflux. Acetic acid (3 ml) was added and the resulting solution heated to reflux for 1.5 h. The solvent was removed in vacuo and the residue was dissolved in 1 M hydrochloric acid (20 ml), washed with ethyl acetate, and the aqueous phase was neutralized with saturated aqueous potassium carbonate. The product was extracted into dichloromethane (2x20ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (eluting with dichloromethane: methanol = 85:15) followed by trituration with ethyl acetate: ether = 1: 3. The title compound was obtained as a buff-colored solid (95mg, 20%), mp 208 ⁰ C.

¹ H-NMR (500MHz, CDCl ₃ ): 2.59 (3Hs,), 2.73 (3H, s), 3.51 (1H, d, J = 15Hz), 4.11 (3H, s), 5.05 (1H, d, J = 15Hz), 7.12 (1H, d, J = 5Hz), 7.44 (1H, dd, J6 and 8Hz), 7.51 (2H, d, J = 8Hz ), 8.38 (2H, d, J = 8Hz), 8.43 (2H, m), 8.66 (1H, d, J6Hz), 9.07 (1H, s), 9.40

Examples 139 to 141

The compounds of Table 16 were prepared by the method of Example 34 using the thiones of Examples 135 and 137, respectively, and conducting the cyclization with formic acid.

Table 16

example R CH ₃ Fp. - From booty Analysis% (Theory in parentheses) CHN 139 268-27O ⁰ C 143! 66.42 5.10 26.44 (66.16 5.07 26.84) ⁺ 140 245-248 ⁰ C 292 ¹ HNMR (SOOMHr ₁ CDCl ₃ ). 2.59 (3H ₁ S), 4.16 (3H, s), 4.2O (2H, brs), 7.13 (lH, d, J = 5Hz), 7:33 (lH, s), 7:48 (5H ₁ Di), 8.11 (lH.d, H = 7Hz), Ν-. 8.16 (lH, d, J-6Hz), 8:40 (3H, m), 9.10 (lH, s) PPRA. 14 i 243-245 ° t 16% 67.19 4.47 25.87 (67.49 4.61 26.23)

+ calculated for hemihydrate

Example 142

1,3-dimethyl-5- [4- (2-methylimidazo [4,5-clpyrid-1-yl) phenyl] -1,6,7,8-tetrahydropyrazolo [3,4-bl [1,4ldiazepin-7 -one (Example 91) (752 mg, 2, OmMoI) was added to a suspension of sodium hydride (80 mg, 60% dispersion in oil, 2, OmMoI) in dry dimethylformamide (10 mL) under nitrogen at room temperature. The mixture was sonicated for 5 min, then stirred for 1 h. Methyl iodide (284 mg, 2, OmMoI) was added and after 30 min further sodium hydride (120 mg, 60% dispersion in oil, 3 mmol). After a further 30 min, methyl iodide (284 mg, 2, OmMoI) was added and the dark brown mixture was stirred at room temperature for a further 2 h. Then the mixture was poured into iced water (50 ml) and extracted with dichloromethane (4x30 ml). The combined extracts were dried (MgSO ₄ ), concentrated under reduced pressure, and the resulting brown resin was purified by column chromatography (Merck silica gel, 70 g, 10-4 mol) eluting with ethyl acetate-diethylamine = 20: 1. Product containing fractions were concentrated and the residue was recrystallized from ethyl acetate / methanol to give the title compound as a white solid; Mp 222-225 ° C. C ₂₃ H ₂₃ N ₇ O · 'Λ H ₂ O calc .: C 65.86 H 5.69 N 23.37% Found: C 66.00 H 5.77 N 23.01%'

Example 143 8,9-Dlchloro-6-methyl-5- [4- (2-methylmethylazo [4,5-c] pyrid-1-yl) -phenyl] -6H-imidazo [1,2-a] [1 , 5] benzodtazepIn

A solution of 8,9-dichloro-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -3H-imidazo [1,2-al- [1,5] benzodiazepine ( 230 mg, 0.5 mmol) in dry dimethyl sulfoxide (2 ml) was added with stirring to a suspension of sodium hydride (20 mg, 60% dispersion in oil, 0.5 mmol) in dry dimethyl sulfoxide (1 ml) under nitrogen and with cooling by means of a cold water bath. The mixture was run at about 15 ° C for 1.5 hours and at room temperature for 30 minutes to give a dark brown solution. Methyl iodide (78 mg, 0.55 mol) was added and the mixture stirred for 45 min. The mixture was poured into dichloromethane (150ml) and washed with water (7x70ml) and brine (50ml). The organic solution was dried (MgSO ₄ ), concentrated under reduced pressure, and the residue was purified on silica gel (20 g, 10-40 μ) eluting with ethyl acetate: diethylamine = 19: 1. The product was further purified by trituration with dry ether to give the title compound as a brown solid (5mg, 2%), m.p. 268-270 ° C.

¹ H-NMROOOMHz, CDCl ₃ ): 2.64 (3H, s), 3.07 (3H, s), 6.28 (1H, s) 7.17 (1H, d, J5Hz), 7.23 (1H, s), 7.28 (1H, s), 7.39 (1H, s), 7.41 (1H, s), 7.47 (2H, d, J 8Hz), 7 , 65 (2H, d, J 8Hz), 8.43 (1H ₂ d, J 5Hz), 9,10 (1H, s).

(a) α-Bromo-α-methYM-nitroisothiazole (J. Chem. Soc, [1959], 3061) (1.12g, 5, OmMoI) was dissolved in ethanol (20ml) at 0 ° C

and gaseous methylamine was bubbled through for 20 minutes. The mixture was stirred at room temperature for 30 min and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (100ml) and washed with saturated aqueous sodium bicarbonate (50ml). The organic layer was dried (MgSO ₄ ), concentrated under reduced pressure, and purified by flash chromatography (eluting with dichloromethane) to give 3-methyl-S-methylamino-nitroisothiazole (662 mg, 77%) as a white solid; Mp 153 ^° C. Analysis for C ₆ H ₇ N ₃ O ₂ S

calc .: C, 34.68; H, 4.07; N, 24.26%; C 34.58 H 4.00 N 23.73% ¹ H-NMR (250 MHz, CDCl ₃ ): 2.65 (3H, s), 3.23 (3H, d, J 5Hz), 8.20 (1H , br s).

(b) 3-Methyl-5-methylamino-4-nitroisothiazole (520 mg, 3, OmMoI) was reduced to 4-amino-3-methyl-5-methylaminoisothiazole (422 mg, 98%) by the method of Preparation 11 (d) ,

¹ H-NMR (250 MHz, CDCl ₃ ): 2.20 (2H, br s), 2.30 (3H, s), 2.95 (3H, s), 4.30 (1H, br s).

(c) A mixture of 4-amino-3-methyl-5-methylaminoisothiazole (420 mg, 2.9 mmol), ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetate ( 969 mg, 3.0 ml) and anhydrous zinc chloride (39 mg, 0.29 mmol) were stirred in ethanol for 18 h at reflux. An additional amount (39 mg) of zinc chloride was added and the mixture was further heated in a closed vessel at 100 ° C for 6 h. The mixture was cooled and sodium fiydride (120 mg, 60% oil dispersion, 3, OmMoI) was added. The mixture was stirred at room temperature for 16h and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (150ml) and washed with brine (50ml). The organic solution was dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: methanol = 9: 1) followed by reverse phase HPLC (C ₁₈ silylated silica, methanol: water = 70:30) to give a solid which was recrystallized from ethyl acetate , The title compound was obtained as a white solid (190mg, 16%), mp. 214-216 ⁰ C.

Analysis for C ₂₁ H ₁₈ N ₆ OS · 0.5H ₂ O calc .: C 61.30 H 4.65 N 20.42% Found: C 61.05 H 4.58 N 20.19%.

Production 1

Ethyl-4 '- (2-methyl [4.5-c] pyrid-1-yl) benzoylacetate

Method A

Essentially the method of Y. Kishi, S. M. Hannick, J. Org. Chem., 1983, 48, 3833.

Zinc dust (894 mg, 13.7 mmol) was suspended in dry 1-hydroxy-hydrofuran (3 ml) under nitrogen and sonicated at room temperature for 10 min. Ethyl bromoacetate (2 drops) was added and the mixture heated at reflux for 5 minutes. A solution of 1- (4-cyanophenyl) -2-methylimidazo [4,5-clpyridine (640 mg, 2.74 mmol) in dry tetrahydrofuran (6 ml) was added and the mixture heated at reflux for 5 min. A solution of ethyl bromoacetate (1.822 g, 10.94 mmol) in dry tetrahydrofuran (2 mL) was added dropwise over 1 h at reflux, and after a further 10 min, the mixture was allowed to cool to room temperature. 50% aqueous potassium carbonate (1 ml) was added and the mixture was stirred for 45 min at room temperature and then filtered through Arbocel filter aid while washing with THF. The filtrate was concentrated under reduced pressure to a yellow resin. This material was treated with a mixture of 20% aqueous trifluoroacetic acid (1 OmI) and dichloromethane (50 ml) at room temperature for 15 min. The mixture was neutralized by the addition of saturated aqueous sodium bicarbonate and then extracted with dichloromethane (2x30 ml). The combined extracts were dried (MgSO ₄ ), concentrated under reduced pressure, and the crude product was purified by flash chromatography (eluting with 10-20% methanol in ethyl acetate) to give ethyl 4 '- (2-methylimidazo (4.5-). c) pyrid-1-yl) benzoylacetate (480mg, 54%) as a yellow resin.

The material obtained by Method A was (after recrystallization from ethyl acetate) a white solid, mp 111-112 ° C.

¹ H-NMR (300MHz, CDCl ₃ ): 1.32 (3H, t, J 6Hz), 2.61 (3H, s), 4.09 (2H, s), 4.28 (2H, q, J 6Hz), 7.16 (1H, d, J 6Hz), 7.55 (2H, d, J 9Hz), 8.23 (2H, d, J 9Hz), 8.46 (1H, d, J 6Hz) , 9.09 (1H, s).

Method B

(a) 4- (4-Acetylphenyl) amlno-3-niupopyrlene hydrochloride

A solution of 4-chloro-3-nitropyridine hydrochloride (9.75g, 50mMoI) in ethanol (40ml) was added to a slurry of p-aminoacetophenone (6.76g, 50ml) in ethanol (25ml) and the mixture became stirred overnight at room temperature. It was cooled in ice and the yellow solid was filtered off and dried in vacuo. Yield 10.1 g (69%), mp. 197-200 ⁰ C.

¹ H-NMROOOMHz, DMSOd ₆ ): 2.61 (3H, s), 7.19 (1H, d, J7Hz), 7.53 (2H, d, J8Hz), 8.07 (2H, d, J8Hz ), 8.33 (1H, d, J7Hz), 9.36 (1H, s), 10.74 (1H, s).

(b) 4- (4-acetylphenyl) -amino-3-aminopyridine

4- (4-Acetylphenyl) amino-3-nitropyridine hydrochloride (2.0 g, 71.8 mmol) was partitioned between aqueous sodium hydroxide and dichloromethane (3x 20 mL). The combined organic phases were heated for 3.5 h.

The catalyst was filtered off and the solvent removed under reduced pressure to give a brown solid (1.8 g) which was used directly without purification for the next reaction; Mp 165-166 ° C (after recrystallization from ethanol). 'H-NMR (300 MHz, DMSO-d'): 2.47 (3H, s), 5.00 (2H, br.s), 7.04 (3H, m), 7.70 (1H , br.s), 7.83 (2H, d, J 8Hz), 7.98 (1H, br.s), 8.12 (1H, s).

(c) 1- (4-Acetyl) phenyl-2-methylimidazo [4,5-c] pyridine

A solution of 4- (4-acetylphenyl) amino-3-aminopyridine (68,0g, 0.3 mmol) in acetic acid (204ml) and acetic anhydride (204ml) was heated 1.5 h at 95 ⁰ C, then cooled and concentrated under reduced pressure concentrated. The residue was dissolved in water (500 ml) and basified by the addition of saturated aqueous ammonia. The product was filtered off, washed with water (2 x 100 ml) and dried in vacuo to give the title compound (61.0 g, 81%) as a brown solid; Mp.

155-156 ⁰ C (after recrystallization from water).

¹ H NMR (300MHz, CDCl ₃ ): 2.59 (3H, s), 2.72 (3H, s), 7.12 (1H, d, J5Hz), 7.53 (2H, d, J 8 Hz), 8.22 (2H, d, J 8 Hz), 8.40 (1H, d, J5Hz),

(d) Ethyl 4 '- (2-methylimidazo [4,5-c] pyrld-1-yl) benzoylacetate

A solution of 1- (4-acetyl) phenyl-2-methylimidazo [4,5-c] pyridine (17.5 g, 69.7 mmol) in dry tetrahydrofuran (175 mL).

was added to a slurry of sodium hydride (3.68 g, 153 mmol) in a mixture of dry tetrahydrofuran (35 ml) and diethyl carbonate (24.7 g, 209 mmol) at reflux with stirring over 45 min. After a further hour the mixture was cooled, hexane (200ml) added and the resulting precipitate filtered off and washed with hexane (2x100ml). The solid was suspended in ethyl acetate (200 ml) and acetic acid (10.2 g) was added. After stirring for 15 minutes, water (200 ml) was added and the organic layer separated. The aqueous phase was extracted with ethyl acetate (100ml) and the combined organic solutions were washed with water (200ml), dried (MgSO ₄ ) and concentrated to a resin (17.3g, 77%). This material could be further purified by flash chromatography (eluting with ethyl acetate. Methanol = 7: 1) to the title compound as a white solid if desired.

Method C

(a) 4- (2-Methylimidazo [4,5-c] pyrld-1-yl) benzoic acid

A mixture of 4- (2-methylimidazo [4,5-c] pyrid-1-yl) benzonitrile (12.0g, 51.3 mmol) and 40% aqueous sodium hydroxide (55 ml) in abs. Ethanol (55 ml) was refluxed for 1.5 h. The solvent was removed under reduced pressure and the brown residue dissolved in water. The solution was cooled to ⁰ ° C. by addition of ice. Glacial acetic acid (about 33ml) was added slowly. The precipitated buff solid was filtered off, washed with water and dried in vacuo at 70 ° C. Yield 9.14g (70%).

¹ H-NMR (300MHz, DMSO-d _s): 2.49 (3H, s), 7.25 (1 H, d, J 6Hz), 7.72 (2H, d, J 6Hz), 8.17 (2H, d, J 6Hz), 8.30 (1H, d, J 6Hz), 8.92

(b) Ethyl 4 '- (2-methylimidazo [4,5-c] pyrl-1-yl) benzoylacetate

Oxalyl chloride (17.0 mL, 184 mmol) was added to a mixture of 4- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoic acid (11.64 g, 46 mmol) and dry dimethylformamide (0.2 mL) in dry Dichloromethane (200ml) was added under nitrogen and with ice cooling. Upon complete addition, the mixture was sonicated at room temperature for 1 h, then concentrated under reduced pressure and resuspended in dry dichloroethane (200 mL).

In a separate flask, isopropylmagnesium chloride (137 mL of a 2M solution in tetrahydrofuran, 274 mmol) was added dropwise over 20 min to a solution of ethylmalonic acid (18.14 g, 137 mmol) in dry dichloromethane (100 mL) at ⁰ ° C. After a further 20 minutes, the solution was added at room temperature to the suspension of the acid chloride formed above. The red mixture was sonicated at room temperature for 30 min and then cooled in ice while 4 N hydrochloric acid (250 mL) was added. The mixture was stirred at room temperature for 10 min, diluted with dichloromethane (200 mL), and the layers were separated. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3x200ml). The combined extracts were dried (MgSO ₄ ) and concentrated under reduced pressure to a yellow resin which slowly crystallized on standing. Yield 12.10g (80%).

Production 2

Ethyl-4 '- (2,4,5-trimethylimidazo [4,5-c] pyrid-1-yl) benzoylacetate

The procedure of Preparation 1, Method A, was repeated using as starting materials zinc dust (11.54 g), 1- (4-cyanophenyl) -2,4,6-trimethylimidazo [4,5-c] pyridine (9.30 g). and ethyl bromoacetate (23.7 g) were used. The yield of title compound was 10.50 g, 84%, as a yellow resin.

¹ H-NMR (300MHz, CDCl ₃ ): 1.37 (3H, t, J 7Hz), 2.60 (3H, s), 2.63 (3H, s), 2.92 (3H, s), 4.11 (2H, s), 4.32 (2H, q, J 7Hz), 6.82 (1H, s).

7.55 (2H, d, J 8Hz), 8.23 (2H, d, J 8Hz).

Production 3

Ethyl 4- (2,6-dlmethylpyrld-3-yl) benzoylacetate

The procedure of Preparation 1, Method A, was repeated except that 3- (4-cyanophenyl) -2,6-dimethylpyridine was used instead of 1- (4-cyanophenyl) -2-methylimidazo [4,5-clpyridine; the title compound was obtained.

¹ HNMR (CDCl ₃ ): 1.30 (3H, t, J 6Hz), 2.52 and 2.62 (each 3H, s), 4.05 (2H, s), 4.25 (2H, q , J 6Hz), 7.11 (1H, d, J 6Hz), 7.45 (3H, m), 8.08 (2H, d, J9Hz).

Preparation 4 Ethyl 2- (2-methylimidazo [4,5-c] pyrid-1-yl) pyrid-5-oyl-acetate

(a) 4-Chloro-1- (5-ethoxycarbonylpyrld-2-yl) -2-methylimidazo [4,5-c] pyridine

4-Chloro-2-methylimidazo [4,5-c] pyridine (prepared by the method described in Chem. Pharm. Bull., 1964, 12, (8), 866-872) (3.34y, 20 mmol) and Ethyl 6-chloronicotinate (3.71 g, 26.2 mmol) was dissolved in N, N-dimethylformamide (42 ml). Potassium carbonate (2.76g, 20mMoI) was added and the mixture was heated at reflux overnight. The reaction mixture was cooled, the solvent removed under reduced pressure and the crude product purified by flash chromatography eluting with ethyl acetate. Product-containing fractions were concentrated and the resulting foam was triturated with ether. The solid was filtered and dried under reduced pressure to give the title compound as a yellow solid (3.2 g, 51%).

¹ H-NMROOOMHz, CDCI ₃ ): 1.47 (3H, t, J 6Hz), 2.84 (3H, s), 4.56 (2H, q, J6Hz), 7.38 (1 H, d, J4Hz), 7.59 (1H, d, J6Hz), 8.25 (1H, d, J4Hz), 8.63 (1H, d, J6Hz), 9, 36 (1H, s).

(b) 1- (5-ethoxycarbonylpyrid-2-yl) -2-methylimidazo [4,5-c] pyridine

A solution of 4-chloro-1- (5-ethoxycarbonylpyrid-2-yl) -2-methylimidazo [4,5-c] pyridine in ethanol (100 ml) was prepared over 30% palladium on carbon (3 g). and magnesium oxide (0.8g) at 50psi (345kPa) for 30h. The mixture was filtered through Arbocel filter aid and the filter cake was washed with boiling ethanol (6 × 50 ml). The filtrate was concentrated under reduced pressure to give the title compound as a white foam (2.75 g, 96%).

¹ H NMR (300MHz methanol-d "): 1.51 (3H, t, J 6Hz), 2.83 (3H, s), 4.53 (2H, q, J 6Hz), 7.70 (1 H, d, J 4Hz), 7.92 (1 H, d, J 6Hz), 8.43 (1 H, d, J 4Hz), 8.72 (1 H, d, J β Hz), 8 , 97 (1H s), 9.32 (1H, s).

(c) 6- (2-Methylimidazo [4,5-c] pyridine-3-carboxylic acid

HS-ethoxycarbonylpyridyl-^D-methylimidazoKS-cipyridine (2.75 g, 9.75 mmol) was dissolved in ethanol (15 mL) and 2N aqueous sodium hydroxide (5.8 mL) was added. The mixture was stirred at room temperature for 3 days, then the solvent was removed under reduced pressure. The residue was neutralized with dilute acid salt (pH 6) and the resulting precipitate filtered off and dried in vacuo. The title compound was obtained as a white solid (1.70 g, 69%).

¹ H-NMR (300MHz, DMSO-d _e ): 2.70 (3H, s), 7.58 (1H, d, J 4Hz), 7.93 (1H, d, J 6Hz), 8.36 ( 1H, d, J Hz), 8.58 (1H, d, J 6Hz), 8.96 (1H, s), 9.18 (1H, s).

(d) Ethyl 2- (2-methylimidazo [4,5-c] pyr! d-1-yl) pyrid-5-oylacetate

The method of Preparation 1, Method C (b), was repeated using the pyridine-3-carboxylic acid of (c) above instead of 4- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoic acid has been. The title compound was an orange resin. ¹ H-NMR (300MHz, CDCl ₃ ): 1.40 (3H, t, J 6Hz), 2.80 (3H, s), 4.11 (2H, s), 4.35 (2H, q, J 6Hz), 7.40 (1H, d, J4Hz), 7.58 (1H, d, J6Hz), 8.38 (1H, d, J4Hz), 8.57 (1H, d, J 6Hz), 9.10 (1H, s), 9.25 (1H, s).

Preparation 5 EthyM'-r.S-chloro-CI.S-dioKolan ^ -yl-methyl-methylamino-M-yl-benzoylacetate

(a) 5-Chloro-1- (4-cyanophenyl) -2-methylimidazole

A solution of 1- (4-cyanophenyl) -2-methylimidazole (3g, 16.4 mmol) and N-chlorosuccinimide (2.18 g, 16.3 mmol) in chloroform (180 mL) was heated at reflux for 4 h, then with water washed, dried over magnesium sulfate and concentrated to a yellow solid. Trituration with ether left a pale yellow solid (2.38 g, 67%). ¹ H NMR (300MHz, CDCl ₃ ): 2.30 (3H, s), 6.99 (1H, s), 7.43 (2H, d, J, 8.5Hz) and 7.88 (2H, d, J 8.5 Hz).

(b) 5-chloro (4-cyanophenyl) -4-iodo-2-yl "/ llmldazo!

Iodine chloride (3.2g, 20mMoI) in acetic acid (10ml) was added rapidly in drops with stirring to a solution of the product of (a) (1.6g, 7.3mmol) and sodium acetate in acetic acid (40ml). After refluxing for 2 hours, the mixture was concentrated to dryness and partitioned between saturated aqueous sodium carbonate (containing excess sodium thiosulfate) and dichloromethane. The organic layer was dried over magnesium sulfate and evaporated. Trituration with ether-pentane (1: 1) gave a pale yellow solid (1.8 g, 72%).

¹ H-NMR (300MHz, CDCl ₃ ): 2.30 (3H, s), 7.42 (2H, d, J 8.5Hz) and 7.88 (2H, d, J 8.5Hz).

(c) 5-Chloro-i - (4-cyanophenyl) -2-methylimidazole-4-carboxaldehyde

A solution of the product of (b), (1.03g, 3m mol) and tetrokis (triphenylphosphine) palladium (0.3g) in THF (70ml)

placed under a carbon monoxide atmosphere and heated to 50 ° C. Tributyltin hydride (0.96 g, 3.3 mmol) in THF (40 mL) was added dropwise through a motor driven tip over 4.5 h. After another half hour, the mixture was stirred with 100 ml of 10% potassium fluoride solution for 15 minutes, then extracted twice with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated to an orange solid.

Flash chromatography (eluting with ethyl acetate: ether = 1: 1) gave a white solid (0.245g, 33%).

¹ H-NMR (300MHz, CDCl ₃ ): 2.34 (3H, s), 7.48 (2H, d, J 8.3Hz), 7.95 (2H, d, J 8.3Hz) and 9.96 ( 1H, s).

(d) S-ChloM-U.a-dloxolan ^ -ylyl-K-cyanophenyll ^ -methyllmldazole

To a solution of the aldehyde from (c) (0.24 g, 1 mmol), 4-toluenesulfonic acid hydrate (0.21 g, 1.1 mmol) and ethane-1,2-diol (0.5 mL, 8 mmol). in dichloromethane (8ml) was heated to reflux with stirring through a Dean-Stark trap containing 4A molecular sieves for 6 hours. After 70h standing at 25 ⁰ C, the mixture was washed with aqueous sodium bicarbonate and concentrated to a tiled solid.

The residue was flash chromatographed (eluting with ethyl acetate: methanol = 9: 1) to give a white crystalline Solid (0.13 g, 45%).

¹ H NMR (300MHz, CDCl ₃ ): 2.30 (3H, s), 4, P8 (2H, m), 4.31 (2H, m), 5.95 (1H, s), 7.41 (2H, d, J 8.3Hz), 7.88 (2H, d, J 8.3Hz).

(e) l

The nitrile obtained from (d) was treated as in Preparation 1 above to give the title compound in 91% yield.

'H-NMR (300MHz, CDCl ₃ ): 1.27 (3H, t, 7Hz), 2.27 (3H, s), 4.04 (4H br, s), 4.28 (4H, m), 5.93 (1H, s), 7.37 (2H, d, J8.3Hz), 8.12 (2H,

Methods for the preparation of other B-ketoesters for use as intermediates in the present invention are disclosed in U.S. Pat EP application 88309039.1 beschiieben. Production 6

7,8-Dimethyl-2-hydrazino-4- benzodiazepln [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -3H- [1,5]

A mixture of 2,3-dihydro-7,8-dimethyl-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1 H- | 1.5] benzodazepine 2-thione

(411mg, 1, OmMoI), hydrazine hydrate (60mg, 1.2 mmol) and p-toluenesulfonic acid (10mg) in n-butanol (5ml) was 1.5 hours at 100 ⁰ C for. The solvent was removed under reduced pressure and the crude product used directly for Examples 29-31.

Production 7

7,8-Dlchlor-2-hydrazlno benzodlazepln-4- [4- (2-methyllmldazo [4,5-c] pyrid-1-yl) phenyl] -3H- [1,5]

A mixture of 7,8-dichloro-2,3-dihydro-4- [4- (2-methylimidazo | 4,5-c] pyrid-1-yl) phenyl] -1 H- | 1.5] benzodiazepine 2-thione

(452mg, 1, OmMoI), hydrazine hydrate (100mg, 2 mmol) and red mercury-II-oxide (217mg, 1, OmMoI) was heated in n-butanol wurde30min to 100 ⁰ C. The mixture was diluted with methanol (300 ml), filtered through Arbocel filter aid and the filtrate concentrated under reduced pressure. The crude product was used directly for Example 32.

Preparation 8 4,5-diamino-1- (1,1-dimethylethyl) -3-methylpyrazole

(a) 5-Amino-1- (1,1-dimethylethyl) -3-methylpyrazole was treated with sodium nitrite in aqueous acetic acid according to the method described in J. Amer. Chem. Soc, 1959, 81, 2456. The precipitated from the reaction mixture red solid product was filtered off, washed with water and dried in vacuo. Yield 76%.

¹ H-NMR (300 MHz, CDCl ₃ ): 1.62 (9H, s), 2.68 (3H, s), 7.10 (2H br s, exchanges with D ₂ O).

(b) 5-Amino-1- (1,1-dimethylethyl) -3-methyl-4-nitrosopyrazole (2.32 g, 12.7 mmol), obtained from (a), in ethanol (150 mL) at 20 psi ( 138 kPa) over 10% palladium on charcoal (230 mg) for 90 min at room temperature. The catalyst was filtered off and the solvent removed under reduced pressure to give the product as an unstable red solid (1.68 g, 73%).

Preparation 9 4,5-D-amino-1- (2-hydroxyethyl) 3-methylpyrazole

(a) 5-Amino-1- (2-hydroxyethyl) -3-methyl-4-nitrosopypyrazole

5-Amino-1- (2-hydroxyethyl) -3-methylpyrazole (Bull. Soc. Chim. France, 255 (1975)) (1.41 g, 10mMoI) was dissolved in a mixture of

Dissolve water (7 ml) and glacial acetic acid (1.4 ml). Sodium nitrite (0.8 g, 11,6mMol) in water (7 ml) was added dropwise at 0 ⁰ C for 0.5 h. The red solution was stirred at 0 ° C, and after 1 h, the precipitated solid was filtered off and in vacuo Title compound as a red solid dried (1.2g, 70%).

¹ H-NMROOOMHz, DMS0-d ₆ ): 2.75 (3H, s), 3.30 (2H, br), 3.62 (2H, t, J = 4Hz), 3.85 (2H, t , J = 4Hz), J, 85 (2H, t, J = 4Hz), 7.50 (1H, wide).

(b) 4,5-diamino-1- (2-hydroxyethyl) -3-methylpyrazole

5-Amino-1- (2-hydroxyethyl) -3-methyl-4-nitrosopyrazole (0.9 g, 5.3 mmol) was dissolved in a mixture of ethanol (40 ml) and dichloromethane (40 ml) and dried over 10% Pd / C (0.1 g) hydrogenated at 20 psi (138 kPa) and 2O ⁰ C for 2 h. The catalyst was filtered on Arbocel and the solvent removed under reduced pressure to give the title compound as a foam (800 mg, 97%).

¹ H-NMR (300MHz, CDCl ₃ ): 2.15 (3H, s), 2.20 (5H, broad), 3.94 (2H, t, J 5Hz), 4.05 (2H, t, J 5 Hz).

Production 10

4,5-Dlamlno-3-methyl-1- (2-pyridyl) pyrazole

(a) 5-Amino-3-methyl-1- (2-pyridyl) pyrazole

3-Aminocrotonitrile (1.98 g, 24.1 mmol) was added with stirring to a solution of 2-hydrazinopyridine (2.63 g, 24.1 mmol) in a

Mixture of conc. Hydrochloric acid (2.5ml) and water (10ml) added. After 10min at room temperature, conc. hydrochloric acid

(5ml) and the mixture is heated at reflux for 30min. It was cooled and basified by the addition of saturated aqueous potassium carbonate. The precipitated solid was filtered off and dried, yielding the

Title compound, 2.43g (58%).

¹ H-NMR (300 MH ;, CDCl ₃ ): 2.25 (3H, s), 5.37 (1H, s), 5.92 (2H, br s), 7.07 (1H, m ), 7.76 (1H, m), 7.94 (1H, d, J = 7Hz), 8.32 (1H, d, J = 6Hz) ppm

Analysis for C ₉ Hi ₀ N ₄

bar .: C62.05 H5.79 N32.16%

c; ef .: C62,05 H5,77 N32,25%

(b) 5-Amino-3-methyl-4-nitroso-1 - (2-pyridyl) pyrazole

By the method of Preparation 8 (a), 5-amino-3-methyl-1- (2-pyridyl) pyrazole (2.21 g, 12.7 mmol) was treated with sodium nitrite in aqueous acetic acid. The precipitated solid was triturated with methanol (250 mL) and the mother liquors were concentrated under reduced pressure to give the title compound as a red-brown solid (1.37 g, 53%). ¹ H-NMR (300 MHz, CDCl ₃ ): 2.84 (SH, s), 7.22 (1H, m), 7.88 (1H, m), 7.97 (1H, d, J = 7 Hz), 8.39 (1 H, d, J = 3 Hz), 9.20 (2 H, br s) ppm.

(c) 4,5-Dlamino-3-methyl-1- (2-pyridyl) pyrazole

Following the method of Preparation 8 (b), 5-amino-3-methyl-4-nitroso-1- (2-pyridyl) pyrazole (1.37 g, 6.75 mmol) in 4: 1 ethanol. Dichloromethane (50 mL) over 10% Pd / C at 20 psi (138 kPa) to give the title compound (1.27 g, 100%). ¹ H NMR (300MHz, CDCl ₃ ): 2.24 (3H, s), 7.05 (1H, m), 7.77 (1H, m), 7.89 (1H, d, J = 6Hz), 8.31 (1H, d, J = 3Hz) ppm.

Furthermore, a very broad resonance was observed between 2 and 6 ppm, presumably corresponding to the t JH ₂ groups.

Preparation 11 2-Hydroxyimino-3-oxo-3-phenylpropanitrile

HOAc / H O

A suspension of benzoylacetonitrile (11.7 g, 80.7 mmol) in a mixture of glacial acetic acid (34ml) and water (1 ml) was stirred vigorously at 10 ⁰ C while an aqueous solution of sodium nitrite (6.1 g, 88, 4 mmol in 7 ml) was added dropwise over 30 min. The mixture was stirred at room temperature for 1 h and then poured into iced water (600 ml). The precipitated yellow solid was filtered off, washed with water (100 ml) and dried to the title compound, 7.8 g (56%); Mp 126-128 ° C (literature mp 117-119 ° C; DOS 2722416 (1978))

Analysis for C ₉ H ₆ N ₂ O ₂ calc .: C 62.07 H 3.47 N 16.08% F: C 62.10 H 3.64 Ni 16.16%.

Preparations 12 to 18

The following 2-hydroxyimino-B-ketonitriles (Table 17) were prepared by the method of Preparation 11, starting from the corresponding B-ketonitrile or, in the case of pyridyl-substituted compounds, the sodium salt of B-ketonitrile.

Table 17

Il

OH

Herst. Ar Cl 104-108 ⁰ C Ausbeut Analysis% (theory in Klannern) CHN 12 C > 130-131 "C. 7 72 ⁺ L3 ⁺

-70- 291 914

ι! first. Ar Mp. ⁰ C Ausbeut Analysis \ .46 I N (Theory .66 i in brackets) ·) ⁰ C C .78 H 14 oil 56 * ♦ .86 15:37 ^0F 3 ° C .76 15:55) 15 168-171 9 Π 46 .86 2.18 23:39 ⁰ C (46 .12 2.24 23.89) 16 211-212 61t 54 .86 3:08 24.02 (54 2.88 23.89) 17 188-190 77% 54 2.93 23:55 (54 2.88 23.99) 18 222-223 66: 55 2.89 (54 2.88

+ known compound: DOS 2,722,416 (1978)

291

Preparation 19 5-Amino-1-methyl-4-nltroso-3-phenylpyrazole

NMe

CN

OH

MeNHNH-

EtOH

A mixture of 2-hydroxyimino-3-oxo-3-phenylpropanenitrile (2.61 g, 15 mmol) and methylhydrazine (1.1 mL, 21 mmol) was stirred at reflux for 2 h in ethanol, cooled and concentrated under reduced pressure. The residue was partitioned between ether (50 mM) and dilute hydrochloric acid (50 ml, 2 N solution). The aqueous phase was separated and made basic by the addition of saturated aqueous potassium carbonate. Dor precipitated red solid was filtered off and dried, yielding the title compound, 1,4Og (46%), Fp.230-231 ° C (literature Fp.230-231 ⁰ C, Gazz. Chim. Ital., [1968], 98 , 569).

Preparations 20 to 28

The following aminonitrosopyrazoles of Table 18 were prepared by the method of Preparation 19 starting from the corresponding 2-hydroxyimino-3-ketonitrile and substituted hydrazine.

Table 18

NO

Ar

RNHNH _n

Ar

NH.

NO

OH

manufacturing

20 21 22 23 24

Ar

CH CH OH

CH

CK

2O5-2O7 ° C

193-197 ° C

2O3-2O6 ° C

27O-273 ° C

251-252 ° C

yield

39%

32Z

222

65Z

58X

Analysis% (TlTeorie in Klamnem) CHN

63.27 (63.39

4.20 4.18

26.24 26.40)

56.88

(56.89

~ 5 ~ Ö79T

(50.75

5.17 5.21

23.90 24.12)

3.92 3.83

23.49 23.67)

50.69 (50.75

3.74 3.63

23.58 23.68)

49.06 (48.89

3.41 3.36

20.37 20.74)

25

235-236 ° C dec.

1ox

46.28 (46.14

3.72 3.87

26.71 26.91)

26

238-24O ° C

502

52.80 (53.20

4.46 4.46

34.77 34.46)

manufacturing Ar R 201-21O ⁰ C yield Analysis% (theory in Klamnern) C H N 27 N ν O CH ₃ 32O-321 ° C 51Z 53.23 4.52 34.47 (53.20 4.46 34.46) 28 CH ₃ 662 53.14 4.34 34.14 (53.20 4.46 34.46)

-74- 291914

Preparation 29 4,5-Diatom-1-methyl-3- (2-thienyl) pyrazole

Γ ³

oil

NO

Pd / C

A suspension of 5-amino-4-nitroso-1-methyl-3- (2-thienyl) pyrazole (1.255 g, 6.03 mmol) in ethanol (90 ml) was treated at 20 psi (138 kPa) above 10% Pd / C (130mg) hydrogenated at room temperature for 2h. The mixture was filtered through Arbocel filter aid and the filtrate concentrated under reduced pressure to give the title compound as a red-brown solid (1,133g, 97%), mp. 154-155 ⁰ C.

¹ H-NMR (300MHz, CDCl ₃ ): 2.60 (2H, br s), 3.38 (2H, br s), 3.74 (3H, s), 7.11 (1H, dd , J2 and 3 Hz), 7.27 (1 H, d, J 3 Hz), 7.41 (1 H, d, J

Preparations 30 to 38

The diaminopyrene of Table 19 was prepared from starting materials by the method of Preparation 29 using the aminonitrosopyrazoles of Preparations 20-28.

Table 19 manufacturing

Ar

ibeute

H NMR (30OMHz, CDCl3 unless otherwise indicated)

30

142-143 ° C

9IZ

2.0-4.O (4H, br), 7.H (IH.m), 7.39-7.5O (3H, b).

81 (lH.in), 7.90 (2H, d, J-6Hz), 8.08 (lH, d, J-6Hz). 8:36 (lH, dJ "4 Hz) ppm.

31

> 300 ° C

98Z

(DMSO-d,) 3.40 (2H, br s), 3.65 (2H, ro), 3.92 (2H.t, J-5Hz), 4.58 (2H.s), 4.92 (IH, c, J-AHz) , 7.17 (lH, tJ = 5Hz). 7.31 (2H, c, J-5Hz), 7.82 (lH, d, J = 5Hz) ppm.

2.6O (4H.br s), 3.75 (3H, s), 7.34 (lH, d, J-5Hz), 7.43 (2H, t, J-SHz), 7.56 (2H, d, J-5Hz) ppm.

32

CH.

240-242 ⁰ C +

90X

(25OMHz, DMSO-d,), 3.55 (3H, a), 5.63 (H, br s) »

7.45 (2H, m), 7.58 (lH, dJ-6Hz) shows especially fine coupling), 7.65 (lH, d, J-8Hz shows especially fine splitting) ,, 8.42 (2H, 3) ppm.

33

CH.

218-22O ° C +

76Z

34

Cl

CH.

184-187 ° C +

91Z

(DMSO-d), 3.51 (3H, d, J-1.5Hz), 7.25 (2H, br s), 7.32 (2H, m), 7.57 (2H, m), 10.07 (2H, br e) ppm.

35

CH.

2 15-217 ⁰ ci

91 *

(CD ₃ CD). 3.78OH.S) 7.76 (lH, t, J-7Hz).

7.86 (IH, d, J = 711z), 7 .92 (lH, d, J-7Hz), 8.02 (lH, s).

manufacturing Ar R 155-16O ° C yield H NMR (300MHz, CuCl ₃ if not stated otherwise) 36 / ^N o- CH ₃ U3-U6 ° C 932 2.95 (4H, br s). 3.78 (3H, s), 7.12 (lH, m) 7.69 (lH, tJ-6Hz), 7.93 (lH.d.J-6H2), 8.55 (lH, d, J-AHz). 37 N-x €> CH., 184-187 ° C 98Z 2.AO (2H.br s), 3.A0 (2H, br s), 3.76 (3H, s). 7.34 (lH, m), 8.H (IH, d, J = 6Hz), 8.56 (lH, d, J = 4Hz), 9.07 (lH.s) ppm. 38 O- CH ₃ 98 ° C (DMSO-d) 3.48 (2H, br s), 3.55 (3H, s). 4.74 (2H, br s), 7.79 (2H, d, J-5Hz), 8.45 (2H, d, J-5Hz) ppm.

-77- 291 914

Preparations 39 to 42

The compounds of Table 20 were prepared according to those described in DOS 2023453 and C.A. Roo, Ber., (1922), 55,295S

Methods produced.

Table 20

Cl

manufacturing 1 R * CH ₃ CH- / * CH ₃ ¹ H NMR (30OMHz, _CDCl3) 39 CH ₃ 2.35 (3H, s), 6.25 (lH, s), 7.31 (lH, m), 7.68 (lH, d, J-SHz), Kt V 7.83 (lH.m), CH ₃ 8:58 (lH, d, J-3Kz). 40 1.25 (6H, d, J "5Hz), 2.9O (lH, d, J = SHs) 3.79 (3H, sep.) 6:03 (lH, s). 3.92 (3H, s), 6.57 (lH, s), 7.3u (lH, dd, J = 5 nd 3Hz), 8.05flH, dc, J ³ 8 Vid 2Hz), 8.57 (lH, dd, J =: and « Hz 3.97flH, d, J-2H ?.).

-78- 291 914

manufacturing • R ¹ R ^{2 1} H NMR (30OMHz, CDCl.) 42 H (500MHz) 1.26 (lH, m), O L.41 (4H, m), 1.74 (lH, d, J 13Hz), 1.82 (2H, m), 1.99 (2H, m), 3.73 (lH, m), 5.97 (lH, s).

Preparation 43 4-Amino-3- (2-methoxyethoxy) methyl-5-methylamino-pyrazole

(a) α-bromomethyl-B-chloro-1-methyl-n-n-pyroprazole

S-Chloro-1S-dimethyl-n-nitropyrazole (43g, 0.29 mmol) was dissolved in carbon tetrachloride (430 mL), bromine (12 mL) was added, and the reaction mixture was heated to reflux for 48 h while illuminating with a 500W light source. A second portion of bromine (12 ml) was added and the reaction heated to reflux for a further 48 hours. The reaction mixture was cooled and chromatographed on silica (gradient elution starting with hexane and increasing the proportion of dichloromethane from 0 to 100%). Product containing fractions were evaporated to give the title compound as a white solid (35g, 47%).

'H NMR (300MHz, CDCl ₃ ): 3.92 (3H, s), 4.64 (2H, s).

(b) 3 · (2 · ΜθΙηοχγθΙηοχν ^ θΙηνΙ · 5 · οηΙθΓ-1-ΓηβΙηγΙ-4 · ηΚκ) ργΓβζοΙ

3-Bromomethyl-5-chloro-1-methyl-4-nitropyrazole (2.42 g, 9.5 mmol) and silver tetrafluoroborate (2.22 g, 11.4 mmol) were stirred in 2-methoxyethanol (25 mL) at reflux for 6 h. The black solid was filtered off and the solvent removed under reduced pressure. The oil was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. The product was purified by chromatography on silica eluting with 10% ethyl acetate in dichloromethane. Product-containing fractions were evaporated to give the title compound as a white solid (1.54 g, 65%).

¹ H-NMR (300 MHz, CDCl ₃ ): 3.41 (3H, s), 3.63 (2H, m), 3.81 (2H, m), 3.92 (3H, s), 4.90 (2H, s).

(c) α-IZ-methoxy-methoxy-methyl-V-methyl-S-methyl-amino-nitropyrazole

3- (2-Methoxyethoxy) methyl-5-chloro-1-methyl-4-nitropyrazole (1.44 g, 5.8 mmol) was suspended in ethanol. Methylamine was bubbled into the suspension with ice cooling for 20 minutes. Then, the solution was heated in a closed vessel at 100 ⁰ C for 3 h, cooled, and the ethanol was removed under reduced pressure. The yellow solid residue was dissolved in dichloromethane (150 ml) and washed with saturated sodium bicarbonate solution (50 ml). The organic phase was separated, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound as a yellow solid (1.34 g, 95%).

¹ H-NMR (300 MHz, CDCl ₃ ): 3.24 (3 H, d, J 5 Hz), 3.40 (3 H, s), 3.63 (2 H, t, J 4 Hz), 3.80 (2H, t, J 4Hz), 3.91 (3H, s), 4.81 (2H, s), 7.01 (1H, brs).

(d) 4-Amino-3- (2-methoxyethoxy) methyl-5-methylamino-pyrazole. 3- (2-Methoxyethoxy) methyl-1-methyl-5-methylamino-4-nitropyrazole (0.73 g, 3 mmol), hydrazine hydrate (0 , 5ml) and Raney Nickel

(200 mg) were stirred (12 mL) at 5O ⁰ C for 1.5 h in ethanol. Raney nickel was filtered off and the ethanol was concentrated under reduced pressure

Removed pressure to give the title compound (0.64 g, 100%).

¹ H-NMR (300 MHz, CDCl ₃ ): 2.83 (6H, m), 3.39 (3H, s), 3.58 (2H, m), 3.65 (2H, m), 3, 68 (3H, s), 4.58 (2H, m).

Preparations 44 and 45 The compounds of Table 21 were prepared according to Preparation 11 (b) using isobutanol or aqueous Dimethylformamide prepared in place of methoxyethanol.

291

manufacturing R (30OtIHz, CDCl ₃₎ 0.94 (6H, d, J 5Hz), 1.96 (IH, α old) 3.39 (2H, d, J 5Hz), 3.93 (3H, s) £ .3O (2H, s) CH ₂ CH (CH ₃ ) ₂ / 30OMHz ₁ CDCl ₃ ) 2.84ÜH, brs); 3.93 (3H, s), «» .91 (2K, s) H

Preparation 46 B-chloro-S-cyclohexyl-i-methyl -n-n-pyroprazole

B-chloro-S-cyclohexyl-i-methylpyrazole (prepared according to US Pat. No. 4,044,013) (7.51 g, 37.8 mmol) was dissolved in conc. Dissolved sulfuric acid (19ml) and cooled to -10 ° C. Fuming nitric acid (12 ml) was added over 0.75 h keeping the temperature below 0 ° C. The reaction mixture was stirred at ⁰ ° C. for 1 h and then at 5 ° C. for 3 h. It was poured onto ice (250 ml) and extracted with dichloromethane (2 × 250 ml). The extracts were concentrated, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound as a white solid (7.7 g, 84%).

¹ H-NMR (300 MHz, CDCl ₃ ): 1.26-1.54 (5H, m), 1.75-1.99 (5H, m), 3.29 (1H, m), 3.88 ( 3H, s).

-80- 291 914

Preparations 47 to 50 The compounds of Table 22 were prepared by the method of Preparation 46 using the appropriately substituted Chloropyrazole produced. Table 22

Cl

manufacturing R ¹ R ^{2 3 1} H-NMR (300 MHz, CDCl ₃ ) 47 CH ₃ / - ^N 2.69 (3H, s), 7.49UH, dd, J = <«and 7Hz), 7.71 (lH, d, J = 7Hz), 8.00 (LH, t, J = 7Hz), 8.68 (lH, d, J = <4 Hz). 48 l-Pr CH ₃ 1.31 (6H, d, J = 5Hz), 3.62 (lH, d ', H = 5Hz), 3.88 (3H, s). 49 O H 1:23 to 1:58 (6H, m). 1.9O (3H, m), 3.A4 (lH, m), L1.05 (lH, br s). 50 2.68 (3H, s), 7.43 (1H ₁ Ki "), 7.7O (lH, d, J-6Hz), 7.98 (lH, m), 8.65 (lH, d, J> 3Hz).

Preparations 51 to 59

The compounds of Table 23 were prepared by the method of Preparation 43 (c) using

Substituted 5-Chloropyrazole prepared.

Table 23

NHR

manufacturing R ¹ R ² ' R ^{3 1} H-NMR (300 MHz, CDCl ₃ ) 51 ο CH ₃ CH ₃ 1.28-1.99 (1OH, m), 3.20 (lH, m), 3.2 <4 (3H, d, J »4Hz, 3.87 (3H, s), 7.15 (lH, s). 52 Vv CH ₃ - * CK ₃ CH ₃ O.92 (6H, d, J = -5Hz), L.97 (1H Di _1), 3.2 =. (3H, d, J-4Hz), 3:39 (2H, d, J-5Hz), 3.92 (3H , s), «« .71 (2H ₁ S) ₁ 7.OKlH, br

-82-291 914

Herstellunc R ¹ R ² R ^{3 1} H. WiR (30OMHz ₁ CDCl ₃ ) 53 CH-OH CH ₃ CH ₃ 3.17 (IH, C ₁ J-SHz), 3.27 (3H, d, J-SHA), 3.92 (3H, s), 4.75 (2H, d, J "5Hz), 7.10 (1H, br s). 5 × 4 CH _{3 of} CH ₃ CH ₃ 1.28 (6H, d, J = 6Hz), V-CH ^CH 3 3.23 (3H, d, J-5Hz), 3.5O (lH, septet), 3.87 (3H, s), 7.16C1H, br s) 55 Λ "ν CH ₃ H 1.28 (lH, m), Vy * 1.47 (4H, m), 1.82 (3H, m), 2.00 (2H, b), 3.24 (LH, m), 3.6 <4 (3H, s), 5.65 (2H, br s). 56 r \> H CH ₃ L. Ui * (i »H, m), 1.65 (3H, m), V_ / 2:07 (3H, m), 3:05 (3H, d, J = 4Hz), 3.26 (lH, m) _f 3.45 (3H, s), 6.52dH.br s).

-83- 291914

manufacturing R ¹ H R ^{3 1K} NMR (300KHz, CDCI ₃₎ 57 (CH ^ OH 1.2-2.1 (UH, complex), 3.3O (lH, m), 3.5O (2H, m), CH ₃ 3.35 (2H, m), 6.85 (LK.m). 58 CH ₃ 3.32 (3H, d, J = 5Hz), 4.O2l3H, s), 7.23 (lH, br s), .7.38 (lH, dd, J-5 _, and 7Hz), 7.97 (lH, d, J «7Hz), 8.68 (lH, dd, J-5 And & 2Hz), 8.87 (lH, d, J-2Hz). 59 CH ₃ CH ₃ 2.55 (3H, s), 3.09 (3H, d, J = UHz), 7.28 (lH, m), 7.89 (2H, m), . 8 "," 5 (lH, d, J-5Hz), 9.OL (IH, br s).

-29- 291914

Preparations 60 to 68 The compounds of Table 24 were prepared by the method of Preparation 43 (d) using

substituted nitropyrazole produced.

Table 24

CH ₁ CH-

N, NH

γ-

NH,

manufacturing R ¹ CH ₂ OH R ² R ^{3 1} H-NMR (30OMHz, CDCI ₃ ) 60 CH ₃ CH ₃ 1.2-2.0 (1OH ₁ In), V> 2.3O (3H, m), 2.6O (lH, t, J = 5Hz), 2.80 (3H, s), 3.63 (3H, s). 61 CH 0 CH ₃ CH ₃ 0.93 (6H ₁ O ₁ J = SHz) ₁ CH ₃ ^ ^X ° ^H 2 1.92 (1H ₁ IIi), 2.6O (3H, br S) ₁ 2.33 (3H, s », 3.26 (2H.d, J = 5H =), 3.68 (3H S _1), r 4.a8 (2H, s). 62 CH ₃ CH ₃ 2.66 ("H, br s), 2.82 (3H, s), 3.66 (3H, s), 4.62 (2H, s).

-85- 291914

ICreating R ¹ CH ₃ R ^{3 1} H-NMR (30OMHz ₁ COCl ₃ ) 63 CH ₃ r CH ₃ CH ₃ 1.30 (6H, d, J = 5Hz), 2:40 (2H, br s), 2.82 (3H, br s), 2.98 (lH, m) 2.8O (2H, br s), 3.67 (3H ₁ S). 6m O H H Compound is not isolated 65 O H CH ₃ Compound is not isolated 66 O (CH ₉ ) ^ OH 1.40 (5H, m), 1.65-1.97 (9H, m), 2.64 (lH, m), 3.00 (3K, br s), 3.29 (2H, c, J = 7Hz), 3.74 (2H, m).

-86- 291914

manufacturing R ¹ CH, R ^{3 1} H NMR (30OMHz ₁ CDCl ₃ ) 67 N-ν CH ₃ 2.87 (3H, s), 2.90OH, br s), 3.79 (3H, s), 7.33 (lH, dd, J = 5 and 7 Hz) 8.10 (lH, d, J = 7Hz), 8:54 (lH, d, J-5Hz), CH ₃ 9.05 (IH, s). 68 CH ₃ 2.23 (3H, s), 2.aO (2H, br s), 3.13 (3H, s), 7:03 (lH, c, J-5Hz), 7.3O (lH, br), 7.9O (lH, d, J = 5Hz), 8.27 (lK, d, J = 5Hz).

Production 69 Ethyl-3- [3- (2-methoxyethoxymethyl) -1-methyl-5-meVhylamlnopyrazol-4-yl] amlno-3- [4 '- (2-methylimldazo [4,5-c] pyrld-1-yl) -

phenylj-propenoate

4-Amino-3- (2-methoxyethoxy) methyl-1-methyl-5-methyl-iminopyrazole (0.64 g, 3 mmol), ethyl 4 '- (2-methylimidazo [4,5-c] pyrid-1 -yl) benzoylacetate (0.97 g, 3 mmol) and zinc chloride (0.8 g, 0.6 mmol) were stirred in ethanol at reflux for 18 h. The reaction mixture was cooled and ethanol removed under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure. The dark red oil was chromatographed on silica eluting with 20% methanol in ethyl acetate. Product-containing fractions were concentrated to give the title compound as a fawn foam (0.72 g, 46%).

-87- 291914

Preparations 70 to 72

The following compounds of Table 25 were prepared by the method of Preparation 69 using the appropriate method

substituted diaminopyrazois prepared.

TABLE 25

manufacturing ό ¹ H NMROUOMHz, CDCL) 70 ⁰ VWH, - r L.36 (3H, C, J 5Hz); l.2u-1.80 (10H, m); 2.36 (lH, a \): 2.52 (3H, s), 2.84 (3H, d, J 5Hz), 3.04 (LH, C, J 5Hz), 3.58 (3H, s), 4.27 (2H, q, J 5Hz), 5.04 (LH, s), 7.OKlH, d, J 5Hz) ₁ 7.30 (2H, d, J 6Hz), 7.76 (2H, d, J 6Hz), 8.40 (LH, d, J 5Hz), 9.06 (1H ₁ S), 9.60 (lH, s). 7L U.93 (6H, d, J 5Hz), L.36 (3H, c, J6Hz), L.93 (lH, m), 2.5O (3H, s), 2.72 (3H, d, J 5Hz) , 2.90 (LH ₁ C ₁ J 5Hz), 3. ^ 8 (2H, d, J 5Hz), 3.57 (3H, s), 4.26 (2H, q, J 6Hz), u.3O (2H, s), 5.02 (lH, s), 7.03 (LH, d, J 5Hz), 7.25CH, q, J 6Hz), 7.68 (2H, dJ 6Hz), 8.38 (LH, d, J 5Hz), 9.06QH ₁ S); 9.78 (lH, s).

-88- 291 914

72 HUCH _n - 1.36OH (IH , C, J 6 Hz) I , 56 (3 H , S) ₁ .60 1.82 OH , C, J 5Hz) , -2 .02 (IH .m); 3 2:32 s); , D.J. 5Hz) , 3 6Kz), .06 7.62 OK, (2Hd , J u.2 6CH, q.J .06 (1H 2H.J.J .s), 7 'JHz) ₁ ( LH. A , .I .d.J 5Kz 5Hs) t ). 7th LH.d.J 5HzΊ, (2H, Π.Η oH = ). S. ilH.s) 9:03 , S) 9:53

Preparation 73 S-Amino-methyl-aminochloroline

(a) Gaseous methylamine was bubbled at ⁰ ° C through a suspension of 2-chloro-3-nitroquinoline (1.06 g, 5.1 mmol) in ethanol (20ml) 15min. The solvent was removed under reduced pressure and the bright red residue was dissolved in dichloromethane (100 ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 2-methylamino-3-nitroquinoline (940mg, 91%) as a red solid; Mp 160 ^° C.

¹ H-NMR (300MHz, CDCl ₃ ): 3.26 (3H, d, J 4Hz), 7.30 (1H, m), 7.74 (3H, m), 7.85 (1H, br s) , 8.97 (1H, s).

(b) 2-Methylamino-3-nitroquinoline (711 mg, 3.5 mmol) was prepared according to the procedure of Preparation 11 (d) to the title compound reduced (590 mg, 97%), mp. 133-136 ⁰ C.

Analysis for C ₁₀ HnN ₃ .0.2H ₂ O calc .: C 67.92 H 6.49 N 23.76% Found: C68.10 H6.38 N 23.58%.

The following compounds were prepared by the methods described in the following respective publications

manufactured:

2,3-diamino-4,6-dimethylpyrazine Bull. Chem. Soc. Jp., 1973, 46, 3277-3280 2,3-diamino-4-methylpyridine 2,3-diamino-6-methylpyridine / 3,4-diamino-2,6-dimethylpyridine Chem. Hos., 63,162,996 3.4 Diamino-2-methoxycarbonyl-5-methylthiphene pharmaceutics, 1970,25,517 4,5-diamino-3-methyl-1-phenylpyrazole J. Het. Chem., 1975, 12, 279 4,5-diamino-1-methyl-3-phenylpyrazole Farmaco Ed. Sci., 1982, 37, 116 4,5-diamino-1,3-dimethylpyrazole Chem-Ztg., 1977, 101, 3,4-diamino-1,5-dimethylpyrazole ZH. Obsch. Khim., 1980, 50, 2106

Claims (10)

claims: A is a fused benzene, pyridine, naphthalene, quinoline, thiophane, benzothiophene, pyrazole or isothiazole ring which may optionally be substituted by 1 or 2 substituents independently selected from C C ₁ -C ₄ -alkyl, C ₁ -C ₆ -cycloalkyl, halogen, perfluoroC-C ₁ -C -alkyl, cyano, C ₁ -C -alkoxy-carbonyl, nitro, amino, amino, substituted by (C ₁ -C ₄ -alkyl) -sulfonyl, amino, substituted by (C ₁ -C ₄ -alkyl) OXaIyI, C ₁ -C ₄ -alkoxy (C ₁ -C ₄ -alkyimino, hydroxy (C ₁ -C ₄ -alkyl), (C ₁ -C ₄ -alkoxy) C ₁ -C ₄ alkyl, (C ₁ -C ₄ alkoxy) - (C ₂ -C ₄ BKOXY) C ₁ -C ₄ alkyl, -CONR ⁵ R ⁶ , wherein R ⁵ and R ⁶ each R ₂ is independently H or C ₁ -C ₆ alkyl or R ₅ is H or C ₁ -C ₄ -A ^ yl and R ₆ is C ₃ -C ₇ alkyl or 2-pyridyl, or R ⁵ and R ⁶ are joined to form a morpholino, pyrrolidino or piperidino group with the nitrogen atom to which they are attached, and phenyl, thionyl or pyridyl, optionally substituted by ch is halogen, cyano, trifluoromethyl, (Cr ^ alkoxyjcarbonyl or carbamoyl; X, O, S or NH; Y is 1,4-phenylene or a group of the formula is; R ^{1 is} either H or C ₁ -C ₄ alkyl, optionally substituted by a substituent selected from phenyl, halophenyl, pyridyl, (C ₁ -C ₄ alkoxy) carbonyl and DMD-C alkylamino, or C ₁ -C ₄ alkyl substituted by hydroxyl or by one or two C ₁ -C ₄ alkoxy groups, or (CH ₂ ) _n CONR ⁷ R ⁸ , wherein η = 1 to 4 and R ⁷ and R ^{8 are} each independently H or C ₁ -C ₄ alkyl mean; R ² HOdBrC ₁ -C ₄ -AIMiSt; R ^{3 is} H or C, -C ₄ alkyl; B is a condensed B-membered heterocyclic ring containing 1 to 4 nitrogen atoms or a condensed 6-membered heterocyclic ring containing 2 nitrogen atoms, wherein the fused 5- or 6-membered ring is optionally substituted by 1 or 2 substituents which are independently selected from C ₁ -C ₄ -Alkyl, Ci-d-haloalkyl, halogen and oxo; and "Het" is either a 5-membered aromatic heterocyclic ring containing 2 or 3 is nitrogen or a pyridine ring which may optionally be fused to a benzene or pyridine ring or to another 5-membered aromatic heterocyclic ring, at least one of these heterocyclic rings optionally being a sulfur or oxygen atom and at least one of these rings is optionally substituted with 1 to 3 substituents independently selected from C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, halogen, CF ₃ , CN and formyl, and wherein the dotted line represents an optional bond, or their pharmaceutically acceptable salts, characterized in that (a) a compound of formula (IV) with a keto-ester of formula (V) to form a compound of Formula (IV) is implemented: .1 (iv ¹ ) wherein R ^{1 is} H or C ₁ -C ₄ alkyl, Q is a separating group and A, Y and Het are as above
with the exception that A is not defined by an amino or carbamoyl group
is substituted, and the compound (IV) is cyclized to a compound of formula (Γ): (b) if necessary, compound (Γ) with phosphorus pentasulfide to give a compound of
Formula (Ie) is implemented: He c (c) if necessary, the compound (Ie) with ammonia to give a compound of the formula (I)
in which R ^{1 is} H or C ₁ -C ₄ alkyl, X is NH and the dashed line is a
Binding means; (d) if necessary, reacting the compound of (c) in which R ^{1 is} H with an alkyl propiolate to give a compound of formula (II) in which B is a pyrimidone ring; (e) if necessary, reacting compound (Ie) in which R ^{1 is} H with an alkyl carbazate and cyclising the product to a compound of formula (II) in which 3 is 3-0x0-1,2,4 - triazole ring is, (f) if necessary, the compound (I e) in which R ^{1 is} H, reacted with hydrazine and either (1) the resulting hydrazide is diazotised into a compound of formula (II) in which B is a fused tetrazole ring, or (2) the obtained hydrazide is reacted with an alkyl formate of the formula R ⁴ C (OAlk) ₃ wherein Alk is an alkyl group and R ^{4 is} H, C ₁ -C ₄ alkyl or haloalkyl to give a compound of formula (II) in which B is a substituted or unsubstituted 1,2,4-triazole ring, or (3) reacting the hydrazide obtained with trifluoroacetic acid to give a compound of formula (II) in which B is a trifluoromethyl group substituted 1,2,4-triazole ring; (g) if necessary, reacting the compound (Ie) in which R ^{1 is} H with an acetal of aminoacetaldehyde or a homologue thereof to give a compound of formula (II) in which B is an unsubstituted or substituted imidazole ring; (h) if necessary, the compound (Ie) in which R ^{1 is} H is reacted with propargylamine or a homologue thereof to give a compound of formula (II) in which B is a substituted imidazole ring; (i) it is necessary to react the compound (I e) in which R ^{1 is} H with ethanolamine or an analog thereof followed by cyclization to a compound of formula (II) in which leg is substituted or unsubstituted Imidazoline or tetrahydropyrimidine ring; (j) if necessary, a compound of formula (I) wherein R ^{1 is} H as above formed with a substituted or unsubstituted alkyl halide, halogen-substituted carboxylic acid ester or halogen-substituted amine or amide to give a compound of formula (I) or (III) is implemented in which R ^{1 has} a meaning other than H; (k) if necessary, a compound of the formula (I), (II) or (III) above in which R ² and R ^{3 are} H, to give a compound of the formula (I), (II) or (III ) is alkylated, in which at least one of the substituents R ² and R ^{3 is} an alkyl group; (I) if necessary, a compound of the formula (I), (II) or (III) obtained above in which ring A bears a nitro substituent, to give a corresponding compound of the formula (I), (II) or (III) is reduced, in which ring A carries an amino substituent; (m) if necessary, a compound of the formula (I), (II) or (III) obtained above in which ring A bears a halogen substituent with carbon monoxide and an amine in the presence of a catalyst to give a corresponding compound of the formula (I ), (II) or (III) in which ring A carries a carbamoyl substituent; (n) if necessary, a compound of the formula (I), (II) or (III) in which the dotted line represents a bond as obtained above to give a compound of the formula (I), (II) or (III) reduced becomes, in which this bond is missing; and (o) if necessary, a compound as obtained above with an acid to a pharmaceutical acceptable salt is reacted. 2. The method according to claim 1, characterized in that the compound (IV) is isolated and then cyclized in the presence of an alkali metal alkoxide. 3. The method according to claim 1, characterized in that the compound (IV) and (V) are heated together with a solvent to form a compound of formula (I '). 4. The method according to claim 1,2 or 3, characterized in that A is a condensed benzene, dimethylbenzene, dichlorobenzene, nitrobenzene, aniline, fluorobenzene, chlorobenzene, pyridine, quinoline, methylpyridine, dimethylpyridine , Ethoxycarbonylpyridine, pyrid-2-yl-carbamoylpyridine, morpholinocarbonylpyridine, diethylcarbamoylpyridine, t-butylcarbamoylpyridine, thiophene, 2-methoxycarbonyl-5-methylthiophene, 1-methyl-3-phenylpyrazole, 1-phenyl-3 -methylpyrazole, 1,2-dimethylpyrazole, 1,3-dimethylpyrazole, 1-pyrid-2-yl-3-methylpyrazole, 1-t-butyl-3-methylpyrazole, 1- (2-hydroxyethyl) - 3-methylpyrazole, i-methyl-S-pyrid-S-ylpyrazole, 1-methyl-3-pyrid-4-ylpyrazole, i-methyl-S-pyridylpyrazole, 1- (2-hydroxyethyl) 3-phenylpyrazole, 3- (2-methoxyethoxymethyl-methylpyrazol-methyl-S-cyclohexylpyrazole, 1-methyl-3-hydroxymethylpyrazole, 3-cyclohexylpyrazole, 1-methyl-3- (3-isobutoxymethyl) -pyrazole , 1-methyl-3- (4-chloronyl) pyrazole, i-methyl-3-isopropylpyrazole, i-pyridyl-S-phenylpyrazole ol, 1-methyl-3- (2-chlorophenyl) pyrazole, 1-methyl-3- (3-trifluoromethyl) phenylpyrazole, 1-methyl-3-thienyl-pyrazole, bromopyridine, 1-ethoxyethyliminobenzene, N-ethylsulfoxyar.iline, 3-methylisothiazole and ethoxycarbonylcarbamidobenzene ring. A process according to any preceding claim, characterized in that R ^{1 is} H, methyl, ethyl, benzyl, 4-chlorobenzyl, -CH ₂ CO ₂ Et, -CH ₂ CH ₂ N (CH ₃ J ₂ , -CH ₂ CON ( CH _{3) 2,} -CH ₂ CH ₂ CH (OCHA) ₂ or 4-hydroxybutyl is. A process according to any one of claims 1 to 4, characterized in that the condensed ring B is an imidazole, methylimidazole, triazole, methyltriazole, trifluoromethyltriazole, triazolone, tetrazole, pyrimidone, imidazoline or tetrahydropyrimidine ring. Process according to any one of the preceding claims, characterized in that R ² and R ^{3 are} independently hydrogen or methyl. Process according to any one of the preceding claims, characterized in that "Het" is selected from dimethylpyridyl, 1,2,4-triazolyl optionally substituted by 1 or 2 Cr-Gj-alkyl groups, or imidazolyl optionally substituted by up to 3 groups is C ₁ -C ₄ -alkyl, halo and formyl, or optionally substituted with a C ₁ -C ₄ alkyl or CF 3 group and fused to a benzene, thiazole or pyridine ring. 9. The method according to claim 8, characterized in that Het 2-methylimidazo [4,5-c] pyrid-1-yl, 2,4,6-trimethylimidazo [4,5-c] pyrid-1-yl, 3, 5-Dimethyl-1,2 _/ 4-triazol-4-yl, 1,6-dimethylpyrid-3-yl, B-chloro-methylimidazol-1-yl, 5-chloro-4-formyl-2-methylimidazole-1 or 4-methylimidazo [2,2-b] thiazol-5-yl. 10. The method according to claim 1,2 or 3, characterized in that the compound produced 8,9-dichloro-5- [4- (2-methyl-1H-imidazol4,5-clpyrid-1-yl) phenyl] -4H -imidazo [1,2-a] [1,5] benzodiazepine, 8,9-dichloro-1-methyl-5- [4- (2-methylimidazo (4,5-c] pyrid-1-yl) -phenyl -4H-imidazo [1,2-a] [1,5] benzodiazepine, 3,5-dihydro-2- (4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -5,7,9-trimethyl-1H-pyrido [2,3-b] [ 1,4] diazepin-4-one, 8-bromo-3,5-dihydro-1-methyl-2- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -4H-pyrido [2,3-b] [ 1,4] diazepin-4-one, 1,3-dihydro-1,8-dimethyl-6-methoxycarbonyl-4- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -2H-thione [3,4-b ] [1,4] diazepin-2-one, 5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -1,6,7,8-tetrahydro-1,3,8-trimethylpyrazolo [3,4-b] [1 , 4] diazepin-7-one, 3-cyclohexyl-1,8-dimethyl-5- [4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl-1,6,7,8-tetrahydro-pyrazolo [3,4-b] [1,4] diazepin-7-one, 8-bromo-5-L4- (2-methylimidazo [4,5-c] pyrid-1-yl) phenyl] -4H-imidazo [1,2-g] pyrido [2,3-b] [1-4 ] diazepin
or 1,6,7,8-Tetrahydro-1,8-dimethyl-5- [4- (2-methyl-1H-imidazo [4,5-c] pyrid-1-yl) phenyl] -7-oxo-3 - (3-pyridyl) pyrazolo [3,4-bl (1,4] diazepine
or a pharmaceutically acceptable salt thereof.