Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them

#This invention relates to bicyclic heterocyclic compounds active as inhibitors of signal transduction mediated by tyrosine kinases. The invention also relates to processes for preparing such compounds and pharmaceutical compositions comprising them.

#Inhibitors of signal transduction mediated by tyrosine kinases useful in the treatment of tumoral diseases as well as benign prostate hyperplasia (BPH) diseases of the lungs and respiratory tract. Tyrosine kinase inhibitors have been reported for the treatment of hyper-secretory respitory diseases. WO 00/10588.

#The present invention relates to bicyclic heterocyclic groups of general formula

#the tautomers, the stereoisomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, as well as benign prostate hyperplasia (BPH), diseases of the lungs and respiratory tract, and the preparation thereof.

#In the above general formula I Ra denotes a hydrogen atom or a C1-4-alkyl group, Rb denotes a phenyl or 1-phenylethyl group, wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, while R1 and R2, which may be identical or different, in each case denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1-4-alkyl, hydroxy, C1-4-alkoxy, C2-3-alkenyl or C2-3-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or a cyano, nitro or amino group, and R3 denotes a hydrogen, fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group, Rc denotes a cyclobutyl, cyclopentyl or cyclohexyl group which is substituted in each case by a group R4—N—R5, while R4 denotes a hydrogen atom or a C1-3-alkyl group and R5 denotes a hydrogen atom or a C1-3-alkyl group, an aminocarbonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl-C1-3-alkyl, di-(C1-3-alkyl)aminocarbonyl-C1-3-alkyl, pyrrolidin-1-ylcarbonyl-C1-3-alkyl, piperidin-1-ylcarbonyl-C1-3-alkyl, homopiperidin-1-ylcarbonyl-C1-3-alkyl, morpholin-4-ylcarbonyl-C1-3-alkyl, homomorpholin-4-ylcarbonyl-C1-3-alkyl, piperazin-1-ylcarbonyl-C1-3-alkyl, 4-C1-3-alkyl-piperazin-1-ylcarbonyl-C1-3-alkyl, homopiperazin-1-ylcarbonyl-C1-3-alkyl or a 4-C1-3-alkyl-homopiperazin-1-ylcarbonyl-C1-3-alkyl group, a hydroxy-C2-4-alkyl, C1-3-alkyloxy-C2-4-alkyl, C1-4-alkyloxy-carbonylamino-C2-4-alkyl, amino-C2-4-alkyl, C1-3-alkylamino-C2-4-alkyl, di-(C1-3-alkyl)amino-C2-4-alkyl, C1-3-alkylcarbonylamino-C2-4-alkyl, aminocarbonylamino-C2-4-alkyl, C1-3-alkylaminocarbonylamino-C2-4-alkyl, di-(C1-3-alkyl)amino-carbonylamino-C2-4-alkyl, pyrrolidin-1-ylcarbonylamino-C2-4-alkyl, piperidin-1-ylcarbonylamino-C2-4-alkyl, morpholin-4-ylcarbonylamino-C2-4-alkyl, C1-3-alkylsulphonyl-C2-4-alkyl or a C1-3-alkylsulphonylamino-C2-4-alkyl group, a (2-oxo-pyrrolidin-1-yl)-C2-4-alkyl, (2-oxopiperidin-1-yl)-C2-4-alkyl, (3-oxo-morpholin-4-yl)-C2-4-alkyl, (2-oxo-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-3-C1-3-alkyl-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-hexahydropyrimidin-1-yl)-C2-4-alkyl or a (2-oxo-3-C1-3-alkyl-hexahydropyrimidin-1-yl)-C2-4-alkyl group, a C1-4-alkylsulphonyl, chloro-C1-4-alkylsulphonyl, bromo-C1-4-alkylsulphonyl, amino-C1-4-alkylsulphonyl, C1-3-alkylamino-C1-4-alkylsulphonyl, di-(C1-3-alkyl)amino-C1-4-alkylsulphonyl, (pyrrolidin-1-yl)-C1-4-alkylsulphonyl, (piperidin-1-yl)-C1-4-alkylsulphonyl, (homopiperidin-1-yl)-C1-4-alkylsulphonyl, (morpholin-4-yl)-C1-4-alkylsulphonyl, (homomorpholin-4-yl)-C1-4-alkylsulphonyl, (piperazin-1-yl)-C1-4-alkylsulphonyl, (4-C1-3-alkyl-piperazin-1-yl)-C1-4-alkylsulphonyl, (homopiperazin-1-yl)-C1-4-alkylsulphonyl or a (4-C1-3-alkyl-homopiperazin-1-yl)-C1-4-alkylsulphonyl group, a C1-4-alkyloxycarbonyl group, a formyl, C1-4-alkyl-carbonyl, C1-3-alkyloxy-C1-4-alkyl-carbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, amino-C1-4-alkyl-carbonyl, C1-3-alkylamino-C1-4-alkyl-carbonyl, di-(C1-3-alkyl)amino-C1-4-alkyl-carbonyl, pyrrolidin-1-yl-C1-4-alkyl-carbonyl, piperidin-1-yl-C1-4-alkyl-carbonyl, (homopiperidin-1-yl)-C1-4-alkyl-carbonyl, morpholin-4-yl-C1-4-alkyl-carbonyl, (homomorpholin-4-yl)-C1-4-alkyl-carbonyl, (piperazin-1-yl)-C1-4-alkyl-carbonyl, (4-C1-3-alkyl-piperazin-1-yl)-C1-4-alkyl-carbonyl, (homo-piperazin-1-yl)-C1-4-alkyl-carbonyl, (4-C1-3-alkyl-homopiperazin-1-yl)-C1-4-alkyl-carbonyl or a C1-3-alkylsulphonyl-C1-4-alkyl-carbonyl group, a cyano, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)amino-carbonyl, (C1-3-alkyloxy-C2-4-alkyl)aminocarbonyl, N-(C1-3-alkyl)-N-(C1-3-alkyloxy-C2-4-alkyl)aminocarbonyl, arylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl, 4-C1-3-alkyl-piperazin-1-ylcarbonyl, homopiperazin-1-ylcarbonyl, 4-C1-3-alkyl-homopiperazin-1-ylcarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)amino-sulphonyl, pyrrolidin-1-yl-sulphonyl, piperidin-1-ylsulphonyl, homopiperidin-1-ylsulphonyl, morpholin-4-ylsulphonyl, homomorpholin-4-ylsulphonyl, piperazin-1-ylsulphonyl, 4-C1-3-alkyl-piperazin-1-ylsulphonyl, homopiperazin-1-ylsulphonyl or a 4-C1-3-alkyl-homopiperazin-1-ylsulphonyl group, a cyclobutyl, cyclopentyl or cyclohexyl group which is substituted in each case by a group R6, where R6 denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-C1-3-alkyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a 2-oxo-3-C1-3-alkyl-hexahydropyrimidin-1-yl group, an azetidin-3-yl group which is substituted in the 1 position by the group R5, while R5 is as hereinbefore defined, a pyrrolidin-3-yl group which is substituted in the 1 position by the group R5, while R5 is as hereinbefore defined, a piperidin-3-yl group which is substituted in the 1 position by the group R5, while R5 is as hereinbefore defined, a piperidin-4-yl group which is substituted in the 1 position by the group R5, while R5 is as hereinbefore defined, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd denotes a hydrogen atom or a fluorine, chlorine or bromine atom, a hydroxy group, a C1-4-alkyloxy group, a methoxy group substituted by 1 to 3 fluorine atoms, an ethyloxy group substituted by 1 to 5 fluorine atoms, a C2-4-alkyloxy group which is substituted by a group R6 or R7, while R6 is as hereinbefore defined and R7 denotes a hydroxy, C1-3-alkyloxy, C3-6-cycloalkyloxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl, 4-C1-3-alkyl-piperazin-1-yl, homopiperazin-1-yl or C1-3-alkyl-homopiperazin-1-yl group, or a formylamino, C1-4-alkylcarbonylamino, C1-3-alkyloxy-C1-3-alkyl-carbonylamino, C1-4-alkyloxycarbonylamino, aminocarbonylamino, C1-3-alkylaminocarbonylamino, di-(C1-3-alkyl)aminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-C1-3-alkyl-piperazin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino or a C1-4-alkylsulphonylamino group, a C3-7-cycloalkyloxy or C3-7-cycloalkyl-C1-4-alkyloxy group, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group, a tetrahydrofuranyl-C1-4-alkyloxy or tetrahydropyranyl-C1-4-alkyloxy group, a C1-4-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the group R8, while R8 denotes a hydrogen atom or a C1-3-alkyl group, or a C1-4-alkoxy group which is substituted by a morpholinyl group substituted in the 4 position by the group R8, while R8 is as hereinbefore defined, and X denotes a methyne group substituted by a cyano group or a nitrogen atom, and by the aryl groups mentioned in the definition of the above groups is meant in each case a phenyl group which is mono- or disubstituted by R9, while the substituents may be identical or different and R9 denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a C1-3-alkyl, hydroxy, C1-3-alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group, by the heteroaryl groups mentioned in the definition of the above groups is meant a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, while the abovementioned heteroaryl groups are each mono- or disubstituted by the group R9, while the substituents may be identical or different and R9 is as hereinbefore defined, and the abovementioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups may be substituted in each case by one or two C1-3-alkyl groups, and unless otherwise stated, the abovementioned alkyl groups may be straight-chained or branched, with the proviso that the compound 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline is excluded.