Patent EP-1956010-A1 (EP)
IPC: C07D239/94
Filed: 2007-02-06
Abstract: Bicyclic heterocycle compounds (I) and their tautomers, stereoisomers and/or salts are new. Bicyclic heterocycle compounds of formula (I) and their tautomers, stereoisomers and/or salts are new. R1a : phenyl, 1-phenylethyl or indane-4-yl, where the phenyl nucleus is replaced by R 1>-R 3> group; R 1>, R 2>H, halo, 1-4C-alkyl-, OH-, 1-4C-alkoxy-, 2-3C-alkenyl-, 2-3C-alkynyl-, (hetero)aryl-, aryloxy-, arylmethyl-, arylmethoxy, heteroaryloxy-, heteroarylmethyl-, heteroarylmethoxy-, 1-3F substituted methyl, methoxy, CN-, NO 2- or NH 2, where aryl is phenyl or mono- or di substituted R 7>, where heteroaryl is pyridyl-, pyridazinyl-, pyrimidinyl-, pyrazinyl or mono- or disubstituted R 7>; R 3>H, F, Cl, Br, methyl or CF 3; R1b : azetidin-1-yl-, pyrrolidin-1-yl-, piperidin-1-yl-, homopiperidin-1-yl-, morpholin-4-yl-, homomorpholin-4-yl, piperazin-1-yl-, 4-(1-4C-alkyl-carbonyl)-piperazin-1-yl-, 4-(1-4C-alkyl-sulfonyl)-piperazin-1-yl-, homopiperazin-1-yl-, 4-(1-4C-alkyl-carbonyl)-homopiperazin-1-yl- or 4-(1-4C-alkyl-sulfonyl)-homopiperazin-1-yl-; R 4>mono-, di- or trisubstituted halo, 1-4C-alkyl-, 2-4C-alkenyl-, 2-4C-alkynyl-, 1-3F substituted methyl, methoxy, NH 2-, 1-4C-alkylamino-, di-(1-4C-alkyl)amino-, 1-4C-alkyl-carbonylamino-, N-(1-4C-alkyl)-1-4C-alkyl-carbonylamino-, 1-4C-alkyl-sulfonylamino-, N-(1-4C-alkyl)-1-4C-alkyl-carbonylamino-, amino-1-4C-alkyl-, 1-4C-alkylamino-1-4C-alkyl-, di-(1-4C-alkyl)amino-1-4C-alkyl-, 1-4C-alkyl-carbonylamino-1-4C-alkyl-, N-(1-4C-alkyl)-1-4C-alkylcarbonylamino-1-4C-alkyl-, 1-4C-alkyl-sulfonylamino-1-4C-alkyl-, N-(1-4C-alkyl)-1-4C-alkyl-sulfonylamino-1-4C-alkyl-, OH-, 1-4C-alkyloxy, 1-4C-alkyl-carbonyloxy-, hydroxy-1-4C-alkyl-, 1-4C-alkyloxy-1-4C-alkyl, 1-4C-alkyl-carbonyloxy-1-4C-alkyl-, 1-4C-alkyl-carbonyl-, CN-, 1-4C-alkyl-oxycarbonyl-, carboxy-, aminocarbonyl-, 1-4C-alkyl-aminocarbonyl-, di-(1-4C-alkyl)amino-carbonyl-, pyrrolidin-1-yl-carbonyl-, piperidin-1-yl-carbonyl-, piperazin-1-yl-carbonyl-4-1-4C-alkyl-piperazin-1-yl-carbonyl-, morpholin-4-yl-carbonyl-, 1-4C-alkylcarbonyl-1-4C-alkyl-, cyano-1-4C-alkyl-, 1-4C-alkyloxycarbonyl-1-4C-alkyl-, aminocarbonyl-1-4C-alkyl-, 1-4C-alkylaminocarbonyl-1-4C-alkyl-, di-(1-4C-alkyl)aminocarbonyl-1-4C-alkyl-, pyrrolidin-1-yl-carbonyl-1-4C-alkyl-, piperidin-1-yl-carbonyl-1-4-alkyl-, piperazin-1-yl-carbonyl-1-4C-alkyl-, 4-1-4C-alkyl-piperazin-1-yl-carbonyl-1-4C-alkyl-, morpholin-4-yl-carbonyl-1-4C-alkyl-, 1-4C-alkylsulfanyl-, 1-4C-alkylsulfinyl-, 1-4C-alkylsulfonyl-, aminosulfonyl-, 1-4C-alkyl-aminosulfonyl-, di-(1-4C-alkyl)amino-sulfonyl-, 1-4C-alkylsulfanyl-1-4C-alkyl-, 1-4C-alkylsulfinyl-1-4C-alkyl-, 1-4C-alkylsulfonyl-1-4C-alkyl-, aminosulfonyl-1-4C-alkyl-, 1-4C-alkyl-aminosulfonyl-1-4C-alkyl- or di-(1-4C-alkyl) amino-sulfonyl-1-4C-alkyl- (where the heterocyclic group is substituted by oxo); R1c : H, halo or 1-4C-alkyl (substituted by R 5>); R 5>OH, 1-3C-alkyloxy-, 3-6C-cycloalkyloxy-, amino-, 1-3C-alkylamino-, di-(1-3C-alkyl)amino-, bis-(2-methoxyethyl)-amino-, pyrrolidin-1-yl-, piperidin-1-yl-, homopiperidin-1-yl-, morpholin-4-yl-, homomorpholin-4-yl-, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl-, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl-, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl-, piperazin-1-yl-, 4-1-3C-alkyl-piperazin-1-yl-, homopiperazin-1-yl-, 1-3C-alkyl-homopiperazin-1-yl-, formylamino-, 1-4C-alkylcarbonylamino-, 1-3C-alkyloxy-1-3C-alkyl-carbonylamino-, 1-4C-alkyloxycarbonylamino-, aminocarbonylamino-, 1-3C-alkylaminocarbonylamino-, di-(1-3C-alkyl)aminocarbonylamino-, pyrrolidin-1-yl-carbonylamino-, piperidin-1-yl-carbonylamino-, piperazin-1-yl-carbonylamino-, 4-1-3C-alkyl-piperazin-1-yl-carbonylamino-, morpholin-4-yl-carbonylamino-, 1-4C-alkylsulfonylamino-, OH, 1-4C-alkoxy, 1-3F substituted methoxy- or ethyloxy-, 2-4C-alkyloxy (substituted by R 5>), 3-7C-cycloalkyloxy-, 3-7C-cycloalkyl-1-4C-alkyloxy-, tetrahydrofuran-3-yl-oxy-, tetrahydropyran-3-yl-oxy- or tetrahydropyran-4-yl-oxy, tetrahydrofuranyl-1-4C-alkyloxy- or tetrahydropyranyl-1-4C-alkyloxy- or 1-4C-alkoxy (substituted by R 6> substituted pyrrolidinyl-, piperidinyl- or homopiperidinyl); R 6>H, 1-3C-alkyl, 1-4C-alkoxy (substituted by morpholinyl), 1-3C-alkyl substituted pyrrolidinyl, piperidinyl, piperazinyl- or morpholinyl; and R 7>H, halo, 1-3C-alkyl-, OH-, 1-3C-alkyloxy-, -CF 2-, CF 3-, difluormethoxy-, trifluoromethoxy- or CN. An independent claim is included for the 8 preparations of (I). [Image] ACTIVITY : Cytostatic; Respiratory-Gen; Gastrointestinal-Gen; Antipsoriatic; Antiinflammatory; Immunomodulator; Antianemic. MECHANISM OF ACTION : tyrosine kinase-mediated signal transduction inhibitor; Epidermal growth factor receptor signal transduction inhibitor. The effect of (I) to inhibit epidermal growth factor receptor signal transduction was tested using non-radioactive cell proliferation assay. The result showed that 4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(morpholin-4-yl)-cyclohexyloxy]-7-methoxy-quinazoline exhibited the IC 5 0 value of 1 nM.