New 6-acylamino-4-amino-quinazoline or quinoline derivatives, are tyrosine kinase-mediated signal transduction inhibitors useful e.g. for treating tumors or respiratory or gastrointestinal diseases

摘要

6-Acylamino-4-amino-quinazoline or quinoline derivatives (I) are new. 6-Acylamino-4-amino-quinazoline or quinoline derivatives of formula (I) and their tautomers, stereoisomers and salts are new. X = C(CN) or N; Ra, Rc = H or T; T = 1-4C alkyl; Rb = Ph', CH2Ph' or CHMePh'; Ph' = phenyl substituted by R1-R3; R1, R2 = H, halo, T, OH, OT, 3-6C cycloalkyl, 4-6C cycloalkoxy, 2-5C alkenyl, 2-5C alkynyl, Ar, OAr, CH2Ar or OCH2Ar; 3-5C alkenyloxy or 3-5C alkynyloxy (both not alpha -unsaturated), S(O)nT or S(O)nCF3, Me or OMe substituted by 1-3 F, Et or OEt substituted by 1-5 F, or CN, NH2, NHT or N(T)2; or R1+R2 = CH=CHCH=CH, CH=CHNH or CH=NNH bonded to adjacent C; n = 0-2; R3 = H, F, Cl, Br, T, CF3 or OCF3; Rd = H, 1-6C alkoxy, 4-7C cycloalkoxy or (3-7C) cycloalkyl-V-O-, 2-6C alkoxy substituted (but not in the 1-position) by OH, OT, 4-7C cycloalkoxy, (3-7C) cycloalkyl-V-O-, N(T)2, pyrrolidino, piperidino, morpholino, piperazino or N-(T)-piperazino (the cyclic imino groups being optionally substituted (os) by 1 or 2 U), or tetrahydrofuran-3-yloxy, tetrahydropyran-(3- or 4-)yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy; U = Me or Et; V = 1-4C alkylene; A = vinylene, vinylidene or 1,3-butadien-1,4-ylene (all os by 1 or 2 CF3 or 1 or 2 Me), or ethynylene; B' = 1-6C alkylene (os by 1 or 2 F), or can also be a direct bond if C' is bonded via C; C' = (i) 2,2-(D)-pyrrolidino, 3,3-(E)-pyrrolidino, 2,2-(D)-piperidino, 2,2-(D)-hexahydroazepino, 3,3- or 4,4-(E)-piperidino, 3,3- or 4,4-(E)-hexahydroazepino or 2,2- or 3,3-(D)-piperazino (os by T in the 4-position); (ii) pyrrolidino or piperidino, having two vicinal C bridged by OCOCH2, CH2OCO, OCO(CH2)2, CH2OCOCH2, (CH2)2OCO, OCOCH2N(R4) or OCOCH2O (all os by 1-2 U), provided that the heteroatom is not bonded to the 2- or 5-position of pyrrolidine or the 2- or 6-position of piperidine; (iii) piperazino or 4-(T)-piperazino, having the 2- and 3-positions bridged by CH2OCOCH2 or (CH2)2OCO (both os by 1 or 2 U); (iv) piperazino having the 3- and 4-positions bridged by COO(CH2)2 or CH2OCOCH2 or (CH2)2OCO (both os by 1 or 2 U), the left-hand end of which is bonded in the 3-position; (v) pyrrolidino, piperidino, hexahydroazepino, 4-(T)-piperazino or 4-(T)-homopiperazino, all C-substituted by R5; (vi) 3-(R'5)-pyrrolidino, 3- or 4-(R'5)-piperidino or 3- or 4-(R'5)-hexahydroazepino; (vii) 4-(R6)-piperazino or 4-(R6)-homopiperazino; (viii) 3-(R'6)-pyrrolidino, 3- or 4-(R'6)-piperidino or 3- or 4-(R'6)-hexahydroazepino; (ix) pyrrolidino, piperidino, hexahydroazepino, 4-(T)-piperazino or 4-(T)-homopiperazino, all substituted by R5-V-, R'6-V- or R4N(R6)CO; (x) pyrrolidino 3-substituted by R5CONR4, R5-V-CONR4, R'6-V-CONR4, R'5-V-CONR4, R5-V-Y- or Y'-Y-; (xi) piperidino or hexahydroazepino, both 3- or 4-substituted by R5CONR4, R5-V-CONR4, R'6-V-CONR4, R'5-V-CONR4, R5-V-Y- or Y'-Y-; (xii) piperazino or homopiperazino, both 4-substituted by R5-V-, R5-V-CO-, R'6-V-CO- or Y'; (xiii) pyrrolidino, piperidino, hexahydroazepino, 4-(T)-piperazino or 4-(T)-homopiperazino, all C-substituted by R'5; (xiv) 3-(Y''-Y-)-pyrrolidino, 3- or 4-(Y''-Y-)-piperidino or 3-or 4-(Y''-Y-)-hexahydroazepino; (xiv) piperazino or homopiperazino, both 4-substituted by R'5-V-CO- or Y''; (xv) pyrrolidinyl or piperidinyl, both 1-substituted by R5-V-, R5-CO-, R'6-V-CO or R'5-VCO-, or by 2-4C alkyl substituted (but not in the 1-position) by R'5 or R'6; (xvi) pyrrolidin-3-yl-N(R4)- or piperidin-(3- or 4-)-yl-N(R4)-, both substituted on the ring N by R5-V-, R5-CO-, R'6-V-CO- or R'5-V-CO-, or by 2-4C alkyl substituted (but not in the 1-position) by R'5 or R'6; (xvii) R5-V-N(R4)-; or (xviii) 2-4C alkyl-N(R4)-, where alkyl is substituted (but not in the 1-position) by R'5 or R'6; D = CH2OCOCH2, (CH2)2OCO, CH2OCO(CH2)2, (CH2)2OCOCH2 or (CH2)3OCO (all os by 1 or 2 U); E = OCO(CH2)2, CH2OCOCH2, (CH2)2OCO, OCO(CH2)3, CH2OCO(CH2)2, (CH2)2OCOCH2, (CH2)3OCO, OCOCH2N(R4)CH2, CH2OCOCH2N(R4), OCOCH2OCH2 or CH2OCOCH2O (all os by 1-2 U); R4 = H or T; R5 = 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1,4-dioxanyl or 2-oxo-4-(T)-morpholinyl; R'5 = 2-oxo-morpholino (os by 1-2 U); R6 = 2-oxo-tetrahydrofuran-(3- or 4)-yl or 2-oxo-tetrahydropyran-(3-, 4- or 5)-yl (both os by 1-2 U); R'6 = NR4R6, OR6 or S(O)nR6; V = 1-4C alkylene; Y = O, S(O)n, NH or NT; Y' = 2-4C alkyl os (but not in the 1-position) by R'6; Y'' = 2-4C alkyl substituted (but not in the 1-position) by R'6; Ar = phenyl os by 1 or 2 R'; R' = halo, U, CF3 or OU; or (R')2 on adjacent C = 3-4C alkylene, OCH2O or CH=CHCH=CH. An Independent claim is also included for the preparation of (I).