Quinazoline derivatives and pharmaceutical compositions containing them and preparation process and use

本文涉及式(I)喹唑啉衍生物或其盐，其中m为1-2的整数；R#+[1]代表氢、羟基、卤基、硝基、三氟甲基、氰基、C#-[1-3]烷基、C#-[1-3]烷氧基、C#-[1-3]烷硫基或-NR#+[5]R#+[6](其中R#+[5]和R#+[6]可以相同或不同，每个代表氢或C#-[1-3]烷基)；R#+[2]代表氢、羟基、卤基、甲氧基、氨基或硝基；R#+[3]代表羟基、卤基、C#-[1-3]烷基、C#-[1-3]烷氧基、C#-[1-3]链烷酰氧基、三氟甲基、氰基、氨基或硝基；X#+[1]代表-O-、-CH#-[2]-、-S-、-SO-、-SO#-[2]-、-NR#+[7]CO-、-CONR#+[8]、-SO#-[2]NR#+[9]、-NR#+[10]SO#-[2]-或-NR#+[11]-(其中R#+[7]、R#+[8]、R#+[9]、R#+[10]和R#+[11]每个独立地代表氢、C#-[1-3]烷基或C#-[1-3]烷氧基C#-[2-3]烷基)；R#+[4]代表可任选取代的5或6元饱和碳环基或杂环基，该基团为链烯基、链炔基或可任选取代的烷基，所述烷基可以含有一个杂原子连接基团，所述链烯基、链炔基或烷基可以带有末端可任选取代的基团，该基团选自烷基和5或6元饱和碳环基或杂环基；本发明涉及它们的制备方法、含有式(I)化合物或其药学上可接受的盐作为活性组分的药用组合物。式(I)化合物及其药学上可接受的盐抑制VEGF的作用，这在治疗包括癌和类风湿性关节炎在内的许多疾病方面是有价值的性质。∴ 4-Anilino-quinazoline derivatives of formula (I) and their salts are new. m = 1 or 2; R1 = H, OH, halo, NO2, CF3, CN, 1-3C alkyl, alkoxy, or alkylthio, or NR5R6; R2 = H, OH, halo, MeO, amino, or NO2; R3 = OH, halo, 1-3C alkyl, alkoxy, or alkanoyloxy, CF3, CN, amino, or NO2; X1 = O, CH2, S, SO, SO2, NR7CO, CONR8, SO2NR9, NR10SO2, or NR11; R5, R6 = H or 1-3C alkyl; R7-R11 = H, 1-3C alkyl, or 1-3C alkoxy(2-3C alkyl); R4 = WR12 (linked through a C atom of R12), WR13, (2-5C alkenylene)-R14, (2-5C alkynylene)-R15, W-X2-W-X3-R16, W-X4-COR22, W-X5-R27, W-X6-W-R33, R39, W-R40, W-R43, or W-R44; when X1 = O, S, SO, or SO2, then R4 can also = 1-3C alkoxy 2-4C alkyl; when X1 = O, then R4 can also = 1-4C alkyl; and provided that, when R4 = W-X2-W-X3-R16, then X1 is not CH2; W = 1-5C alkylene; X2, X3 = as X1, but not CH2; X4 = O or NR23; X5 = OCO, or as X1, but not CH2; X6 = as X1, but not CH2; R12, R14, R15 = Het; Het = 5 or 6 membered saturated heterocyclyl, containing 1 or 2 heteroatoms from O, S, N (optionally containing 1 or 2 substituents G); G = oxo, OH, halo, 1-4C alkyl, alkoxy, or hydroxyalkyl, 1-4C alkanoyl, 2-5C alkoxycarbonyl, carbamoyl, or mono- or di- (1-4C alkyl)carbamoyl; R13 = pyrrolidin-1-yl, imidazolidin-1-yl, or thiomorpholinyl (optionally containing 1 or 2 substituents G); R16 = H or 1-3C alkyl; R22 = NR24R25 or OR26; R23-R26 = as R7; R27, R33 = cyclopentyl, cyclohexyl, or Het (all optionally containing 1 or 2 substituents G), or 1-3C alkyl; provided that, when R27 = 1-3C alkyl, then X5 is a group containing S, and X1 is not CH2; R39 = pyrrolidin-3-yl, piperidin-3-yl, or piperidin-4-yl (all optionally containing 1 or 2 substituents G); R40 = piperazin-1-yl (substituted by 1 or more 1-4C alkanoyl or hydroxyalkyl, 2-5C alkoxycarbonyl, or CONR41R42); R41, R42 = H or 1-4C alkyl; R43 = morpholinyl (optionally containi