MTKI QUINAZOLINE DERIVATIVES

摘要

The present invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents NH; Y represents -C_3-9alkyl-,-C_1-5alkyl-NR¹³-C_1-5alkyl-, -C_1-5alkyl-NR¹⁴-CO-C_1-5alkyl-, -C_1-2alkyl-NR²¹-H₂-CO-NH-C_1-3alkyl- or -C_1-2alkyl-NR²³-CO-CR¹⁶R¹⁷-NH-; X¹ represents O or -O-C_1-2alkyl-; X² represents a direct bond, C_1-2alkyl, -CO-C_1-2alkyl or NR¹²-C_1-2alkyl; R¹ represents hydrogen or halo; R² represents halo, acetylene or Het¹; R³ represents hydrogen or cyano; R⁴ represents Ar⁴-C_1-4alkyloxy-, C_1-4alkyloxy- or C_1-4alkyloxy substituted with one or where possible two or more substituents selected from Het², NR⁷R⁸, hydroxy and C_1-4alkyloxy-C_1-4alkyloxy-; R⁷ represents hydrogen or C_1-4alkyl; R⁸ represents C_1-4alkyl substituted with NR²⁵R²⁶ or C_1-4alkylsulfonyl ; R¹² represents hydrogen or C_1-4alkyl-; R¹³ represents Ar⁶-sulfonyl or C_1-6alkyloxycarbonyl optionally substituted with phenyl; R¹⁶ and R¹⁷ represents hydrogen, C_1-4alkyl or R¹⁶ and R¹⁷ taken together with the carbon atom to which they are attached from a C_3-6cycloalkyl; R²³ represents C_1-4alkyl and R²³ represents hydrogen when R¹⁶ and R¹⁷ taken together with the carbon atom to which they are attached from a C_3-6cycloalkyl; R²⁵, R²⁶, R²⁷ and R²⁸ each independently represent hydrogen or C_1-4alkylcarbonyl; Het¹ represents 2-bora-l,3-dioxolanyl; Het² represents piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl wherein said Het² is optionally substituted with C_1-4alkyloxycarbonyl or NR²⁷R²⁸-C_1-4alkyl; Ar⁴ and Ar⁵ represents phenyl; Ar⁶ represents phenyl optionally substituted with nitro.