MACROCYCLIC QUINAZOLINE DERIVATIVES AND THEIR USE AS MTKI

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 -C3-9alkyl-, -C1-5alkyl-NR13-C1-5alkyl-, -C1-5alkyl-NR14-CO-C1-5alkyl-, -C1-2alkyl-NR21-H2-CO-NH-C1-3alkyl- or -C1-2alkyl-NR23-CO-CR16R17-NH-; X1 represents O or -O-C1-2alkyl-; X2 represents a direct bond, C1-2alkyl, -CO-C1-2alkyl or NR12-C1-2alkyl; R1 represents hydrogen or halo; R2 represents halo, acetylene or Het1; R3 represents hydrogen or cyano; R4 represents Ar4-C1-4alkyloxy-, C1-4alkyloxy- or C1-4alkyloxy substituted with one or where possible two or more substituents selected from Het2, NR7R8, hydroxy and C1-4alkyloxy-C1-4alkyloxy-; R7 represents hydrogen or C1-4alkyl; R8 represents C1-4alkyl substituted with NR25R26 or C1-4alkylsulfonyl; R12 represents hydrogen or C1-4alkyl-; R13 represents Ar6-sulfonyl or C1-6alkyloxycarbonyl optionally substituted with phenyl; R16 and R17 represents hydrogen, C1-4alkyl or R16 and R17 taken together with the carbon atom to which they are attached from a C3-6cycloalkyl; R23 represents C1-4alkyl and R23 represents hydrogen when R16 and R17 taken together with the carbon atom to which they are attached from a C3-6cycloalkyl; R25, R26, R27 and R28 each independently represent hydrogen or C1-4alkylcarbonyl; Het1 represents 2-bora-1,3-dioxolanyl; Het represents piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl wherein said Het2 is optionally substituted with C1-4alkyloxycarbonyl or NR27R28-C1-4alkyl; Ar4 and Ar5 represents phenyl; Ar6 represents phenyl optionally substituted with nitro.