Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents

The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a1-a2=a3-a4 represents a divalent radical selected from N-CH CH-CH, N-CH N-CH or CH-CH N-CH; Z represents NH; Y represents -C3-9alkyl-, -C1-5alkyl-NR13-C1-5alkyl-, -C1-6alkyl-NH-CO- or -CO-NH-C1-6alkyl-; X1 represents -O- or -NR11-; X2 represents -C1-2alkyl-, -O-C1-2alkyl, -O- or -O-CH2-; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen; R4 represents hydroxy, C1-4alkyloxy-, Ar4-C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R11 represents hydrogen; R12 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R13 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.