Macrocylic quinazoline derivatives as antiproliferative 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 Z represents NH; Y represents -C 3-9 alkyl-, -C 2-9 alkenyl-, -C 3-7 alkyl-CO-NH optionally substituted with amino, mono - or di(C 1-4 alkyl)amino or C 1-4 alkyloxycarbonylamino-, -C 3-7 alkenyl-CO-NH- optionally substituted with amino, mono- or di(C 1- 4 alkyl)amino- or C 1-4 alkyloxycarbonylamino-, C 1-5 alkyl-NR 13 -C 1-5 alkyl-, -C 1-5 alkyl-NR 14 -CO-C 1-5 alkyl-, -C 1-6 alkyl-CO-NH-, -C 1-5 alkyl-CO NR 15 -C 1-5 alkyl-, -C 1-3 alkyl-NH-CO-Het 20 -, -C 1-2 alkyl-CO-Het 21 -CO-, -C 1-2 alkyl-NH-CO-CR 16 R 17 -NH-, -C 1-2 alkyl-CO-NH-CR 18 R 19 -CO-, -C 1-2 alkyl-CO-NR 20 -C 1-3 alkyl-CO-, or -NR 22 -CO-C 1-3 alkyl-NH-; X 1 represents a direct bond, O or-O-C 1-2 alkyl-; X 2 represents a direct bond, -CO-C 1- 2 alkyl-, NR 12 , -NR 12 -C 1-2 alkyl-, -O-N=CH- or -C 1-2 alkyl-; R 1 and R 2 each independently represents hydrogen or halo; R 3 represents hydrogen; R 4 represents hydrogen or C 1-4 alkyloxy; R 12 and R 13 each independently represents hydrogen or C 1-4 alkyl; R 14 and R 15 represents hydrogen; R 16 and R 17 each independently represent hydrogen or C 1-4 alkyl; R 18 and R 19 each independently represent hydrogen or C 1-4 alkyl optionally substituted with phenyl or hydroxy; R 20 and R 21 each independently represent hydrogen or C 1-4 alkyl optionally substituted with C 1-4 alkyloxy; Het 20 , Het 21 and Het 22 each independently represent a heterocycle selected from the group consisting pyrrolidinyl, 2-pyrrolidinonyl or piperidinyl optionally substituted with hydroxy.