Cyclic anilino—pyridinotriazines

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 m represents 1, n represents 1, Z represents N or C, in particular N; —X1— represents C1-4alkyl, in particular methyl; —X2— represents —C1-4alkyl- or —C1-4alkyl-NR7—, in particular propyl, -ethyl-NR7— or -propyl-NR7—; —Y— represents —NR2—C1-6alkyl-CO—NR4—, -Het1-C1-6alkyl-CO—NR5— or -Het2-CO—NR6— and wherein the —C1-6alkyl-linker of —NR2—C1-6alkyl-CO—NR4— or -Het1-C1-6alkyl-CO—NR5— is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo and phenyl; R1 represents hydrogen, chloro, fluoro or bromo; R2 represents —C1-4alkyl-, in particular ethyl or methyl; R7 represents hydrogen; R8 represents hydrogen; R4, R5 and R6 represent hydrogen; Het1 is selected from piperazinyl or piperidinyl, in particular -piperazinyl; Het2 selected from pyrrolidinyl or piperidinyl, in particular pyrrolidinyl wherein said pyrrolidinyl is optionally substituted with hydroxy.;

主权项

1. A compound having the formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein m represents an integer from 1 to 4; n represents an integer from 1 to 4; Z represents N or C; Y represents —NR2—C1-6alkyl-CO—NR4—, —C1-4alkyl-NR9—C1-4alkyl-, C1-6alkyl-CO-Het10-, -Het11-CO—C1-6alkyl-, -Het12-C1-6alkyl-, —CO-Het13-C1-6alkyl-, —CO—NR10—C1-6alkyl-, -Het1-C1-6alkyl-CO—NR5—, or -Het2-CO—NR6— wherein the —C1-6alkyl-linker in —NR2—C1-6alkyl-CO—NR4— or -Het1-C1-6alkyl-CO—NR5— is optionally substituted with one or where possible two or more substituents selected from hydroxy, methoxy, aminocarbonyl, halo, phenyl, indolyl, methylsulfide, thiol, hydroxyphenyl, cyanophenyl, amino and hydroxycarbonyl; X1 represents a direct bond, C1-4alkyl, C1-4alkyloxy-, C1-4alkyl-CO—, C2-4alkenyl, C2-4alkynyl, or C1-4alkyl-NR3—, wherein said C1-4alkyl or C2-4alkenyl is optionally substituted with one or where possible two or more halo substituents; X2 represents a direct bond, C1-4alkyl, C1-4alkyloxy-, C1-4alkyl-CO—, C2-4alkenyl, C2-4alkynyl, or C1-4alkyl-NR7—, wherein said C1-4alkyl or C2-4alkenyl is optionally substituted with one or where possible two or more halo substituents; R1 and R8 each independently represent hydrogen, Het14, cyano, halo, hydroxy, C1-6alkoxy-, C1-6alkyl-, mono- or di(C1-4alkyl)amino-carbonyl-, mono- or di(C1-4alkyl)amino-sulfonyl, C1-6alkoxy- substituted with halo or R1 represents C1-6alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R2 and R9 each independently represents hydrogen, C1-4alkyl, C2-4alkenyl, Het3, Het4-C1-4alkyl-, Het5-C1-4alkylcarbonyl-, mono- or di(C1-4alkyl)amino-C1-4alkyl-carbonyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-; R3 and R7 each independently represent hydrogen, C1-4alkyl, Het6, Het7-C1-4alkyl-, C2-4alkenylcarbonyl- optionally substituted with C2-4alkenylsulfonyl-, C1-4alkyloxyC1-4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-; R4, R5, R6 and R10 each independently represent hydrogen or C1-4alkyl optionally substituted with hydroxy, Het9 or C1-4alkyloxy; Het1 and Het2 each independently represent a heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolidinyl or pyrazolidinyl wherein said Het1 and Het2 are optionally substituted with amino, hydroxy, C1-4alkyl, hydroxy-C1-4alkyl-, phenyl, phenyl-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl- mono- or di(C1-4alkyl)amino- or amino-carbonyl-; Het3 and Het6 each independently represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said Het3 and Het6 are optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-; Het4, Het7 and Het9 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het4, Het7 and Het9 are optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-; Het5 represents a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het5 is optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-; Het10, Het11 and Het13 each independently represent a heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolidinyl or pyrazolidinyl wherein said Het10, Het11 and Het13 are optionally substituted with amino, hydroxy, C1-4alkyl, hydroxy-C1-4alkyl-, phenyl, phenyl-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl-, amino-carbonyl- or mono- or di(C1-4alkyl)amino-; Het12 represents a heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolidinyl or pyrazolidinyl wherein said Het12 is optionally substituted with amino, hydroxy, C1-4alkyl, hydroxy-C1-4alkyl-, phenyl, phenyl-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl-; mono- or di(C1-4alkyl)amino- or amino-carbonyl-; and Het14 represents a heterocycle selected from morpholinyl; pyrrolidinyl; piperazinyl; imidazolyl; pyrrolyl; 2,3,4-triazapyrrolyl; 1,2,3-triazolyl; pyrazolyl; or piperidinyl wherein said Het14 is optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-.