QUINAZOLINE DERIVATIVES

摘要

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 —C3-9alkyl-, —C2-9alkenyl-, —C3-7alkyl-CO—NH optionally substituted with amino, mono- or di(C1-4alkyl)amino or C1-4alkyloxycarbonylamino-,
—C3-7alkenyl-CO—NH— optionally substituted with amino, mono- or di(C1-4alkyl)amino- or C1-4alkyloxycarbonylamino-,C1-5alkyl-NR13—C1-5alkyl-, —C1-5alkyl-NR14—CO—C1-5alkyl-, —C1-6alkyl-CO—NH—,—C1-5alkyl-CO NR15—C1-5alkyl-, —C1-3alkyl-NH—CO-Het20-,—C1-2alkyl-CO-Het21-CO—, —C1-2alkyl-NH—CO—CR16R17—NH—,—C1-2alkyl-CO—NH—CR18R19—CO—, —C1-2alkyl-CO—NR20—C1-3alkyl-CO—, or—NR22—CO—C1-3alkyl-NH—;X1 represents a direct bond, O or —O—C1-2alkyl-; X2 represents a direct bond, —CO—C1-2alkyl-, NR12, —NR12—C1-2alkyl-, —O—N═CH— or —C1-2alkyl-;R1 and R2 each independently represents hydrogen or halo;R3 represents hydrogen; R4 represents hydrogen or C1-4alkyloxy;R12 and R13 each independently represents hydrogen or C1-4alkyl;R14 and R15 represents hydrogen; R16 and R17 each independently represent hydrogen or C1-4alkyl;R18 and R19 each independently represent hydrogen or C1-4alkyl optionally substituted with phenyl or hydroxy;R20 and R21 each independently represent hydrogen or C1-4alkyl optionally substituted with C1-4alkyloxy;Het20, Het21 and Het22 each independently represent a heterocycle selected from the group consisting pyrrolidinyl, 2-pyrrolidinonyl or piperidinyl optionally substituted with hydroxy.

主权项

1. A compound having the formulathe N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
Z represents O, CH2, NH or S; in particular Z represents NH; Y represents —C3-9alkyl-, —C3-9alkenyl-, —C3-9alkynyl-, —C3-7alkyl-CO—NH— optionally substituted with amino, mono- or di(C1-4alkyl)amino or C1-4alkyloxycarbonylamino-,
—C3-7alkenyl-CO—NH— optionally substituted with amino, mono- or di(C1-4alkyl)amino or C1-4alkyloxycarbonylamino-,—C3-7alkynyl-CO—NH— optionally substituted with amino, mono- or di(C1-4alkyl)amino or C1-4alkyloxycarbonylamino-, —C1-5alkyl-oxy-C1-5alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-5alkyl-NR14—CO—C1-5alkyl-,—C1-5alkyl-CO—NR15—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO—,—C1-3alkyl-NH—CS-Het20-, —C1-3alkyl-NH—CO-Het20-, C1-2alkyl-CO-Het21-CO—,-Het22-CH2—CO—NH—C1-3alkyl-, —CO—NH—C1-6alkyl-, —NH—CO—C1-6alkyl-,—CO—C1-7alkyl-, —C1-7alkyl-CO—, —C1-6alkyl-CO—C1-6alkyl-,—C1-2alkyl-NH—CO—CR16R17—NH—, —C1-2alkyl-CO—NH—CR18R19—CO—,—C1-2alkyl-CO—NR20—C1-3alkyl-CO—, —C1-2alkyl-NR21—CH2—CO—NH—C1-3alkyl-, or—NR22—CO—C1-3alkyl-NH—; X1 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR11,
—NR11—C1-2alkyl-, —CH2—, —O—N═CH— or —C1-2alkyl-; X2 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR12,
—NR12—C1-2alkyl-, —CH2—, —O—N═CH— or —C1-2alkyl-; R1 represents hydrogen, cyano, halo, hydroxy, formyl, C1-6alkoxy-, C1-6alkyl-,
halo-phenyl-carbonylamino-,C1-6alkoxy- substituted with halo,C1-4alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R2 represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het16-carbonyl-,
C1-4alkyloxycarbonyl-, C1-4alkylcarbonyl-, aminocarbonyl-, mono- or di(C1-4alkyl)aminocarbonyl-, Het1, formyl, C1-4alkyl-, C2-6alkynyl-, C3-6cycloalkyl-,C3-6cycloalkyloxy-, C1-6alkoxy-, Ar5, Ar1-oxy-, dihydroxyborane,C1-6alkoxy- substituted with halo,C1-4alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR5R6,C1-4alkylcarbonyl- wherein said C1-4alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C1-4alkyl-oxy-; R3 represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one or more substituents selected from halo, C1-4alkyloxy-, amino-, mono- or di(C1-4alkyl)amino-,
C1-4alkyl-sulfonyl- or phenyl; R4 represents hydrogen, hydroxy, Ar3-oxy, Ar4—C1-4alkyloxy-, C1-4alkyloxy-,
C2-4alkenyloxy- optionally substituted with Het12 or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy-, hydroxy, halo, Het2-, —NR7R8, -carbonyl-NR9R10 or Het3-carbonyl-; R5 and R6 are each independently selected from hydrogen or C1-4alkyl; R7 and R8 are each independently selected from hydrogen, C1-4alkyl, Het8,
aminosulfonyl-, mono- or di (C1-4alkyl)-aminosulfonyl, hydroxy-C1-4alkyl-,C1-4alkyl-oxy-C1-4alkyl-, hydroxycarbonyl-C1-4alkyl-, C3-6cycloalkyl,Het9-carbonyl-C1-4alkyl-, Het10-carbonyl-, polyhydroxy-C1-4alkyl-, Het11-C1-4alkyl- or Ar2—C1-4alkyl-; R9 and R10 are each independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl,
Het4, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl- or polyhydroxy-C1-4alkyl-; R11 represents hydrogen, C1-4alkyl, Het5, Het6-C1-4alkyl-, C2-4alkenylcarbonyl-optionally substituted with Het7-C1-4alkylaminocarbonyl-, 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-; R12 represents hydrogen, C1-4alkyl, C1-4alkyl-oxy-carbonyl-, Het18-C1-4alkyl-,
phenyl-C1-4alkyl-oxy-carbonyl-, Het17, C2-4alkenylcarbonyl- optionally substituted with Het19-C1-4alkylaminocarbonyl-, C2-4alkenylsulfonyl-, C1-4alkyloxyC1-4alkyl- or R12 represents phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-; R13 represents hydrogen, C1-4alkyl, Het13, Het14-C1-4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-; R14 and R15 are each independently selected from hydrogen, C1-4alkyl, Het15-C1-4alkyl- or C1-4alkyloxyC1-4alkyl-; R16 and R17 each independently represents hydrogen or C1-4alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl,
aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R18 and R19 each independently represents hydrogen or C1-4alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl,
aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino; R20 and R22 each independently represents hydrogen or C1-4alkyl optionally substituted with hydroxy or C1-4alkyloxy; R21 represents hydrogen, C1-4alkyl, Het23-C1-4alkylcarbonyl- or
R21 represents mono- or di(C1-4alkyl)amino-C1-4alkyl-carbonyl- optionally substituted with hydroxy, pyrimidinyl, dimethylamine or C1-4alkyloxy; Het1 represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl,
furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het1 is optionally substituted with amino, C1-4alkyl, hydroxy-C1-4alkyl-, phenyl, phenyl-C1-4alkyl-,C1-4alkyl-oxy-C1-4alkyl- mono- or di(C1-4alkyl)amino- or amino-carbonyl-; Het2 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl,
pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het2 is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C1-4alkyl-, hydroxy-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl-,hydroxy-C1-4alkyl-oxy-C1-4alkyl-, mono- or di(C1-4alkyl)amino-, mono- or di(C1-4alkyl)amino-C1-4alkyl-, aminoC1-4alkyl-, mono- or di(C1-4alkyl)amino-sulfonyl-, aminosulfonyl-; Het3, Het4 and Het8 each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,
oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het3, Het4 or Het8 is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C1-4alkyl-,C3-6cycloalkyl-C1-4alkyl-, aminosulfonyl-, mono- or di(C1-4alkyl)aminosulfonyl or amino-C1-4alkyl-; Het5 represent a heterocycle selected from pyrrolidinyl or piperidinyl 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-; Het6 and Het7 each independently represent a heterocycle selected from morpholinyl,
pyrrolidinyl, piperazinyl or piperidinyl 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-; Het9 and Het10 each independently represent a heterocycle selected from furanyl,
piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl,imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het9 or Het10 is optionally substituted C1-4alkyl, C3-6cycloalkyl-C1-4alkyl- or amino-C1-4alkyl-; Het11 represents a heterocycle selected from indolyl or Het12 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl,
pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het12 is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C1-4alkyl-, hydroxy-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl-,hydroxy-C1-4alkyl-oxy-C1-4alkyl-, mono- or di(C1-4alkyl)amino- or mono- or di(C1-4alkyl)amino-C1-4alkyl-; Het13 represent a heterocycle selected from pyrrolidinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4allkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-; Het14 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4allkyl-,
C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-; Het15 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl 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-; Het16 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl,
1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C1-4alkyl; and Het17 represent a heterocycle selected from pyrrolidinyl or piperidinyl 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-; Het18 and Het19 each independently represent a heterocycle selected from morpholinyl,
pyrrolidinyl, piperazinyl or piperidinyl 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-; Het20, Het21 and Het22 each independently represent a heterocycle selected from pyrrolidinyl, 2-pyrrolidinonyl, piperazinyl or piperidinyl optionally substituted with one or where possible two or more substituents selected from hydroxy,
C1-4alkyl, hydroxy-C1-4alkyl- or polyhydroxy-C1-4alkyl-; Het23 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl 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-; Ar1, Ar2, Ar3, Ar4 and Ar5 each independently represent phenyl optionally substituted with cyano, C1-4alkylsulfonyl-, C1-4alkylsulfonylamino-, aminosulfonylamino-,
hydroxy-C1-4alkyl, aminosulfonyl-, hydroxy-, C1-4alkyloxy- or C1-4alkyl.