3-cyano-quinoline derivatives with antiproliferative activity

A method of treating ovarian cancer, the method comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound

• having the formula
• the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
• Z represents O, NH or S;
• Y represents —C3-9alkyl-, —C3-9alkenyl-, —C1-5alkyl-oxy-C1-5alkyl-, —C1-5alkyl-NR12—C1-5alkyl-, —C1-5alkyl-NR13—CO—C1-5alkyl-, —C1-5alkyl-CO—NR14—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO-, —CO—NH—C1-6alkyl-, —NH—CO—C1-6alkyl-, —CO—C1-7alkyl-, —C1-7alkyl-CO—, C1-6alkyl-CO—C1-6alkyl, —C1-2alkyl-NH—CO—CH2R15—NH—;
• X1 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR10, —NR10—C1-2alkyl-, NR16—CO—, NR16—CO—C1-2alkyl, —O—N═CH— or C1-2alkyl;
• X2 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR11, NR11—C1-2alkyl-, NR17—CO—, NR17—CO—C1-2alkyl, Het20-C1-2alkyl, —O—N═CH— or C1-2alkyl;
• R1 represents hydrogen, cyano, halo, hydroxy, formyl, C1-6alkoxy-, C1-6alkyl-, C1-6alkoxy- substituted with halo,
• C1-4-alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo;
• R2 represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het16-carbonyl-, C1-4-alkyloxycarbonyl-, C1-4-alkylcarbonyl-, aminocarbonyl-, mono- or di(C1-4-alkyl)aminocarbonyl-, Het1, formyl, C1-4-alkyl-, C2-6alkynyl-, C3-6cycloalkyl-, C3-6cycloalkyloxy-, C1-6alkoxy-, Ar5, Ar1-oxy-, dihydroxyborane, C1-6alkoxy- substituted with halo,
• C1-4-alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR4R5,
• C1-4-alkylcarbonyl- wherein said C1-4-alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C1-4-alkyl-oxy-;
• R3 represents hydrogen, hydroxy, Ar3-oxy, Ar4—C1-4-alkyloxy-, C1-4-alkyloxy-, C2-4alkenyloxy- optionally substituted with Het12 or R3 represents C1-4-alkyloxy substituted with one or where possible two or more substituents selected from C1-4-alkyloxy-, hydroxy, halo, Het-, —NR6R7, -carbonyl- NR8R9 or Het3-carbonyl-;
• R4 and R5 are each independently selected from hydrogen or C1-4-alkyl;
• R6 and R7 are each independently selected from hydrogen, C1-4-alkyl, Het8, aminosulfonyl-, mono- or di (C1-4-alkyl)-aminosulfonyl, hydroxy-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl-, hydroxycarbonyl-C1-4-alkyl-, C3-6cycloalkyl, Het9-carbonyl-C1-4-alkyl-, Het10-carbonyl-, polyhydroxy-C1-4-alkyl-, Het11-C1-4-alkyl- or Ar2—C1-4-alkyl-;
• R8 and R9 are each independently selected from hydrogen, C1-4-alkyl, C3-6cycloalkyl, Het4, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl- or polyhydroxy-C1-4-alkyl-;
• R10 represents hydrogen, C1-4-alkyl, Het5, Het6-C1-4-alkyl-, C2-4alkenylcarbonyl- optionally substituted with Het7-C1-4-alkylaminocarbonyl-, C2-4alkenylsulfonyl-, C1-4-alkyloxyC1-4-alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4-alkyloxy-;
• R11 represents hydrogen, C1-4-alkyl, C1-4-alkyl-oxy-carbonyl-, Het17, Het18-C1-4-alkyl-, C2-4alkenylcarbonyl- optionally substituted with Het19-C1-4-alkylaminocarbonyl-, C2-4alkenylsulfonyl-, C1-4-alkyloxyC1-4-alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-;
• R12 represents hydrogen, C1-4-alkyl, Het13, Het14-C1-4-alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4-alkyloxy-;
• R13 and R14 are each independently selected from hydrogen, C1-4-alkyl, Het15-C1-4-alkyl- or C1-4alkyloxyC1-4-alkyl-;
• R15 represents hydrogen or C1-4-alkyl optionally substituted with phenyl, indolyl, methylsulfide, hydroxy, thiol, hydroxyphenyl, aminocarbonyl, hydroxycarbonyl, amine, imidazoyl or guanidino;
• R16 and R17 are each independently selected from hydrogen, C1-4-alkyl, Het21-C1-4-alkyl or C1-4alkyloxyC1-4-alkyl;
• 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 amino, C1-4-alkyl, hydroxy-C1-4alkyl-, phenyl, phenyl-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl- mono- or di(C1-4-alkyl)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, C1-4-alkyl-, hydroxy-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl-, hydroxy-C1-4-alkyl-oxy-C1-4alkyl-, mono- or di(C1-4-alkyl)amino-, mono- or di(C1-4-alkyl)amino-C1-4-alkyl-, aminoC1-4-alkyl-, mono- or di(C1-4-alkyl)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-, C1-4-alkyl-, C3-6cycloalkyl-C1-4-alkyl-, aminosulfonyl-, mono- or di(C1-4-alkyl)aminosulfonyl or amino-C1-4-alkyl-;
• Het5 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said Het5 optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
• Het6 and Het7 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het6 and Het7 are optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl 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 C1-4-alkyl, C3-6cycloalkyl-C1-4-alkyl- or amino-C1-4-alkyl-;
• 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, C1-4-alkyl-, hydroxy-C1-4-alkyl-, C1-4-alkyl-oxy-C1-4-alkyl-, hydroxy-C1-4-alkyl-oxy-C1-4alkyl-, mono- or di(C1-4-alkyl)amino- or mono- or di(C1-4-alkyl)amino-C1-4-alkyl-;
• Het13 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said Het13 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-allyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
• Het14 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het14 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-allyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4-alkyl-;
• Het15 and Het21 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycles are optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4-alkyl-;
• 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 C1-4-alkyl;
• and
• Het17 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said Het17 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
• Het18 and Het19 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het18 and Het19 are optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4alkyl-;
• Het20 represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl or pyrazolidinyl wherein said Het20 is optionally substituted with one or where possible two or more substituents selected from C1-4-alkyl, C3-6cycloalkyl, hydroxy-C1-4-alkyl-, C1-4-alkyloxyC1-4-alkyl or polyhydroxy-C1-4-alkyl-;
• and
• Ar1, Ar2, Ar3, Ar4 and Ar5 each independently represent phenyl optionally substituted with cyano, C1-4-alkylsulfonyl-, C1-4-alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C1-4alkyl, aminosulfonyl-, hydroxy-, C1-4-alkyloxy- or C1-4-alkyl.