Sulfonyl-derivatives as novel inhibitors of histone deacetylase

A compound of formula (I),

• or an N-oxide form, pharmaceutically acceptable addition salt or stereo-chemically isomeric form thereof, wherein
• n is 1;
• t is 0 and a direct bond is intended;
• Q is
• X is
• Y is nitrogen;
• Z is nitrogen;
• R1 is —C(O)NR7R8, —N(H)C(O)R9, —C(O)—C1-6alkanediylSR9, —NR10C(O)N(OH)R9, —NR10C(O)C1-6alkanediylSR9, —NR10C(O)C═N(OH)R9 or another Zn-chelating-group wherein R7 and R8 are each independently selected from hydrogen, hydroxy, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl and aminoaryl;
• R9 is independently selected hydrogen, C1-6alkyl, C1-6alkylcarbonyl, arylC1-6alkyl, C1-6alkylpyrazinyl, pyridinone, pyrrolidinone and methylimidazolyl;
• R10 is independently selected from hydrogen and C1-6alkyl;
• R2 is hydrogen, halo, hydroxy, amino, nitro, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, di(C1-6alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;
• -L- is a direct bond;
• each R3 represents a hydrogen atom and one hydrogen atom is optionally replaced by aryl;
• R4 is hydrogen, hydroxy, amino, hydroxyC1-6alkyl, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl, aminocarbonyl, hydroxycarbonyl, aminoC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonylC1-6alkyl, hydroxyaminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylamino C1-6alkyl or di(C1-6alkyl)amino C1-6alkyl;
• is a radical selected from
• wherein each s is independently 0, 1, 2, 3, 4 or 5;
• each R5 is independently selected from hydrogen;
• halo;
• hydroxy;
• amino;
• nitro;
• trihaloC1-6alkyl;
• trihaloC1-6alkyloxy;
• C1-6alkyl;
• C1-6alkyl substituted with aryl and C3-10cycloalkyl;
• C1-6alkyloxy;
• C1-6alkyloxyC1-6alkyloxy;
• C1-6alkylcarbonyl;
• C1-6alkyloxycarbonyl;
• C1-6alkylsulfonyl;
• cyanoC1-6alkyl;
• hydroxyC1-6alkyl;
• hydroxyC1-6alkyloxy;
• hydroxyC1-6alkylamino;
• aminoC1-6alkyloxy;
• di(C1-6alkyl)amino carbonyl;
• di(hydroxyC1-6alkyl)amino;
• (aryl)(C1-6alkyl)amino;
• di(C1-6alkyl)amino C1-6alkyloxy;
• di(C1-6alkyl)amino C1-6alkylamino;
• di(C1-6alkyl)amino C1-6alkylamino C1-6alkyl;
• arylsulfonyl;
• arylsulfonylamino;
• aryloxy;
• aryloxyC1-6alkyl;
• arylC2-6 alkenediyl;
• di(C1-6alkyl)amino;
• di(C1-6alkyl)aminoC1-6alkyl;
• di(C1-6alkyl)amino(C1-6alkyl)amino;
• di(C1-6alkyl)amino(C1-6alkyl)aminoC1-6alkyl;
• di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)amino;
• di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl;
• aminosulfonylamino(C1-6alkyl)amino;
• aminosulfonylamino(C1-6alkyl)aminoC1-6alkyl;
• di(C1-6alkyl)aminosulfonylamino(C1-6alkyl)amino;
• di(C1-6alkyl)aminosulfonylamino(C1-6alkyl)aminoC1-6alkyl;
• cyano;
• thiophenyl;
• thiophenyl substituted with di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylpiperazinylC1-6alkyl, hydroxyC1-6alkylpiperazinylC1-6alkyl, hydroxyC1-6alkyloxyC1-6alkylpiperazinylC1-6alkyl, di(C1-6alkyl)aminosulfonylpiperazinylC1-6alkyl, C1-6alkyloxypiperidinyl, C1-6alkyloxypiperidinylC1-6alkyl, morpholinylC1-6alkyl, hydroxyC1-6alkyl(C1-6alkyl)aminoC1-6alkyl, or di(hydroxyC1-6alkyl)aminoC1-6alkyl;
• furanyl;
• furanyl substituted with hydroxyC1-6alkyl;
• benzofuranyl;
• imidazolyl;
• oxazolyl;
• oxazolyl substituted with aryl and C1-6alkyl;
• C1-6alkyltriazolyl;
• tetrazolyl;
• pyrrolidinyl;
• pyrrolyl;
• piperidinylC1-6alkyloxy;
• morpholinyl;
• C1-6alkylmorpholinyl;
• morpholinylC1-6alkyloxy;
• morpholinylC1-6alkyl;
• morpholinylC1-6alkylamino;
• morpholinylC1-6alkylaminoC1-6alkyl;
• piperazinyl;
• C1-6alkylpiperazinyl;
• C1-6alkylpiperazinylC1-6alkyloxy;
• piperazinylC1-6alkyl;
• naphtalenylsulfonylpiperazinyl;
• naphtalenylsulfonylpiperidinyl;
• naphtalenylsulfonyl:
• C1-6alkylpiperazinylC1-6alkyl;
• C1-6alkylpiperazinylC1-6alkylamino;
• C1-6alkylpiperazinylC1-6alkylaminoC1-6alkyl;
• C1-6alkylpiperazinylsulfonyl;
• aminosulfonylpiperazinylC1-6alkyloxy;
• amino sulfonylpiperazinyl;
• amino sulfonylpiperazinylC1-6alkyl;
• di(C1-6alkyl)amino sulfonylpiperazinyl;
• di(C1-6alkyl)aminosulfonylpiperazinylC1-6alkyl;
• hydroxyC1-6alkylpiperazinyl;
• hydroxyC1-6alkylpiperazinylC1-6alkyl;
• C1-6alkyloxypiperidinyl;
• C1-6alkyloxypiperidinylC1-6alkyl;
• piperidinylaminoC1-6alkylamino;
• piperidinylaminoC1-6alkylaminoC1-6alkyl;
• (C1-6alkylpiperidinyl)(hydroxyC1-6alkyl)aminoC1-6alkylamino;
• (C1-6alkylpiperidinyl)(hydroxyC1-6alkyl)aminoC1-6alkylamino C1-6alkyl;
• hydroxyC1-6alkyloxyC1-6alkylpiperazinyl;
• hydroxyC1-6alkyloxyC1-6alkylpiperazinylC1-6alkyl;
• (hydroxyC1-6alkyl)(C1-6alkyl)amino;
• (hydroxyC1-6alkyl)(C1-6alkyl)amino C1-6alkyl;
• hydroxyC1-6alkylaminoC1-6alkyl;
• di(hydroxyC1-6alkyl)amino C1-6alkyl;
• pyrrolidinylC1-6alkyl;
• pyrrolidinylC1-6alkyloxy;
• pyrazolyl;
• thiopyrazolyl;
• pyrazolyl substituted with two substituents selected from C1-6alkyl or trihaloC1-6alkyl;
• pyridinyl;
• pyridinyl substituted with C1-6alkyloxy, aryloxy or aryl;
• pyrimidinyl;
• tetrahydropyrimidinylpiperazinyl;
• tetrahydropyrimidinylpiperazinylC1-6alkyl;
• quinolinyl;
• indolyl;
• phenyl;
• phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, C1-6alkyl, C1-6alkyloxy, hydroxyC1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC1-4alkyloxy, C1-4alkylsulfonyl, C1-4alkyloxyC1-4alkyloxy, C1-4alkyloxycarbonyl, amino C1-4alkyloxy, di(C1-4alkyl)amino C1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)amino carbonyl, di(C1-4alkyl)amino C1-4alkyl, di(C1-4alkyl)amino C1-4alkylamino C1-4alkyl, di(C1-4alkyl)amino(C1-4alkyl)amino, di(C1-4alkyl)amino(C1-4alkyl)amino C1-4alkyl, di(C1-4alkyl)amino C1-4alkyl(C1-4alkyl)amino, di(C1-4alkyl)amino C1-4alkyl(C1-4alkyl)amino C1-4alkyl, aminosulfonylamino(C1-4alkyl)amino, aminosulfonylamino(C1-4alkyl)amino C1-4alkyl, di(C1-4alkyl)amino sulfonylamino(C1-4alkyl)amino, di(C1-4alkyl)amino sulfonylamino(C1-4alkyl)amino C1-6alkyl, cyano, piperidinylC1-4alkyloxy, pyrrolidinylC1-4alkyloxy, amino sulfonylpiperazinyl, aminosulfonylpiperazinylC1-4alkyl, di(C1-4alkyl)amino sulfonylpiperazinyl, di(C1-4alkyl)amino sulfonylpiperazinylC1-4alkyl, hydroxyC1-4alkylpiperazinyl, hydroxyC1-4alkylpiperazinylC1-4alkyl, C1-4alkyloxypiperidinyl, C1-4alkyloxypiperidinylC1-4alkyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinylC1-4alkyl, (hydroxyC1-4alkyl)(C1-4alkyl)amino, (hydroxyC1-4alkyl)(C1-4alkyl)amino C1-4alkyl, di(hydroxyC1-4alkyl)amino, di(hydroxyC1-4alkyl)aminoC1-4alkyl, furanyl, furanyl substituted with —CH═CH—CH═CH—, pyrrolidinylC1-4alkyl, pyrrolidinylC1-4alkyloxy, morpholinyl, morpholinylC1-4alkyloxy, morpholinylC1-4alkyl, morpholinylC1-4alkylamino, morpholinylC1-4alkylamino C1-4alkyl, piperazinyl, C1-4alkylpiperazinyl, C1-4alkylpiperazinylC1-4alkyloxy, piperazinylC1-4alkyl, C1-4alkylpiperazinylC1-4alkyl, C1-4alkylpiperazinylC1-4alkylamino, C1-4alkylpiperazinylC1-4alkylamino C1-6alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC1-4alkyl, piperidinylamino C1-4alkylamino, piperidinylamino C1-4alkylamino C1-4alkyl, (C1-4alkylpiperidinyl)(hydroxyC1-4alkyl)amino C1-4alkylamino, (C1-4alkylpiperidinyl)(hydroxyC1-4alkyl)amino C1-4alkylamino C1-4alkyl, pyridinylC1-4alkyloxy, hydroxyC1-4alkylamino, hydroxyC1-4alkylamino C1-4alkyl, di(C1-4alkyl)amino C1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC1-4alkyloxy, and thiophenylC1-4alkylamino;
• the central
• moiety is optionally bridged with a methylene, ethylene or propylene bridge;
• each R5 optionally replaces the hydrogen on the nitrogen;
• and
• aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.