Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase

A compound of formula (I),

• the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
• each X is CH:
• R1 is phenyl, naphtalenyl or heterocyclyl;
• wherein
• each of said phenyl or naphtalenyl is optionally substituted with one or two substituents each independently selected from halo, C1-6alkyl, polyhaloC1-6alkyl, aryl, hydroxy, cyano, amino, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, hydroxycarbonyl, C1-6alkyloxycarbonyl, hydroxyC1-6alkyl, C1-6alkyloxymethyl, aminomethyl, C1-6alkylaminomethyl, C1-6alkylcarbonylaminomethyl, C1-6alkylsulfonylaminomethyl, aminosulfonyl, C1-6alkylaminosulfonyl or heterocyclyl;
• R2 is hydrogen, —CH2—R5, trifluoromethyl, —C(═O)—R6, or —CH2—NR7R8;
• wherein
• each R5 is independently selected from hydrogen, hydroxy, C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkylcarbonyloxy, piperazinyl, N-methylpiperazinyl, morpholinyl, thiomorpholinyl, imidazolyl or triazolyl;
• each R6 is independently selected from hydroxy, C1-6alkyloxy, amino or mono- or di(C1-6alkyl)amino, C1-6cycloalkylamino, hydroxyC1-6alkylamino, piperazinyl, mono- or di(C1 6alkyl)aminoC1-6alkylamino N-methylpiperazinyl, morpholinyl or thiomorpholinyl;
• each R7 and R8 arc independently selected from hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, or mono-or di(C1-4alkyl)aminosulfonyl;
• R3 is hydrogen, hydroxymethyl, aminomethyl or mono- or di(C1-6alkyl)aminomethyl;
• R4 is hydrogen or C1-6alkyl;
• aryl is phenyl or naphtalenyl;
• wherein
• each of said phenyl or naphtalenyl is optionally substituted with one or two substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl;
• and
• heterocyclyl is furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrolidinyl, dioxolyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, trithianyl, indolizinyl, indolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, cinnolinyl, phthlazinyl, quinazolinyl, quinoxalinyl or naphthyridinyl;
• wherein each of said heterocycles is optionally substituted with one or two substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, amino, mono-or di(C1-4alkyl)amino.