Inhibitors of histone deacetylase

1. A compound of formula (I),

an N-oxide form, a pharmaceutically acceptable addition salt or a stereo-chemically isomeric form thereof, wherein

n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;

Q is

X is

Y is

Z is nitrogen;

R 1 is —C(O)NR 5 R 6 , —C(O)—C 1-6 alkanediylSR 7 , —NR 8 C(O)N(OH)R 7 , —NR 8 C(O)C 1-6 alkanediylSR 7 , or —NR 8 C(O)C═N(OH)R 7

wherein R 5 and R 6 are each independently hydrogen, hydroxy,

C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl or aminoaryl;

R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, arylC 1-6 alkyl, C 1-6 alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;

R 8 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen, halo, hydroxy, amino, nitro, C 1-6 alkyl, C 1-6 alkyloxy, trifluoromethyl, di(C 1-6 alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;

R 3 is arylC 2-6 alkenediyl, furanylcarbonyl, naphthalenylcarbonyl, C 1-6 alkylaminocarbonyl, aminosulfonyl, di(C 1-6 alkyl)aminosulfonylaminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl,

C 1-12 alkylsulfonyl, di(C 1-6 alkyl)aminosulfonyl, trihaloC 1-6 alkylsulfonyl, di(aryl)C 1-6 alkylcarbonyl, thiophenylC 1-6 alkylcarbonyl, pyridinylcarbonyl or arylC 1-6 alkylcarbonyl;

R 4 is hydrogen, hydroxy, amino, hydroxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyloxy, arylC 1-6 alkyl, aminocarbonyl, hydroxycarbonyl, aminoC 1-6 alkyl, aminocarbonylC 1-6 alkyl, hydroxycarbonylC 1-6 alkyl, hydroxyaminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylaminoC 1-6 alkyl or di(C 1-6 alkyl)aminoC 1-6 alkyl;

aryl in the above is phenyl, or phenyl substituted with one or more substituents each that are each independently halo, C 1-6 alkyl, C 1-6 alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.

2. The compound as claimed in claim 1 , the N-oxide form, the pharmaceutically acceptable addition salt or the stereo-chemically isomeric form thereof wherein

R 1 is —C(O)NR 5 R 6 , —C(O)—C 1-6 alkanediylSR 7 , —NR 8 C(O)N(OH)R 7 , —NR 8 C(O)C 1-6 alkanediylSR 7 , or —NR 8 C(O)C═N(OH)R 7

wherein R 5 and R 6 are each independently hydrogen, hydroxy, hydroxyC 1-6 alkyl or aminoC 1-6 alkyl;

R 2 is hydrogen, halo, hydroxy, amino, nitro, C 1-6 alkyl, C 1-6 alkyloxy, trifluoromethyl or di(C 1-6 alkyl)amino; and

R 4 is hydrogen, hydroxy, amino, hydroxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyloxy, arylC 1-6 alkyl, aminocarbonyl, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl or di(C 1-6 alkyl)aminoC 1-6 alkyl.

3. The compound as claimed in claim 1 , the N-oxide form, the pharmaceutically acceptable addition salt or the stereo-chemically isomeric form thereof wherein

n is 0 or 1;

R 1 is —C(O)NH(OH) or —NHC(O)C 1-6 alkanediylSH;

R 2 is hydrogen or nitro; and

R 4 is hydrogen.

4. The compound as claimed in claim 1 , the N-oxide form, the pharmaceutically acceptable addition salt or the stereo-chemically isomeric form thereof wherein n is 1; R 1 is —C(O)NH(OH); R 2 is hydrogen; R 3 is naphthalenylcarbonyl, C 1-12 alkylsulfonyl or di(aryl)C 1-6 alkylcarbonyl; and R 4 is hydrogen.

5. A compound that is

or the N-oxide form, the pharmaceutically acceptable addition salt or the stereo-chemically isomeric form thereof.

6. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .

7. A process of preparing a pharmaceutical composition as claimed in claim 6 wherein the pharmaceutically acceptable carriers and the compound are intimately mixed.

8. A method of treating ovarian carcinoma comprising administering to a patient in need of such treatment, an anti-proliferative disease-effective amount of a compound of claim 1 .

9. A process for preparing a compound of formula (I-a), comprising

reacting an intermediate of formula (II) with an acid to provide the compound of formula (I-a)

and wherein

n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;

Q is

X is

Y is

Z is nitrogen;

R 2 is hydrogen, halo, hydroxy, amino, nitro, C 1-6 alkyl, C 1-6 alkyloxy, trifluoromethyl, di(C 1-6 alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;

R 3 is C 1-6 alkyl, arylC 2-6 alkenediyl, furanylcarbonyl, naphthalenylcarbonyl, C 1-6 alkylaminocarbonyl, aminosulfonyl, di(C 1-6 alkyl)aminosulfonylaminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-12 alkylsulfonyl, di(C 1-6 alkyl)aminosulfonyl, trihaloC 1-6 alkylsulfonyl, di(aryl)C 1-6 alkylcarbonyl, thiophenylC 1-6 alkylcarbonyl, pyridinylcarbonyl or arylC 1-6 alkylcarbonyl

R 4 is hydrogen, hydroxy, amino, hydroxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyloxy, arylC 1-6 alkyl, aminocarbonyl, hydroxycarbonyl, aminoC 1-6 alkyl, aminocarbonylC 1-6 alkyl, hydroxycarbonylC 1-6 alkyl, hydroxyaminocarbonyl,

C 1-6 alkyloxycarbonyl, C 1-6 alkylaminoC 1-6 alkyl or di(C 1-6 alkyl)aminoC 1-6 alkyl; aryl in the above is phenyl, or phenyl substituted with one or more substituents that are each independently halo, C 1-6 alkyl, C 1-6 alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.

10. A method of detecting or identifying a histone deacetylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a compound as defined in claim 1 that has been labeled and a HDAC.

11. The pharmaceutical composition of claim 6 , further comprising another anti-cancer agent.

12. The process of claim 9 , wherein the acid is trifluoro acetic acid.

13. The compound of claim 1 that is: