Spirocyclic derivatives as histone deacetylase inhibitors

1. Compounds of formula (I)

wherein:

m, n are independently zero or an integer from 1 to 4;

p is, zero or an integer from 1 to 3;

R is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or hetero(C 2 -C 9 )aryl; (CO)R 2 ; (SO 2 )R 3 ; C 3 -C 8 cycloalkyl; C 6 -C 10 aryl or hetero(C 2 -C 9 )aryl;

R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;

Y is CH 2 or NR 4 ;

Z is C═R 5 ;

R 2 is C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; C 6 -C 10 aryl; hetero(C 2 -C 9 )aryl; O—C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl; O—(C 6 -C 10 -aryl) or NR 6 R 7 ;

R 3 is C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; C 6 -C 10 aryl or hetero(C 2 -C 9 )aryl;

R 4 is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl;

R 5 is oxygen or NOR 8 ;

R 6 is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; C 6 -C 10 aryl or hetero(C 2 -C 9 )aryl;

R 7 is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; or R 6 and R 7 together with the nitrogen to which they are bound form a C 4 -C 9 -heterocyclic ring, optionally containing one or more further heteroatoms in the ring selected from NR 9 , O or S;

R 8 is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl;

R 9 is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; C 6 -C 10 aryl; hetero(C 2 -C 9 )aryl; (CO)R 10 ; or (SO 2 )R 11 ;

R 10 is C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; O—C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl; O—(C 6 -C 10 -aryl) or NR 12 R 13 ;

R 11 is C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; C 6 -C 10 aryl or hetero(C 2 -C 9 )aryl;

R 12 is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or by hetero(C 2 -C 9 )aryl; C 6 -C 10 aryl or hetero(C 2 -C 9 )aryl;

R 13 is hydrogen; C 1 -C 6 alkyl, optionally substituted by C 6 -C 10 aryl or hetero(C 2 -C 9 )aryl;

and the pharmaceutically acceptable salts thereof; provided that when p is zero, then n and m cannot be both 1.

2. Compounds according to claim 1 , wherein:

m, n are independently zero or an integer from 1 to 4;

p is zero or 1;

R is hydrogen; C 1 -C 4 alkyl, optionally substituted by C 3 -C 8 cycloalkyl, phenyl, or hetero(C 2 -C 9 )aryl; (CO)R 2 ; C 3 -C 8 cycloalkyl; phenyl; or hetero(C 2 -C 9 )aryl;

R 1 is halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkoxy;

Y is CH 2 or NR 4 ;

Z is C═R 5 ;

R 2 is C 1 -C 4 alkyl, optionally substituted by phenyl or by hetero(C 2 -C 9 )aryl; phenyl; hetero(C 2 -C 9 )aryl; O—C 1 -C 4 alkyl; or NR 6 R 7 ;

R 4 is hydrogen; C 1 -C 4 alkyl, optionally substituted by phenyl;

R 5 is oxygen or NOR 8 ;

R 6 is hydrogen; C 1 -C 4 alkyl, optionally substituted by phenyl; or phenyl;

R 7 is hydrogen; C 1 -C 4 alkyl, optionally substituted by phenyl;

R 8 is hydrogen; C 1 -C 4 alkyl, optionally substituted by phenyl;

and the pharmaceutically acceptable salts thereof.

3. Compounds according to claim 1 , selected from:

(±)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(−)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(+)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Benzoyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(−)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(+)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Benzoyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Benzoyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(E)-3-[4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(E)-3-{1-[2-(4-Fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-N-hydroxy-acrylamide;

(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(E)-3-[1′-Benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-{3,4-Dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide;

(±)-(E)-3-{1′-Benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-Methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-{1′-(4-Fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide;

(±)-(E)-3-{1′-(2-Phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide;

(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-{1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide;

(±)-(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide;

(±)-(E)-3-(1′-Ethyl-4-oxospiro[chromane-2,3′-piperidine]-6-yl)-N-hydroxy-acrylamide;

(±)-(E)-3-(1′-Isopropyl-4-oxospiro[chromane-2,3′-piperidine]-6-yl)-N-hydroxy-acrylamide;

(±)-(E)-3-(1′-Cyclopentyl-4-oxospiro[chromane-2,3′-piperidine]-6-yl)-N-hydroxy-acrylamide;

(E)-3-(1′-Benzyl-8-fluoro-4-oxospiro[chromane-2,4′-piperidine]-6-yl)-N-hydroxy-acrylamide;

(E)-3-(1′-Benzyl-8-methyl-4-oxospiro[chromane-2,4′-piperidine]-6-yl)-N-hydroxy-acrylamide;

(E)-3-(1′-(4-Fluorobenzyl)-4-(methoxyimino)spiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide;

(E)-3-(1′-Cyclopentyl-4-(hydroxyimino)spiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide;

(E)-3-(4-(Benzyloxyimino)-1′-phenethylspiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide.

4. Compounds as described in claim 1 , for use as HDAC inhibitors.

5. Pharmaceutical composition comprising one or more compounds of formula (I) as described in claim 1 .

6. Pharmaceutical composition according to claim 5 , in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable or infusible liquid solutions, suspensions, emulsions, suppositories, ointments, creams, lotions, gels, pastes, transdermal delivery devices.

7. Process for preparing a compound according to claim 1 , in which Z is C═O, comprising the transformation of a compound of formula A1 into a compound of formula A2, and the subsequent transformation of a compound of formula A2 into a compound of formula (I), as represented in Scheme A below:

wherein:

Z is C═O

PG and PG 1 are protecting groups wherein PG is a methyl or tert-butyl group and

PG 1 is a O-(tetrahydro-2H-pyran-2-yl) group.