Hydroxamates as inhibitors of histone deacetylase

1. A compound of formula (I), or a salt, or N-oxide thereof:

wherein

n is 0 or 1;

Q, V and W independently represent —N═ or —C═;

B is a divalent radical selected from (B1), (B2), (B3), (B4), (B5) and (B6):

wherein the bond marked * is linked to the ring containing Q, V and W;

A is an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system;

-[Linker]- represents a bond, or a divalent linker radical;

Z 1 is (a) a radical of formula R 1 R 2 CHNH—Y-L 1 -X 1 —(CH 2 ) n — or (b) a radical of formula R-L 1 -Y 1 —(CH 2 ) z —, wherein:

R is a radical of formula (X) or (Y)

R 1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group;

R 6 is hydrogen; or optionally substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl or heteroaryl or —(C═O)R 3 , —(C═O)OR 3 , or —(C═O)NR 3 wherein R 3 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;

R 2 is the side chain of a natural or non-natural alpha amino acid;

Y is a bond, —C(═O)—, —S(═O) 2 —, —C(═O)O—, —C(═O)NR 3 —, —C(═S)—NR 3 , —C(═NH)—NR 3 or —S(═O) 2 NR 3 — wherein R 3 is hydrogen or optionally substituted C 1 -C 6 alkyl;

Y 1 is a bond, —(C═O)—, —S(O 2 )—, —C(═O)O—, —OC(═O)—, —NR 3 (C═O)—, —S(O 2 )NR 3 —, —NR 3 S(O 2 )—, or —NR 3 (C═O)NR 4 —, wherein R 3 and R 4 are independently hydrogen or optionally substituted (C 1 -C 6 )alkyl,

L 1 is a divalent radical of formula -(Alk 1 ) m (Q) n (Alk 2 ) p - wherein

m, n and p are independently 0 or 1,

Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where p is 0, a divalent radical of formula -Q′-X 2 — wherein X 2 is —O—, —S— or NR A — wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl, and Q′ is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members,

Alk 1 and Alk 2 independently represent optionally substituted divalent C 3 -C 7 cycloalkyl radicals, or optionally substituted straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NR A —) link wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl;

X 1 is a bond, —C(═O)—; or —S(═O) 2 —; —NR 4 C(═O)—, —C(═O)NR 4 —, —NR 4 C(═O)—NR 5 —, —NR 4 S(═O) 2 —, or —S(═O) 2 NR 4 — wherein R 4 and R 5 are independently hydrogen or optionally substituted C 1 -C 6 alkyl; and

z is 0 or 1.

2. A compound as claimed in claim 1 wherein Q is —C═ and V and W are each —N═.

3. A compound as claimed in claim 1 wherein A is one of the following ring systems, optionally substituted:

wherein R 10 is hydrogen or C 1 -C 6 alkyl, the bond intersected by the wavy line connects to the -[Linker]- radical, and R is attached to an available ring atom.

4. A compound as claimed in claim 1 wherein ring A is selected from optionally substituted phenyl, cyclohexyl, naphthyl, quinolin-2-yl, and 1,3-dihydro-isoindol-2-yl.

5. A compound as claimed in claim 4 wherein optional substituents in ring A are selected from fluoro and chloro.

6. A compound as claimed in claim 1 wherein -[Linker]- is selected from:

(i) a bond;

(ii) —O—, —S—, —C(═O)—, —S(═O) 2 —, —NR C —, —C(═O)NR C —, —S(═O) 2 NR C —, —NR C S(═O) 2 —, —NR C (CH 2 ) m —, —NR C C(═O)(CH 2 ) m —, —NR C S(═O) 2 (CH 2 ) m , —NR D C(═O)NR C —, or —NR C C(═O)(CH 2 ) m Ar—, or —NR C S(═O) 2 (CH 2 ) m Ar— wherein R C and R D are independently hydrogen, C 1 -C 4 alkyl or a nitrogen substituent, m is 1, 2 or 3, and Ar is a divalent phenyl radical or a divalent mono-, or bi-cyclic heteroaryl radical having 5 to 13 ring members; and

(iii) an optionally substituted, straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene radical which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NR A —) link wherein R A is hydrogen, C 1 -C 3 alkyl or a nitrogen substituent.

7. A compound as claimed in claim 6 wherein —Ar— is present in -[Linker]- and is a divalent radical selected from the following:

wherein X is O, S or NH.

8. A compound as claimed in claim 6 wherein —Ar— is present in -[Linker]- and is a divalent phenylene radical.

9. A compound as claimed in claim 1 wherein -[Linker]- is a bond when n is 0.

10. A compound as claimed in claim 1 wherein z is 0.

11. A compound as claimed in claim 1 wherein Y is —S(═O) 2 —, —C(═S)—NR 3 , —C(═NH)—NR 3 or —S(═O) 2 NR 3 — wherein R 3 is hydrogen or C 1 -C 6 alkyl.

12. A compound as claimed in claim 1 wherein Y is a bond.

13. A compound as claimed in claim 1 wherein, in the radical L 1 , Alk 1 and Alk 2 , when present, are selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, and divalent cyclopropyl, cyclopentyl and cyclohexyl radicals.

14. A compound as claimed in claim 1 wherein, in the radical L 1 , Q 1 is a divalent phenyl radical or a mono-, or bi-cyclic heteroaryl radical having 5 to 13 ring members.

15. A compound as claimed in claim 12 wherein Q 1 is 1,4-phenylene.

16. A compound as claimed in claim 1 wherein, in the radical L 1 , p and r are 0.

17. A compound as claimed in claim 1 wherein, in the radical L 1 , q and r are 0 and p is 1.

18. A compound as claimed in claim 1 wherein, in the radical L 1 , p, q and r are all 0.

19. A compound as claimed in claim 1 wherein Z 1 is a radical of formula R 1 R 2 CHNH—Y-L 1 -X 1 —(CH 2 ) z — wherein the radical —Y-L 1 -X 1 -[CH 2 ] z — is selected from —C(═O)—, —C(═O)NH—, —(CH 2 ) v —, —(CH 2 ) v O—, —C(═O)—(CH 2 ) v —, —C(═O)—(CH 2 ) v O—, —C(═O)—NH—(CH 2 ) w —, —C(═O)—NH—(CH 2 ) w O—

wherein v is 1, 2, 3 or 4 and w is 1, 2 or 3.

20. A compound as claimed in claim 1 wherein Z 1 is a radical of formula R 1 R 2 CHNH—Y-L 1 -X 1 —(CH 2 ) z — wherein the radical —Y-L 1 -X 1 —[CH 2 ] z — is —CH 2 —, —CH 2 O—, —C(═O)—CH 2 —, —C(═O)—CH 2 O—, —C(═O)—NH—CH 2 —, or —C(═O)—NH—CH 2 O—.

21. A compound as claimed in claim 1 wherein R 1 is an ester group of formula —(C═O)OR 9 wherein R 9 is R 7 R 8 CH— wherein

(i) R 7 is hydrogen or optionally substituted (C 1 -C 3 )alkyl-(Z 1 ) a -[(C 1 -C 3 )alkyl] b — or (C 2 -C 3 )alkenyl-(Z 1 ) a -[(C 1 -C 3 )alkyl] b — wherein a and b are independently 0 or 1 and Z 1 is —O—, —S—, or —NR 10 — wherein R 10 is hydrogen or C 1 -C 3 alkyl, and R 8 is hydrogen or (C 1 -C 3 )alkyl-;

(ii) R 7 is hydrogen or optionally substituted R 10 R 11 N—(C 1 -C 3 )alkyl- wherein R 10 is hydrogen or C 1 -C 3 alkyl and R 11 is hydrogen or C 1 -C 3 alkyl; or R 10 and R 11 together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocyclic ring of 5- or 6-ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R 8 is hydrogen or (C 1 -C 3 )alkyl-; or

(iii) R 7 and R 8 taken together with the carbon to which they are attached form an optionally substituted monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms.

22. A compound as claimed in claim 21 wherein R 9 is methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- or 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbornyl, dimethylaminoethyl, or morpholinoethyl.

23. A compound as claimed in claim 21 wherein R 9 is cyclopentyl.

24. A compound as claimed in claim 1 wherein Z 1 is a radical of formula R 1 R 2 CHNH—Y-L 1 -X 1 —(CH 2 ) z — and wherein R 2 is cyclohexylmethyl, pyridin-3-ylmethyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, or phenylethyl.

25. A compound as claimed in claim 1 wherein Z 1 is a radical of formula R 1 R 2 CHNH—Y-L 1 -X 1 —(CH 2 ) z — and wherein R 2 is hydrogen.

26. A compound as claimed in claim 1 wherein Z 1 is a radical of formula R 1 R 2 CHNH—Y-L 1 -X 1 —(CH 2 ) z — and wherein R 2 is phenyl, benzyl, iso-butyl, cyclohexyl or t-butoxymethyl.

27. A pharmaceutical composition comprising a compound as claimed in claim 1 , together with a pharmaceutically acceptable carrier.

28. A compound as claimed in claim 1 wherein

n is 0 or 1;

Q, V and W independently represent —N═ or —C═;

B is a divalent radical selected from (B1), (B2), (B3), (B4), (B5) and (B6):

wherein the bond marked * is linked to the ring containing Q, V and W;

A is an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system;

-[Linker]- is selected from:

(i) a bond;

(ii) —O—, —S—, —C(═O)—, —S(═O) 2 —, —NR C —, —C(═O)NR C —, —S(═O) 2 NR C —, —NR C S(═O) 2 —, —NR C (CH 2 ) m —, —NR C C(═O)(CH 2 ) m —, —NR C S(═O) 2 (CH 2 ) m —, —NR D C(═O)NR C —, or —NR C C(═O)(CH 2 ) m Ar—, or —NR C S(═O) 2 (CH 2 ) m Ar— wherein R C and R D are independently hydrogen, C 1 -C 4 alkyl or a nitrogen substituent, m is 1, 2 or 3, and Ar is a divalent phenyl radical or a divalent mono-, or bi-cyclic heteroaryl radical having 5 to 13 ring members; and

(iii) an optionally substituted, straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene radical which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NR A —) link wherein R A is hydrogen, C 1 -C 3 alkyl or a nitrogen substituent;

Z 1 is (a) a radical of formula R 1 R 2 CHNH—Y-L 1 -X 1 —(CH 2 ) n — or (b) a radical of formula R-L 1 -Y 1 —(CH 2 ) z —, wherein:

R is a radical of formula (X) or (Y)

R 1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group;

R 6 is hydrogen; or optionally substituted C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl or heteroaryl or —(C═O)R 3 , —(C═O)OR 3 , or —(C═O)NR 3 wherein R 3 is hydrogen or optionally substituted (C 1 -C 6 )alkyl.

R 2 is the side chain of a natural or non-natural alpha amino acid;

Y is a bond, —C(═O)—, —S(═O) 2 —, —C(═O)O—, —C(═O)NR 3 —, —C(═S)—NR 3 , —C(═NH)—NR 3 or —S(═O) 2 NR 3 — wherein R 3 is hydrogen or optionally substituted C 1 -C 6 alkyl;

Y′ is a bond, —(C═O)—, —S(O 2 )—, —C(═O)O—, —OC(═O)—, —NR 3 (C═O)—, —S(O 2 )NR 3 —, —NR 3 S(O 2 )—, or —NR 3 (C═O)NR 4 —, wherein R 3 and R 4 are independently hydrogen or optionally substituted (C 1 -C 6 )alkyl,

L 1 is a divalent radical of formula -(Alk 1 ) m (Q) n (Alk 2 ) p — wherein

m, n and p are independently 0 or 1,

Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where p is 0, a divalent radical of formula -Q 1 -X 2 —wherein X 2 is —O—, —S— or NR A — wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl, and Q′ is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members,

Alk 1 and Alk 2 independently represent optionally substituted divalent C 3 -C 7 cycloalkyl radicals, or optionally substituted straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NR A —) link wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl;

X 1 is a bond, —C(═O)—; or —S(═O) 2 —; —NR 4 C(═O)—, —C(═O)NR 4 —, —NR 4 C(═O)—NR 5 —, —NR 4 S(═O) 2 —, or —S(═O) 2 NR 4 — wherein R 4 and R 5 are independently hydrogen or optionally substituted C 1 -C 6 alkyl; and

z is 0 or 1.