Hydroxybenzamide derivatives and their use as inhibitors of Hsp90

1. A compound of the formula (V):

or salts, tautomers, hydrates and N-oxides thereof; wherein:

R 1 is hydrogen or hydroxy; R 2a is hydroxy or methoxy; provided that at least one of R 1 and R 2a is hydroxy; R 3d is selected from ethyl and secondary and tertiary alkyl groups of 3 to 6 carbon atoms, R 4a is selected from hydrogen, fluorine, chlorine and methoxy; R 8 is hydrogen or fluorine; and R 5 and R 6 together with the nitrogen atom to which they are attached form a bicyclic group selected from tetrahydro-quinoline and tetrahydro-isoquinoline; wherein the bicyclic group is optionally substituted by one or more substituents R 10 ;

R 10 is selected from: halogen;

hydroxy;

trifluoromethyl;

cyano;

nitro;

carboxy;

amino;

mono- or di-C 1-4 hydrocarbylamino;

carbocyclic and heterocyclic groups having from 3 to 12 ring members; and a group R a -R b ; wherein:

R a is a bond, O, X 1 C(X 2 ), C(S)X 1 , C(═NR c )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , SO 2 NR c or NR c SO 2 ; and

R b is selected from hydrogen; carbocyclic and heterocyclic groups having from 3 to 12 ring members; and C 1-10 hydrocarbyl optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino, and carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C 1-10 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(S)X 1 , C(═NR c )X 1 , or X 1 C(X 2 )X 1 ;

R c is selected from R b , hydrogen and C 1-4 hydrocarbyl; and

X 1 is O, S or NR c and X 2 is ═O, ═S or NR c .

2. A compound according to claim 1 wherein R 3d is selected from ethyl, isopropyl and tert-butyl.

3. A compound according to claim 2 wherein R 3d is isopropyl.

4. A compound of the formula (VI):

or salts, tautomers, hydrates and N-oxides thereof; wherein:

wherein R 1 is hydroxy or hydrogen; R 2a is hydroxy or methoxy provided that at least one of R 1 and R 2a is hydroxy, ring B is an aromatic ring containing no nitrogen heteroatom ring members; T is a group (CHR 10b ) j and Q is a group (CHR 10b ) k where j and k are each 0, 1, 2 or 3 provided that the sum of j and k is 3; n is 0, 1, 2 or 3; R 4a is selected from hydrogen, fluorine, chlorine and methoxy; R 8 is hydrogen or fluorine; R 3 is selected from secondary alkyl and alkenyl groups and cycloalkyl groups; and R 10b is selected from the group consisting of halogen, OH, NH 2 , CH 2 OH, CH 2 NH 2 , O—C 1-6 -alkyl, NH—C 1-6 alkyl, aryl, heteroaryl, C 3-7 cycloalkyl, heterocyclyl, O-heteroaryl, O—C 3-7 cycloalkyl, O-heterocycloalkyl, C(═O)C 1-6 alkyl, C(═O)OC 1-6 alkyl, C(═O)NH 2 , C(═O)NHC 1-6 alkyl, C(═O)N(C 1-6 alkyl) 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHC(═O)C 1-6 alkyl, C 6 aryl, OC 6 aryl, C(═O)C 6 aryl, C(═O)OC 6 aryl, C(═O)NHC 6 aryl, C(═O)N(C 6 aryl) 2 , NH(C 6 aryl), N(C 6 aryl) 2 , NHC(═O)C 6 aryl, C 5-6 heterocyclyl, OC 5-6 heterocyclyl, C(═O)C 5-6 heterocyclyl, C(═O)OC 5-6 heterocyclyl, C(═O)NHC 5-6 heterocyclyl, C(═O)N(C 5-6 heterocyclyl) 2 , NH(C 5-6 heterocyclyl), N(C 5-6 heterocyclyO 2 , NC(═O)C 5-6 heterocyclyl, C 5-6 aryl, S(═O)C 1-6 alkyl, S(═O)NH—C 1-6 alkyl and SO 2 NH—C 1-6 alkyl; and a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from the following groups

5. A compound according to claim 4 wherein R 2a is hydroxy.

6. A compound according to claim 4 wherein R 3 is selected from isopropyl and tert-butyl.

7. A pharmaceutical composition comprising a compound of the formula (V):

or salts, tautomers, hydrates and N-oxides thereof; wherein:

R 1 is hydrogen or hydroxy; R 2a is hydroxy or methoxy; provided that at least one of R 1 and R 2a is hydroxy; R 3d is selected from ethyl and secondary and tertiary alkyl groups of 3 to 6 carbon atoms; R 4a is selected from hydrogen, fluorine, chlorine and methoxy; R 8 is hydrogen or fluorine; and R 5 and R 6 together with the nitrogen atom to which they are attached form a bicyclic group selected from tetrahydro-quinoline and tetrahydro-isoquinoline; wherein the bicyclic group is optionally substituted by one or more substituents R 10 ;

R 10 is selected from:

halogen;

hydroxy;

trifluoromethyl;

cyano;

nitro;

carboxy;

amino;

mono- or di-C 1-4 hydrocarbylamino;

carbocyclic and heterocyclic groups having from 3 to 12 ring members; and

a group R a -R b ; wherein:

R a is a bond, O, X 1 C(X 2 ), C(S)X 1 , C(═NR c )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ; and

R b is selected from hydrogen; carbocyclic and heterocyclic groups having from 3 to 12 ring members; and C 1-10 hydrocarbyl optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino, and carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C 1-10 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(S)X 1 , C(═NR c )X 1 , or X 1 C(X 2 )X 1 ;

R c is selected from R b , hydrogen and C 1-4 hydrocarbyl; and

X 1 is O, S or NR c and X 2 is ═O, ═S or ═NR c ;

and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition according to claim 7 which is in a form suitable for i.v. administration.

9. A pharmaceutical composition comprising a compound of the formula (VI):

or salts, tautomers, hydrates and N-oxides thereof; wherein:

wherein R 1 is hydroxy or hydrogen; R 2a is hydroxy or methoxy provided that at least one of R 1 and R 2a is hydroxy, ring B is an aromatic ring containing no nitrogen heteroatom ring members; T is a group (CHR 10b ) j and Q is a group (CHR 10b ) k where j and k are each 0, 1, 2 or 3 provided that the sum of j and k is 3; n is 0, 1, 2 or 3; R 4a is selected from hydrogen, fluorine, chlorine and methoxy; R 8 is hydrogen or fluorine; R 3 is selected from secondary alkyl and alkenyl groups and cycloalkyl groups; and R 10b is selected from the group consisting of halogen, OH, NH 2 , CH 2 OH, CH 2 NH 2 , O—C 1-6 -alkyl, NH—C 1-6 alkyl, aryl, heteroaryl, C 3-7 cycloalkyl, heterocyclyl, O-heteroaryl, O—C 3-7 cycloalkyl, O-heterocycloalkyl, C(═O)C 1-6 alkyl, C(═O)O—C 1-6 alkyl, C(═O)NH 2 , C(═O)NHC 1-6 alkyl, C(═O)NHC 1-6 alkyl) 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NhC(═O)C 1-6 alkyl, C 6 aryl, OC 6 aryl, C(═O)C 6 aryl, C(═O)OC 6 aryl, C(═O)NHC 6 aryl, C(═O)N(C 6 aryl) 2 , NH(C 6 aryl), N(C 6 aryl) 2 , NHC(═O)C 6 aryl, C 5-6 heterocyclyl, OC 5-6 heterocyclyl, C(═O)C 5-6 heterocyclyl, C(═O)OC 5-6 heterocyclyl, C(═O)NHC 5-6 heterocyclyl, C(═O)N(C 5-6 heterocyclyl) 2 , NH(C 5-6 heterocyclyl), N(C 5-6 heterocyclyl) 2 , NHC(═O)C 5-6 heterocyclyl, C 5-6 aryl, S(═O)C 1-6 alkyl, S(═O)NH—C 1-6 alkyl and SO 2 NH—C 1-6 alkyl; and a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from the following groups

and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition according to claim 9 which is in a form suitable for i.v. administration.

11. A compound according to claim 1 wherein R 2a is hydroxy.

12. A compound according to claim 1 wherein R 8 is hydrogen.

13. A compound according to claim 1 wherein R 4a is hydrogen.

14. A compound according to claim 1 wherein R 8 is hydrogen.

15. A compound according to claim 1 wherein R 4a is hydrogen.