Benzamide derivatives and their use as hsp90 inhibtors

Abstract

The invention provides a compound which is (a) a phenylamide derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein. The compounds are useful in the treatment of diseases mediated by HSP90.

1 . A method of treating a patient suffering from or susceptible to a disorder mediated by HSP90 which method comprises administering to said patient an effective amount of a compound which is (a) a phenylamide derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen or hydroxy; 
 R 2 , R 3 , R 4  and R 5  are the same or different and represent hydrogen or halogen atoms or C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, hydroxy, cyano, nitro or —NR′R″ groups wherein R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-4  alkyl, and with the proviso that no more than two of R 2 , R 3 , R 4  and R 5  are cyano or nitro; 
 either: 
 (iii) R 6  is selected from C 1-4  alkyl and R 7  represents —CR 8 R 9 -A wherein R 8  and R 9  are the same or different and represent a hydrogen or halogen atom or a C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkoxy, hydroxy or —NR′R″ group where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-4  alkyl, and A represents a phenyl ring or a 5- or 6-membered heteroaryl group and is substituted with a group W; or 
 (iv) R 6  and R 7 , together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclyl group which is either (a) unfused, or (b) fused to a phenyl ring or a 5- to 6-membered heteroaryl group, and wherein either the heterocyclyl group or, when fused, the heterocyclyl group or the phenyl ring or heteroaryl group to which it is fused, is substituted with a group W; 
 W represents a group -Alk 1 -R; 
 Alk 1  represents a bond, a C 1-4  alkylene group or a group —(C 1-4  alkylene)-NR′—(C 1-4  alkylene)- wherein R′ represents hydrogen or C 1-4  alkyl; 
 R represents a group of formula (X) or (Y): 
 
       
         
           
           
               
               
           
         
         R 10 , where present, represents a hydrogen atom or a C 1-4  alkyl group; 
         Alk 2  represents a group of formula —C(R 12 )(R 13 )— when R is of formula (X) or —C(R 12 )— when R is of formula (Y), wherein R 12  and R 13  are the same or different and represent hydrogen or the α-substituents of an α-substituted or α,α-disubstituted glycine or glycine ester compound; 
         ring D, where present, is a 5- to 6-membered heterocyclyl group containing Alk 2  and wherein R 11  is linked to ring D via Alk 2 , and ring D is optionally fused to a second ring comprising a phenyl, 5- to 6-membered heteroaryl, C 3-7  carbocyclyl or 5- to 6-membered heterocyclyl; and 
         R 11  is a group —COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a —COOH group; 
       
       and wherein, unless otherwise stated:
 the alkyl, alkenyl and alkynyl groups and moieties in R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , Alk 1 , R 12  and R 13  are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkoxy, C 2-4  alkenyloxy, C 1-4  haloalkyl, C 2-4  haloalkenyl, C 1-4  haloalkoxy, C 2-4  haloalkenyloxy, hydroxyl, —SR′, cyano, nitro, C 1-4  hydroxyalkyl and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl; and 
 the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in R 6  and R 7  are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, C 1-4  alkyl, C 1-4  alkoxy, C 2-4  alkenyl, C 2-4  alkenyloxy, C 1-4  haloalkyl, C 2-4  haloalkenyl, C 1-4  haloalkoxy, C 2-4  haloalkenyloxy, hydroxyl, C 1-4  hydroxyalkyl, —SR′ and —NR′R″ groups wherein each R′ and R″ is the same or different and represents hydrogen or unsubstituted C 1-4  alkyl, or from substituents of formula —COOH, —COOR A , —COR A , —SO 2 R A , —CONH 2 , —SO 2 NH 2 , —CONHR A , —SO 2 NHR A , —CONR A R B , —SO 2 NR A R B , —OCONH 2 , —OCONHR A , —OCONR A R B , —NHCOR A , —NR B COR A , —NHCOOR A , —NR B COOR A , —NR B COOH, —NHCOOH, —NHSO 2 R A , —NR B SO 2 R A , —NHSO 2 OR A , —NR B SO 2 OH, —NHSO 2 H, —NR B SO 2 OR A , —NHCONH 2 , —NR A CONH 2 , —NHCONHR B , —NR A CONHR B , —NHCONR A R B  or —NR A CONR A R B  wherein R A  and R B  are the same or different and represent unsubstituted C 1-6  alkyl, C 3-6  cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R A  and R B  when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group. 
 
     
     
         2 . A method as claimed in  claim 1  wherein R 1  is hydroxy. 
     
     
         3 . A method as claimed in  claim 1  wherein R 2 , R 3 , R 4  and R 5  are the same or different and represent hydrogen or halogen atoms or hydroxy, unsubstituted C 1-4  alkyl or unsubstituted C 1-4  alkoxy groups. 
     
     
         4 . A method as claimed in  claim 1  wherein either:
 (i) R 6  represents —CH 3 , R 7  represents —CR 8 R 9 -A wherein R 8  and R 9  are the same or different and represent a hydrogen or halogen atom or an unsubstituted C 1-4  alkyl or C 1-4  alkoxy group, and A represents a phenyl ring substituted with a group W; or 
 (ii) R 6  and R 7 , together with the nitrogen atom to which they are bonded, form a pyrrolidinyl, piperidinyl or isoindolinyl group which is substituted with a group W and is optionally further substituted with 1 or 2 groups which are the same or different and are selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl, cyano, nitro, —SR′ and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl. 
 
     
     
         5 . A method as claimed in  claim 1  wherein Alk 1  represents a bond, an unsubstituted C 1-4  alkylene group, or an unsubstituted —(C 1-2  alkylene)-NH—(C 1-4  alkylene)- group. 
     
     
         6 . A method as claimed in  claim 1  wherein either:
 (iii) R 12  and R 13  are the same or different and represent hydrogen, C 1-6  alkyl, C 3-7  carbocyclyl, C 6-10  aryl, —(C 1-4  alkyl)-(C 6-10 aryl ), or —(C 1-4  alkyl)-(C 3-7  carbocyclyl); or 
 (iv) R 12  and R 13 , together with the carbon atom to which they are bonded, form a C 3-7  carbocyclyl group, 
 
       wherein the alkyl groups and moieties are unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxy and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl, and wherein the aryl and carbocyclyl groups and moieties are unsubstituted or substituted with 1 or 2 substituents selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl, cyano, nitro, —SR′ and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl. 
     
     
         7 . A method as claimed in  claim 6  wherein either:
 (i) R 12  and R 13  are the same or different and represent a hydrogen atom or an unsubstituted group selected from C 1-4  alkyl, C 3-7  carbocyclyl, phenyl, -hydroxy-(C 1-4 )alkyl, —(C 1-4 )alkoxy-(C 1-4 )alkyl, —(C 1-2 )alkyl-phenyl or —(C 1-2 )alkyl-(C 3-7 )carbocyclyl; or 
 (ii) R 12  and R 13 , together with the carbon atom to which they are bonded, form an unsubstituted C 3-7  carbocyclyl group. 
 
     
     
         8 . A method as claimed in  claim 1  wherein R represents a group of formula (X) and R 10  represents a hydrogen atom. 
     
     
         9 . A method as claimed in  claim 1  wherein R 11  is selected from —COOH and —COOR 20  wherein R 20  represents unsubstituted C 1-4  alkyl or C 3-7  carbocyclyl. 
     
     
         10 . A method as claimed in  claim 1  wherein the compound which is administered is (a) a phenylamide derivative of formula (IA) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  represents an unsubstituted C 1-4  alkyl group; 
 either:
 R 6  represents —CH 3 , R 7  represents —CR 8 R 9 -A wherein R 8  and R 9  are the same or different and represent a hydrogen or halogen atom or an unsubstituted C 1-4  alkyl or C 1-4  alkoxy group, and A represents a phenyl ring substituted with a group W; or 
 R 6  and R 7 , together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine or isoindoline group which is substituted with a group W and which is optionally further substituted with 1 or 2 groups which are the same or different and are selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl, cyano, nitro, —SR′ and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl; 
 
 Alk 1  represents a bond, an unsubstituted C 1-4  alkylene group, or an unsubstituted —(C 1-2  alkylene)-NH—(C 1-4  alkylene)- group; 
 R represents a group of formula (X) wherein R 10  represents hydrogen; 
 Alk 2  represents a group of formula —C(R 12 )(R 13 )— and either:
 R 12  and R 13  are the same or different and represent hydrogen, C 1-6  alkyl, C 3-7  carbocyclyl, C 6-10  aryl, —(C 1-4  alkyl)-(C 6-10  aryl), or —(C 1-4  alkyl)-(C 3-7  carbocyclyl); or 
 R 12  and R 13 , together with the carbon atom to which they are bonded, form a C 3-7  carbocyclyl group, 
 
 wherein the alkyl groups and moieties in R 12  and R 13  are unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxy and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl, and wherein the aryl and carbocyclyl groups and moieties in R 12  and R 13  are unsubstituted or substituted with 1 or 2 substituents selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl, cyano, nitro, —SR′ and —NR′R″ groups where R′ and R″ are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl; and 
 R 11  is selected from —COOH and —COOR 20  wherein R 20  represents unsubstituted C 1-4  alkyl or C 3-7  carbocyclyl. 
 
     
     
         11 . A method as claimed in  claim 10  wherein R 4  represents isopropyl. 
     
     
         12 . A method as claimed in  claim 10  wherein either:
 R 6  represents —CH 3 , R 7  represents —CH 2 -phenyl wherein the phenyl ring is substituted with a single group W; or 
 R 6  and R 7 , together with the nitrogen atom to which they are bonded, form a pyrrolidinyl, piperidinyl or isoindolinyl group which is substituted with a single group W. 
 
     
     
         13 . A method as claimed in  claim 10  wherein one of R 12  and R 13  is hydrogen or unsubstituted C 1-2  alkyl and the other of R 12  and R 13  is an unsubstituted group selected from C 1-4  alkyl, C 3-7  carbocyclyl, phenyl, -hydroxy-(C 1-4 )alkyl, —(C 1-4 )alkoxy-(C 1-4 )alkyl, —(C 1-2 )alkyl-phenyl or —(C 1-2 )alkyl-(C 3-7 )carbocyclyl. 
     
     
         14 . A method as claimed in  claim 1  wherein the compound which is administered is selected from:
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-leucinate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-2-methylalaninate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-valinate; 
 cyclopentyl (2S)-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)amino](phenyl)ethanoate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-alaninate; 
 tert-butyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-leucinate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-3-yl)-L-leucinate; 
 tert-butyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-alaninate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-phenylalaninate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-norleucinate; 
 tert-butyl O-tert-butyl-N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-serinate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-D-leucinate; 
 cyclopentyl 3-cyclohexyl-N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-alaninate; 
 cyclopentyl (2S)-cyclohexyl[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)amino]ethanoate; 
 tert-butyl (2S)-cyclohexyl[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)amino]ethanoate; 
 tert-butyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-phenylalaninate; 
 cyclopentyl O-tert-butyl-N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-serinate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-serinate; 
 tert-butyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-D-leucinate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}pyrrolidin-3-yl)-L-leucinate; 
 cyclopentyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-leucinate; 
 cyclopentyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-alaninate; 
 cyclopentyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-phenylalaninate; 
 tert-butyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-leucinate; 
 tert-butyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-phenylalaninate; 
 tert-butyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-alaninate; 
 tert-butyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-D-leucinate; 
 cyclopentyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-D-leucinate; 
 cyclopentyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-valinate; 
 cyclopentyl (2S)-cyclohexyl{[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]amino}ethanoate; 
 tert-butyl (2S)-cyclohexyl{[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]amino}ethanoate; 
 cyclopentyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-2-methyl-L-alaninate; 
 cyclopentyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-serinate; 
 cyclopentyl O-tert-butyl-N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-serinate; 
 tert-butyl O-tert-butyl-N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-serinate; 
 cyclopentyl (2S)-{[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]amino}(phenyl)ethanoate; 
 tert-butyl N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-serinate; 
 cyclopentyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-leucinate; 
 cyclopentyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-alaninate; 
 cyclopentyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-phenylalaninate; 
 tert-butyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-phenylalaninate; 
 tert-butyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-leucinate; 
 tert-butyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-alaninate; 
 cyclopentyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-2-methylalaninate; 
 cyclopentyl O-tert-butyl-N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-serinate; 
 cyclopentyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-valinate; 
 cyclopentyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-serinate; 
 cyclopentyl (2S)-cyclohexyl{[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]amino}ethanoate; 
 tert-butyl (2S)-cyclohexyl{[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]amino}ethanoate; 
 tert-butyl (2S)-{[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]amino}(phenyl)ethanoate; 
 cyclopentyl (2S)-{[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]amino}(phenyl)ethanoate; 
 tert-butyl N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-serinate; 
 tert-butyl O-tert-butyl-N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-serinate; 
 cyclopentyl N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-L-leucinate; 
 cyclopentyl N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-2-methylalaninate; 
 tert-butyl N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-L-alaninate; 
 ethyl N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-L-alaninate; 
 propan-2-yl N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-L-alaninate; 
 cyclopentyl N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-L-alaninate; 
 cyclopentyl 1-{[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]amino}cyclopentanecarboxylate; 
 cyclopentyl N-[2-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)ethyl]-L-leucinate; 
 tert-butyl N-[2-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)ethyl]-L-leucinate; 
 cyclopentyl 1-{[2-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)ethyl]amino}cyclopentanecarboxylate; 
 cyclopentyl N-[3-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)propyl]-L-leucinate; 
 cyclopentyl 1-{[3-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)propyl]amino}cyclopentanecarboxylate; 
 cyclopentyl N-(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-L-leucinate; 
 cyclopentyl N-(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-2-methylalaninate; 
 cyclopentyl 1-[(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)amino]cyclopentanecarboxylate; 
 cyclopentyl (2S)-[(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)amino](phenyl)ethanoate; 
 cyclopentyl N-(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-L-leucinate; 
 cyclopentyl (2S)-[(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)amino](phenyl)ethanoate; 
 cyclopentyl N-(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-2-methylalaninate; 
 cyclopentyl N-[2-(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}phenyl)ethyl]-2-methylalaninate; 
 cyclopentyl N-{[(2R)-1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}pyrrolidin-2-yl]methyl}-L-leucinate; 
 cyclopentyl N-{[(2S)-1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}pyrrolidin-2-yl]methyl}-L-leucinate; 
 cyclopentyl N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}pyrrolidin-3-yl)-D-leucinate; 
 N-(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-L-leucine; 
 N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-L-leucine; 
 N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-2-methylalanine; 
 N-[3-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)propyl]-L-leucine; 
 N-[2-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)ethyl]-L-leucine; 
 N-[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]-L-alanine; 
 1-{[(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)methyl]amino}cyclopentanecarboxylic acid; 
 N-(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-L-leucine; 
 (2S)-[(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)amino](phenyl)ethanoic acid; 
 N-(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-2-methylalanine; 
 N-(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)-2-methylalanine; 
 1-[(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)amino]cyclopentanecarboxylic acid; 
 (2S)-[(3-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}benzyl)amino](phenyl)ethanoic acid; 
 1-{[3-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)propyl]amino}cyclopentanecarboxylic acid; 
 N-[2-(4-{[{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}(methyl)amino]methyl}phenyl)ethyl]-2-methylalanine; 
 N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-alanine; 
 1-{[2-(2-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)ethyl]amino}cyclopentanecarboxylic acid; 
 N-{[(2S)-1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}pyrrolidin-2-yl]methyl}-L-leucine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}pyrrolidin-3-yl)-L-leucine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-leucine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-2-methylalanine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-valine; 
 (2S)-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)amino](phenyl)ethanoic acid; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-alanine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-phenylalanine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-3-yl)-L-leucine; 
 N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-leucine; 
 N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-leucine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-norleucine; 
 N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-alanine; 
 N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-phenylalanine; 
 N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-D-leucine; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-D-leucine; 
 3-cyclohexyl-N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-alanine; 
 N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-phenylalanine; 
 N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-valine; 
 (2S)-cyclohexyl[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)amino]ethanoic acid; 
 N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-2-methylalanine; 
 O-tert-butyl-N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-serine; 
 (2S)-cyclohexyl{[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]amino}ethanoic acid; 
 N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-2-methylalanine; 
 N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-serine; 
 O-tert-butyl-N-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]-L-serine; 
 (2S)-{[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)methyl]amino}(phenyl)ethanoic acid; 
 N-[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]-L-valine; 
 O-tert-butyl-N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-serine; 
 (2S)-cyclohexyl{[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]amino}ethanoic acid; 
 (2S)-{[2-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)ethyl]amino}(phenyl)ethanoic acid; 
 N-(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)-L-serine; 
 cyclopentyl N-{3-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)amino]propyl}-L-leucinate; and 
 N-{3-[(1-{[2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl}piperidin-4-yl)amino]propyl}-L-leucine 
 
     
     
         15 . A method of treating a patient suffering from or susceptible to a disorder mediated by HSP90 which method comprises administering to said patient an effective amount of a pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         16 . A method as claimed in  claim 1  wherein the disorder mediated by HSP90 is selected from cell proliferative disease, polyglutamine disease, neurodegenerative disease, autoimmune disease, diabetes, haematological disease, inflammatory disease, cardiovascular disease, atherosclerosis, primary biliary cirrhosis, Wegener's granulomatosis, and the inflammatory sequelia of infection. 
     
     
         17 . A method as claimed in  claim 16  wherein the disorder mediated by HSP90 is rheumatoid arthritis.