Hydroxybenzamide derivatives and their use as inhibitors of hsp90

Abstract

This invention provides methods for treating, alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth in a mammal, which comprise administering to the mammal a compound, salt, hydrate, tautomer or N-oxide according to formula (I): wherein R 1 is hydroxy or hydrogen; R 2 is hydroxyl, methoxy or hydrogen; provided that at least one of R 1 and R 2 is hydroxy; R 3 is selected from hydrogen; halogen; cyano; optionally substituted C 1-5 hydrocarbyl and optionally substituted C 1-5 hydrocarbyloxy; R 4 is selected from hydrogen; a group —(O) n .R 7 where n is 0 or 1 and R 7 is an optionally substituted acyclic C 1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono or di-C 1-5 hydrocarbyl-amino; or R 3 and R 4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR 5 R 6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The compounds have activity as Hsp90 inhibitors.

1 - 8 . (canceled) 
   
   
       9 . A method for treating, alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth in a mammal, the method comprising administering to the mammal a compound, salt, hydrate, tautomer or N-oxide according to formula: 
     
       
         
         
             
             
         
       
       wherein 
       R 3  is C 1-5  hydrocarbyl; 
       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 , NC(═O)C 1-6  alkyl, C 6  aryl, OC 6  aryl, C(═O)C 6 aryl, C(═O)OC 6 aryl, C(═O)NH 2 , C(═O)NHC 6 aryl, C(═O)N(C 6  aryl) 2 , NH(C 6  aryl), N(C 6  aryl) 2 , NC(═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 , NC(═O)C 5-6  heterocyclyl, C(═O)NHC 1-6  alkyl, C 5-6  aryl, S(═O)C 1-6  alkyl, S(═O)N—C 1-6 alkyl and SO 2 N—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 
     
     
       
         
         
             
             
         
       
       
         wherein n is 0, 1, 2 or 3; 
         in an amount effective in inhibiting abnormal cell growth. 
       
     
   
   
       10 - 14 . (canceled) 
   
   
       15 . A method according to  claim 9 , wherein R 3  is selected from cyclopropyl and branched C 3-5  alkyl. 
   
   
       16 . A method according to  claim 9 , wherein R 3  is selected from isopropyl and tert-butyl. 
   
   
       17 . A method according to  claim 9 , wherein R 3  is isopropyl. 
   
   
       18 . A method according to  claim 9 , wherein n is 1 or 2 and R 10b  is selected from the group consisting of halogen, O—C 1-6 -alkyl, aryl, heterocyclyl, C(═O)OC 1-6  alkyl, C(═O)C 5-6  heterocyclyl, NH(C 5-6  heterocyclyl), and a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from the following groups 
     
       
         
         
             
             
         
       
     
   
   
       19 . A method according  claim 9  wherein the compound is a salt. 
   
   
       20 . A method for treating, alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth in a mammal, the method comprising administering to the mammal a compound, salt, hydrate, tautomer or N-oxide according to formula: 
     
       
         
         
             
             
         
       
       wherein 
       R 3  is C 1-5  hydrocarbyl; 
       R 10b  is selected from the group consisting of heterocyclyl, NH(C 5-6  heterocyclyl); and a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from the following groups: 
     
     
       
         
         
             
             
         
       
     
     and
 wherein n is 1 or 2; 
 in an amount effective in inhibiting abnormal cell growth. 
 
   
   
       21 . A method according to  claim 18  wherein n is one. 
   
   
       22 . A method for treating, alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a compound, salt, hydrate, tautomer or N-oxide according to formula: 
     
       
         
         
             
             
         
       
       wherein 
       R 3  is C 1-5  hydrocarbyl; 
       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 , NC(═O)C 1-6  alkyl, C 6  aryl, OC 6  aryl, C(═O)C 6 aryl, C(═O)OC 6 aryl, C(═O)NH 2 , C(═O)NHC 6 aryl, C(═O)N(C 6  aryl) 2 , NH(C 6  aryl), N(C 6  aryl) 2 , NC(═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 , NC(═O)C 5-6 heterocyclyl, C(═O)NHC 1-6  alkyl, C 5-6  aryl, S(═O)C 1-6  alkyl, S(═O)N—C 1-6  alkyl and SO 2 N—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 
     
     
       
         
         
             
             
         
       
       
         wherein n is 0, 1, 2 or 3; and 
         a pharmaceutically acceptable carrier, 
         in an amount effective in inhibiting abnormal cell growth. 
       
     
   
   
       23 . A method according to  claim 20 , wherein said pharmaceutically acceptable carrier is a carrier for intravenous administration. 
   
   
       24 . A method according to  claim 9  wherein said disease or condition is cancer. 
   
   
       25 . A method according to  claim 9  wherein said disease or condition is cancer chosen from: carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, ovary, pancreas, stomach, thyroid, prostate, gastrointestinal system, skin, a hematopoieitic tumor of lymphoid or myeloid lineage, and a tumor of the central or peripheral nervous system. 
   
   
       26 . A method according to  claim 9  wherein said disease or condition is cancer chosen from: colon adenocarcinoma, colon adenoma, colorectal carcinoma, small cell lung cancer, non-small cell lung carcinoma, exocrine pancreatic carcinoma, gastrointestinal stromal tumors, leukaemia, acute lymphocytic leukaemia, chronic lymphocytic leukaemia, B-cell lymphoma, T-cell lymphoma, Burkett's lymphoma, acute myelogenous leukaemia, chronic myelogenous leukaemia, Imatinib sensitive and refractory chronic myelogenous leukaemia, myeloproliferative disease, melanoma, bortezomib sensitive multiple myeloma, thyroid follicular cancer and glioma. 
   
   
       27 . A method according to  claim 9  wherein said disease or condition is cancer chosen from: carcinoma of the prostate, gastrointestinal stromal tumors, acute lymphocytic leukaemia, chronic lymphocytic leukaemia, B-cell lymphoma, T-cell lymphoma, Burkett's lymphoma, acute myelogenous leukaemia, chronic myelogenous leukaemia, bortezomib sensitive multiple myeloma, non-small cell lung cancer, thyroid, follicular cancer, melanoma, and ErbB2-postitive breast cancer. 
   
   
       28 . A method according to  claim 20  wherein said disease or condition is cancer. 
   
   
       29 . A method according to  claim 20  wherein said disease or condition is cancer chosen from: carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, ovary, pancreas, stomach, thyroid, prostate, gastrointestinal system, skin, a hematopoieitic tumor of lymphoid or myeloid lineage, and a tumor of the central or peripheral nervous system. 
   
   
       30 . A method according to  claim 20  wherein said disease or condition is cancer chosen from: colon adenocarcinoma, colon adenoma, colorectal carcinoma, small cell lung cancer, non-small cell lung carcinoma, exocrine pancreatic carcinoma, gastrointestinal stromal tumors, leukaemia, acute lymphocytic leukaemia, chronic lymphocytic leukaemia, B-cell lymphoma, T-cell lymphoma, Burkett's lymphoma, acute myelogenous leukaemia, chronic myelogenous leukaemia, Imatinib sensitive and refractory chronic myelogenous leukaemia, myeloproliferative disease, melanoma, bortezomib sensitive multiple myeloma, thyroid follicular cancer and glioma. 
   
   
       30 . A method according to  claim 20  wherein said disease or condition is cancer chosen from: carcinoma of the prostate, gastrointestinal stromal tumors, acute lymphocytic leukaemia, chronic lymphocytic leukaemia, B-cell lymphoma, T-cell lymphoma, Burkett's lymphoma, acute myelogenous leukaemia, chronic myelogenous leukaemia, bortezomib sensitive multiple myeloma, non-small cell lung cancer, thyroid, follicular cancer, melanoma, and ErbB2-postitive breast cancer.