2-benzoylaminobenzamide derivatives as bcl-3 inhibitors

Abstract

The invention relates to a compound of general formula (I):wherein R1, R2, R3, R4, Q, m and n are as defined herein. The compounds are inhibitors of Bcl3 and are useful for the treatment of cancer, particularly metastatic cancer.

1 . A compound of general formula (Ia): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         each R 1  is independently halo, nitro, methyl, trifluoromethyl, OH, methoxy or trifluoromethoxy, and further wherein at least one R 1  is 2-fluoro; 
         each of R 5  and R 6  is independently hydrogen, C 1-6  alkyl or C 1-6  haloalkyl; 
         m is 1 or 2; 
         Q is (CH 2 ) p ; 
         p is 2; 
         R 3  is morpholinyl; and 
         n is 0; 
         provided that the compound is not 2-[(2-fluorobenzoyl)amino]-N-2-(morpholin-4-ylethyl)benzamide. 
       
     
     
         2 . A compound according to  claim 1  selected from:
 2,6-difluoro-N-(2-[(2-morpholin-4-ylethyl) carbamoyl]phenyl)benzamide; and 
 2,4-difluoro-N-(2-[(2-morpholin-4-ylethyl)carbamoyl]phenyl)benzamide; 
 
       or pharmaceutically or veterinarily acceptable salts thereof. 
     
     
         3 . A process for the preparation of a compound according to  claim 1 , the process comprising reacting a compound of general formula (IIa): 
       
         
           
           
               
               
           
         
       
       with a compound of general formula (IIIa): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , m, R 3  and n are as defined in  claim 1 . 
     
     
         4 . A method for the treatment of cancer, the method comprising administering to a patient in need of such treatment an effective amount of one of a compound according to  claim 1  or 2-[(2-fluorobenzoyl)amino]-N-2-(morpholin-4-ylethyl)benzamide. 
     
     
         5 . The method of  claim 4 , wherein the cancer is leukaemia or lymphoma. 
     
     
         6 . The method of  claim 5 , wherein the cancer is anaplastic large cell lymphoma (ALCLs), classic Hodgkin lymphoma (cHL), non-Hodgkin's lymphoma or solid tumour cancer. 
     
     
         7 . The method of  claim 6 , wherein the solid tumour cancer is breast cancer, melanoma, lung cancer, pancreatic cancer, oesophageal cancer, colorectal cancer, nasopharyngeal carcinoma or hepatocarcinoma. 
     
     
         8 . The method according to  claim 4 , wherein the treatment comprises the treatment or prevention of metastasis in cancers. 
     
     
         9 . The method according to  claim 7 , wherein the cancer is breast cancer. 
     
     
         10 . The method according to  claim 9 , wherein the cancer is triple negative breast cancer or HER2 enriched breast cancer. 
     
     
         11 . The method according to  claim 4 , wherein the selected compound is administered in combination with one or more additional active agents which are useful in the treatment of cancer. 
     
     
         12 . The method according to  claim 11 , wherein the one or more additional active agents is selected from:
 anti-HER2 agents;   standard adjuvant therapy regimens; and   anti-angiogenic/antimetastatic agents.   
     
     
         13 . The method according to  claim 12 , wherein:
 the anti-HER2 agents are selected from the group consisting of: trasfuzumab and perfuzumab;   the standard adjuvant therapy regimens are selected from the group consisting of: 5-fluorouracil, doxorubicin, cyclophosphamide (FAC), a combination of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), a combination of doxorubicin and cyclophosphamide (AC), a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), and a combination of docetaxel, doxorubicin, cyclophosphamide (TAC); and   the anti-angiogenic/antimetastatic agent is bevacizumab.   
     
     
         14 . A pharmaceutical composition comprising one of a compound according to  claim 1  or 2-[(2-fluorobenzoyl)amino]-N-2-(morpholin-4-ylethyl)benzamide together with a pharmaceutically or veterinarily acceptable excipient or carrier. 
     
     
         15 . A pharmaceutical composition according to  claim 14  which is formulated for parenteral administration. 
     
     
         16 . A process for the preparation of a pharmaceutical composition according to  claim 13 , the process comprising bringing the compound according to  claim 1  or 2-[(2-fluorobenzoyl)amino]-N-2-(morpholin-4-ylethyl)benzamide into association with a pharmaceutically or veterinarily acceptable excipient or carrier.