Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor

Abstract

The invention relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof: Formula (I) which possess inhibitory activity against activating mutant forms of EGFR, and are accordingly useful for their anti-cancer activity and in methods of treatment of the human or animal body. The invention also relates pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm-blooded animal such as man.

1 . A succinate salt of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         2 . A succinate salt as claimed in  claim 1 , which is 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate succinate. 
     
     
         3 . The succinate salt as claimed in  claim 1 , which is in crystalline form. 
     
     
         4 . The succinate salt as claimed in  claim 3 , which is in crystalline form having an X-ray powder diffraction pattern with at least three specific peaks at about 2-theta=6.5°, 17.7° and 14.7°. 
     
     
         5 . The succinate salt as claimed in  claim 4 , which is in crystalline form having an X-ray powder diffraction pattern with specific peaks at about 2-theta=6.5, 17.7, 14.7, 9.2, 26.5, 20.2, 13.1, 27.3, 24.0°. 
     
     
         6 . The succinate salt as claimed in  claim 1 , in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
         7 . A method for the inhibition of activating mutant EGFR in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of the succinate salt of  claim 1 . 
     
     
         8 . The method of  claim 7 , wherein the warm-blooded animal is man. 
     
     
         9 . A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the succinate salt of  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein the cancer is non-small-cell lung cancer. 
     
     
         11 . The method of  claim 10 , wherein the non-small-cell lung cancer is metastatic non-small-cell lung cancer. 
     
     
         12 . The method of  claim 10 , wherein the non-small-cell lung cancer is non-small-cell lung cancer with CNS metastasis. 
     
     
         13 . The method of  claim 12 , wherein the CNS metastasis is brain metastasis. 
     
     
         14 . The method of  claim 12 , wherein the CNS metastasis is leptomeningeal metastasis. 
     
     
         15 . The method of  claim 9 , wherein the succinate salt of  claim 1  is provided in combination with an anti-tumour agent selected from:
 (i) an anti-CTLA-4 antibody; 
 (ii) 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide or a pharmaceutically acceptable salt thereof; 
 (iii) an anti-PD-L1 antibody; 
 (iv) 1-[(1S)-1-(imidazo[1,2-a]pyridin-6-yl)ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine or a pharmaceutically acceptable salt thereof; 
 (v) an anti-PD-1 antibody; or 
 (vi) an OX40 agonist antibody. 
 
     
     
         16 . A succinate salt as claimed in  claim 1 , in combination with an anti-tumour agent selected from:
 (i) an anti-CTLA-4 antibody;   (ii) 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide or a pharmaceutically acceptable salt thereof;   (iii) an anti-PD-L1 antibody;   (iv) 1-[(1S)-1-(imidazo[1,2-a]pyridin-6-yl)ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine or a pharmaceutically acceptable salt thereof;   (v) an anti-PD-1 antibody; or   (vi) an OX40 agonist antibody.   
     
     
         17 . A compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 17  or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.