Novel compounds

Abstract

Benzodiazepine compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and their use in therapy.

1 . A compound of formula (I) or a salt thereof 
       
         
           
           
               
               
           
         
         where 
         R 1  is C 1-3 alkyl; 
         R 2  is —NR 2a R 2a′  or —OR 2b ; 
         wherein one of R 2a  or R 2′a  is hydrogen, and R 2b  or the other of R 2a  or R 2′a  is selected from C 1-6 alkyl, haloC 1-6 alkyl, R 2c R 2′c N—C 1-6 alkyl, carbocyclyl, carbocyclylC 1-4 alkyl, heterocyclyl and heterocyclylC 1-4 alkyl, 
         wherein any of the carbocyclyl or heterocyclyl groups are optionally substituted by one or more groups selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, carbonyl, —CO-carbocyclyl, azido, amino, hydroxyl, nitro and cyano, wherein the —CO-carbocyclyl group may be optionally substituted by one or more groups selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, azido, nitro and cyano; 
         or two adjacent groups on any of the carbocyclyl or heterocyclyl groups together with the interconnecting atoms form a 5- or 6-membered ring which ring may contain 1 or 2 heteroatoms independently selected from O, S and N; or R 2a  and R 2′a  together with the N-atom to which they are attached form a 4-, 5-, 6- or 7-membered ring which optionally contains 1 or 2 heteroatoms independently selected from O, S and N; wherein the 4-, 5-, 6- or 7-membered ring is optionally substituted by C 1-6 alkyl, hydroxyl or amino; 
         R 2c  and R 2′c  are independently hydrogen or C 1-6 alkyl; 
         each R 3  is independently selected from hydrogen, hydroxyl, halo, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, CF 3 , —OCF 3 , —COOR 5 , —C 1-4 alkylNR 6 R 7  and —C 1-4 alkylOH; 
         R 4  is hydroxyl, halo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, nitro, cyano, CF 3 , —OCF 3 , —COOR 5 ; or —OS(O) 2 C 1-4 alkyl; 
         R 5  is C 1-3 alkyl; and 
         n is an integer 1 to 5. 
       
     
     
         2 . A compound or a salt thereof according to  claim 1 , wherein R 1  is methyl. 
     
     
         3 . A compound or a salt thereof according to  claim 1 , wherein R 2  is —OR 2b  and R 2b  is C 1-6 alkyl. 
     
     
         4 . A compound or a salt thereof according to  claim 1 , wherein R 2  is —NR 2a R 2a′ . 
     
     
         5 . A compound or a salt thereof according to  claim 4 , wherein R 2a  is hydrogen and R 2′a  is C 1-6 alkyl. 
     
     
         6 . A compound or a salt thereof according to  claim 4 , wherein R 2′a  is selected from R 2c R 2′c N—CH 2 —, R 2c R 2′c N—CH 2 CH 2 —, R 2c R 2′c N—CH 2 CH 2 CH 2 — and R 2c R 2′c N—CH 2 CH 2 CH 2 CH 2 —, and wherein R 2c  and R 2′c  are selected from hydrogen and methyl. 
     
     
         7 . A compound or a salt thereof according to  claim 4 , wherein R 2a  is hydrogen and R 2′a  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound or a salt thereof according to  claim 4 , wherein R 2a  is hydrogen and R 2′a  is heterocyclylC 1-4 alkyl, wherein the heterocyclyl is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound or a salt thereof according to  claim 1 , wherein R 4  is 8-MeO. 
     
     
         10 . A compound or a salt thereof according to  claim 1  wherein the chiral carbon atom depicted by * is the S-enantiomer. 
     
     
         11 . A compound or a salt thereof according to  claim 1  which is any one of Examples 1-82 or a salt thereof. 
     
     
         12 . A compound which is 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         13 . A pharmaceutical composition which comprises a compound or a salt thereof according to  claim 12  and one or more pharmaceutically acceptable carriers, diluents or excipients. 
     
     
         14 . A combination pharmaceutical product comprising a compound or a salt thereof according to  claim 12  together with one or more other therapeutically active agents. 
     
     
         15 . A method for treatment of a disease or condition, for which a bromodomain inhibitor is indicated, in a subject in need thereof which comprises administering a therapeutically effective amount of compound or a salt thereof according to  claim 12 . 
     
     
         16 . A method for treatment according to  claim 15 , wherein the disease or condition is a chronic autoimmune and/or inflammatory condition. 
     
     
         17 . A method for treatment according to  claim 15 , wherein the disease or condition is cancer. 
     
     
         18 . A method for treatment according to  claim 15 , wherein the subject is a human. 
     
     
         19 . A method for inhibiting a bromodomain which comprises contacting the bromodomain with a compound or a salt thereof according to  claim 12 .