Pyrazolopyrrolidine derivatives and their use in the treatment of disease

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

1 .- 19 . (canceled) 
     
     
         20 . A method of treating a disease which is mediated by inhibition of a BET protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         ring C is selected from 
       
       
         
           
           
               
               
           
         
         A is selected from 
       
       
         
           
           
               
               
           
         
         B is selected from 
       
       
         
           
           
               
               
           
         
         R 3  is selected from H, methyl, ethyl, —CH 2 F, —CF3, isopropyl, —OH, ethoxy, methoxy, cyclopropyl, —CH 2 OCH 3  and —CH 2 OH; 
         R 4a  is selected from H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, —(CH 2 ) 2 —OH, —(CH 2 ) 2 —O—CH 3 , —C(O)—NH(CH 3 ), —C(O)—N(CH 3 ) 2 , 
       
       
         
           
           
               
               
           
         
         R 4b  is selected from H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, —(CH 2 ) 2 —OH, —(CH 2 ) 2 —O—CH 3 , —(CH 2 ) 2 —O—CH 2 —CF 3 , —(CH 2 )—CH(OH)—CF 3, , —C(O)—NH(CH 3 ), —C(O)—N(CH 3 ) 2 , 
       
       
         
           
           
               
               
           
         
         R 5  is H; 
         R 1  is selected from H, methyl, chloro and fluoro; 
         R 2  is selected from bromo, chloro, fluoro, —O—CF 3  and —CF 3 ; 
         R 2a  is fluoro; 
         R 8  is methyl; 
         R 15 , R 16 , R 18  and R 21  are all methoxy; 
         R 17  is methyl or methoxy; 
         R 22 , R 23 , R 26 , R 27 , R 28 , R 30 , R 32  and R 33  are all methyl; 
         R 24  is methyl or —CHF 2 ; 
         R 25  is methyl or —NR 9 R 10 ; 
         R 29  is H or methyl; 
         R 31  is H, methyl or methoxy; 
         R 34  is H or methyl; 
         R 9  is H or methyl; 
         R 10  is H, methyl or —C(O)—(C 1 -C 3 )alkyl; 
         R 35  is H, methyl, —C(O)CH 3  or —C(O)OCH 2 CH 3 ; 
         and 
         * indicates the point of attachment to the remainder of the molecule; 
         with the proviso that 
         when ring C is i: 
       
       
         
           
           
               
               
           
         
         A is: 
       
       
         
           
           
               
               
           
         
         R 1  is selected from methyl, chloro and fluoro, 
         B is: 
       
       
         
           
           
               
               
           
         
         R 2  is chloro, fluoro or —CF 3 , 
         and the remaining substituents are as defined herein, 
         then R 3  is selected from H, methyl, ethyl, —CH 2 F, —CF 3 , —OH, ethoxy, methoxy, —CH 2 OCH 3  and —CH 2 OH. 
       
     
     
         21 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         4-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one. 
       
     
     
         22 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         (R)-4-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one. 
       
     
     
         23 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         4-(4-chlorophenyl)-1-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one. 
       
     
     
         24 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         (R)-4-(4-chlorophenyl)-1-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one. 
       
     
     
         25 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one. 
       
     
     
         26 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         (R)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one. 
       
     
     
         27 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         4-(4-chlorophenyl)-1-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one. 
       
     
     
         28 . The method of  claim 20 , wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is: 
       
         
           
           
               
               
           
         
         (R)-4-(4-chlorophenyl)-1-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one.