Cyclic phosphate substituted nucleoside derivatives for the treatment of liver diseases

Abstract

The present invention relates to Compounds of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate or enantiomer thereof, wherein A, B, R 1 , R 2 , R 3 , R 4 , Q and V are as defined herein. The present invention also relates to pharmaceutical compositions comprising a Compound of Formula (I) or Formula (II) and to their use in therapy.

1 . A compound according to Formula I or Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof wherein:
 A is selected from O, S, CH 2 , CF and C═CH 2 , such that if R 2  is OH and R 3 , R 4  and V are hydrogen, then A is other than S; and if A is CF or C═CH 2 , then V is absent; 
 B is selected from the following groups: 
 
       
       
         
           
           
               
               
           
         
         
           each Q is independently O or S; 
           V is hydrogen, halogen, —N(R 13 ) 2 , —OR 13 , alkyl, alkenyl, alkynyl, haloalkyl, N 3  or CN; 
           W is N, CH or CF; 
           R 1  is —CH 2 —X—Y—R 16 ; 
           X is —C(R 14 ) 2 ; 
           Y is —C(R 15 ) 2 , or C 3 -C 6 cycloalkylene; 
           R 2  is hydrogen, fluoro, chloro, —OR 13 , —CN, —N(R 13 ) 2 , N 3 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 6 alkenyl or C 2 -C 3 alkynyl; 
           R 3  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —OR 13 , fluoro, chloro, N 3 , —CN or —N(R 13 ) 2  such that if R 2  is fluoro or chloro, then R 3  is other than fluoro or chloro; 
           R 4  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —OR 13 , fluoro, chloro, N 3 , —CN or —N(R 13 ) 2 ; 
           R 5 , R 6 , R 8  and R 9  are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halogen, —OR 18 , —SR 18  and —N(R 18 ) 2 ; 
           R 7 , R 10 , R 11  and R 12  are each independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6  alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C 6 heteroaryl, C 9 -C 10 heteroaryl, halogen, —OR 18 , —SR 18 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 N(R 18 ) 2 , —NHC(O)OR 18 , —NHC(O)N(R 18 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 18 ) 2 , —NH(C 1 -C 6 alkylene)-(C 5 -C 6 heteroaryl), —NH(C 1 -C 6  alkylene)-(C 9 -C 10 heteroaryl), —C(O)R 18 , —C(O)OR 18 , —C(O)N(R 18 ) 2  and —NHC(O)R 18 , wherein said C 2 -C 6 alkenyl group and said C 2 -C 6 alkynyl group are optionally substituted with one or more halogen; 
           each occurrence of R 13  is independently selected from hydrogen, C 1 -C 6 alkyl —C(O)R 18 , or —C(O)OR 18 ; 
           R 14  is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 6 -C 10 aryl-, OR 17 , —OC(O)R 17 , —N(R 12 )C(O)OR 17  or —C(O)OR 17 ; 
           each occurrence of R 15  is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 6 -C 10 aryl-, OR 17 , —OC(O)R 17 , —N(R 12 )C(O)OR 17  and —C(O)OR 17  or both R 15  groups together with the carbon atom to which they are attached can join to form a 3- to 6-membered spirocyclic cycloalkyl group; 
           R 16  is —C(O)OR 17 ; 
           each occurrence of R 17  is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl; 
           each occurrence of R 18  is independently selected from hydrogen, C 1 -C 15 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(C 4 -C 7 heterocycloalkyl), —(C 1 -C 3 alkylene) m -(C 5 -C 6 heteroaryl) and —(C 1 -C 3 alkylene) m -(C 9 -C 10 heteroaryl) and 
           each occurrence of m is independently 0 or 1; 
           or the compound 
         
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt or solvate thereof. 
         
       
     
     
         2 . The compound of  claim 1  wherein A is O or S. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
         and wherein R 15  and R 17  are each independently selected from C 1 -C 6 alkyl. 
       
     
     
         4 . The compound of  claim 1 , wherein R 2  is hydrogen, fluoro or hydroxyl. 
     
     
         5 . The compound of  claim 1 , wherein R 3  is hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 4  is hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein V is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein B is 
       
         
           
           
               
               
           
         
         wherein 
         Q is O; 
         W is N; 
         R 5  and R 6  are hydrogen; 
         R 7  is NH 2  or NHC(O)aryl; 
         R 8  is hydrogen; 
         R 9  is hydrogen or trifluoromethyl; 
         R 10  is —NH 2  or —O—C 1 -C 6 alkyl and 
         R 11  is —NH 2  or halogen. 
       
     
     
         9 . A compound of  claim 1  selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         11 . (canceled) 
     
     
         12 . A method for treating a liver disease in a patient, the method comprising administering to the patient a compound of  claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         13 . The method of  claim 12 , where the liver disease being treated is liver cancer. 
     
     
         14 . The method of  claim 12 , where the liver disease being treated is HBV infection. 
     
     
         15 . A method for treating Ebola virus infection in a patient, the method comprising administering to the patient a compound of  claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         16 . (canceled) 
     
     
         17 . The composition of  claim 10  further comprising one or more additional therapeutic agents.