Fused indazole pyridone compounds as antivirals

Abstract

as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by hepatitis B virus, and reducing the occurrence of serious conditions associated with HBV.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H or halo; 
 R 2  is independently selected at each occurrence from halo, CN, C 1 -C 3  haloalkyl, C 1 -C 3  haloalkoxy, —OR 3 , —N(R)R 3 , and C 1 -C 3  alkyl optionally substituted with up to three groups selected from R 3 ,—N(R)R 3 , CN, —OH, —CONR 2 , —COOR, and —OR 3 ;
 R 3  is a C 1 -C 4  alkyl that is optionally substituted with one to three groups selected from halo, C 1 -C 3  haloalkyl, —OH, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, oxo, CN, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —COOR, —CONR 2 , C 3 -C 5  cycloalkyl, and a 4-6 membered cyclic ether, wherein the C 3 -C 5  cycloalkyl and 4-6 membered cyclic ether are each optionally substituted with one or two groups selected from halo, —OH, C 1 -C 3  alkoxy, and C 1 -C 3  alkyl; 
 or R 3  is a C 3 -C 5  cycloalkyl ring or 4-6 membered cyclic ether, wherein the C 3 -C 5  cycloalkyl ring or 4-6 membered cyclic ether are each optionally substituted with one to three groups selected from halo, C 1 -C 3  alkyl, —OH, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, C 1 -C 3  haloalkyl, —NH 2 , —NH(C 1 -C 3  alkyl), and —N(C 1 -C 3  alkyl) 2 ; 
 
 
       n is 0, 1, or 2;
 W is —COOR 4 , —C(O)NH—SO 2 R 5 , —C(O)NH—SO 2 NR 2 , 5-tetrazolyl, or 1,2,4-oxadiazol-3-yl-5 (4H)-one; 
 R 4  is H or C 1 -C 6  alkyl that is optionally substituted with one to three groups selected from halo, —OR, oxo, CN, and —NR 2 ; 
 R 5  is C 1 -C 6  alkyl that is optionally substituted with one to three groups selected from halo, —OR, oxo, CN, and —NR 2 ; 
 R 6  is H or C 1 -C 6  alkyl; 
 R 7  is H or C 1 -C 6  alkyl,
 or R 7  taken together with R 9  and the atoms connecting R 7  with R 9  forms a ring as described below; 
 
 R 8  is H or C 1 -C 6  alkyl; 
 R 9  is selected from:
 (1) H; 
 (2) C 1 -C 6  alkyl optionally substituted with up to three groups selected from C 3 -C 6  cycloalkyl, —OR, —NR 2 , halo, CN, COOR, CONR 2 , and oxo; and 
 (3) a ring selected from (a) C 3 -C 6  cycloalkyl, (b) phenyl, (c) 5-6 membered heterocyclyl containing one or two heteroatoms selected from N, O and S as ring members, and (d) 5-6 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members, wherein each of rings (a) through (d) is optionally substituted with up to three groups selected from C 1 -C 2  alkyl, (CH 2 ) 0-2 —OR, —NR 2 , halo, CN, COOR, and CONR 2 ;
 or R 9  taken together with R 7  and the atoms connecting R 9  with R 7  forms a 3-7 membered cycloalkyl ring, or a 3-7 membered heterocyclic ring containing N, O or S as a ring member; wherein the cycloalkyl or heterocyclic ring is optionally substituted with up to three groups selected from R, —OR, —NR 2 , halo, CN, COOR, CONR 2 , and oxo; 
 R is independently selected at each occurrence from H and C 1 -C 3  alkyl optionally substituted with one to three groups selected from halo, —OH, C 1 -C 3  alkoxy, oxo, CN, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , and cyclopropyl;
 and two R groups directly attached to the same atom can optionally be taken together with the atom to which both are attached to form a 3-6 membered ring that can optionally contain a heteroatom selected from N, O and S as a ring member, and can be substituted by up to two groups selected from —OH, oxo, C 1 -C 3  alkyl, and C 1 -C 3  alkoxy; 
 
 
 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound according to  claim 1 , which is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of  claim 1 , which is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the individual enantiomers of any one of these; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A pharmaceutical composition, comprising a compound of  claim 1  admixed with at least one pharmaceutically acceptable carrier. 
     
     
         6 . A method to treat a subject having a hepatitis B infection, which comprises administering to the subject a compound of  claim 1 . 
     
     
         7 . A method to inhibit replication of hepatitis B virus, which comprises contacting the hepatitis B virus, either in vitro or in vivo, with a compound according to  claim 1 . 
     
     
         8 . A pharmaceutical combination, comprising a compound of  claim 1  and at least one additional therapeutic agent. 
     
     
         9 . A compound according to  claim 1  for use in therapy. 
     
     
         10 . Use of a compound according  claim 1  in the manufacture of a medicament.