Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals

Abstract

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

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein:
 R 1  is —C 1 -C 8 -alkyl; —(C 0 -C 8 -alkylene)-(C 1 -C 8 -alkoxy) x , or —(C 0 -C 8 -alkylene)-(C 3 -C 8 -cycloalkyl); each of which is optionally substituted with one or two groups selected from halo, —OR 10 , ═O, —CN, —NR 10   2 , —COOR 10 , —CONR 10   2 , and —(C 0 -C 8 -alkylene)-aryl; 
 a 5-6 membered aryl or heteroaryl group; wherein the 5-6 membered aryl or heteroaryl group of R 1  is independently substituted by one or more groups selected from the group consisting of —H, —CN, —(C 0 -C 8 -alkylene)-(—OR 10 ) x , and halo; 
 or taken together with R 2  to form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R 10 , —OR 10 , —NR 10   2 , -halo, —CN, —COOR 10 , —CONR 10   2 , and ═O; 
 x represents the number groups which replace a hydrogen on the group to which it is attached; 
 R 2  is H, C 1 -C 8 -alkyl, halo, —CN; or taken together with R 1  to form a 5-7 membered heterocyclic or heteroaryl containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R 10 , —OR 10 , —NR 10   2 , -halo, —CN, —COOR 10 , —CONR 10   2 , and ═O; 
 R 3  is H, hydroxyl, halo or C 1 -C 8 -alkyl; 
 each R 4 , R 5 , R 6 , R 7 , or R 8  is independently —H, —C 1 -C 8 -alkyl, —C 1 -C 8 -haloalkyl, —CN, —C 1 -C 8 -alkoxy, —C 3 -C 8  cycloalkyl, aryl, or a 5- or 6-membered heteroaryl containing up to three heteroatoms selected from N, O and S as ring members; where each —C 1 -C 8 -alkyl, —C 3 -C 8  cycloalkyl, aryl or a 5- or 6-membered heteroaryl is optionally substituted with up to three groups selected from —OR 10 , —NR 10   2 , -halo, —CN and —SO 2 R 9 ; or R 5  taken together with R 7  or R 6  taken together with R 8  form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R 10 , —OR 10 , —NR 10   2 , -halo, —CN, —COOR 10 , —CONR 10   2 , and ═O; 
 W is —COOR 9 , —C(O)NH—SO 2 R 10 , —C(O)NH—SO 2 NR 10   2 , -5-tetrazolyl, or -1,2,4-oxadiazol-3-yl-5(4H)-one; 
 R 9  is H or C 1 -C 8  alkyl; the C 1 -C 8  alkyl optionally substituted with one or two groups selected from halo, —OR 10 , ═O, —CN, —NR 10   2 , —COOR 10 , and —CONR 10   2 ; 
 R 10  is independently selected at each occurrence from —H, —C 1 -C 8  alkyl and aryl, each of —C 1 -C 8  alkyl and aryl optionally substituted with one to three groups selected from halo, —OH, —C 1 -C 8  alkoxy, ═O, —CN, —NH 2 , —NH(C 1 -C 8  alkyl), —N(C 1 -C 8  alkyl) 2 , and -cyclopropyl; and two R 10  groups directly attached to the same atom, which may be C or N, can optionally be taken together 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, ═O, —C 1 -C 8  alkyl, and —C 1 -C 8  alkoxy. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is —C 1 -C 8 -alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is —C 1 -C 8 -alkoxy; optionally substituted by one or more —OR 10 . 
     
     
         4 . The compound of  claim 1 , wherein R 1  is a 5-6 membered aryl group; wherein the 5-6 membered aryl group of R 1  is independently substituted by one or more groups selected from the group consisting of —H or —OR 10 . 
     
     
         5 . The compound of  claim 1 , wherein R 2  is H or halo. 
     
     
         6 . The compound of  claim 1 , wherein W is —COOR 9 . 
     
     
         7 . The compound of  claim 1 , wherein R 4  is H. 
     
     
         8 . The compound of  claim 1 , wherein R 5  is H. 
     
     
         9 . The compound of  claim 1 , wherein R 7  is H. 
     
     
         10 . The compound of  claim 1 , wherein R 8  is H. 
     
     
         11 . The compound of  claim 1 , wherein R 6  is C 1 -C 8  alkyl. 
     
     
         12 . The compound of  claim 1 , wherein R 9  is H. 
     
     
         13 . The compound of  claim 1 , wherein R 10  is —C 1 -C 8 -alkyl. 
     
     
         14 . The compound of of  claim 1 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound according to  claim 14 , wherein R 1  is phenyl. 
     
     
         16 . A compound according to  claim 14 , wherein R 9  is H. 
     
     
         17 . The compound of  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . A pharmaceutical composition, comprising a compound of  claim 1  admixed with at least one pharmaceutically acceptable carrier. 
     
     
         19 . A method to treat a subject having a hepatitis B infection, which comprises administering to the subject a compound of any of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the compound of any one of  claims 1 - 17  or the pharmaceutical composition of  claim 18  is used in combination with an additional therapeutic agent selected from an interferon or peginterferon, an HBV polymerase inhibitor, a viral entry inhibitor, a viral maturation inhibitor, a capsid assembly inhibitor, an HBV core modulator, a reverse transcriptase inhibitor, a TLR-agonist, or an immunomodulator. 
     
     
         21 . A method to inhibit replication of hepatitis B virus, which comprises contacting the hepatitis B virus with a compound according to  claim 1 . 
     
     
         22 . A pharmaceutical combination, comprising a compound of  claim 1  and at least one additional therapeutic agent.