Substituted pyrrolizine compounds and uses thereof

Abstract

This application relates generally to certain substituted pyrrolizine compounds, and pharmaceutical compositions which inhibit HBV replication, and methods of making and using them.

1 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein:
 R 1  is C 1-6  alkyl optionally substituted with 1 to 3 R 1A , C 3-8  cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ; 
 each R 1A  is independently halogen, —OH, —CN, C 1-2  haloalkyl, —C(O)NR X R Y , C 6-10  aryl optionally substituted with 1 to 3 R 1D , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1D  provided no more than 1 R 1A  is C 6-10  aryl optionally substituted with 1 to 3 R 1D  or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; 
 each R 1B  is independently —CN, halogen, C 1-6  alkyl optionally substituted with 1 to 3-OH or —NR a R b , C 2-4  alkynyl, C 1-4  alkoxy, C 1-2  haloalkyl, C 3-6  cycloalkyl, —C(O)NR X R Y , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1B  is C 3-6  cycloalkyl or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; 
 each R 1C  is independently C 1-6  alkyl, oxo, C 1-4  haloalkyl, —C(O)H, —C(O)C 1-4  alkyl, —C(O)OC 1-4  alkyl, —C(O)NR X R Y , or a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D  provided no more than 1 R 1C  is a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; 
 each R X  is independently —H, C 3-6  cycloalkyl, C 1-6  alkyl optionally substituted with 1 to 3 R Z , 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ; 
 each R Y  is independently —H or C 1-6  alkyl optionally substituted with 1 to 3 R Z ; 
 or R X  and R Y  are taken together to form a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ; 
 wherein each R Z  is independently halogen, methyl, ethyl, oxo, —OH, —S(O) 2 C 1-3  alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S; 
 each R a  is —H, C 1-3  alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ; 
 each R b  is —H or C 1-3  alkyl; or 
 R a  and R b  taken together form a 3 to 8 membered monocyclic or bicyclic heterocycle optionally substituted with 1 to 3 R Z ; 
 each of R 2A , R 2B , R 2C , R 2D , R 2E , and R 2F  are independently —H, halogen, C 1-3  alkyl, —OH, or —OC 1-3  alkyl, or R 2C  or R 2D  may be taken together with R 2A  or R 2B  or with R 2E  or R 2F  to form a cyclopropyl group; 
 R 3  is —H, halogen, or C 1-4  alkyl; 
 R 4  is C 6-10  aryl optionally substituted with 1 to 5 R 4A , or 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 4 R 4B ; and 
 each R 1D , R 4A , and R 4B  are independently —CN, halogen, C 1-4  alkyl optionally substituted with —Si(C 1-4  alkyl) 3 , —OC 1-4  alkyl, —OC 1-4  haloalkyl, or C 1-4  haloalkyl. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 1  is C 1-6  alkyl optionally substituted with 1 to 3 R 1A , C 3-8  cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ;   each R 1A  is independently halogen, —OH, —CN, C 1-2  haloalkyl, —C(O)NR X R Y , C 6-10  aryl optionally substituted with 1 to 3 R 1D , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1A  is C 6-10  aryl optionally substituted with 1 to 3 R 1D  or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;   each R 1B  is independently halogen, C 1-6  alkyl optionally substituted with 1 to 3-OH or —NR a R b , C 1-4  alkoxy, C 1-2  haloalkyl, C 2-6  alkyne, —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1B  is 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;   each R 1C  is independently C 1-6  alkyl, oxo, C 1-4  haloalkyl, —C(O)H, —C(O)C 1-4  alkyl, —C(O)OC 1-4  alkyl, —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D ;   each R X  is independently —H, C 3-6  cycloalkyl, C 1-6  alkyl optionally substituted with 1 to 3 R Z , 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;   each R Y  is independently —H or C 1-6  alkyl optionally substituted with 1 to 3 R Z ;   or R X  and R Y  are taken together to form a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;   wherein each R Z  is independently halogen, methyl, ethyl, oxo, —OH, —S(O) 2 C 1-3  alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;   each R a  is —H, C 1-3  alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;   each R b  is —H or C 1-3  alkyl; or   R a  and R b  taken together form a 3 to 8 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1 to 3 R Z ;   each of R 2A , R 2B , R 2C , R 2D , R 2E , and R 2F  are independently —H, halogen, C 1-3  alkyl, —OH, or —OC 1-3  alkyl, or R 2C  or R 2D  may be taken together with R 2A  or R 2B  or with R 2E  or R 2F  to form a cyclopropyl group;   R 3  is halogen or methyl;   R 4  is phenyl optionally substituted with 1 to 5 R 4A , or pyridinyl, optionally substituted with 1 to 4 R 4B ; and   each R 1D , R 4A , and R 4B  are independently —CN, halogen, C 1-4  alkyl optionally substituted with —Si(C 1-4  alkyl) 3 , —OC 1-4  alkyl, —OC 1-4  haloalkyl, or C 1-4  haloalkyl.   
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 1  is C 3-6  cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 6 membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ;   each R 1B  is independently halogen, C 1-6  alkyl optionally substituted with 1-OH, C 2-6  alkyne, —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1B  is 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;   each R 1C  is independently —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D ;   each R 1D  is independently C 1-4  alkyl optionally substituted with —Si(C 1-4  alkyl) 3 ;   each R X  is independently —H, or C 1-6  alkyl;   each R Y  is independently —H or C 1-6  alkyl;   each of R 2A , R 2B , R 2C , R 2D , R 2E , and R 2F  are —H, or R 2C  or R 2D  may be taken together with R 2A  or R 2B  or with R 2E  or R 2F  to form a cyclopropyl group;   R 3  is methyl;   R 4  is phenyl substituted with 1 to 5 R 4A , or pyridinyl substituted with 1 to 4 R 4B ;   each R 4A  is independently —CN, halogen, or C 1-4  haloalkyl; and   each R 4B  is independently halogen, or C 1-4  haloalkyl.   
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIa): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIb): 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (V): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Va): 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (Vb): 
       
         
           
           
               
               
           
         
       
     
     
         11 .- 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         21 .- 27 . (canceled) 
     
     
         28 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         29 .- 33 . (canceled) 
     
     
         34 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         36 .- 46 . (canceled) 
     
     
         47 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         48 . The compound of claim  461 , or a pharmaceutically acceptable salt thereof, wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         49 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, which is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         50 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, which is 
       
         
           
           
               
               
           
         
       
     
     
         51 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         52 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         53 .- 56 . (canceled) 
     
     
         57 . A method of treating or preventing a HBV infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         58 .- 69 . (canceled)