Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

Abstract

Compounds for use in the treatment of human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following Formula (I):including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, X, Y1, Y2, or L are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

What is claimed is: 
     
         1 . A compound having the following Formula (I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof,
 wherein:
 Y 1  and Y 2  are each, independently, hydrogen, C 1-3 alkyl or C 1-3 haloalkyl; 
 R 1  is phenyl substituted with one to three halogen atoms; 
 X is —O—, —NR 2 —, —CHR 3 — or a bond; 
 R 2  and R 3  are each, independently, hydrogen or C 1-3 alkyl; and 
 L is —C(R a ) 2 C(R a ) 2 —; and 
 each R a  is, independently, hydrogen, halo, hydroxyl, or C 1-4 alkyl, and 
 
 wherein two R a  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a carbocyclic ring having the following structure: 
 
       
         
           
           
               
               
           
         
         wherein each R b  is, independently, hydrogen or halo. 
       
     
     
         2 . A compound of  claim 1  having the following Formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof,
 wherein:
 Y 1  and Y 2  are each, independently, hydrogen, C 1-3 alkyl or C 1-3 haloalkyl; 
 R 1  is phenyl substituted with one to three halogen atoms; 
 X is —O—, —NR 2 —, —CHR 3 — or a bond; 
 R 2  and R 3  are each, independently, hydrogen or C 1-3 alkyl; and 
 L is —C(R a ) 2 C(R a ) 2 —; and 
 each R a  is, independently, hydrogen, halo, hydroxyl, or C 1-4 alkyl, and 
 
 wherein two R a  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a carbocyclic ring having the following structure: 
 
       
         
           
           
               
               
           
         
         wherein each R b  is, independently, hydrogen or halo. 
       
     
     
         3 . A compound of  claim 1  having the following Formula (Ib): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof,
 wherein:
 Y 1  and Y 2  are each, independently, hydrogen, C 1-3 alkyl or C 1-3 haloalkyl; 
 R 1  is phenyl substituted with one to three halogen atoms; 
 X is —O—, —NR 2 —, —CHR 3 — or a bond; 
 R 2  and R 3  are each, independently, hydrogen or C 1-3 alkyl; and 
 L is —C(R a ) 2 C(R a ) 2 —; and 
 each R a  is, independently, hydrogen, halo, hydroxyl, or C 1-4 alkyl, and 
 
 wherein two R a  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a carbocyclic ring having the following structure: 
 
       
         
           
           
               
               
           
         
         wherein each R b  is, independently, hydrogen or halo. 
       
     
     
         4 . A compound of  claim 1  having the following Formula (Ic): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof,
 wherein:
 Y 1  and Y 2  are each, independently, hydrogen, C 1-3 alkyl or C 1-3 haloalkyl; 
 R 1  is phenyl substituted with one to three halogen atoms; 
 X is —O—, —NR 2 —, —CHR 3 — or a bond; 
 R 2  and R 3  are each, independently, hydrogen or C 1-3 alkyl; and 
 L is —C(R a ) 2 C(R a ) 2 —; and 
 each R a  is, independently, hydrogen, halo, hydroxyl, or C 1-4 alkyl, and 
 
 wherein two R a  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a carbocyclic ring having the following structure: 
 
       
         
           
           
               
               
           
         
         wherein each R b  is, independently, hydrogen or halo. 
       
     
     
         5 . A compound of  claim 1  having the following Formula (Id): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof,
 wherein:
 Y 1  and Y 2  are each, independently, hydrogen, C 1-3 alkyl or C 1-3 haloalkyl; 
 R 1  is phenyl substituted with one to three halogen atoms; 
 X is —O—, —NR 2 —, —CHR 3 — or a bond; 
 R 2  and R 3  are each, independently, hydrogen or C 1-3 alkyl; and 
 L is —C(R a ) 2 C(R a ) 2 —; and 
 each R a  is, independently, hydrogen, halo, hydroxyl, or C 1-4 alkyl, and 
 
 wherein two R a  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a carbocyclic ring having the following structure: 
 
       
         
           
           
               
               
           
         
         wherein each R b  is, independently, hydrogen or halo. 
       
     
     
         6 . A compound of  claim 1  having the following Formula (Ie): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof,
 wherein:
 Y 1  and Y 2  are each, independently, hydrogen, C 1-3 alkyl or C 1-3 haloalkyl; 
 R 1  is phenyl substituted with one to three halogen atoms; 
 X is —O—, —NR 2 —, —CHR 3 — or a bond; 
 R 2  and R 3  are each, independently, hydrogen or C 1-3 alkyl; and 
 L is —C(R a ) 2 C(R a ) 2 —; and 
 each R a  is, independently, hydrogen, halo, hydroxyl, or C 1-4 alkyl, and 
 
 wherein two R a  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a carbocyclic ring having the following structure: 
 
       
         
           
           
               
               
           
         
         wherein each R b  is, independently, hydrogen or halo. 
       
     
     
         7 . A compound of any one of  claims 1 - 6  wherein X is —O—. 
     
     
         8 . A compound of any one of  claims 1 - 6  wherein X is —NH—. 
     
     
         9 . A compound of any one of  claims 1 - 6  wherein X is —CH 2 —. 
     
     
         10 . A compound of any one of  claims 1 - 6  wherein X is a bond. 
     
     
         11 . A compound of any one of  claims 1 - 11  wherein Y 1  is C 1-4 alkyl and Y 2  is hydrogen. 
     
     
         12 . A compound of  claim 11  wherein Y 1  is methyl and Y 2  is hydrogen. 
     
     
         13 . A compound of any one of  claims 1 - 5  wherein Y 1  is C 1-4 haloalkyl and Y 2  is hydrogen. 
     
     
         14 . A compound of  claim 13  wherein Y 1  is CF 3  and Y 2  is hydrogen. 
     
     
         15 . A compound of any one of  claims 1 - 11  wherein Y 1  is hydrogen, methyl or CF 3  and Y 2  is hydrogen. 
     
     
         16 . A compound of any one of  claims 1 - 11  wherein Y 1  and Y 2  are both hydrogen. 
     
     
         17 . A compound of any one of  claims 1 - 16  wherein R 1  is substituted with one halogen. 
     
     
         18 . A compound of  claim 17  wherein R 1  is 4-fluorophenyl or 2-fluorophenyl. 
     
     
         19 . A compound of any one of  claims 1 - 16  wherein R 1  is substituted with two halogens. 
     
     
         20 . A compound of  claim 19  wherein R 1  is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. 
     
     
         21 . A compound of  claim 20  wherein R 1  is 2,4-difluorophenyl. 
     
     
         22 . A compound of any one of  claims 1 - 16  wherein R 1  is substituted with three halogens. 
     
     
         23 . A compound of  claim 22  wherein R 1  is 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, or 2,4,5-trifluorophenyl. 
     
     
         24 . A compound of  claim 22  wherein R 1  is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. 
     
     
         25 . A compound of  claim 24  wherein R 1  is 2,4,6-trifluorophenyl. 
     
     
         26 . A compound of  claim 24  wherein R 1  is 2,4,5-trifluorophenyl. 
     
     
         27 . A compound of any one of  claims 1 - 26  wherein each R b  is independently hydrogen. 
     
     
         28 . A compound of any one of  claims 1 - 26  wherein each R b  is independently halogen. 
     
     
         29 . A compound of  claim 28  wherein each R b  is fluoro. 
     
     
         30 . A compound of  claim 1  that is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . A compound of  claim 1  that is: 
       
         
           
           
               
               
           
         
       
     
     
         32 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 31 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         33 . A pharmaceutical composition of  claim 32  further comprising one to three additional therapeutic agents. 
     
     
         34 . A pharmaceutical composition of  claim 33  wherein the one to three one additional therapeutic agents is an anti-HIV agent. 
     
     
         35 . A pharmaceutical composition of  claim 33  wherein the one to three additional therapeutic agents is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, and combinations thereof. 
     
     
         36 . A pharmaceutical composition of  claim 32 , further comprising a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and lamivudine 
     
     
         37 . A method of treating an HIV infection in a human having or at risk of having the infection by administering to the human a therapeutically effective amount of a compound of any one of  claims 1 - 31  or a pharmaceutical composition of any one of  claims 32  to  36 . 
     
     
         38 . Use of a compound of any one of  claims 1 - 31  or a pharmaceutical composition of any one of  claims 32  to  36  for the treatment of an HIV infection in a human having or at risk of having the infection. 
     
     
         39 . A compound as described in any one of  claims 1 - 31 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of  claims 32  to  36  for use in medical therapy. 
     
     
         40 . A compound as described in any one of  claims 1 - 31 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of  claims 32  to  36  for use in the prophylactic or therapeutic treatment of an HIV infection.