Compounds useful to treat influenza virus infections

Abstract

The invention provides compounds that may inhibit influenza virus replication, and are accordingly useful for treatment of viral infections caused by influenza virus. The invention further provides pharmaceutical compositions containing these compounds and methods of using these compounds to treat or prevent viral infections caused by influenza virus.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein: 
         each R 1  is independently selected from the group consisting of H and halo; 
         each R 2  is independently selected from the group consisting of H and halo; 
         R 3  is selected from the group consisting of H, halo, Me, CN, and P(O)Me 2 ; 
         each R 4  is independently selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl, wherein any two of R 4  are optionally taken, together with the atoms to which they are attached, to form a C 3 -C 6  cycloalkyl; 
         n and m are each independently 0, 1, 2, 3, or 4; 
         p is 0, 1, 2, or 3; and 
         G is H or is selected from the group consisting of C(O)R, C(O)OR, C(O)NR′R, C(R′) 2 —O—C(O)R, C(R′) 2 —O—C(O)OR, and C(R′) 2 —O—C(O)NR′R, wherein
 each R is selected from the group consisting of C 1 -C 6  alkyl, phenyl, pyridyl, C 3 -C 6  cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O and S as ring members, wherein the C 1 -C 6  alkyl, phenyl, pyridyl, C 3 -C 6  cycloalkyl, and 4-6 membered heterocyclic ring of R are independently optionally substituted with one or two substituents selected from the group consisting of H, halo, CN, OH, NH 2 , C 1 -C 3  alkyl, phenyl, C 1 -C 4  alkoxy, C 1 -C 3  haloalkyl, and C 1 -C 3  haloalkoxy; and 
 each R′ is independently selected from the group consisting of H and C 1 -C 3  alkyl. 
 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is of Formula (I-1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or solvate thereof. 
       
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is of Formula (I-2): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or solvate thereof. 
       
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is of Formula (I-3): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or solvate thereof. 
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein G is H. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein G is selected from the group consisting of C(O)R, C(O)OR, C(O)NR′R, C(R′) 2 —O—C(O)R, C(R′) 2 —O—C(O)OR, and C(R′) 2 —O—C(O)NR. 
     
     
         7 . The compound of  claim 6 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein G is selected from the group consisting of C(O)R, C(O)OR, C(R′) 2 —O—C(O)R, and C(R′) 2 —O—C(O)OR. 
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein G is selected from the group consisting of C(O)R, C(O)OR, CH 2 —O—C(O)R, and CH 2 —O—C(O)OR, where each R is independently C 1 -C 6  alkyl, and the C 1 -C 6  alkyl is optionally substituted with one group selected from H, halo, CN, OH, and NH 2 . 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein G is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R 3  is selected from the group consisting of H, F, Cl, Br, Me, CN, and P(O)Me 2 . 
     
     
         11 . The compound of  claim 10 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R 3  is P(O)Me 2 . 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is selected from the group consisting of:
 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-1),   8-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-11H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-2),   7-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-11H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-3),   8,9-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-4),   10-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-5),   6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-11H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-6),   7,8,10-trifluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-7),   7,10-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-11H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-8),   9-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-11H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-9),   (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-1),   (R)-12-((S)-8-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-2),   (R)-12-((S)-7-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-3),   (R)-12-((S)-8,9-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-4),   (R)-12-((S)-10-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-5),   (R)-12-((S)-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-6),   (R)-12-((S)-7,8,10-trifluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-7),   (R)-12-((S)-7,10-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-8)   (R)-12-((S)-9-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-9),   (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-1),   (((R)-12-((S)-8-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-2),   (((R)-12-((S)-7-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-3),   (((R)-12-((S)-8,9-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-4),   (((R)-12-((S)-10-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-5),   (((R)-12-((S)-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-6),   (((R)-6,8-dioxo-12-((S)-7,8,10-trifluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-7),   (((R)-12-((S)-7,10-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-8),   (((R)-12-((S)-9-fluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (C-9),   (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl ethyl carbonate (D-1),   1-(((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)ethyl methyl carbonate (D-2),   (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl acetate (D-3),   (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl isopropyl carbonate (D-4),   (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl acetate (D-5),   (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl (2-methoxyethyl) carbonate (D-6),   (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl L-valinate (D-7),   1-(((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)ethyl L-valinate (D-8), and   (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenepin-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl L-leucinate (D-9),   or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.   
     
     
         13 . A compound of Formula (II), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein: 
         each R 1  is independently selected from the group consisting of H and halo; 
         each R 2  is independently selected from the group consisting of H and halo; 
         R 3  is P(O)Me 2  or P(O)Et 2 ; 
         each R 4  is independently selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl, wherein any two of R 4  are optionally taken, together with the atoms to which they are attached, to form a C 3 -C 6  cycloalkyl; 
         n and m are each independently 0, 1, 2, 3, or 4; 
         p is 0, 1, 2, or 3; and 
         G is H or is selected from the group consisting of C(O)R, C(O)OR, C(O)NR′R, C(R′) 2 —O—C(O)R, C(R′) 2 —O—C(O)OR, and C(R′) 2 —O—C(O)NR′R, wherein
 each R is selected from the group consisting of C 1 -C 6  alkyl, phenyl, pyridyl, C 3 -C 6  cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O and S as ring members, wherein the C 1 -C 6  alkyl, phenyl, pyridyl, C 3 -C 6  cycloalkyl, and 4-6 membered heterocyclic ring of R are independently optionally substituted with one or two substituents selected from the group consisting of H, halo, CN, OH, NH 2 , C 1 -C 3  alkyl, phenyl, C 1 -C 4  alkoxy, C 1 -C 3  haloalkyl, and C 1 -C 3  haloalkoxy; and 
 each R′ is independently selected from the group consisting of H and C 1 -C 3  alkyl. 
 
       
     
     
         14 - 21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         23 . A method of treating influenza, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, or a pharmaceutical composition of  claim 22 . 
     
     
         24 . A compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, or a pharmaceutical composition of  claim 22  for use in treating influenza. 
     
     
         25 . Use of a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, or a pharmaceutical composition of  claim 22  in the manufacture of a medicament for use in treating influenza.