Compositions and methods for inhibiting viral polymerase

Abstract

Provided are compounds of Formula I: as described herein. Compounds of Formula I are useful in methods of inhibiting viral RNA polymerase activity and viral replication. Also provided are pharmaceutical compositions comprising compounds of Formula I, as well as methods of treating viral infections using compounds of Formula I.

1 - 46 . (canceled) 
     
     
         47 . A method of inhibiting replication of a virus, comprising contacting a virus with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         L 1 , L 2 , and L 3 , each independently, are a bond or —C(R 0 ) 2 —O—;
 wherein when L 1 , L 2 , or L 3  is —C(R 0 ) 2 —O—, the —C(R 0 ) 2 — moiety of the —C(R 0 ) 2 —O— group is attached to the oxygen on the pyrrolidine ring and the —O— atom of the —C(R 0 ) 2 —O— group is attached to R 1 , R 2 , or R 3 , respectively; 
 
         L 4 , L 5 , and L 6  are each a bond; 
         R 0 , independently for each occurrence, is H or (C 1 -C 6 )alkyl; 
         R 1 , R 2 , and R 3 , each independently, are selected from the group consisting of H, aminoacyl, aminothionyl, acyl, R 10 OC(O)—, phosphoryl, and aminophosphoryl; 
         or R 1  and R 2 , taken together, or R 2  and R 3 , taken together, may be selected from the group consisting of carbonyl, thiocarbonyl, phosphoryl, and (C 1 -C 6 )alkylphosphoryl; 
         R 4 , R 5 , and R 6  are each H; 
         R 7  is H; 
         R 10 , independently for each occurrence, is selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; 
         provided that the compound represented by Formula (I) is not 
       
       
         
           
           
               
               
           
         
         wherein the virus is: 
         a) a virus selected from the group consisting of viruses of the orthomyxoviridae, paramyxoviridae, arenaviridae, bunyaviridae, flaviviridae, filoviridae, togaviridae, picornaviridae, and coronaviridae viral families; or 
         b) a virus selected the group consisting of adenovirus, rhinovirus, hepatitis A virus, hepatitis C virus, polio virus, measles virus, Ebola virus, Coxsackie virus, West Nile virus, smallpox virus, yellow fever virus, Dengue Fever virus, influenza A virus, influenza B virus, lassa virus, lymphocytic choriomeningitis virus, Junin virus, machuppo virus, guanarito virus, hantavirus, Rift Valley Fever virus, La Crosse virus, California encephalitis virus, Crimean-Congo virus, Marburg virus, Japanese encephalitis virus, Kyasanur Forest virus, Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, severe acute respiratory syndrome (SARS) virus, parainfluenza virus, respiratory syncytial virus, Punta Toro virus, Tacaribe virus, and Pichinde virus. 
       
     
     
         48 . A method of treating a viral infection in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         L 1 , L 2 , and L 3 , each independently, are a bond or —C(R 0 ) 2 —O—;
 wherein when L 1 , L 2 , or L 3  is —C(R 0 ) 2 —O—, the —C(R 0 ) 2 — moiety of the —C(R 0 ) 2 —O— group is attached to the oxygen on the pyrrolidine ring and the —O— atom of the —C(R 0 ) 2 —O— group is attached to R 1 , R 2 , or R 3 , respectively; 
 
         L 4 , L 5 , and L 6  are each a bond; 
         R 0 , independently for each occurrence, is H or (C 1 -C 6 )alkyl; 
         R 1 , R 2 , and R 3 , each independently, are selected from the group consisting of H, aminoacyl, aminothionyl, acyl, R 10 OC(O)—, phosphoryl, and aminophosphoryl; 
         or R 1  and R 2 , taken together, or R 2  and R 3 , taken together, may be selected from the group consisting of carbonyl, thiocarbonyl, phosphoryl, and (C 1 -C 6 )alkylphosphoryl; 
         R 4 , R 5 , and R 6  are each H; 
         R 7  is H; 
         R 10 , independently for each occurrence, is selected from the group consisting of H, (C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; 
         provided that the compound represented by Formula (I) is not 
       
       
         
           
           
               
               
           
         
         wherein the virus is: 
         a) a virus selected from the group consisting of viruses of the orthomyxoviridae, paramyxoviridae, arenaviridae, bunyaviridae, flaviviridae, filoviridae, togaviridae, picornaviridae, and coronaviridae viral families; or 
         b) a virus selected the group consisting of adenovirus, rhinovirus, hepatitis A virus, hepatitis C virus, polio virus, measles virus, Ebola virus, Coxsackie virus, West Nile virus, smallpox virus, yellow fever virus, Dengue Fever virus, influenza A virus, influenza B virus, lassa virus, lymphocytic choriomeningitis virus, Junin virus, machuppo virus, guanarito virus, hantavirus, Rift Valley Fever virus, La Crosse virus, California encephalitis virus, Crimean-Congo virus, Marburg virus, Japanese encephalitis virus, Kyasanur Forest virus, Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, severe acute respiratory syndrome (SARS) virus, parainfluenza virus, respiratory syncytial virus, Punta Toro virus, Tacaribe virus, and Pichinde virus. 
       
     
     
         49 - 53 . (canceled) 
     
     
         54 . The method of  claim 48 , wherein L 1 -R 1  and L 2 -R 2  are identical, L 2 -R 2  and L 3 -R 3  are identical, or L 1 -R 1  and L 3 -R 3  are identical. 
     
     
         55 . The method of  claim 54 , wherein L 3 -R 3  is H. 
     
     
         56 . The method of  claim 54 , wherein L 1 -R 1  is H. 
     
     
         57 . The method of  claim 54 , wherein L 2 -R 2  is H. 
     
     
         58 . The method of  claim 48 , wherein L 1 -R 1 , L 2 -R 2 , and L 3 -R 3  are identical. 
     
     
         59 . The method of  claim 48 , wherein independently for each occurrence aminoacyl is —C(═O)CH(NH 2 )(CH 2 ) n CHR 30 R 31 , wherein
 n is 0 or 1; and 
 R 30  and R 31  each independently are selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. 
 
     
     
         60 . The method of  claim 48 , wherein independently for each occurrence aminothionyl is —C(═S)CH(NH 2 )(CH 2 ) n CHR 30 R 31 , wherein
 n is 0 or 1; and 
 R 30  and R 31  each independently are selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. 
 
     
     
         61 . The method of  claim 48 , wherein independently for each occurrence acyl is —C(═O)R 40 , wherein R 40  is selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. 
     
     
         62 . The method of  claim 48 , wherein independently for each occurrence aminophosphoryl is —P(═O)(OR 50 )NR 51 R 52 , wherein
 R 50  is selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, arylalkyl, heteroaryl, heteroaralkyl, and —(CH 2 ) m SC(═O)C(CH 3 ) 2 CH 2 OH; 
 m is 1 or 2; 
 R 51  is H or (C 1 -C 6 )alkyl; and 
 R 52  is selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and —CR 60 R 61 C(═O)OR 62 , wherein 
 R 60  and R 61  each independently are H or (C 1 -C 6 )alkyl; and 
 R 62  is selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl. 
 
     
     
         63 . The method of  claim 62 , wherein R 52  is —CR 60 R 61 C(═O)OR 62 . 
     
     
         64 . The method of  claim 63 , wherein R 60  is H; R 61  is (C 1 -C 6 )alkyl; and R 62  is (C 1 -C 6 )alkyl. 
     
     
         65 . The method of  claim 48 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         66 . The method of  claim 48 , wherein the compound of Formula (I) is represented by 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         67 . The method of  claim 48 , wherein the compound of Formula (I) is selected from the group consisting of:
 (S)-((2R,3R,4S,5S)-5-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-3,4-dihydroxypyrrolidin-2-yl)methyl 2-amino-3-methylbutanoate;   (2S,3S)-((2R,3R,4S,5S)-5-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-3,4-dihydroxypyrrolidin-2-yl)methyl 2-amino-3-methylpentanoate;   (S)-((2R,3R,4S,5S)-5-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-3,4-dihydroxypyrrolidin-2-yl)methyl 2-amino-4-methylpentanoate;   (2S,2′S)-(2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diyl bis(2-amino-3-methylbutanoate);   (S)-(2R,3R,4S,5S)-5-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 2-amino-3-methylbutanoate;   (S)-(2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-4-hydroxy-5-(hydroxymethyl)pyrrolidin-3-yl 2-amino-3-methylbutanoate; and   pharmaceutically acceptable salts thereof.   
     
     
         68 . The method of  claim 48 , wherein the virus is selected from the group consisting of adenovirus, Dengue Fever virus, Marburg virus, influenza A virus, influenza B virus, Junin virus, measles virus, parainfluenza virus, Pichinde virus, Punta Toro virus, respiratory syncytial virus, rhinovirus, Rift Valley Fever virus, SARS virus, Tacaribe virus, Venezuelan equine encephalitis virus, West Nile virus, and yellow fever virus. 
     
     
         69 . The method of  claim 48 , wherein the virus is selected from the group consisting of Ebola virus, yellow fever virus, Marburg virus, influenza A virus, and influenza B virus.