Tricyclic-Nucleoside Compounds for Treating Viral Infections

Abstract

Disclosed are compounds represented by formulae I, II, and III, and the compositions and methods thereof for treating viral infections caused by a Flaviviridae family virus.

1 . A compound represented by formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 R is selected from the group consisting of hydrogen and C 1 -C 3  alkyl; 
 X is selected from the group consisting of hydrogen, halo, and OW 2 ; 
 Y is selected from the group consisting of a bond, O, and CH 2 ; 
 Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2  group; 
 V is selected from the group consisting of N and C-G; 
 Z is selected from the group consisting of N and C-G′; 
 G and G′ are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; 
 provided that V and Z are not identical; 
 provided that when V is C—H, Z is N; 
 T 1  and T 2  are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; and 
 each of W, W 1 , and W 2  is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, and a prodrug group; or 
 a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof. 
 
   
   
       2 . A compound according to  claim 1  represented by formula Ia: 
     
       
         
         
             
             
         
       
     
     wherein:
 Q, G, T 1 , T 2 , Y, W, W 1 , X, and R are described in  claim 1 . 
 
   
   
       3 . A compound according to  claim 1  represented by formula Ib: 
     
       
         
         
             
             
         
       
     
     wherein:
 G is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, —SO 3 H, —SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, 
 where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; and 
 Q, T 1 , T 2 , Y, W, W 1 , X, and R are described in  claim 1 . 
 
   
   
       4 . A compound according to  claim 1  represented by formula Ic: 
     
       
         
         
             
             
         
       
     
     wherein:
 Q, G′, T 1 , T 2 , Y, W, W 1 , X, and R are described in  claim 1 . 
 
   
   
       5 . A compound according to  claim 4  wherein G′is selected from the group consisting of azido, amino, aminocarbonyl, acylamino, alkoxyamino, cyano, halo, hydroxyamino, and hydrazino. 
   
   
       6 . A compound according to  claim 5  wherein G′is selected from the group consisting of azido, amino, acylamino, cyano, and halo. 
   
   
       7 . A compound according to  claim 6  wherein R is methyl. 
   
   
       8 . A compound according to  claim 7  wherein Q is O. 
   
   
       9 . A compound represented by formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R is C 1 -C 3  alkyl; 
 X is selected from the group consisting of hydrogen, halo, and OW 2 ; 
 Q′ is selected from the group consisting of NH, O, and S; 
 G′is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, —SO 3 H, —SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR′NCHR″C(O)NH—, azido, cyano, halo, hydroxyamino, and hydrazino, where R′ is hydrogen and R″ is a side-chain of an amino acid or where R′ and R″ together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; 
 Y is selected from the group consisting of a bond, O, and CH 2 ; and 
 each of W, W 1 , and W 2  is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, and a prodrug group; or 
 a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof. 
 
   
   
       10 . A compound according to  claim 9  wherein G′is selected from the group consisting of azido, amino, aminocarbonyl, acylamino, alkoxyamino, cyano, halo, hydroxyamino, and hydrazino. 
   
   
       11 . A compound according to  claim 10  wherein G′is selected from the group consisting of azido, amino, acylamino, cyano, and halo 
   
   
       12 . A compound according to  claim 11  wherein Q′ is O. 
   
   
       13 . A compound according to  claim 12  wherein R is methyl. 
   
   
       14 . A compound according to  claim 13  wherein Y is O. 
   
   
       15 . A compound according to  claim 9  represented by formula Ia: 
     
       
         
         
             
             
         
       
     
     wherein:
 Q′, G′, W, W 1 , and W 2  are as described in  claim 9 . 
 
   
   
       16 . A compound according to  claim 15  wherein G′is selected from the group consisting of azido, amino, aminocarbonyl, acylamino, alkoxyamino, cyano, halo, hydroxyamino, and hydrazino. 
   
   
       17 . A compound according to  claim 16  wherein G′is selected from the group consisting of azido, amino, acylamino, cyano, and halo. 
   
   
       18 . A compound according to  claim 17  wherein Q′ is O. 
   
   
       19 . A compound according to  claim 18  wherein W, W 1 , and W 2  are hydrogen. 
   
   
       20 . A compound represented by formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
 A and B are independently selected from the group consisting of C=Q, NH, and methylene optionally substituted with 1 to 2 halo groups, provided that A and B are not both NH; 
 D is NH, or -D-A-B- together form a —N═CH—NH—, —(C=Q)-CH 2 —(C=Q)-, —(C=Q)-NH—(C=Q)-, —(CX′)═(CX′)—(C-Q)-, or —CH═CH—NH— group where X′ is halo; 
 each Q is independently selected from the group consisting of O, S, and NH; 
 R is selected from the group consisting of hydrogen and C 1 -C 3  alkyl; 
 X is selected from the group consisting of hydrogen, halo, and OW 2 ; 
 T 1  and T 2  are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -thioalkoxy, amino, substituted amino, and halo; 
 Y is selected from the group consisting of a bond, O, and CH 2 ; and 
 each of W, W 1 , and W 2  is independently selected from the group consisting of hydrogen, C 1 -C 4  alkyl, and a prodrug group; or 
 a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof. 
 
   
   
       21 . A compound according to  claim 20  wherein A is C═O. 
   
   
       22 . A compound according to  claim 21  wherein B is methylene. 
   
   
       23 . A compound according to  claim 22  wherein R is methyl. 
   
   
       24 . A compound selected from the group consisting of 
     9-amino-2-(β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-β-D-ribofuranosyl)-9-methylamino-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-β-D-ribofuranosyl)-2,6,7,9-tetrahydro-2,3,5,6,9-pentaaza-benzo[cd]azulen-8-one; 
     9-acetamido-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-hydrazino-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-fluoro-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-formamido-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-methoxyamino-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-amino-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-hydroxyamino-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     8-fluoro-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-amino-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,8-pentaaza-benzo[cd]azulen-7-one; 
     9-chloro-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-iodo-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-amino-2-(2′-O-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,8-pentaaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-β-D-ribofuranosyl)-2,6,7,9-tetrahydro-2,3,5,6,7,9-hexaaza-benzo[cd]azulen-8-one; 
     2-(2′-methyl-β-D-ribofaranosyl)-2,9-dihydro-6H-2,3,5,6,9-pentaaza-benzo[cd]azulene-7,8-dione; 
     9-cyano-2-(2′-methyl-β-D-ribofaranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-amino-8-fluoro-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-fluoro-2-(2′-methyl-β-D-ribofuranosyl)-6,7-dihydro-2,3,5,6-tetraaza-benzo[cd]azulene; 
     9-amino-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulene-7-thione; 
     8-amino-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-carbamoyl-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     8-cyano-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     8-carbamoyl-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-β-D-ribofuranosyl)-6,7-Dihydro-2,3,5,6,7-pentaaza-benzo[cd]azulene; 
     2-(2′-methyl-β-D-ribofuranosyl)-6,7-Dihydro-2,3,5,6,7,9-hexaaza-benzo[cd]azulene; 
     8-fluoro-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,-tetraaza-benzo[cd]azulene-7,9-dione; 
     2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,-tetraaza-benzo[cd]azulene-7,9-dione; 8,9-difluoro-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,8-pentaaza-benzo[cd]azulene-7,9-dione; 
     9-fluoro-2-(2′-methyl-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,8-pentaaza-benzo[cd]azulen-7-one; 
     9-fluoro-2-(2′-methyl-β-D-ribofuranosyl)-6,7-dihydro-2,3,5,6-tetraaza-benzo[cd]azulene; 
     9-amino-2-(5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-9-methylamino-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6,7,9-tetrahydro-2,3,5,6,9-pentaaza-benzo[cd]azulen-8-one; 
     9-acetamido-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-hydrazino-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-fluoro-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-formamido-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-methoxyamino-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-amino-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-hydroxyamino-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     8-fluoro-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-amino-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,8-pentaaza-benzo[cd]azulen-7-one; 
     9-chloro-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-iodo-2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; 
     9-amino-2-(2′-O-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one; and 
     2-(2′-methyl-5′-triphospho-β-D-ribofuranosyl)-2,6-dihydro-2,3,5,6,-tetraaza-benzo[cd]azulene-7,9-di one;
 or a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof. 
 
   
   
       25 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, a tautomer, or a pharmaceutically acceptable salt of a tautomer thereof, of any one of  claims 1 ,  9 , or  20  or a mixture of two or more of such compounds. 
   
   
       26 . A method for treating or preventing a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses, comprising administering to said mammal a composition of  claim 25 . 
   
   
       27 . The method of  claim 26  in combination with a therapeutically effective amount of one or more agents active against hepatitis C virus. 
   
   
       28 . The method of  claim 27  wherein said agent active against hepatitis C virus is an inhibitor of HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, or inosine 5′-monophosphate dehydrogenase. 
   
   
       29 . The method of  claim 27  wherein said active agent against HCV is Ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of NS3 serine protease, an inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, or pegylated interferon-alpha. 
   
   
       30 . The method of  claim 26  wherein said mammal is a human.