Nucleoside compounds for treating viral infections

Abstract

Disclosed are compounds, compositions and methods for treating viral infections caused by a flaviviridae family virus, such as hepatitis C virus.

1 - 45 . (canceled)  
     
     
         46 . A method for treating a viral infection in a mammal mediated at least in part by a virus in the  flaviviridae  family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 Y is selected from the group consisting of a bond, —CH 2 — or —O—;  
 each of W, W 1  and W 2  is independently selected from the group consisting of hydrogen, acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —C(O)CHR 30 NH 2  where R 30  is selected from the group consisting of hydrogen, alkyl, substituted alkyl aryl, substituted aryl, heteroaryl, substituted heteroaryl, and a sidechain of an amino acid; and  
 T is selected from the group consisting of  
 a) —-C≡C—R, where R is selected from the group consisting of 
 i) tri(C 1 -C 4 )alkylsilyl, —C(O)NR 1 R 2 , alkoxyalkyl, heteroaryl, and substituted heteroaryl, and phenyl substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, aminoacyl, amidino, amino, substituted amino, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, guanidino, halo, heteroaryl substituted heteroaryl, hydrazino, hydroxyl, nitro, thiol, and —S(O) m R 3 ;  
 where R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that only one of R 1  and R 2  is amino or substituted amino, and further wherein R 1  and R 2 , together with the nitrogen atom pendant thereto, form a heterocyclyl or substituted heterocyclyl;  
 R 3  is selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl; and  
 m is an integer equal to 0, 1 or 2;  
 ii) —C(O)OR 14 , where R 14  is hydrogen, alkyl or substituted alkyl;  
 
 b) —C(O)H;  
 c) —CH═NNHR 15 , where R 15  is H or alkyl;  
 d) —CH═N(OR 15 ), where R 15  is as defined above;  
 e) —CH(OR 16 ) 2  where R 16  is (C 3 -C 6 )alkyl and  
 f) —B(OR 15 ) 2  where R 15  is as defined above;  
 and pharmaceutically acceptable salts or partial salts thereof, wherein  
 substituted alkyl refers to an alkyl group having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;  
 alkoxy refers to alkyl-O—;  
 substituted alkoxy refers to (substituted alkyl)-O—;  
 alkoxyalkyl refers to -alkylene(alkoxy) n  or -alkylene(substituted alkoxy) n , where alkylene is a divalent straight or branched chain alkylene group of from 1 to 3 carbon atoms;  
 acyl refers to a moiety selected from the group consisting of alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynl-C(O)— cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O), heterocyclyl-C(O)—, and substituted heterocyclyl-C(O)—;  
 acylamino refers to the group —C(O)NR 4 R 4  where each R 4  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl and where each R 4  is joined to form together with the nitrogen atom a heterocyclyl or substituted heterocyclyl ring;  
 acyloxy refers to a moiety selected from the group consisting of alkyl-C(O)O—, substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclyl-C(O)O—, and substituted heterocyclyl-C(O)O—;  
 oxyacyl refers to a moiety selected from the group consisting of alkyl-OC(O)—, substituted alkyl-OC(O)—, alkenyl-OC(O)—, substituted alkenyl-OC(O)—, alkynyl-OC(O)—, substituted alkynyl-OC(O)—, aryl-OC(O)—, substituted aryl-OC(O)—, cycloalkyl-OC(O)—, substituted cycloalkyl-OC(O)—, heteroaryl-OC(O)—, substituted heteroaryl-OC(O)—, heterocyclyl-OC(O)—, and substituted heterocyclyl-OC(O)—;  
 substituted alkenyl refers to an alkenyl group having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl with the proviso that any hydroxyl substitution is not attached to an unsaturated carbon atom;  
 substituted alkynyl refers to an alkynyl group having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;  
 amino refers to —NH 2 .  
 substituted amino refers to —NR′R″, where R′ and R″ independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl and where R′ and R″ are joined, together with the nitrogen bound thereto to form a heterocyclyl or substituted heterocyclyl group provided that R′ and R″ are both not hydrogen;  
 amidino refers to —C(═NR 11 )NR 11 R 11  where each R 11  independently is hydrogen or alkyl;  
 aminoacyl refers to a moiety selected from the group consisting of —NR 5 C(O)alkyl, —NR 5 C(O)substituted alkyl, —NR 5 C(O)cycloalkyl, —NR 5 C(O)substituted cycloalkyl, —NR 5 C(O)alkenyl, —NR 5 C(O)substituted alkenyl, —NR 5 C(O)alkynyl, —NR 5 C(O)substituted alkynyl, —NR 5 C(O)aryl, —NR 5 C(O)substituted aryl, —NR 5 C(O)heteroaryl, —NR 5 C(O)substituted heteroaryl, —NR 5 C(O)heterocyclyl, and —NR 5 C(O)substituted heterocyclyl where R 5  is hydrogen or alkyl;  
 aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1 4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom;  
 substituted aryl refers to an aryl group which is substituted with from 1 to 3 substituents selected from the group consisting of hydroxyl, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxyl, carboxyl esters, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclyl, substituted thioheterocyclyl, cycloalkyl, substituted cycloalkyL, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy;  
 aryloxy refers to the group aryl-O—;  
 substituted aryloxy refers to (substituted aryl)-O—;  
 carboxyl refers to —COOH or salts thereof;  
 carboxyl ester refers to a moiety selected from the group consisting of —C(O)O-alkyl, —C(O)O-(substituted alkyl), —C(O)O-aryl, and —C(O)O-(substituted aryl);  
 cycloalkyl refers to a cyclic alkyl group of from 3 to 10 carbon atoms having single or multiple cyclic rings;  
 substituted cycloalkyl refers to a cycloalkyl having from 1 to 5 substituents selected from the group consisting of oxo (═O), thioxo (═S), alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;  
 cycloalkoxy refers to —O-cycloalkyl,  
 substituted cycloalkoxy refers to —O-(substituted cycloalkyl);  
 guanidino refers to —NR 12 C(═NR 12 )NR 12 R 12  where each R 12  independently is hydrogen or alkyl;  
 halogen refers to fluoro, chloro, bromo and iodo;  
 heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring wherein the nitrogen and/or sulfur is optionally oxidized ((N→O) —S(O)—, or —SO 2 —), wherein the heteroaryl group can have a single ring or multiple condensed rings where the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an aromatic ring atom;  
 substituted heteroaryl refers to a heteroaryl group that is substituted with from 1 to 3 substituents selected from the group consisting of hydroxyl, acyl, acylamino, acyloxy, alkyl substituted alkyl alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxyl carboxyl esters, cyano, thiol thioalkyl substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclyl, substituted thioheterocyclyl, cycloalkyl, substituted cycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy;  
 heteroaryloxy refers to the group —O-heteroaryl;  
 substituted heteroaryloxy refers to the group —O-(substituted heteroaryl);  
 heterocyclyl refers to a saturated or unsaturated group, but not heteroaryl, having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur within the ring wherein the nitrogen and/or sulfur atoms can be optionally oxidized ((N→O), —S(O)— or —SO 2 —) and further wherein, in fused ring systems, one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the heterocyclyl ring;  
 substituted heterocyclyl refers to a heterocycle group that is substituted with from 1 to 3 substituents selected from the group consisting of oxo (═O), thioxo (═S), alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroary, heterocyclyl, and substituted heterocyclyl;  
 heterocyclyloxy refers to the group —O-heterocyclyl;  
 substituted heterocyclyloxy refers to the group —O-(substituted heterocyclyl; hydrazino refers to the group —NR 13 NR 13 R 13  wherein each R 1   3  independently is hydrogen or alkyl;  
 phosphate refers to the groups —OP(O)(OH) 2  (monophosphate), —OP(O)(OH)OP(O)(OH) 2  (diphosphate) and —OP(O)(OH)OP(O)(OH)OP(O)(OH) 2  (triphosphate) or salts thereof including partial salts thereof;  
 phosphate ester refers to a mono-, di- or tri-phosphate, wherein one or more of the hydroxyl group is replaced by an alkoxy group;  
 phosphonate refers to a moiety selected from the group consisting of —OP(O)(R 6 )(OH) and —OP(O)(R 6 )(OR 6 ) and salts thereof, including partial salts thereof, wherein each R 6  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl carboxylic acid, and carboxyl ester;  
 phosphorodiamidate refers to  
                     
  where each R 7  may be the same or different and each is hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;  
 phosphoramidate monoester refers to  
                     
  where R 30  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and a sidechain of an amino acid and R 8  is hydrogen or alkyl;  
 phosphoramidate diester refers to  
                     
  where R 30  is selected from the group consisting of hydrogen, alkyl, substituted alkyl aryl substituted aryl and a sidechain of an amino acid, R 8  is hydrogen or alkyl and R 10  is selected from the group consisting of alkyl, substutituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;  
 cyclic phosphoramidate refers to  
                     
  where n is 1 to 3;  
 cyclic iphosphorodiamidate refers to  
                     
  where n is 1 to 3;  
 phosphonamidate refers  
                     
  where R 14  is hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;  
 thiol refers to —SH;  
 thioalkyl refers to —S-alkyl;  
 substituted thioalkyl refers to —S-(substituted alkyl);  
 thiocycloalkyl refers to —S-cycloalkyl;  
 substituted thiocycloalkyl refers to —S-(substituted cycloalkyl);  
 thioaryl refers to —S-aryl;  
 substituted thioaryl refers to —S-(substituted aryl);  
 thioheteroarml refers to —S-heteroaryl;  
 substituted thioheteroaryl refers to —S-(substituted heteroaryl);  
 thioheterocyclyl refers to —S-heterocyclyl; and  
 substituted thioheterocyclyl refers to —S-(substituted heterocyclyl).  
 
     
     
         47 . (canceled)  
     
     
         48 . The method of  claim 46 , wherein the viral infection is mediated at least in part by a hepatitis C virus (HCV) and wherein the method further comprises administration of a therapeutically effective amount of one or more agents active against HCV in combination with the compound.  
     
     
         49 . The method of  claim 48  wherein said active agent against is Ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, pegylated interferon-alpha, alone or in combination with Ribavirin or levovirin.  
     
     
         50 . The method of  claim 49  wherein said agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with Ribavirin or levovirin.