Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
1 . A compound of the structural formula:
or a pharmaceutically aceptable salt thereof;
wherein R a and R h are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, mercapto, amino, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4 alkoxy, C 1-4 alkylthio, or one to three fluorine atoms;
R b is C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4 alkoxy, C 1-4 alkylthio, or one to three fluorine atoms;
R c is hydrogen, fluorine, hydroxy, marcapto, C 1-4 alkoxy, or C 1-4 alkyl; or R b and R c together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC 0-4 alkyl;
R d is hydrogen, cyano, nitro, C 1-3 alkyl, NHCONH 2 , CONR j R j , CSNR j R j , COOR j , C(═NH)NH 2 , hydroxy, C 1-3 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halogen, (1,3-oxazol-2-yl), (1,3-thiazol-2-yl), or (imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;
R e and R f are each independently hydrogen, hydroxy, halogen, C 1-4 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, di(C 3-6 cycloalkyl)amino, or C 4-6 cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C 1-4 alkyl, and C 1-4 alkoxy;
R g is hydrogen, C 1-4 alkyl, C 2-4 alkynyl, halogen, cyano, carboxy, C 1-4 alkyloxycarbonyl, azido, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, (C 1-4 alkyl) 0-2 aminomethyl, or C 4-6 cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C 1-4 alkyl, and C 1-4 alkoxy;
R i is hydrogen, C 1-10 alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or P(O)R m R n ;
each R j is independently hydrogen or C 1-6 alkyl;
R k and R l are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl; and
R m and R n are each independently hydroxy, OCH 2 CH 2 SC(═O)C 1-4 alkyl, OCH 2 O(C═O)OC 1-4 alkyl, NRCHMeCO 2 Me, OCH(C 1-4 alkyl)O(C═O)C 1-4 alkyl,
with the proviso that when R a and R c are α-hydroxy, R e is amino, R b is β-methyl and R h is hydrogen or R h is β-methyl and R b is hydrogen, and R f , R g , R i , R k , and R l are hydrogen, then R d is not cyano or CONH 2 .
2 . The compound of claim 1 of the structural formula:
wherein R a is hydrogen, halogen, hydroxy, amino, or C 1-4 alkoxy;
R b is C 1-3 alkyl, wherein alkyl is optionally substituted with hydroxy, amino, C 1-3 alkoxy, C 1-3 alkylthio, or one to three fluorine atoms;
R c is hydroxy, fluoro, or C 1-3 alkoxy;
Rd is hydrogen, cyano, methyl, halogen, or CONH 2 ;
R g is hydrogen, amino, or C 1-4 alkylamino;
R i is hydrogen, P 3 O 9 H 4 , P 2 O 6 H 3 , or PO 3 H 2 ; and
R e and R f are each independently hydrogen, halogen, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, or C 3-6 cycloalkylamino;
with the proviso that when R a and R c are α-hydroxy, R e is amino, R b is β-methyl, and R f , R g , and R i are hydrogen, then R d is not cyano or CONH 2 .
3 . The compound of claim 2 wherein
R b is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;
R c is hydroxy, fluoro, or methoxy;
R a is hydrogen, fluoro, hydroxy, amino, or methoxy;
R i is hydrogen or P 3 O 9 H 4 ;
R g is hydrogen or amino;
R d is hydrogen, cyano, methyl, halogen, or CONH 2 ; and
R e and R f are each independently hydrogen, fluoro, hydroxy, or amino;
with the proviso that when R b is β-methyl, R a and R c are α-hydroxy, R e is amino, and R f , R g , and R i are hydrogen, then R d is not cyano or CONH 2 .
4 . The compound of claim 1 selected from the group consisting of:
4-amino-7-(2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-methylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-dimethylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-cyclopropylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-vinyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-hydroxymethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-fluoromethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-methyl-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,
4-amino-5-bromo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2,4-diamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-cyclopropylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-5-methyl-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
4-amino-7-(3-deoxy-2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-deoxy-2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine,
4-amino-2-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-C-methyl-β-D-xylofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2,4-di-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and
4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
and the corresponding 5′-triphosphates;
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 4 selected from the group consisting of:
4-amino-7-(2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-fluoromethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-methyl-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-bromo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and
4-amino-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
and the corresponding 5′-triphosphates;
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 5 which is
4-amino-7-(2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 5 which is
4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 5 which is
4-amino-7-(2-C-fluoromethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 5 which is
4-amino-5-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 5 which is
4-amino-5-bromo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 5 which is
4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.
12 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
13 . The pharmaceutical composition of claim 12 useful for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA replication, and/or treating RNA-dependent RNA viral infection.
14 . The pharmaceutical composition of claim 13 wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase, said RNA-dependent RNA viral replication is HCV replication, and said RNA-dependent RNA viral infection is HCV infection.
15 . A method of inhibiting RNA-dependent RNA viral polymerase and/or inhibiting RNA-dependent RNA viral replication comprising administering to a mammal in need of such inhibition an effective amount of a compound according to claim 1 .
16 . The method of claim 15 wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase and said RNA-dependent RNA viral replication is HCV viral replication.
17 . A method of treating RNA-dependent RNA viral infection comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1 .
18 . The method of claim 17 wherein said RNA-dependent RNA viral infection is HCV infection.
19 . The method of claim 18 in combination with a therapeutically effective amount of another agent active against HCV.
20 . The method of claim 19 wherein said agent active against HCV is ribavirin; levovirin; thymosin alpha-1; an inhibitor of NS3 serine protease; an inhibitor of inosine monophosphate dehydrogenase; interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.
21 . The method of claim 20 wherein said agent active against HCV is interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.