US 2004/0110717 A1 · Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

Abstract

The present invention provides nucleoside derivatives 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 derivatives 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 derivatives of the present invention.

A method of inhibiting RNA-dependent RNA viral polymerase or inhibiting RNA-dependent RNA viral replication comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula I which is of the stereochemical configuration:

183
or a pharmaceutically acceptable salt thereof;
wherein B is selected from the group consisting of
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A, G, and L are each independently CH or N;
D is N, CH, C—CN, C—NO2, C—C1-3 alkyl, C—CNHCONH2, C—CONR11R11, C—CSNR11R11, C—COOR11, C—C(═NH)NH2, C-hydroxy, C—C1-3 alkoxy, C-amino, C—C1-4 alkylamino, C-di(C1-4 alkyl)amino, C-halogen, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl);
wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
E is N or CR5;
W is O or S;
Y is H, C1-10 alkylcarbonyl, P3O9H4, P2O6H3, or P(O)R9R10;
R1 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R2 and R3 is hydroxy or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C-1-10 alkoxy, optionally substituted with C1-3 alkoxy or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino;
or
R2 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R1 and R3 is hydroxy or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with hydroxy, C1-3 alkoxy, carboxy, or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino;
or
R1 and R2 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 NC0-4 alkyl;
R4 and R6 are each independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R14 is H, CF3, C1-4 alkyl, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
R12 and R13 are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl;
and
R9 and R10 are each independently hydroxy, OCH2CH2SC(═O)C1-4 alkyl, OCH2O(C═O)OC1-4 alkyl, NHCHMeCO2Me, OCH(C1-4 alkyl)O(C═O)C1-4 alkyl,
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with the provisos that (a) when R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is fluoro, then the other of R3 and R4 is not hydrogen, halogen, azido, trifluoromethyl, C1-4 alkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, or C1-10 alkoxy;
(b) when R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is halogen, hydroxy, C1-6 alkoxy, or C2-6 alkenyloxy, then the other of R3 and R4 is not hydrogen, fluoro, or azido;
and (c) when R1 and R3 are hydrogen and R2 is hydroxy, then R4 is not hydroxy.

51 more elements

Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

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Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

Life of this patent

Abstract

Claims41