NUCLEOSIDE DERIVATIVES AS INHIBITORS OF VIRAL POLYMERASES

1 . Compounds of structural formula (I):

and pharmaceutically acceptable salts thereof; wherein:

X is an optionally substituted basic ring system found in nucleosides and nucleotide analogues X being linked to the carbohydrate ring through a N atom of the basic ring system;

Z is a 5 or 6 membered heterocyclic ring, containing one to three heteroatoms optionally substituted by an oxo, S(O) n , S(O) n R 4 , C 1-4 alkyl, C 1-4 haloalkyl, CH 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , NR 4 C(O)R 5 or NR 4 R 5 groups wherein R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl; and Z is attached to a ring atom of X that is two ring atoms from the N atom that links X to the carbohydrate ring;

R 1 is hydrogen, hydroxy, halo or C 1-6 alkyl optionally substituted by fluoro;

R 2 is hydroxy, halo, OMe, C 1 -C 16 -alkylcarbonyl or hydrogen;

R 3 is hydrogen or an azido, ethynyl, cyano or a C 1-6 aliphatic group optionally substituted by fluoro;

Q 1 is hydrogen or a mono-, di- or tri-phosphate group or a protecting group Q 3 and

Q 2 is hydrogen or a protecting group Q 4 .

2 . A compound according to claim 1 wherein X is a purine, pyrrolopyrimidine, pyrazolopyrimidine or pyrimidine ring optionally substituted by halo, one or more oxo or hydroxy groups, or by one or more amino groups optionally substituted by COR 6 , wherein R 6 is a C 1-6 aliphatic group or phenyl.

3 . A compound according to claim 2 wherein Z is a 5 membered heterocyclic ring that contains two or three heteroatoms selected from oxygen and nitrogen, of which at most one is oxygen.

4 . A compound according to claim 3 wherein R 1 is methyl or fluorine; R 2 is hydroxy or fluoro; and R 3 is hydrogen.

5 . A compound according to claim 4 wherein Q 1 is selected from hydrogen, monophosphate, diphosphate, or triphosphate, or C 1 -C 16 -alkylcarbonyl or a monophosphate prodrug residue

wherein R 7 is hydrogen, methyl or benzyl; more suitably hydrogen or methyl; R 8 is hydrogen or methyl; more suitably hydrogen; R 9 is Ph, CO 2 R 11 or CR 13 R 14 OC(O)R 12 and R 10 is hydroxyl or OR 16 ; wherein R 16 is an aromatic or heteroaromatic ring or CH 2 CH 2 SR 17 , where R 17 is C 1 -C 6 alkylcarbonyl, optionally substituted with a hydroxyl group.

6 . A compound according to claim 5 wherein Q 1 is hydrogen or triphosphoryl.

7 . A compound according to claim 6 wherein Q 2 is selected from hydrogen, C 1 -C 16 -alkylcarbonyl or an amino acyl residue of the structure:

wherein R 18 is hydrogen or C 1 -C 5 alkyl and R 19 is hydrogen.

8 . A compound according to claim 1 wherein the compound is selected from the formula (II), (III), (IV) and (V):

and pharmaceutically acceptable salts thereof; wherein R 1 to R 6 , Z, Q 1 and Q 2 are as hereinbefore defined.

9 . A compound according to claim 1 wherein the compound is selected from:

5-(2-methoxy-1,3-thiazol-4-yl)-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-pyrimidin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(1,3-oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(1,2,4-oxadiazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(2-thienyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1-methyl-1H-tetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(2-methyl-2H-tetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1,3-oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

5-(2-methoxy-1,3-thiazol-4-yl)-7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1,2,4-oxadiazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-deoxy-2-fluoro-2-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-deoxy-2-fluoro-2-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1,3-oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-pyrimidin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-deoxy-2-fluoro-2-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1,2,4-oxadiazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-deoxy-2-fluoro-2-methyl-β-D-ribofuranosyl)-5-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-deoxy-2-fluoro-2-methyl-β-D-ribofuranosyl)-5-(1,2,4-oxadiazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-deoxy-2-fluoro-2-methyl-β-D-ribofuranosyl)-5-(1,3-oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

1-(2-C-methyl-β-D-ribofuranosyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

1-[5-O-(hydroxy{[hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl)-2-C-methyl- -D-ribofuranosyl]-3-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine,

7-(2-C-methyl-β-D-ribofuranosyl)-5-(1,3,4-oxadiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(2-C-methyl-5-triphospho-β-D-ribofuranosyl)-5-(1,3,4-oxadiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

Ethyl 2-{[(R)-({(2R,3S,4R,5R)-5-[4-amino-5-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-4-methyltetrahydro furan-2-yl}methoxy)(phenoxy)phosphoryl]amino}propanoate,

Ethyl 2-{[(R)-({(2R,3S,4R,5R)-5-[4-amino-5-(1,3-oxazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-4-methyltetrahydro furan-2-yl}methoxy)(phenoxy)phosphoryl]amino}propanoate

and pharmaceutically acceptable salts thereof.

10 . A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier.

11 - 13 . (canceled)

14 . A method of inhibiting HCV NS5B polymerase, inhibiting HCV replication, or treating HCV infection with an effective amount of a compound according to claim 1 .

15 . (canceled)