4′-substituted nucleoside derivatives as inhibitors of HCV RNA replication

1. A method of treating a disease mediated by the HCV virus comprising administering to a patient in need thereof an effective amount of a compound of formula I

wherein

R is hydrogen or —[P(O)(OH)—O] n H and n is 1, 2 or 3;

R 1 is alkyl, alkenyl, alkynyl, haloalkyl, alkylcarbonyl, hydroxyalkyl, alkoxyalkyl, alkoxy, cyano, azido, hydroxyiminomethyl, alkoxyiminomethyl, halogen, alkylcarbonylamino, alkylaminocarbonyl, or aminomethyl, alkylaminomethyl, dialkylaminomethyl or heterocyclyl;

R 2 is hydrogen, hydroxy, alkyl, alkoxy, halogen or cyano;

R 3 and R 4 (i) independently are hydrogen, hydroxy, alkoxy or halogen, provided that at least one of R 3 and R 4 is hydrogen; or

(ii) together represent ═CH 2 or ═N—OH, or

(iii) both represent fluorine;

R 11 is hydrogen, halogen or alkyl

X is O, S or CH 2 ;

or pharmaceutically acceptable salts thereof.

2. The method of claim 1 wherein

R 1 is alkenyl, alkynyl, haloalkyl, alkylcarbonyl, alkoxy, hydroxymethyl, cyano, azido, alkoxyiminomethyl, alkylcarbonylamino, alkylaminomethyl or dialkylaminomethyl;

R 2 is hydrogen, hydroxy, alkoxy, or halogen;

R 3 and R 4 (i) are independently hydrogen, hydroxy, alkoxy, halogen or hydroxyalkyl, provided that at least one of R 3 and R 4 is hydrogen; or

(ii) together are ═CH 2 ; or,

(ii) both represent fluorine;

R 11 is hydrogen; and,

X is O or CH 2 .

3. The method of claim 1 wherein:

R is hydrogen;

R 1 is C 2-6 alkynyl, azido or hydroxymethyl;

R 2 is hydrogen, hydroxyl, alkoxy or halogen;

R 3 and R 4 (i) independently are hydrogen, hydroxyl, alkoxy or halogen, or

(ii) both are fluorine; and,

X is O.

4. The method of claim 1 wherein:

R is —[P(O)OH)—O] n H and n is 1, 2 or 3;

R 1 is C 2-6 alkynyl, azido or hydroxymethyl;

R 2 is hydrogen, hydroxyl, alkoxy or halogen;

R 3 and R 4 (i) independently are hydrogen, hydroxyl, alkoxy or halogen, or

(ii) both are fluorine; and,

X is O.

5. The method of claim 1 , wherein the compound is delivered in a dose of between 1 and 100 mg/kg/ body weight of the patient/day.

6. The method of claim 1 , further comprising administering an immune system modulator.

7. The method of claim 6 , wherein the immune system modulator is an interferon, interleukin, tumor necrosis factor or colony stimulating factor, an antiviral agent or an anti-inflammatory agent.

8. The method of claim 7 , wherein the immune system modulator is an interferon.

9. The method of claim 7 , wherein the immune system modulator is an antiviral agent.