Cyclic phosphate substituted nucleoside compounds and methods of use thereof for the treatment of viral diseases

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

A is selected from O, S and CH 2 ;

B is:

Q is O or S;

V is H, halo or —N(R 12 ) 2 ;

R 1 is —(CH 2 ) m —C(O)OR 13 ;

R 2 is selected from H, F, Cl, C 1 -C 3 alkyl and C 2 -C 3 alkynyl;

R 3 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OR 12 , F, Cl, —N 3 , —CN and N(R 12 ) 2 , such that if R 2 is F or C 1 , then R 3 is other than F or Cl;

R 4 , R 5 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, —OR 14 , —SR 14 and —N(R 14 ) 2 ;

R 6 , R 9 , R 10 and R 11 are each independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, halo, —OR 14 , —SR 14 , —S(O)R 14 , —S(O) 2 R 14 , —S(O) 2 N(R 14 ) 2 , —NHC(O)OR 14 , —NHC(O)N(R 14 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 14 ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), —C(O)R 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 and —NHC(O)R 14 , wherein said C 2 -C 6 alkenyl group and said C 2 -C 6 alkynyl group may be optionally substituted with halo;

each occurrence of R 12 is independently selected from H, C 1 -C 6 alkyl, —C(O)R 14 and —C(O)OR 14 ;

each occurrence of R 13 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl;

each occurrence of R 14 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) n -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) n -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) n -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) n -(5- or 6-membered monocyclic heteroaryl) and —(C 1 -C 3 alkylene) n -(9- or 10-membered bicyclic heteroaryl);

m is 1, 2, 3, 4 or 5; and

each occurrence of n is independently 0 or 1.

2. The compound of claim 1 , wherein A and Q are each O.

3. The compound of claim 1 , wherein R 2 is methyl.

4. The compound of claim 1 , wherein R 3 is selected from —OH, F, Cl, —N 3 , —CN, —C≡CH and —NH 2 .

5. The compound of claim 1 , having the formula (Ia):

or a pharmaceutically acceptable salt thereof,

wherein:

B is uracil;

R 3 is selected from —OH, F, C 1 , N 3 , —CN, —C≡CH and —NH 2 ;

R 13 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; and

V is H or F; and

m is 1, 2, 3, 4 or 5.

6. The compound of claim 1 , wherein m is 1.

7. The compound of claim 1 , wherein m is 2.

8. The compound of claim 1 , wherein m is 3.

9. The compound of claim 1 , wherein m is 4.

10. The compound of claim 1 , wherein m is 5.

11. The compound of claim 1 , wherein R 13 is methyl, ethyl, isopropyl, n-butyl or cyclopentyl.

12. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

15. The pharmaceutical composition of claim 14 , further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

16. A method of treating a patient infected with HCV comprising the step of administering an amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, effective to treat infection by HCV in said patient.

17. The method of claim 16 , further comprising the step of administering to said patient a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.