CYCLIC PHOSPHATE SUBSTITUTED NUCLEOSIDE DERIVATIVES 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 selected from one of the following groups:

R 1 is —CH(R 13 )—X—Y—Z—R 19 ;

Q is O or S;

V is H, halo or —N(R 12 ) 2 ;

W is N, CH or CF;

X is a bond or —C(R 14 ) 2 —;

Y is selected from a bond, O, —S(O) 2 — and —C(R 15 ) 2 —, such that when Y is O or —S(O) 2 —, then X is —C(R 14 ) 2 —;

Z is selected from a bond, —C(R 16 ) 2 — and C 3 -C 6 cycloalkylene, such that if X and Y are each a bond, then Z is —C(R 16 ) 2 — or C 3 -C 6 cycloalkylene;

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 , and —CN, such that (a) —OR 12 cannot be OH; and (b) if R 2 is F or Cl, then R 3 is other than 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 18 , —SR 18 and —N(R 18 ) 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 18 , —SR 18 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 N(R 18 ) 2 , —NHC(O)OR 18 , —NHC(O)N(R 18 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 18 ) 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 18 , —C(O)OR 18 , —C(O)N(R 18 ) 2 and —NHC(O)R 18 , 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 18 and —C(O)OR 18 ;

R 13 is selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —OR 17 , —O—C(O)R 17 , —N(R 12 )C(O)OR 17 and —C(O)OR 17 ;

each occurrence of R 14 is independently selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —OR 17 , —O—C(O)R 17 , —N(R 12 ) 2 , —N(R 12 )C(O)OR 17 and —C(O)OR 17 , or both R 14 groups, together with the common carbon atom to which they are attached, can join to form a C 3 -C 6 spirocyclic cycloalkyl group;

each occurrence of R 15 is independently selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —OR 17 , —O—C(O)R 17 , —N(R 12 ) 2 , —N(R 12 )C(O)OR 17 and —C(O)OR 17 , or both R 15 groups, together with the common carbon atom to which they are attached, can join to form a C 3 -C 6 spirocyclic cycloalkyl group;

each occurrence of R 16 is independently selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —OR 17 , —O—C(O)R 17 , —N(R 12 )C(O)OR 17 and —C(O)OR 7 , or both R 16 groups, together with the common carbon atom to which they are attached, can join to form a C 3 -C 6 spirocyclic cycloalkyl group;

each occurrence of R 17 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl;

each occurrence of R 18 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) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) and —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl);

R 19 is —C(O)OR 17 or:

and

each occurrence of m is independently 0 or 1,

such that at least one of R 13 , R 14 , R 15 and R 16 is other than H.

2 . The compound of claim 1 , wherein A is O, or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 , wherein R 2 is methyl, or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 2 , wherein R 3 is selected from Cl, —N 3 , —CN, and —C≡CH, or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 4 , wherein B is 9-guaninyl, 1-cytosinyl, 9-adeninyl, or 1-urcilyl, or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof,

wherein:

V is H or F;

X is a bond or —C(R 14 ) 2 —;

Y is selected from a bond, O, S(O) 2 and —C(R 15 ) 2 —; such that when Y is O or —S(O) 2 —, then X is —C(R 15 ) 2 —;

Z is selected from a bond, —C(R 16 ) 2 — and C 3 -C 6 cycloalkylene, such that if X and Y are each a bond, then Z is —C(R 16 ) 2 — or C 3 -C 6 cycloalkylene;

R 3 is selected from Cl, N 3 , —CN, and —C≡CH;

each occurrence of R 13 is independently selected from H, phenyl and C 1 -C 6 alkyl;

each occurrence of R 14 is independently selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —OR 17 , —O—C(O)R 17 , —N(R 12 ) 2 , —N(R 12 )C(O)OR 17 and —C(O)OR 17 ;

each occurrence of R 15 is independently selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —OR 17 , —O—C(O)R 17 , —N(R 12 ) 2 , —N(R 12 )C(O)OR 17 and —C(O)OR 17 ;

each occurrence of R 16 is independently selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, —OR 17 , —O—C(O)R 17 , —N(R 12 )C(O)OR 17 and —C(O)OR 17 , or two R 16 groups that are attached to the same carbon atom, together with the common carbon atom to which they are attached, can join to form a C 3 -C 6 spirocyclic cycloalkyl group;

each occurrence of R 17 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl; and

each occurrence of m is independently 0 or 1.

7 . The compound of claim 1 , wherein X is a bond, or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 7 , wherein Y is a bond, or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 1 , wherein R 17 is methyl, ethyl, isopropyl, t-butyl, n-pentyl, cyclopentyl or cyclohexyl, or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 1 , wherein R 1 is selected from:

11 . The compound of claim 1 , wherein X is a bond and Z is —CHR 16 —, and wherein R 16 is selected from H, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl) and —O—C(O)—(C 1 -C 6 alkyl), or a pharmaceutically acceptable salt thereof.

12 . The compound of claim 10 , wherein R 13 is H and Y is —CH 2 — or —CH(CH 3 )—, or a pharmaceutically acceptable salt thereof.

13 . A compound having the structure:

or a pharmaceutically acceptable salt thereof.

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

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

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

17 . (canceled)

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

19 . The method of claim 18 , further comprising the step of administering to said patient a second therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors, and HCV NS5B polymerase inhibitors.

20 . (canceled)

21 . (canceled)