2′-disubstituted 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 —NH 2 ;

X is O, N, S or CH 2 ;

Y is N or —C(R 6 )—;

R 1 is H,

R 2 is H, —C(O)—(C 1 -C 6 alkyl) or

or R 1 and R 2 join to form a group having the formula:

R 3 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 7 cycloalkyl;

R 4 and R 5 are each independently selected from H, —OR 12 , —NHC(O)OR 12 , —NHC(O)N(R 12 ) 2 , —N(R 12 ) 2 and —NHC(O)R 12 ;

R 6 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, —OR 12 , —SR 12 , —N(R 12 ) 2 , C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl;

R 7 is H, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, or —(C 1 -C 3 alkylene)-C(O)O—(C 1 -C 6 alkyl), wherein said C 6 -C 10 aryl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with R 13 ,

R 8 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or benzyl, wherein said C 1 -C 6 alkyl can be optionally substituted with a group selected from halo, —OR 12 , —SR 12 , guanidino, —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NHC(O)R 12 , 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C 1 -C 6 alkyl, halo and —OR 12 ;

R 9 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or benzyl, wherein said C 1 -C 6 alkyl can be optionally substituted with a group selected from halo, —OR 12 , —SR 12 , guanidino, —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NHC(O)R 12 , 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C 1 -C 6 alkyl, halo and —OR 12 ;

R 10 is H, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl) or —(C 1 -C 3 alkylene) m -adamantyl, wherein said C 1 -C 20 alkyl group, said C 2 -C 20 alkenyl group, said C 6 -C 10 aryl group and said adamantyl group can be optionally substituted with up to three groups, each independently selected from halo, —OR 12 , —C(O)OR 12 , CN, NO 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —N(R 12 ) 2 , —C(O)N(R 12 ) 2 —SR 12 , —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 12 ) 2 , —NHC(O)R 12 , —NHC(O)OR 12 and —NHC(O)N(R 12 ) 2 ;

R 11 is H, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene) m -C 6 -C 10 aryl or —(C 1 -C 3 alkylene) m -adamantyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, wherein said C 1 -C 20 alkyl group, said C 2 -C 20 alkenyl group, said C 6 -C 10 aryl group, said adamantyl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with up to five groups, each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, halo, —OR 12 , —SR 12 , —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 12 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 and —NHC(O)R 12 , —NHC(O)OR 12 and —NHC(O)N(R 12 ) 2 ;

each occurrence of R 12 is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl) m -(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) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl), wherein said C 3 -C 7 cycloalkyl group, said C 6 -C 10 aryl group, said 4 to 7-membered heterocycloalkyl group, said -5- or 6-membered monocyclic heteroaryl group or said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with R 16 ;

R 13 represents from one to five substituent groups, each independently selected from C 1 -C 6 alkyl, halo, —OR 12 , —SR 12 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 and —NHC(O)R 12 , or any two R 13 groups on adjacent ring carbon atoms can combine to form —O—R 14 —O—;

R 14 is [C(R 15 ) 2 ] n —;

each occurrence of e is independently H or C 1 -C 6 alkyl;

R 16 represents from one to five substituent groups, each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, —OR 17 , —SR 17 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 17 ) 2 , —C(O)OR 17 , —C(O)N(R 17 ) 2 and —NHC(O)R 17 ;

each occurrence of R 17 is independently 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) m -(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) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl);

R 18 is H, C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), C 1 -C 6 alkynyl, C 1 -C 6 alkenyl, or CN; and

each occurrence of m is independently 0 or 1, and

each occurrence of n is independently 1, 2, or 3.

2. The compound of claim 1 , wherein X is O.

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

4. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is H,

R 2 is H, or R 1 and R 2 join to form a group having the formula:

R 4 is H, OH or —N(R 12 ) 2 ;

R 5 is H or NH 2 ,

R 18 is H, —CN or —OCH 3 ;

R 7 is —(C 1 -C 3 alkylene)-C(O)O—(C 1 -C 6 alkyl) or phenyl, wherein said phenyl group can be optionally substituted with a halo group;

R 8 and R 9 are each independently H or C 1 -C 6 alkyl;

R 10 is C 1 -C 6 alkyl; and

R 11 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.

5. The compound of claim 4 , wherein R 1 is:

6. The compound of claim 4 , wherein R 1 and R 2 join to form a group having the formula:

7. The compound of claim 5 , wherein R 1 is:

8. The compound of claim 6 , wherein R 1 and R 2 join to form a group having the structure:

9. The compound of claim 4 , wherein Y is N or CH, R 4 is NH 2 and R 5 is H.

10. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

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

12. The pharmaceutical composition according to claim 11 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

13. The pharmaceutical composition according to claim 12 , further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

14. A method of treating a patient infected with HCV comprising the step of administering an amount of (i) the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier effective to treat infection by HCV in said patient.

15. The method according to claim 14 , further comprising the step of administering pegylated-interferon alpha and an HCV protease inhibitor to said patient.

16. The method according to claim 14 further comprising the step of administering ribavirin to said patient.