5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases

1. A compound having the structure:

or a pharmaceutically acceptable salt thereof,

wherein:

X is O, S or CH 2 ;

Y is H or C 1 -C 6 alkyl;

Z is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(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 group), —(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 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, halo, —OR 20 , —SR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 ;

B is:

R 1 is H, —C(O)—C 1-6 alkyl,

R 2 is H or —C(O)—C 1-6 alkyl, or R 1 and R 2 join to form a group having the formula:

R 3 is —OH, halo, 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 3′ is —OH, halo, 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, with the proviso that R 3 and R 3′ cannot both be —OH;

R 4 is H, halo, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or 5- or 6-membered monocyclic heteroaryl;

R 5 and R 6 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 20 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —NHC(O)N(R 20 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 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 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 , wherein said C 2 -C 6 alkenyl group and said C 2 -C 6 alkynyl group can be optionally substituted with a halo group;

R 12 is H or —(C 1 -C 6 alkylene)-T-R 21 ;

R 13 is H or —(C 1 -C 6 alkylene)-T-R 21 , or R 12 and R 13 can join to form a C 2 -C 4 alkylene group between the oxygen atoms that R 12 and R 13 are attached to, wherein said C 2 -C 4 alkylene group is substituted with at least one C 6 -C 10 aryl group;

R 14 is H, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein said C 6 -C 1 ° 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 22 ;

R 15 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 20 , —SR 20 , guanidino, —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —NHC(O)R 20 , 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 20 ;

R 16 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 20 , —SR 20 , guanidino, —N(R 20 ) 2 , —C(O) OR 20 , —C(O)N(R 20 ) 2 , —NHC(O)R 20 , 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 20 ;

R 17 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 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 20 , —C(O)OR 20 , 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 20 ) 2 , —C(O)N(R 20 ) 2 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —NHC(O)R 20 , —NHC(O)OR 20 and —NHC(O)N(R 20 ) 2 and;

R 18 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene) m -C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, 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 up to five groups, each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, —OR 20 , —SR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 ;

each occurrence of R 20 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), —(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 26 ;

each occurrence of R 21 is independently H, 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, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —OR 20 , —O—(C 1 -C 6 haloalkyl) or —N(R 20 ) 2 , wherein said C 2 -C 6 alkenyl group, said C 2 -C 6 alkynyl group, said C 3 -C 7 cycloalkyl group, said C 3 -C 7 cycloalkenyl group, said C 6 -C 10 aryl group, said 5- or 6-membered monocyclic heteroaryl group or 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, halo, —OR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 ;

R 22 represents from one to five substituent groups, each independently selected from C 1 -C 6 alkyl, halo, —OR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 , or any two R 22 groups on adjacent ring carbon atoms can combine to form —O—R 23 —O—;

R 23 is —[C(R 24 ) 2 ] n —;

each occurrence of R 24 is independently H or C 1 -C 6 alkyl;

each occurrence of R 25 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), 4 to 7-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein said C 1 -C 6 alkyl group, said C 2 -C 6 alkenyl group, said C 2 -C 6 alkynyl group, 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 26 ; or two R 25 groups, together with the common nitrogen atom to which they are attached, join to form a 4- to 7-membered heterocycloalkyl group;

R 26 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 27 , —SR 27 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 27 ) 2 , —C(O)OR 27 , —C(O)N(R 27 ) 2 and —NHC(O)R 27 ;

each occurrence of R 27 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), —(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);

each occurrence of T is independently —S—, —O—, —SC(O)—, —SC(S)—, —OC(O)— or —OC(S)—;

each occurrence of m is independently 0 or 1; and

each occurrence of n is independently 1 or 2.

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

3. The compound of claim 1 , wherein Z is C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein R 3 is C 1-6 alkyl.

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

and pharmaceutically acceptable salts thereof,

wherein:

B is:

Y is H or methyl;

Z is methyl or ethyl;

R 1 is H,

R 3′ is —OH or halo;

R 4 is H, halo or 5- or 6-membered monocyclic heteroaryl;

R 14 is phenyl or naphthyl; and

R 17 is C 1 -C 6 alkyl.

6. The compound of claim 5 , wherein B is:

7. The compound of claim 5 , wherein Y is H and Z is methyl.

8. The compound of claim 5 , wherein Y is H and Z is ethyl.

9. The compound of claim 5 , wherein R 1 is H.

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

R 14 is phenyl or naphthyl, each of which can be optionally substituted with halo; and

R 17 is methyl, ethyl, isopropyl, isobutyl or n-butyl.

11. The compound of claim 5 , wherein R 3′ is F or —OH.

12. The compound of claim 5 , wherein R 3′ is F.

13. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

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

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

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

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

18. The method of claim 17 , further comprising the step of administering an HCV protease inhibitor to said patient.

19. The method of claim 17 , further comprising the step of administering ribavirin to said patient.