Nucleosides with antiviral and anticancer activity

1. A compound of formula I:

wherein:

R 1 is guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 U; wherein each U is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, hydroxy(C 1 -C 6 )alkyl, —(CH 2 ) 1-4 P(═O)(OR w ) 2 , aryl, aryl(C 1 -C 6 )alkyl, or NR x R y ;

R 2 is halo;

R 6 and R 7 are independently H or (C 1 -C 6 )alkyl;

R 3 is hydroxy;

R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aryl(C 1 -C 6 )alkyl, or 2-cyanoethyl;

R 5 is an amino acid;

X is oxy, thio, or methylene;

each R w is independently hydrogen or (C 1 -C 6 )alkyl;

R x and R y are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, phenethyl, or (C 1 -C 6 )alkanoyl; or R x and R y together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;

wherein any (C 1 -C 6 )alkyl of R 1 , R 4 -R 7 , R w , R x , and R y is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, heteroaryl, alkyl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj and R ak is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

and wherein any aryl or heteroaryl may optionally be substituted with one or more substituents selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, and amino;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 wherein R 1 is guanine, cytosine, thymine, 3-deazaadenine, or uracil.

3. The compound or salt of claim 1 wherein R 1 is cytosine, thymine, 3-deazaadenine, or uracil.

4. The compound or salt of claim 1 wherein R 1 is cytosine, thymine, or uracil.

5. The compound or salt of claim 1 wherein R 1 is a nitrogen linked radical of formula VI:

wherein R af is hydrogen, halo, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or trifluoromethyl; and R ag is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, trifluoromethyl, hydroxy(C 1 -C 6 )alkyl, or —(CH 2 ) 1-4 P(═O)(OR w ) 2 .

6. The compound or salt of claim 1 wherein R 2 is fluoro.

7. The compound or salt of claim 1 wherein R 5 is a nitrogen linked radical of formula III:

wherein R h , is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 )alkyl; wherein any aryl or heteroaryl may optionally be substituted with 1, 2, or 3 Z; R j is hydrogen, (C 1 -C 6 )alkyl, phenyl, benzyl, or phenethyl; and wherein each Z is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino.

8. The compound or salt of claim 7 wherein R h is hydrogen, (C 1 -C 6 )alkyl, phenylmethyl, or 3-indolylmethyl.

9. The compound or salt of claim 8 wherein R j is H or (C 1 -C 6 )alkyl.

10. The compound or salt of claim 8 wherein the carbon bearing R h has the (R) absolute configuration.

11. The compound or salt of claim 1 wherein R 5 is a (C 1 -C 6 )alkyl ester of L-alanine.

12. The compound or salt of claim 11 wherein R 7 is hydrogen.

13. A method for treating a viral infection in an animal comprising administering to an animal in need of such treatment an effective amount of a compound or salt of formula I according to claim 1 .

14. The method of claim 13 wherein R 1 is guanine, cytosine, thymine, 3-deazaadenine, or uracil.

15. The method of claim 13 wherein R 1 is cytosine, thymine, 3-deazaadenine, or uracil.

16. The method of claim 13 wherein R 1 is cytosine, thymine, or uracil.

17. The method of claim 13 wherein R 1 is a nitrogen linked radical of formula VI:

wherein R af is hydrogen, halo, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or trifluoromethyl; and R ag is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, trifluoromethyl, hydroxy(C 1 -C 6 )alkyl, or —(CH 2 ) 1-4 P(═O)(OR w ) 2 .

18. The method of claim 13 wherein R 2 is fluoro.

19. The method of claim 13 wherein R 5 is a nitrogen linked radical of formula III:

wherein R h , is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 )alkyl; wherein any aryl or heteroaryl may optionally be substituted with 1, 2, or 3 Z; R j is hydrogen, (C 1 -C 6 )alkyl, phenyl, benzyl, or phenethyl; and wherein each Z is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino.

20. The method of claim 19 wherein R h is hydrogen, (C 1 -C 6 )alkyl, phenylmethyl, or 3-indolylmethyl.

21. The method of claim 20 wherein R j is H or (C 1 -C 6 )alkyl.

22. The method of claim 20 wherein the carbon bearing R h has the (R) absolute configuration.

23. The method of claim 13 wherein R 5 is a (C 1 -C 6 )alkyl ester of L-alanine.

24. The method of claim 23 wherein R 7 is hydrogen.

25. The method of claim 13 wherein the viral infection is caused by HCV.

26. The method of claim 13 wherein the animal is a human.

27. The method of claim 26 wherein the compound or salt of formula I is orally administered.

28. A pharmaceutical composition comprising a compound or salt of formula I as described in claim 1 and a pharmaceutically acceptable vehicle or carrier.