IP Library › Granted Patent US 8,399,428

Granted Patent B2

US 8,399,428 · App. 11/721,325 · Granted Mar 19, 2013

Nucleosides with antiviral and anticancer activity

Inventor: Carston R. Wagner (St. Paul, MN)

Assignee: Regents of the University of Minnesota

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Quick Facts

Patent No.: US 8,399,428
App. No.: 11/721,325
Granted: Mar 19, 2013
Kind: B2

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Abstract

The invention provides a compound of formula (I), wherein R 1 -R 6 and X have any of the values described, as well as pharmaceutical compositions comprising such compounds and therapeutic methods comprising the administration of such compounds.

Claims (175)

1. A compound of formula I:

wherein:

R 1 is adenine, 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 and R 6 are each independently hydrogen, 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, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae , provided that one of R 2 and R 6 is hydroxyl, halo, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, trifluoromethyl, cyano, or NR ad R ae ;

R 3 is hydrogen, 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, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ;

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 NR a R b ;

R 7 is hydrogen, 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, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ;

X is oxy, thio, or methylene;

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or Het; or R a and R b together with the nitrogen to which they are attached form a nitrogen-linked Het;

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;

R z is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

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

R ac is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ad is hydrogen (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ae is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R w , R x , R y , R z , R aa , R ab , R ae , R ad , and R ae 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, Het, aryl(C 1 -C 6 )alkyl, or Het(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;

wherein any (C 1 -C 6 )alkyl of R a and R b is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, (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, Het, aryl(C 1 -C 6 )alkyl, or Het(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 1 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

and wherein any aryl or Het 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 of claim 1 which is a compound of formula I:

wherein:

R 2 and R 6 are each independently hydrogen, 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, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae , provided that one of R 2 and R 6 is hydroxy halo, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, trifluoromethyl, cyano, or NR ad R ae ;

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 NR a R b ;

X is oxy, thio, or methylene;

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or aryl(C 1 -C 6 )alkyl; or R a and R b together with the nitrogen to which they are attached form a pyrrolidino, piperidino or morpholino;

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

R z is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ac is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ad is hydrogen (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ae is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R w , R x , R y , R z , R aa , R ab , R ac , R ad , and R ae 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, aryl(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;

provided that R 2 and R 3 are each not hydroxy when R 1 is adenine, guanine, cytosine, thymine, or uracil, X is oxy, R 6 is hydrogen, and R 7 is hydrogen.

3. The compound of claim 1 wherein R a is (C 1 -C 6 )alkyl optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, (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, Het, aryl(C 1 -C 6 )alkyl, or Het(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.

4. The compound of claim 1 wherein R a is (C 1 -C 6 )alkyl optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, cyano, aryl, or Het.

5. The compound of claim 1 wherein R a is (C 1 -C 6 )alkyl optionally substituted with one or more aryl or Het.

6. The compound of claim 5 wherein R a is (C 1 -C 6 )alkyl substituted with a phenyl, naphthyl, pyridyl, indolyl, isoindolyl, furyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, imidazolyl, thiazoyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholino ring, which ring is optionally 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.

7. The compound of claim 5 wherein R a is (C 1 -C 6 )alkyl substituted with a phenyl or indolyl ring, which ring is optionally 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.

8. The compound of claim 5 wherein R a is (C 1 -C 6 )alkyl substituted with a phenyl ring.

9. The compound of claim 5 wherein R a is (C 1 -C 6 )alkyl substituted with an indolyl ring.

10. The compound of claim 1 wherein R a is phenylmethyl, phenethyl, indolylmethyl, or 2-indolylethyl.

11. The compound of claim 1 wherein R a is 2-indol-3-ylethyl.

12. The compound of claim 1 wherein R b is hydrogen.

13. The compound of claim 1 which has the formula R 5 —B, wherein B is a phosphorous-linked 9-beta-D-arabinofuranosyladenosine monophosphate, 9-beta-D-arabinofuranosylguanosine monophosphate, or 9-beta-D-arabinofuranosylcytosine monophosphate.

14. The compound of claim 13 wherein R 5 is NR a R b ; R a is 2-indol-3-ylethyl; and R b is hydrogen.

15. The compound of claim 1 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 .

16. The compound of claim 1 wherein R 1 is adenine, 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 .

17. The compound of claim 1 wherein R 1 is adenine, guanine, cytosine, thymine, 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 .

18. The compound of claim 1 wherein R 1 is 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 .

19. The compound of claim 1 wherein R 1 is 3-deazaadenine optionally substituted by 1, 2, or 3 U; wherein each U is independently halo, hydroxy, 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 .

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

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

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

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

24. The compound 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 .

25. The compound of claim 1 wherein R 2 is hydroxy.

26. The compound of claim 1 wherein R 2 is halo.

27. The compound of claim 1 wherein R 2 is fluoro.

28. The compound of claim 1 wherein R 2 is chloro.

29. The compound of claim 1 wherein R 2 is (C 1 -C 6 )alkoxy.

30. The compound of claim 1 wherein R 2 is methoxy.

31. The compound of claim 1 wherein R 2 trifluoromethyl.

32. The compound of claim 1 wherein R 2 is cyano.

33. The compound of claim 1 wherein R 2 is amino, methylamino, dimethylamino, ethylamino, or dimethylamino.

34. The compound of claim 1 wherein R 3 is hydroxy.

35. The compound of claim 1 wherein R 3 is hydrogen.

36. The compound of claim 1 wherein R 3 is halo.

37. The compound of claim 1 wherein R 3 is fluoro.

38. The compound of claim 1 wherein R 3 is chloro.

39. The compound of claim 1 wherein R 3 is trifluoromethyl.

40. The compound of claim 1 wherein R 3 is azido.

41. The compound of claim 1 wherein R 3 is cyano.

42. The compound of claim 1 wherein R 3 is amino, methylamino, dimethylamino, ethylamino, or dimethylamino.

43. The compound of claim 1 wherein R 4 is hydrogen.

44. The compound of claim 1 wherein R 4 is methyl or ethyl.

45. The compound of claim 1 wherein R 4 is 2-cyanoethyl.

46. The compound of claim 1 wherein R 5 is a nitrogen linked radical of formula II:

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;

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; and

R k is hydrogen or (C 1 -C 5 )alkyl that is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano or NR ad R ae .

47. The compound of claim 46 wherein R h is hydrogen, (C 1 -C 6 )alkyl, phenylmethyl, or 3-indolylmethyl.

48. The compound of claim 46 wherein R h is phenylmethyl or 3-indolylmethyl.

49. The compound of claim 46 wherein R k is hydrogen.

50. The compound of claim 46 wherein the carbon bearing R h has the (R) absolute configuration.

51. The compound of claim 1 wherein R 6 is hydrogen or (C 1 -C 6 )alkyl.

52. The compound of claim 1 wherein R 2 is hydrogen or alkyl; and R 6 is 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, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae .

53. The compound of claim 1 wherein R 7 is hydrogen or (C 1 -C 6 )alkyl.

54. The compound of claim 1 wherein R 3 is hydrogen or alkyl; and R 7 is 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, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae .

55. A process for preparing a compound of formula I as described in claim 1 , wherein R 4 is hydrogen, comprising deprotecting a corresponding compound of formula I:

wherein Pg is a suitable removable protecting group.

56. A method for treating a viral infection in an animal comprising administering an animal in need of such treatment an effective amount of a compound as described in claim 1 .

57. A method for treating a viral infection in an animal comprising administering an effective amount of a compound as described in claim 1 to an animal in need of such treatment.

58. A method for treating HCV in an animal comprising administering an effective amount of a compound as described in claim 1 to an animal in need of such treatment.

59. A method for treating a metabolic liver disorder, in an animal comprising administering an effective amount of a compound as described in claim 1 to an animal in need of such treatment.

60. A method for treating a cancer in the liver of an animal comprising administering an effective amount of a compound as described in claim 1 to an animal in need of such treatment.

61. A method for treating cancer in the brain of an animal comprising administering an effective amount of a compound as described in claim 1 to an animal in need of such treatment.

62. A method for treating breast cancer, lung cancer or ovarian cancer in an animal comprising administering an effective amount of as described in claim 1 to an animal in need of such treatment.

63. The compound of claim 1 wherein:

R 2 and R 6 are each independently hydrogen, halo, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, azido, cyano, provided that one of R 2 and R 6 is hydroxy halo, (C 1 -C 6 )alkoxy, trifluoromethyl or cyano;

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 NR a R b ;

R 7 is hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, azido, or cyano;

X is oxy, thio, or methylene;

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or Het; or R a and R b together with the nitrogen to which they are attached form a nitrogen-linked Het;

R z is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ac is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ad is hydrogen (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

R ae is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;

wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R a , R b , R w , R x , R y , R z , R aa , R ab , R ac , R ad , and R ae 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, Het, aryl(C 1 -C 6 )alkyl, or Het(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;

or a pharmaceutically acceptable salt thereof.

64. The compound of claim 1 wherein:

R 1 is guanine 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 and R 6 are each independently hydrogen, hydroxy or (C 1 -C 6 )alkyl provided that one of R 2 and R 6 is hydroxyl;

R 3 is hydroxy;

R 4 is hydrogen;

R 5 is NR a R b ;

R 7 is hydrogen or (C 1 -C 6 )alkyl;

X is oxy, thio, or methylene;

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or Het; or R a and R b together with the nitrogen to which they are attached form a nitrogen-linked Het;

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

wherein any (C 1 -C 6 )alkyl of R 1 , R 2 , R 6 , 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, Het, aryl(C 1 -C 6 )alkyl, or Het(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;

or a pharmaceutically acceptable salt thereof.

65. The compound of claim 1 wherein:

R 1 is guanine;

R 2 is hydroxy;

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

R 3 is hydroxy;

R 4 is hydrogen;

R 5 is NR a R b ;

R 7 is hydrogen or (C 1 -C 6 )alkyl;

X is oxy, thio, or methylene;

R a is (C 1 -C 6 )alkyl substituted with a phenyl ring;

R b is hydrogen;

or a pharmaceutically acceptable salt thereof.

66. The compound of claim 1 wherein:

R 1 is guanine;

R 2 is hydroxy;

R 6 is (C 1 -C 6 )alkyl;

R 3 is hydroxy;

R 4 is hydrogen;

R 5 is NR a R b ;

R 7 is hydrogen;

X is oxy;

R a is phenylmethyl;

R b is hydrogen;

or a pharmaceutically acceptable salt thereof.

67. The compound of claim 1 wherein:

R 2 is hydroxy;

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

R 3 is hydroxy;

R 7 is hydrogen or (C 1 -C 6 )alkyl;

R a is (C 1 -C 6 )alkyl substituted with a phenyl ring; and

R b is hydrogen.

68. The compound of claim 1 wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R a , R b , R w , R x , R y , R z , R aa , R ab , R ae , R ad , and R ae is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, (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, Het, aryl(C 1 -C 6 )alkyl, or Het(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.

Assignments (1)

CONFIRMATORY LICENSE Recorded May 4, 2015

From: UNIVERSITY OF MINNESOTA

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 035570/0888 →

Continuity (2)

Provisional Application 60634677 · Dec 9, 2004

Related Publication 20090306007A1 · Dec 10, 2009