Substituted nucleosides, nucleotides and analogs thereof

• US RE48,171 E1
• Filed: 09/13/2018
• Issued: 08/25/2020
• Est. Priority Date: 03/21/2012
• Status: Active Grant

• Current Assignee: Janssen Biopharma, Inc. (Johnson & Johnson)
• Original Assignee: Janssen Biopharma, Inc. (Johnson & Johnson)
• Inventors: Wang, Guangyi, Smith, David Bernard, Beigelman, Leonid, Deval, Jerome, Prhavc, Marija
• Primary Examiner(s): Jones, Dwayne C.
• Application Number:
  US16/130,971
• Time in Patent Office: 712 Days
• CPC Class Codes: N/A

Abstract

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.

Claims

1. A method for ameliorating or treating a viral infection caused by a virus comprising administering to or contacting a cell in a subject with an effective amount of a compound selected from Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt of the foregoing, wherein the virus is selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus and a metapneumovirus, and wherein the compound is selected from Formula (I), Formula (II), and Formula (III) has one of the following structures:

2. The method of claim 1, wherein the virus is selected from the group consisting of a henipavirus, a morbillivirus and a rubulavirus.

3. The method of claim 1, wherein the virus is a respirovirus.

4. The method of claim 3, wherein the respirovirus is human parainfluenza virus 1.

5. The method of claim 3, wherein the respirovirus is human parainfluenza virus 3.

6. The method of claim 2, wherein the rubulavirus is human parainfluenza virus 2 and/or human parainfluenza virus 4.

7. The method of claim 1, wherein the virus is a metapneumovirus.

8. The method of claim 7, wherein the metapneumovirus is human metapneumovirus.

9. The method of claim 1, wherein the compound is a compound of Formula (I).

10. The method of claim 9, wherein R^1A is

11. The method of claim 10, wherein R^6A and R^7A are both hydrogen or absent.

12. The method of claim 10, wherein one of R^6A and R^7A is hydrogen, and the other of R^6A and R^7A is selected from the group consisting of an optionally substituted C_1-24 alkyl, an optionally substituted C_2-24 alkenyl, an optionally substituted C_2-24 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted C_3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(C_1-6 alkyl);

wherein both R^6A and R^7A are independently selected from the group consisting of an optionally substituted C_1-24 alkyl, an optionally substituted C_2-24 alkenyl, an optionally substituted C_2-24 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted C_3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(C_1-6 alkyl);

wherein at least one of R^6A and R^7A are selected from the group consisting of

13. The method of claim 10, wherein R^6A and R^7A are both

14. The method of claim 10, wherein Z^1A, Z^2A and Z^3A is O.

15. The method of claim 10, wherein Z^1A, Z^2A and Z^3A is S.

16. The method of claim 10, wherein R^8A is selected from the group consisting of absent, hydrogen, an optionally substituted C_1-24 alkyl, an optionally substituted C_2-24 alkenyl, an optionally substituted C_2-24 alkynyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_3-6 cycloalkenyl;

and R^9A is independently selected from the group consisting of an optionally substituted C_1-24 alkyl, an optionally substituted C_2-24 alkenyl, an optionally substituted C_2-24 alkynyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_3-6 cycloalkenyl;

wherein R^8A is hydrogen, and R^9A is NR^3OAR^31A NR^30AR^31A, wherein R³⁰ R^30A and R³¹ R^31A are independently selected from the group consisting of hydrogen, an optionally substituted C_1-24 alkyl, an optionally substituted C_2-24 alkenyl, an optionally substituted C_2-24 alkynyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_3-6 cycloalkenyl;

wherein R^8A is absent or hydrogen; and

R^9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;

or wherein R^8A is an optionally substituted aryl; and

R^9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

17. The method of claim 10, wherein R^9A is selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof;

or wherein R^9A is selected from the group consisting of alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester;

or wherein R^9A has the structure

18. The method of claim 17, wherein R^34A is an optionally substituted C_1-6-alkyl;

R^35A is hydrogen; and

/or R^33A is an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 cycloalkyl or an optionally substituted benzyl.

19. The method of claim 10, wherein R^10A and R^11A are both an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;

wherein R^10A and R^11A are independently selected from selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof;

wherein R^10A and R^11A are independently selected from the group consisting of alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester;

or wherein R^10A and R^11A are independently have the structure

20. The method of claim 19, wherein R^37A is an optionally substituted C_1-6-alkyl;

R^38A is hydrogen and/or R^36A is an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 cycloalkyl or an optionally substituted benzyl.

21. The method of claim 10, wherein R^6A is

22. The method of claim 21, wherein m is 0, and R^12A and R^13A are independently absent or hydrogen.

23. The method of claim 21, wherein m is 1, and R^12A, R^13A and R^14A are independently absent or hydrogen.

24. The method of claim 9, wherein R^1A is H.

25. The method of claim 9, wherein R^1A is an optionally substituted acyl.

26. The method of claim 25, wherein the optionally substituted acyl is —

C(═

O)R^39A, wherein R^39A is selected from the group consisting of an optionally substituted C_1-12 alkyl, an optionally substituted C_2-12 alkenyl, an optionally substituted C_2-12 alkynyl, an optionally substituted C_3-8 cycloalkyl, an optionally substituted C_5-8 cycloalkenyl, an optionally substituted C_6-10 aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C_1-6 alkyl), an optionally substituted heteroaryl(C_1-6 alkyl) and an optionally substituted heterocyclyl(C_1-6 alkyl).

27. The method of claim 26, wherein R^39A is an unsubstituted C_1-12 alkyl.

28. The method of claim 9, wherein R^1A is an optionally substituted O-linked amino acid.

29. The method of claim 9, wherein B^1A is selected from the group consisting of:

30. The method of claim 29, wherein B^1A is

31. The method of claim 29, wherein B^{1A is} is

32. The method of claim 29, wherein B^1A is

33. The method of claim 9, wherein R^2A is a halogen substituted C_1-6 alkyl or a sulfenyl substituted C_1-6 alkyl, and R^3A is selected from the group consisting of OH, —

OC(═

O)R″

^A and an optionally substituted O—

linked amino acid.

34. The method of claim 33 9, wherein R^2A is an unsubstituted C_1-6 alkyl.

35. The method of claim 33 9, wherein R^2A is an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted —

O—

C_1-6 alkyl, an optionally substituted —

O—

C_3-6 alkenyl, an optionally substituted —

O—

C_3-6 alkynyl or cyano.

36. The method of claim 9, wherein R^3A is OH.

37. The method of claim 9, wherein R^3A is —

OC(═

O)R″

^A, wherein R″

^A is an optionally substituted C_1-8 alkyl.

38. The method claim 9, wherein R^3A is O-linked amino acid.

39. The method of claim 38, wherein the O-linked amino acid is selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine;

or wherein R^3A is

40. The method of claim 39, wherein R^42A is an optionally substituted C_1-6-alkyl;

and/or R^43A is hydrogen.

41. The method of claim 9, wherein R^5A is hydrogen.

42. The method of claim 9 wherein R^5A is halogen.

43. The method of claim 9, wherein R^4A is fluoro.

44. The method of claim 9, wherein the compound of Formula (I) is selected from the group consisting of:

45. The method of claim 9, wherein the compound of Formula (I) is selected from the group consisting of:

46. The method of claim 9, wherein the compound of Formula (I) is selected from the group consisting of:

47. The method of claim 9, wherein the compound of Formula (I) is selected from the group consisting of:

48. The method of claim 34 9, wherein R^2A is a halogen substituted C_1-6 alkyl, a hydroxy substituted C_1-6 alkyl, an alkoxy substituted C_1-6 alkyl or a sulfenyl substituted C_1-6 alkyl.

49. The method of claim 34 48, wherein R^2A is a halogen substituted C_1-6 alkyl.

50. The method of claim 9, wherein the compound of Formula (I) is

51. The method of claim 50, wherein the compound of Formula (I)

52. The method of claim 50 9, wherein the compound of Formula (I) is

53. The method of claim 50, wherein the compound of Formula (I) is

54. The method of claim 33, wherein R^2A is a sulfenyl substituted C_1-6 alkyl.

55. The method of claim 33, wherein R^2A is a halogen substituted C_1-6 alkyl.

56. The method of claim 9, wherein the metapneumovirus virus is human metapneumovirus and wherein the compound is a pharmaceutically acceptable salt of

57. The method of claim 9, wherein the respirovirus is human parainfluenza virus 3 and wherein the compound is