INHIBITORS OF INFLUENZA VIRUSES REPLICATION

• US 20130345218A1
• Filed: 06/14/2013
• Published: 12/26/2013
• Est. Priority Date: 12/16/2010
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charifson, Paul S., Clark, Michael P., Bandarage, Upul K., Deng, Hongbo, Davies, Ioana, Duffy, John P., Farmer, Luc J., Gao, Huai, Gu, Wenxin, Kennedy, Joseph M., Ledeboer, Mark W., Ledford, Brian, Maltais, Francois, Perola, Emanuele, Wannamaker, Marion W., Wang, Tiansheng, Salituro, Francesco G.
• Application Number:
  US13/918,115
• Publication Number:
  US 20130345218A1
• Time in Patent Office: Days
• US Class Current: 514/234.5
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A compound is represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

Claims

1. A compound represented by Structural Formula (I):

2. The compound of claim 1, wherein at least one of Z¹-Z⁴ is N;

X is —

Cl, —

Br, —

F, —

CN, —

O(C_1-4 alkyl), C_1-6 alkyl, or C_1-6haloalkyl;

Ring S is selected from;

6. The compound of claim 2, wherein

X is —

Cl, —

Br, —

F, —

CN, —

CH₃, or CF₃;

Q¹ is —

CO₂—

, —

O(CR^tR^s)_k—

C(O)O—

, —

P(O)(OR)O—

, —

OP(O)(OR^a)O—

, —

P(O)₂O—

, —

CO₂SO₂—

or —

(CR^tR^s)_p—

Y¹—

;

Y¹ is —

CO₂—

, —

O(CR^tR^s)_k—

C(O)O—

, —

P(O)(OR)O—

, —

OP(O)(OR^a)O—

, —

P(O)₂O—

, or —

CO₂SO₂—

; and

Ring S is

8. The compound of claim 6, wherein Ring T is an optionally substituted, bridged, C₅-C₁₀ carbocyclic group, or an optionally substituted, monocyclic, C₅-C₈ carbocyclic group.

46. A pharmaceutical composition, comprising a compound according to any one of claims 1, 2, 6, 8, 15, 16, 20, 21, 25, 26, 27, 29, 32, 34, 36, 38, 44, and 45, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

47. A method of inhibiting the replication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound as described in any one of claims 1, 2, 6, 8, 15, 16, 20, 21, 25, 26, 27, 29, 32, 34, 36, 38, 44, and 45.

50. A method of reducing the amount of influenza viruses in a biological sample or in a patient, comprising administering to said biological sample or patient an effective amount of a compound as described in any one of claims 1, 2, 6, 8, 15, 16, 20, 21, 25, 26, 27, 29, 32, 34, 36, 38, 44, and 45.

51. A method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound as described in any one of claims 1, 2, 6, 8, 15, 16, 20, 21, 25, 26, 27, 29, 32, 34, 36, 38, 44, and 45.

52. A method preparing a compound represented by Structural Formula (I):

54. A method preparing a compound represented by Structural Formula (I):

55. A method preparing a compound represented by Structural Formula (I):

57. A compound represented by Structural Formula (XX):

59. The compound of claim 57, represented by any one of the following structural formulae:

60. The compound of claim 57, represented by any one of the following structural formulae:

3. (canceled)

4. (canceled)

5. (canceled)

7. (canceled)

9. (canceled)

10. (canceled)

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. The compound of claim, wherein Ring S is selected from:

16. The compound of claim 15, wherein Ring T is:

20. The compound of claim 16, wherein Ring S is selected from:

21. The compound of claim 20, wherein:

(a) R¹², R¹³, and R¹⁴ are each and independently —

H, halogen, cyano, hydroxy, —

O(C₁-C₆ alkyl), or optionally substituted C₁-C₆ alkyl;

R¹⁵ is —

H or optionally substituted C₁-C₆ alkyl; and

R^t and R^s are each independently —

H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

or

(b) R¹² and R¹³ are each independently —

H, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —

O(C₁-C₆ alkyl);

R¹⁴ and R¹⁵ are each independently —

H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R^t and R^s are each independently —

H or C₁-C₆ alkyl.

25. The compound of claim 21, wherein Ring A and R¹⁵, Ring A and R¹⁴, or Ring A and R¹³ independently form an optionally substituted, bridged carbocyclic group.

26. The compound of claim 25, wherein Ring T is:

27. The compound of claim 26, wherein:

R¹⁴ and each R¹⁵ are each independently —

H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —

H, halogen, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.

29. The compound of claim 27, wherein

Q¹ is independently —

C(O)O—

, —

NRC(O)—

, or —

C(O)NR—

R¹ is independently —

H or an optionally substituted C₁-C₆ aliphatic group; and

R and R′

are each and independently —

H or —

CH₃;

or optionally R¹, together with R′ and

the nitrogen to which they are attached, form an optionally substituted, 4-8 membered heterocyclic group.

32. The compound of claim 29, wherein

Ring T is:

34. The compound of claim 32 any one of claims 26-32, wherein:

R¹ is H or optionally substituted C_1-6 alkyl;

R¹⁴, R¹⁵, R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —

H; and

q is 1.

36. The compound of claim 21, wherein

Ring T is selected from:

38. The compound of claim 36, wherein:

Q¹ is independently —

NRC(O)—

, —

C(O)NR—

, or —

NRC(O)NR′

—

;

R¹⁴ and each R¹⁵ are each independently —

H or C_1-6 alkyl;

each of Rings A8-A11 is independently and optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and —

O(C₁-C₄ alkyl); and

R and R′

are each and independently —

H or —

CH₃.

17. (canceled)

18. (canceled)

19. (canceled)

22. (canceled)

23. (canceled)

24. (canceled)

28. (canceled)

30. (canceled)

31. (canceled)

33. (canceled)

35. (canceled)

37. (canceled)

39. (canceled)

40. (canceled)

41. (canceled)

42. (canceled)

43. (canceled)

44. A compound selected from any of one of the structures depicted below or a pharmaceutically acceptable salt thereof:

45. A compound selected from any of one of the structures depicted below or a pharmaceutically acceptable salt thereof:

48. (canceled)

49. (canceled)

53. (canceled)

56. (canceled)

58. (canceled)