INHIBITORS OF INFLUENZA VIRUSES REPLICATION

• US 20150191468A1
• Filed: 03/24/2015
• Published: 07/09/2015
• Est. Priority Date: 08/01/2011
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charifson, Paul S., Clark, Michael P., Bandarage, Upul K., Bethiel, Randy S., Davies, Ioana, Deng, Hongbo, Duffy, John P., Farmer, Luc J., Gao, Huai, Gu, Wenxin, Kennedy, Joseph M., Ledford, Brian, Ledeboer, Mark W., Maltais, Francois, Perola, Emanuele, Wang, Tiansheng, Boyd, Micheal J.
• Granted Patent: US 9,394,302 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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 X¹ is —

F or —

Cl.

3. The compound of claim 1 or 2, wherein X² is —

F or —

Cl.

4. The compound of any one of claims 1-3, wherein Z¹ is CH.

5. The compound of any one of claims 1-3, wherein Z¹ is N.

6. The compound of any one of claims 1-5, wherein Z² is N, C—

F, or C—

CN.

7. The compound of any one of claims 1-6, wherein R¹, R², and R³ are each and independently —

CH₃ or —

C₂H₅;

or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring.

8. The compound of any one of claims 1-6, wherein R¹, R², and R³ are each and independently —

CH₃, —

CH₂F, —

CF₃, or —

C₂H₅;

or R¹ is —

CH₃, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.

9. The compound of claim 8, wherein each of R¹, R², and R³ is independently —

CH₃ or —

C₂H₅;

or R¹ is —

CH₃, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.

10. The compound of any one of claims 1-9, wherein:

R⁶ and R⁷ are each and independently —

H, —

OH, —

CH₃, or —

CF₃.

11. The compound of any one of claims 1-10, wherein each Q is independently —

C(O)OR, —

OH, —

CH₂OH, —

S(O)₂R′

, —

S(O)₂—

NR″

R′

″

, or a 5-membered heterocycle selected from the group consisting of;

12. The compound of claim 11, wherein Q is —

C(O)OR, —

OH, —

S(O)₂R′

, or —

S(O)₂—

NR″

R′

″

.

13. The compound of any one of claims 1-12, wherein:

R′

is —

OH or —

CH₂C(O)OH;

R″

is —

H; and

R′

″

is —

H, a 3-6 membered carbocyclic ring, or optionally substituted C_1-4 alkyl.

14. The compound of any one of claims 1-13, wherein R is —

H.

15. The compound of any one of claims 1-14, wherein the compound is represented by Structural Formula II:

16. The compound of claim 1, wherein the compound is represented by Structural Formula

17. The compound of claim 16, wherein X¹ is —

F or —

Cl.

18. The compound of claim 16 or 17, wherein X² is —

F or —

Cl.

19. The compound of any one of claims 16-18, wherein Z¹ is CH.

20. The compound of any one of claims 16-18, wherein Z¹ is N.

21. The compound of any one of claims 16-20, wherein Z² is N, C—

F, or C—

CN.

22. The compound of any one of claims 16-21, wherein R¹, R², and R³ are each and independently —

CH₃ or —

C₂H₅;

or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring.

23. The compound of any one of claims 16-21, wherein R¹, R², and R³ are each and independently —

CH₃, —

CH₂F, —

CF₃, or —

C₂H₅;

or R¹ is —

CH₃, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.

24. The compound of claim 23, wherein each of R¹, R², and R³ is independently —

CH₃ or —

C₂H₅;

or R¹ is —

CH₃, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.

25. The compound of any one of claims 16-24, wherein Q is —

C(O)OR, —

OH, —

S(O)₂R′

, or —

S(O)₂—

NR″

R′

″

.

26. The compound of any one of claims 16-25, wherein:

R′

is —

OH or —

CH₂C(O)OH;

R″

is —

H; and

R′

″

is —

H, a 3-6 membered carbocyclic ring, or optionally substituted C_1-4 alkyl.

27. The compound of any one of claims 16-26, wherein R is —

H.

28. The compound of any one of claims 16-27, wherein the compound is represented by Structural Formula (IV) or (V):

29. The compound of claim 1, wherein the compound is represented by any one of Structural Formulae (VI)-(X):

30. The compound of claim 29, wherein X¹ is —

F or —

Cl.

31. The compound of claim 29 or 30, wherein X² is —

F or —

Cl.

32. The compound of any one of claims 29-31, wherein Z¹ is CH.

33. The compound of any one of claims 29-31, wherein Z¹ is N.

34. The compound of any one of claims 29-33, wherein Z² is N, C—

F, or C—

CN.

35. The compound of any one of claims 29-34, wherein R¹, R², and R³ are each and independently —

CH₃ or —

C₂H₅.

36. The compound of any one of claims 29-35, wherein:

R′

is —

OH or —

CH₂C(O)OH;

R″

is —

H; and

R′

″

is —

H, a 3-6 membered carbocyclic ring, or optionally substituted C_1-4 alkyl.

37. The compound of any one of claims 29-36, wherein R is —

H.

38. The compound of claim 1, selected from any one of the compounds depicted in FIG. 1 or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition, comprising a compound according to any one of claims 1-38, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

40. 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 1-38.

41. The method of claim 40, further comprising co-administering an additional therapeutic agent.

42. The method of claim 41, wherein the additional therapeutic agent is selected from an antiviral agent or an Influenza vaccine.

43. 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 1-38.

44. 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 1-38.

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

46. The method of claim 45, wherein L² is Br or Cl.

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

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

49. The method of claim 48, wherein L¹ is Br or Cl.

50. A compound represented by Structural Formula (XX) or a pharmaceutically acceptable salt thereof: