Antiviral compounds

• US 8,178,491 B2
• Filed: 06/26/2008
• Issued: 05/15/2012
• Est. Priority Date: 06/29/2007
• Status: Expired due to Fees

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Cho, Aesop, Clarke, Michael O'Neil Hanrahan, Kim, Choung U., Link, John O., Pyun, Hyung-jung, Sheng, Xiaoning C., Wu, Qiaoyin
• Primary Examiner(s): Tsang, Cecilia J
• Assistant Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US12/215,605
• Publication Number:
  US 20090257978A1
• Time in Patent Office: 1,419 Days
• Field of Search: None
• US Class Current: 514/3.7
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07K 5/0804 and aliphatic
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/0819 with the first amino acid being acidic
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Abstract

The invention is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Claims

1. A compound of formula I:

2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is O.

3. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Z¹ is selected from the following structures:

4. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein R_c is a heteroaryl ring selected from:

5. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein each R_c is selected from:

6. The compound of claim 3, or pharmaceutically acceptable salt thereof, wherein R_b is H or Cl.

7. The compound of claim 3, or pharmaceutically acceptable salt thereof wherein R_a is H, methoxy, N-(2-cyanoethyl)amino, N-(3,3,3-trifluoroethyl)amino, 2-methoxyethoxy, 2-hydroxyethoxy, 2-hydroxy-2-methylpropoxy, 2-amino-2-methylpropoxy, N,N-dimethylaminocarbonylmethoxy, morpholinocarbonylmethoxy, 2-[N-(2,2,2-trifluoroethyl)amino]ethoxy, 2-morpholinoethoxy, cyanomethoxy, 2-piperazin-1-ylethoxy, 2-(N,N-dimentylamino)ethoxy, 2-(3,3-dimethylmorpholino)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, or carboxymethoxy.

8. The compound of claim 3, or pharmaceutically acceptable salt thereof wherein R_a is H, methoxy, N-(2-cyanoethyl)amino, N-(3,3,3-trifluoroethyl)amino, 2-methoxyethoxy, 2-hydroxyethoxy, 2-hydroxy-2-methylpropoxy, 2-amino-2-methylpropoxy, N,N-dimethylaminocarbonylmethoxy, morpholinocarbonylmethoxy, 2-[N-(2,2,2-trifluoroethyl)amino]ethoxy, or 2-morpholinoethoxy.

9. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Z¹ is selected from the following structures:

10. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Z¹ is selected from the following structures:

11. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Z¹ is selected from the following structures:

12. The compound of claim 1, or pharmaceutically acceptable salt thereof wherein Q¹ is vinyl or ethyl.

13. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Z^2a is tert-butyl.

14. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Y is a bridged carbocyclic ring system.

15. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Y comprises a bridged ring system selected from:

16. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Y comprises a fused ring system selected from:

17. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Y is selected from:

18. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein Y is selected from:

19. The compound of claim 1 which is selected from:

20. The compound of claim 1 which is selected from:

21. The compound of claim 1 which is selected from:

22. The compound of claim 1 which is selected from:

23. The compound of claim 1 which is selected from:

24. The compound of claim 1 which is a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound of claim 1, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25, further comprising at least one additional therapeutic agent.

27. The pharmaceutical composition of claim 26, wherein said additional therapeutic agent is selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

28. The pharmaceutical composition according to claim 25, further comprising a nucleoside analogue.

29. The pharmaceutical composition according to claim 28, further comprising an interferon or pegylated interferon.

30. The pharmaceutical composition according to claim 28, wherein said nucleoside analogue is selected from ribavirin, viramidine, levovirin, a L-nucleoside, and isatoribine and said interferon is α

-interferon or pegylated interferon.

31. A method of treating hepatitis C, said method comprising administering to an individual a pharmaceutical composition which comprises a therapeutically effective amount of the compound of claim 1.

32. A compound which is:

33. A pharmaceutical composition comprising the compound,