Antiviral compounds

• US 8,513,186 B2
• Filed: 06/26/2008
• Issued: 08/20/2013
• Est. Priority Date: 06/29/2007
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Cottell, Jeromy J., Link, John O., Schroeder, Scott D., Taylor, James, Tse, Winston C., Vivian, Randall W., Yang, Zheng-Yu
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US12/215,601
• Publication Number:
  US 20090186869A1
• Time in Patent Office: 1,881 Days
• Field of Search: None
• US Class Current: 514/4.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 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: C07D 495/04 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 5/0812 and aromatic or cycloaliphatic
• 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 wherein Z¹ is selected from the following structures:

3. The compound of claim 1 wherein Z¹ is selected from the following structures:

4. The compound of claim 1 which is

5. The compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein:

Z¹ is;

6. The compound of formula (I) as described in claim 5 or a pharmaceutically acceptable salt thereof, wherein Z¹ is selected from the following structures:

7. The compound of claim 1 wherein R_c is selected from:

8. The compound of claim 1 wherein R_c is selected from:

9. The compound of claim 5 wherein R_a is H, methoxy, trifluoromethoxy, chloro, 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.

10. The compound of claim 1 wherein Z¹ is selected from the following structures:

11. The compound of claim 1 wherein R_c is

12. The compound of claim 1 wherein R^f is cyclopropyl optionally substituted by up to three A³.

13. The compound of claim 1 wherein R^f is cyclopropyl optionally substituted by one A³.

14. The compound of claim 1 wherein R^f is phenyl, cyclopropyl, 2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-methylphenyl, 2,2-dimethylpropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, or 1-methylcyclopropyl.

15. The compound of claim 1 wherein R^f is cyclopropyl.

16. The compound of claim 1 wherein R^f is 1-methylcyclopropyl.

17. A compound of claim 1, wherein the compound of formula I is a compound of formula (II):

18. The compound of claim 1 wherein Q¹ is vinyl, ethyl, cyanomethyl, propyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2-cyanoethyl.

19. The compound of claim 1 wherein Q¹ and Z^2a taken together with the atoms to which they are attached form a 12-18 membered heterocycle, wherein said heterocycle may optionally be substituted with one or more oxo (═

O) or A³.

20. A compound of claim 1, wherein the compound of formula I is a compound of formula (III):

21. A compound of claim 1, wherein the compound of formula I is a compound of formula (IV):

22. The compound of claim 1 wherein Z^2a is tert-butyl, 1-methylcyclohexyl, tetrahydropyran-4-yl, 1-methylcyclohexyl, 4,4-difluorocyclohexyl, 2,2,2-trifluoro-1-trifluoromethylethyl, or cyclopropyl.

23. A pharmaceutical composition comprising the compound as described in claim 1 or a pharmaceutically acceptable salt thereof;

and at least one pharmaceutically acceptable carrier.

24. The pharmaceutical composition according to claim 23 for use in treating HCV.

25. The pharmaceutical composition of claim 23, further comprising at least one additional therapeutic agent.

26. The pharmaceutical composition of claim 25, 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.

27. The pharmaceutical composition according to claim 23, further comprising a nucleoside analogue.

28. The pharmaceutical composition according to claim 27, further comprising an interferon or pegylated interferon.

29. 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.

30. 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 as described in claim 1 or a pharmaceutically acceptable salt thereof.

31. A compound of formula (V):

32. The compound of claim 31 wherein:

X is a bond; and

Y⁴ is pyrrol-1-yl, morpholino, or (C2-10)alkyl.

33. The compound of claim 31 wherein:

X is O; and

Y⁴ is tert-butyl, cyclopentyl, 1,1-dimethylethyl, cyclopropyl, tetrahydrofuranyl, isopropyl, 2,2-dimethylpropyl, cyclobutyl or

34. The compound of claim 31 wherein:

X is NH; and

Y⁴ is (C2-10)alkyl that is optionally substituted with one or more halo.

35. The compound of claim 31 wherein:

R^f is alkyl, aryl, or cycloalkyl, optionally substituted with one or more R_g independently selected from alkyl, halo, —

C(═

O)OR_d, and trifluoromethyl, wherein each alkyl of R_g is optionally substituted with one or more halo, alkoxy, or cyano.

36. The compound of claim 31 wherein:

R^f is phenyl, cyclopropyl, 2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-methylphenyl, 2,2-dimethylpropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-methylcyclopropyl, 1-isopropylcyclopropyl, 1-propylcyclopropyl, 2,2,2-trifluoro-1,1-dimethylethyl, 1-(methoxycarbonyl)cyclopropyl, 1-ethylcyclopropyl, 1-trifluoromethylcyclobutyl, 1-(methoxymethyl)cyclopropyl, 1-(2-cyanoethyl)cyclopropyl, or 1-(2,2,2-trifluoroethyl)cyclopropyl.

37. The compound of claim 31 wherein:

Q¹ is hydrogen, methyl, ethyl, vinyl, cyanomethyl, propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2-cyanoethyl, 2-methoxyethyl, 2-methylsulfonylethyl, or cyclopropyl.