Macrocyclic inhibitors of flaviviridae viruses

• US 8,513,184 B2
• Filed: 12/08/2011
• Issued: 08/20/2013
• Est. Priority Date: 12/10/2010
• Status: Expired due to Fees

• Current Assignee: Cypralis Limited (Eurofins Scientific SE), Gilead Sciences Inc.
• Original Assignee: Selcia Ltd. (Eurofins Scientific SE), Gilead Sciences Inc.
• Inventors: Appleby, Todd, Fliri, Hans G., Keats, Andrew J., Lazarides, Linos, Mackman, Richard L., Pettit, Simon N., Poullennec, Karine G., Sanvoisin, Jonathan, Steadman, Victoria A., Watt, Gregory M.
• Primary Examiner(s): Cordero Garcia, Marcela M
• Assistant Examiner(s): YANG, KAIPEEN E
• Application Number:
  US13/315,069
• Publication Number:
  US 20130022573A1
• Time in Patent Office: 621 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 38/06 Tripeptides
• 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 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 498/08 Bridged systems
• CPC Class Codes: C07D 498/18 Bridged systems
• CPC Class Codes: C07K 5/02 containing at least one abnormal peptide link
• CPC Class Codes: C07K 5/06052 Val-amino acid

Abstract

Provided are compounds of Formula I:

and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.

Claims

1. A compound of Formula I:

2. The compound of claim 1 represented by Formula II

3. The compound of claim 2 wherein each R^8b and R^9b is H.

4. The compound of claim 3 wherein R⁸ is methyl.

5. The compound of claim 2 wherein A¹ is optionally substituted (C₄)alkylene or optionally substituted (C₄)alkenylene.

6. The compound of claim 5 wherein A¹ is

7. The compound of claim 6 wherein R¹⁵ is H.

8. The compound of claim 2 wherein A² is optionally substituted arylene.

9. The compound of claim 8 wherein A² is

10. The compound of claim 2 wherein A² is

11. The compound of claim 10 wherein each R¹⁰ or R¹¹ is independently H, optionally substituted (C₁-C₄)alkyl or halogen.

12. The compound of claim 11 wherein each R¹⁰ and R¹¹ is H.

13. The compound of claim 2 wherein R⁷ is optionally substituted (C₁-C₈)alkyl, optionally substituted aryl, or optionally substituted aryl(C₁-C₄)alkyl.

14. The compound of claim 13 wherein R⁷ is optionally substituted (C₁-C₈)alkyl.

15. The compound of claim 2 wherein R⁵ is optionally substituted aryl(C₀-C₄)alkyl.

16. The compound of claim 15 wherein R⁵ is optionally substituted benzyl.

17. The compound of claim 16 wherein R⁵ is optionally substituted

18. The compound of claim 17 wherein R⁶ is OR⁴, CH₂OR⁴, N(R¹)₂, NHCOR¹, NHC(O)OR¹, NHC(O)N(R¹)₂, NHC(NR¹)R¹, NHC(NR¹)N(R¹)₂, C(O)N(R¹)₂, S(O)₂N(R¹)₂, NHS(O)₂OR¹, NHS(O)₂R¹⁶ or NHS(O)₂N(R¹)₂.

19. The compound of claim 18 wherein R⁶ is OH.

20. The compound of claim 2 wherein R⁷ is isopropyl and R⁵ is

21. The compound of claim 20 wherein R⁹ is O(C₁-C₄)alkyl.

22. The compound of claim 21 wherein R⁸ is (C₁-C₄)alkyl.

23. The compound of claim 2 or a pharmaceutically acceptable salt thereof,

wherein:

X¹ is O or NR¹;

each R¹ is independently H, optionally substituted (C₁-C₄)alkyl, optionally substituted (C₂-C₄)alkenyl or optionally substituted (C₂-C₄)alkynyl;

each R⁴ is independently H, optionally substituted (C₁-C₄)alkyl, optionally substituted (C₂-C₄)alkenyl, optionally substituted (C₂-C₄)alkynyl, cyano, C(O)R⁷, C(O)OR⁷, CON(R⁷)₂, S(O)R¹⁶, S(O)₂R¹⁶, S(O)₂OR⁷ or S(O)₂N(R⁷)₂;

R⁵ is aryl(C₀-C₄)alkyl, optionally substituted with one or more R⁶;

each R⁶ is independently halo, CF₃, OR⁴, CH₂OR⁴, SR⁴, S(O)R¹⁶, S(O)₂R¹⁶, N(R¹)₂, NHCOR¹, NHC(O)OR¹, NHC(O)N(R¹)₂, NHC(NR¹)R¹, NHC(NR¹)N(R¹)₂, C(O)R¹, C(O)N(R¹)₂, CO₂R¹, S(O)₂OR¹, S(O)₂N(R¹)₂, NHS(O)₂OR¹, NHS(O)₂R¹⁶, NHS(O)₂N(R¹)₂, P(O)(OR¹)₂, P(O)(OR¹)(N(R¹)₂), P(O)(R⁷)(OR¹), OP(O)(OR¹)₂, OP(O)(OR¹)(N(R¹)₂), NHP(O)(OR¹)₂ or NHP(O)(OR¹)(N(R¹)₂);

each R¹⁶ is optionally substituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl, optionally substituted (C₂-C₈)alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryl(C₁-C₄)alkyl, optionally substituted cycloalkyl(C₁-C₄)alkyl or optionally substituted heterocyclyl(C₁-C₄)alkyl;

each R⁷ is optionally substituted (C₁-C₈)alkyl or optionally substituted aryl(C₁-C₄)alkyl;

each R⁸, R^8b, R⁹ or R^9b is independently H, optionally substituted (C₁-C₈)alkyl, or OR⁴;

A¹ is optionally substituted (C₂-C₅)alkylene or optionally substituted (C₂-C₅)alkenylene, and A² is optionally substituted arylene or optionally substituted heteroarylene, or A¹ is aryl(C₀-C₂)alkylene and A² is optionally substituted (C₁-C₃)alkylene or optionally substituted (C₂-C₃)alkenylene;

R¹² is H or optionally substituted (C₁-C₄)alkyl;

each R^a is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl, heterocyclyl, aryl(C₁-C₈)alkyl, cycloalkyl or cycloalkyl(C₁-C₈)alkyl; and

wherein when R¹, R⁴, R⁷, R⁸, R⁹, R^8b, R^9b, R¹², R¹⁶, A¹ or A² is substituted, the substitutent is, independently, one or more substituents selected from the group consisting of halo, CN, CF₃, N₃, N(R^a)₂, SR^a, OR^a, R^a, NHCOR^a, NHC(O)OR^a, NHC(O)N(R^a)₂, NHC(NR^a)R^a, NHC(NR^a)N(R^a)₂, C(O)R^a, C(O)N(R^a)₂, CO₂R^a, S(O)₂OR^a, S(O)₂N(R^a)₂, NHS(O)₂OR^a, NHS(O)₂N(R^a)₂, OP(O)(OR^a)₂, OP(O)(OR^a)(N(R^a)₂), NHP(O)(OR^a)₂ and NHP(O)(OR^a)(N(R^a)₂).

24. The compound of claim 2 or a pharmaceutically acceptable salt thereof,

wherein:

X¹ is O or NH;

R⁵ is

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claims 1 or 25 and a pharmaceutically acceptable carrier or excipient.

27. The pharmaceutical composition of claim 26, further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, and TLR-7 agonists;

or mixtures thereof.

25. A compound selected from the group consisting of