Peptide epoxyketone immunoproteasome inhibitors

• US RE47,302 E1
• Filed: 06/23/2017
• Issued: 03/19/2019
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: McMinn, Dustin, Johnson, Henry, Bowers, Simeon, Moebius, David C.
• Primary Examiner(s): Jones, Dwayne C.
• Application Number:
  US15/631,276
• Time in Patent Office: 634 Days
• CPC Class Codes: A61K 31/336 having three-membered rings, e.g. oxirane, fumagillin
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 303/32 by aldehydo- or ketonic radicals
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 5/06 Dipeptides
• CPC Class Codes: C07K 5/06069 Ser-amino acid
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06121 the second amino acid being aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06147 and His-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/06173 and Glp-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Abstract

Provided herein are tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X):

and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of diseases including inflammation and neurodegenerative disease.

Claims

1. A compound of Formula (X):

2. The compound of claim 1, having the formula:

3. The compound of claim 2 having a structure selected from the group consisting of:

5. The compound of claim 3 having a structure selected from the group consisting of:

6. The compound of claim 2 having a structure selected from the group consisting of:

7. The compound of claim 6 1 having a structure selected from the group consisting of:

8. The compound of claim 1, wherein K is O.

9. The compound of claim 1, wherein E is N.

10. The compound of claim 1, wherein

11. The compound of claim 1, wherein R¹ is C_1-3alkyl.

12. The compound of claim 1, wherein R² is CH₂-heteroaryl or CH₂-aryl.

13. The compound of claim 12, wherein R² is selected from the group consisting of:

14. The compound of claim 1, wherein R³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, dihydropyranyl or and dihydrofuranyl.

15. The compound of claim 1, wherein:

16. The compound of claim 1, wherein

17. The compound of claim 1, wherein R¹ is CH₃, CH₂OH, CH(OH)CH₃, or CH₂CN.

18. The compound of claim 1, wherein R² is selected from the group consisting of:

19. The compound of claim 1, wherein R³ is selected from the group consisting of:

20. The compound of claim 12, wherein the heteroaryl is a thiophene.

21. The compound of claim 1 having a structure of

22. The compound of claim 1 having a structure of

23. The compound of claim 1 having a structure of

24. The compound of claim 1 having a structure of

25. The compound of claim 1 having a structure of

26. The compound of claim 1 having a structure of

27. The compound of claim 1 having a structure of

28. The compound of claim 1 having a structure of

29. The compound of claim 1 having a structure of

30. The compound of claim 1 having a structure of

31. The compound of claim 1 having a structure of

4. A compound having a structure selected from the group consisting of: