Tripeptide epoxy ketone protease inhibitors

• US 9,434,761 B2
• Filed: 03/14/2014
• Issued: 09/06/2016
• Est. Priority Date: 03/14/2013
• Status: Expired

• 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): Gudibande, Satyanarayana R
• Assistant Examiner(s): Fischer, Joseph
• Application Number:
  US14/210,806
• Publication Number:
  US 20140336106A1
• Time in Patent Office: 907 Days
• Field of Search: None
• US Class Current: 1/1
• 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: A61K 38/06 Tripeptides
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 407/12 : 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: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 5/0202 : containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/0205 : containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 5/06026 : the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06034 : the side chain containing 2 to 4 carbon atoms
• CPC Class Codes: C07K 5/0606 : the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• CPC Class Codes: C07K 5/06069 : Ser-amino acid
• CPC Class Codes: C07K 5/06078 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06113 : Asp- or Asn-amino acid
• CPC Class Codes: C07K 5/06121 : the second amino acid being aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• 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 5/0806 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0808 : the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/081 : the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• 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
• CPC Class Codes: C07K 5/0823 : and Pro-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/0827 : containing heteroatoms different from O, S, or N

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 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, tetrohydrofuranyl, tetrahydropyranyl, pyrrolindinyl, pyrrolidinonyl, dihydropyranyl or 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, 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.

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