Tripeptide epoxy ketone protease inhibitors

• US 10,647,744 B2
• Filed: 08/30/2016
• Issued: 05/12/2020
• 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): Katakam, Sudhakar
• Application Number:
  US15/251,688
• Publication Number:
  US 20160368946A1
• Time in Patent Office: 1,351 Days
• 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 method of treating an autoimmune disease in which inhibition of the immunoproteasome is effective in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (X) or a pharmaceutically acceptable salt thereof:

2. The method of claim 1, wherein

3. The method of claim 1, wherein

4. The method of claim 1, wherein R¹ is C_1-6 alkyl.

5. The method of claim 1, wherein R¹ is CH₃, CH₂OH, CF₃, CH(OH)CH₃, CH₂CN, or CH₂CH₃.

6. The method of claim 1, wherein R² is C_1-2 alkylene-aryl.

7. The method of claim 1, wherein R² is selected from the group consisting of

8. The method of claim 1, wherein R² is selected from the group consisting of:

9. The method of claim 1, wherein R³ is C_3-7cycloalkyl.

10. The method of claim 1, wherein R³ is C_3-7cycloalkenyl.

11. The method of claim 1, wherein R³ is selected from the group consisting of:

12. The method of claim 1, wherein R³ is selected from the group consisting of

13. The method of claim 1, wherein R⁴ is methyl.

14. The method of claim 1, wherein:

m and n are each independently 2;

p is 1;

q is 1;

K is CR⁵R⁶ or O;

E is N or CR⁷;

R¹ is CH₃, CH₂OH, CH(OH)CH₃, or CH₂CN;

R² is

15. The method of claim 1, wherein the compound of formula (X) has a structure selected from the group consisting of:

16. The method of claim 1, wherein the compound of formula (X) has a structure selected from the group consisting of:

17. The method of claim 15, wherein the compound has a stereochemical configuration:

18. The method of claim 16, wherein the compound has a stereochemical configuration:

19. The method of claim 1, wherein the administering is oral, parenteral, via injection, via inhalation, transdermal, or transmucosal.

20. The method of claim 1, wherein the autoimmune disease is psoriasis, dermatitis, systemic scleroderma, sclerosis, Crohn'"'"'s disease, ulcerative colitis;

respiratory distress syndrome, meningitis;

encephalitis;

uveitis;

colitis;

glomerulonephritis;

eczema, asthma, chronic inflammation;

atherosclerosis;

leukocyte adhesion deficiency;

rheumatoid arthritis;

systemic lupus erythematosus (SLE);

diabetes mellitus;

multiple sclerosis;

Reynaud'"'"'s syndrome;

autoimmune thyroiditis;

allergic encephalomyelitis;

Sjogren'"'"'s syndrome;

juvenile onset diabetes;

tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis;

pernicious anemia (Addison'"'"'s disease);

diseases involving leukocyte diapedesis;

central nervous system (CNS) inflammatory disorder;

multiple organ injury syndrome;

hemolytic anemia;

myasthenia gravis;

antigen-antibody complex mediated diseases;

anti-glomerular basement membrane disease;

antiphospholipid syndrome;

allergic neuritis;

Graves'"'"' disease;

Lambert-Eaton myasthenic syndrome;

pemphigoid bullous;

pemphigus;

autoimmune polyendocrinopathies;

Reiter'"'"'s disease;

stiff-man syndrome;

Bechet disease;

giant cell arteritis;

immune complex nephritis;

IgA nephropathy;

IgM polyneuropathies;

or autoimmune thrombocytopenia (ITP).

21. The method of claim 20, wherein the autoimmune disease is SLE, polymyositis, hemolytic anemia, or ITP.

22. The method of claim 1, wherein the autoimmune disease is rheumatoid arthritis, lupus, psoriasis, inflammatory bowel disease, multiple sclerosis, or Crohn'"'"'s disease.

23. The method of claim 1, wherein the autoimmune disease is rheumatoid arthritis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus (SLE), multiple sclerosis, ischemia, restenosis, stenosis, pancreatitis, fibrosis, autoimmune nephritis, graft-versus-host disease, autoimmune thyroiditis, or myasthenia gravis.

24. The method of claim 21, wherein the compound is

25. The method of claim 21, wherein the compound is

26. The method of claim 21, wherein the compound is

27. The method of claim 21, wherein the compound is

28. The method of claim 21, wherein the compound is

29. The method of claim 21, wherein the compound is

30. The method of claim 21, wherein the compound is

31. The method of claim 21, wherein the compound is

32. The method of claim 21, wherein the compound is

33. The method of claim 21, wherein the compound is

34. The method of claim 21, wherein the compound is

35. The method of claim 27, wherein the autoimmune disease is SLE.

36. The method of claim 27, wherein the autoimmune disease is polymyositis.

37. The method of claim 27, wherein the autoimmune disease is hemolytic anemia.

38. The method of claim 27, wherein the autoimmune disease is ITP.