Necroptosis inhibitors and methods of use therefor

• US 9,643,977 B2
• Filed: 03/12/2012
• Issued: 05/09/2017
• Est. Priority Date: 03/11/2011
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Yuan, Junying
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US14/004,474
• Publication Number:
  US 20140066466A1
• Time in Patent Office: 1,884 Days
• 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: C07C 211/52 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 235/38 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 209/82 Carbazoles; Hydrogenated carbazoles
• CPC Class Codes: C07D 215/08 with acylated ring nitrogen atom
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 235/30 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 237/18 Sulfur atoms
• CPC Class Codes: C07D 261/14 Nitrogen atoms
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 277/46 by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 277/54 Nitrogen and either oxygen or sulfur atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

Described herein are compositions that inhibit the production of TNFα downstream of CD40 activation. As such, also described are various methods of using compositions exhibiting this activity for the treatment or prevention of inflammatory diseases associated with TNFα production or CD40 activation.

Claims

1. A compound having formula I:

6. The compound of claim 1, wherein {circle around (A)} is unsubstituted.

7. The compound of claim 1, wherein {circle around (A)} represents substituted or unsubstituted isothiazole.

8. The compound of claim 1, wherein R¹ is —

H.

9. The compound of claim 1, wherein at least one instance of R¹ is alkyl.

10. The compound of claim 1, wherein at least one instance of R¹ is methyl, ethyl, n-propyl, or isopropyl.

11. The compound of claim 1, wherein at least one instance of R¹ is methyl.

12. The compound of claim 1, wherein at least one instance of R¹ is ethyl.

13. The compound of claim 1, wherein one instance of R¹ is methyl, ethyl, n-propyl, or isopropyl.

14. The compound of claim 1, wherein one instance of R¹ is methyl.

15. The compound of claim 1, wherein one instance of R¹ is ethyl.

16. The compound of claim 1, wherein X represents —

NR¹—

.

17. The compound of claim 1, wherein X represents —

NH—

.

18. The compound of claim 1, wherein X represents —

N(CH₃)—

.

2. A method of treating an inflammatory disease or other disease associated with RIP1 kinase-mediated TNFα

production, comprising administering to a subject a therapeutically effective amount of a compound having formula I;

3. The method of claim 2, wherein the compound is selected from the group consisting of

4. The method of claim 2, wherein the subject is a subject in need thereof;

and the subject in need thereof is a subject who has been diagnosed with an inflammatory disease or a subject who is at high risk for an inflammatory disease.

5. The method of claim 2, wherein the method is a method of treating an inflammatory disease;

and the inflammatory diseases is inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, psoriasis, diabetes mellitus, Alzheimer'"'"'s disease, refractory asthma, multiple sclerosis, atherosclerosis, or vasculitis.

19. The method of claim 2, wherein {circle around (A)} represents an unsubstituted 5-membered heteroaryl.

20. The method of claim 2, wherein {circle around (A)} represents substituted or unsubstituted furan, imidazole, isoxazole, isothiazole, oxadiazole, oxazole, pyrazole, pyrrole, thiazole, thiadiazole, thiophene, or triazole.

21. The method of claim 2, wherein {circle around (A)} represents

22. The method of claim 2, wherein {circle around (A)} represents

23. The method of claim 2, wherein {circle around (A)} represents

24. The method of claim 2, wherein R¹ is —

H.

25. The method of claim 2, wherein at least one instance of R¹ is alkyl.

26. The method of claim 2, wherein at least one instance of R¹ is methyl, ethyl, n-propyl, or isopropyl.

27. The method of claim 2, wherein at least one instance of R¹ is methyl.

28. The method of claim 2, wherein at least one instance of R¹ is ethyl.

29. The method of claim 2, wherein one instance of R¹ is methyl, ethyl, n-propyl, or isopropyl.

30. The method of claim 2, wherein one instance of R¹ is methyl.

31. The method of claim 2, wherein one instance of R¹ is ethyl.

32. The method of claim 2, wherein X represents —

NR¹—

.

33. The method of claim 2, wherein X represents —

NH—

.

34. The method of claim 2, wherein X represents —

N(CH₃)—

.

35. The method of claim 5, wherein the disease is Alzheimer'"'"'s disease.