Small molecule activators of NRF2 pathway

• US 9,737,525 B2
• Filed: 06/06/2014
• Issued: 08/22/2017
• Est. Priority Date: 06/07/2013
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.), Regents of the University of California (University of California)
• Inventors: Kazantsev, Aleksey G., Thompson, Leslie M., Abagyan, Ruben, Casale, Malcolm
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US14/892,353
• Publication Number:
  US 20160101098A1
• Time in Patent Office: 1,173 Days
• Field of Search: 514314, 514311
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings

Abstract

This disclosure relates to compounds that act as activators of the NRF2/KEAP1/ARE pathway. Specifically, the compounds provided herein can act as high affinity reversible bindings for the NRF2 inhibitor, KEAP1. In some cases, NRF2/KEAP1/ARE pathway activation compounds are capable of repressing expression of inflammatory markers and/or reducing levels of TNFa to provide neuroprotective anti-inflammatory effects in the CNS. Such compounds are useful in the treatment of a variety of diseases including Huntington'"'"'s disease, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, inflammation, and cancer.

Claims

1. A method for treating a neurodegenerative disorder selected from the group consisting of:

Parkinson'"'"'s disease (PD), Huntington'"'"'s disease (HD), multiple sclerosis (MS), frontotemporal dementia, and amyotrophic lateral sclerosis (ALS) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of;

2. The method of claim 1, wherein the compound is:

3. The method of claim 1, wherein the compound is:

4. The method of claim 1, wherein the compound is:

5. The method of claim 1, wherein the compound is:

6. The method of claim 1, wherein the compound is:

7. The method of claim 1, wherein the neurodegenerative disorder is Huntington'"'"'s disease (HD).

8. The method of claim 1, wherein the neurodegenerative disorder is Parkinson'"'"'s disease (PD).

9. The method of claim 1, wherein the neurodegenerative disorder is multiple sclerosis (MS).

10. The method of claim 1, wherein the neurodegenerative disorder is frontotemporal dementia.

11. The method of claim 1, wherein the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS).