Nrf2 activating compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10844040-B2
Application number	US-201916723881-A
Country	US
Kind code	B2
Filing date	Dec 20, 2019
Priority date	Feb 3, 2016
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

Aspects of the present disclosure include compounds that activate Nrf2. Such compounds find use in the treatment of autoimmune and inflammatory diseases and disorders, such as for example psoriasis and multiple sclerosis. Embodiments of the present disclosure also relate to pharmaceutical compositions that include these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

First claim

What is claimed is:

1. A method of treating an autoimmune disease in a subject having said autoimmune disease, the method comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I):

wherein:
X 1 and X 2 are each independently selected from N and CH, wherein at least one of X 1 and X 2 is N;
either Y 1 is sulfonyl and Y 2 is hydrogen, or Y 2 is sulfonyl and Y 1 is hydrogen; and
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and R 15 , wherein R 15 comprises a linking group and a compound of formula (I);
or a salt or stereoisomer thereof.

2. The method of claim 1 , wherein said autoimmune disease is multiple sclerosis.

3. The method of claim 1 , wherein said autoimmune disease is psoriasis.

4. The method of claim 3 , wherein said psoriasis is plaque psoriasis.

5. The method of claim 1 , wherein the compound is a compound of formula (II):

or
wherein the compound is a compound of formula (III):

or
wherein the compound is a compound of formula (IV):

6. The method of claim 1 , wherein the sulfonyl is selected from alkyl-SO 2 —, substituted alkyl-SO 2 —, alkenyl-SO 2 —, substituted alkenyl-SO 2 —, cycloalkyl-SO 2 —, substituted cycloalkyl-SO 2 —, heterocycloalkyl-SO 2 —, substituted heterocycloalkyl-SO 2 —, aryl-SO 2 —, substituted aryl-SO 2 —, heteroaryl-SO 2 —, and substituted heteroaryl-SO 2 —.

7. The method of claim 1 , wherein R 1 is alkyl, substituted alkyl, heteroaryl, or substituted heteroaryl.

8. The method of claim 1 , wherein the compound is selected from:

9. A method of treating inflammation in a subject having an inflammation associated with a disease or disorder, the method comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I):

wherein:
X 1 and X 2 are each independently selected from N and CH, wherein at least one of X 1 and X 2 is N;
either Y 1 is sulfonyl and Y 2 is hydrogen, or Y 2 is sulfonyl and Y 1 is hydrogen; and
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and R 15 , wherein R 15 comprises a linking group and a compound of formula (I);
or a salt or stereoisomer thereof.

10. The method of claim 9 , wherein said disease or disorder is alcoholic steatohepatitis or non-alcoholic steatohepatitis.

11. The method of claim 10 , wherein said disease or disorder is alcoholic steatohepatitis.

12. The method of claim 10 , wherein said disease or disorder is non-alcoholic steatohepatitis.

13. The method of claim 9 , wherein said disease or disorder is pulmonary arterial hypertension.

14. The method of claim 9 , wherein said disease or disorder is traumatic brain injury.

15. The method of claim 9 , wherein said disease or disorder is radiation exposure.

16. The method of claim 9 , wherein said disease or disorder is exposure to one or more toxic chemicals.

17. The method of claim 9 , wherein said toxic chemical is cyanide.

18. The method of claim 9 , wherein the compound is a compound of formula (II):

or
wherein the compound is a compound of formula (III):

or
wherein the compound is a compound of formula (IV):

19. The method of claim 9 , wherein the sulfonyl is selected from alkyl-SO 2 —, substituted alkyl-SO 2 —, alkenyl-SO 2 —, substituted alkenyl-SO 2 —, cycloalkyl-SO 2 —, substituted cycloalkyl-SO 2 —, heterocycloalkyl-SO 2 —, substituted heterocycloalkyl-SO 2 —, aryl-SO 2 —, substituted aryl-SO 2 —, heteroaryl-SO 2 —, and substituted heteroaryl-SO 2 —.

20. The method of claim 9 , wherein R 1 is alkyl, substituted alkyl, heteroaryl, or substituted heteroaryl.

21. The method of claim 9 , wherein the compound is selected from:

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Duncton Matthew
• Singh Rajinder

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• A61K31/22

  of acyclic acids, e.g. pravastatin · CPC title

• A61K31/216 Primary

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title