Nrf2 activating compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10647697-B2
Application number	US-201715811170-A
Country	US
Kind code	B2
Filing date	Nov 13, 2017
Priority date	Feb 3, 2016
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

Aspects of the present disclosure include compounds that activate Nrf2. Such compounds may 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 compound of formula (II):

wherein:
either Y 11 is C(═O)—N—R 21 R 22 and Y 12 is hydrogen, or Y 12 is C(═O)—N—R 21 R 22 and Y 11 is hydrogen;
R 1 is R 15 , wherein R 15 comprises a linking group and a compound of formula (II); and
each R 21 and R 22 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or wherein R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group;
or a salt or stereoisomer thereof.

2. The compound of claim 1 , wherein Y 11 is —C(═O)—N—R 21 R 22 and Y 12 is hydrogen.

3. The compound of claim 1 , wherein Y 12 is —C(═O)—N—R 21 R 22 and Y 11 is hydrogen.

4. The compound of claim 1 , wherein the linking group is —(CH 2 ) w —Z x —(CH 2 ) y —,
wherein
w is an integer from 1 to 6;
x is 0 or 1;
y is 0 or an integer from 1 to 6; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—.

5. The compound of claim 1 , wherein each R 21 and R 22 is independently selected from hydrogen, alkyl, substituted alkyl, or wherein R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group.

6. The compound of claim 1 , wherein each R 21 and R 22 is independently selected from alkyl and substituted alkyl.

7. The compound of claim 6 , wherein each R 21 and R 22 is methyl.

8. The compound of claim 1 , wherein R 21 and R 22 are joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group.

9. The compound of claim 8 , wherein R 21 and R 22 are joined together with the nitrogen bound thereto to form a pyrrolidinyl.

10. The compound of claim 1 , wherein the compound is of the formula:

wherein
R 21a , R 21b , R 22a and R 22b are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or wherein R 21a and R 22a are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group, or wherein R 21b and R 22b are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—,
or a salt or stereoisomer thereof.

11. The compound of claim 1 , wherein the compound is of the formula:

wherein
R 21a , R 21b , R 22a and R 22b are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or wherein R 21a and R 22a are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group, or wherein R 21b and R 22b are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—,
or a salt or stereoisomer thereof.

12. The compound of claim 1 , wherein the compound is of the formula:

wherein
R 21a , R 21b , R 22a and R 22b are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or wherein R 21a and R 22a are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group, or wherein R 21b and R 22b are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—,
or a salt or stereoisomer thereof.

13. The compound of claim 1 , wherein the compound is of the formula:

wherein
R 21a , R 21b , R 22a and R 22b are each independently selected from hydrogen, alkyl, substituted alkyl, are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or wherein R 21a and R 22a are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group, or wherein R 21b and R 22b are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—,
or a salt or stereoisomer thereof.

14. The compound of claim 1 , wherein the compound is of the formula:

wherein
R 21a , R 21b , R 22a and R 22b are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or wherein R 21a and R 22a are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group, or wherein R 21b and R 22b are optionally joined together with the nitrogen bound thereto to form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl group; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—,
or a salt or stereoisomer thereof.

15. The compound of claim 1 , wherein the compound is of the formula:

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Duncton Matthew
• Singh Rajinder

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P29/00

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