Nrf2 activating compounds and uses thereof
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.
1. A compound of formula (I):
wherein:
either Y 1 is aminoacyl and Y 2 is hydrogen, or Y 2 is aminoacyl 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 compound of claim 1 , wherein the compound is a compound of formula (Ia):
wherein X a is aminoacyl.
3. The compound of claim 1 , wherein R 1 is heteroaryl or substituted heteroaryl.
4. The compound of claim 3 , wherein R 1 is pyridinyl.
5. The compound of claim 1 , wherein the compound is selected from:
6. 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;
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 (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, and where 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.
7. The compound of claim 6 , wherein the compound is a compound of formula (IIa):
8. The compound of claim 6 , wherein the compound is a compound of formula (IIb):
9. The compound of claim 1 , wherein:
R 1 is R 15 ; and
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—.
10. The compound of claim 6 , 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.
11. The compound of claim 6 , wherein each R 21 and R 22 is independently selected from alkyl and substituted alkyl.
12. The compound of claim 11 , wherein each R 21 and R 22 is methyl.
13. The compound of claim 6 , 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.
14. The compound of claim 13 , wherein R 21 and R 22 are joined together with the nitrogen bound thereto to form a pyrrolidinyl.
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
16. A method of activating Nrf2, the method comprising:
contacting Nrf2 with a compound of claim 1 , wherein the contacting is sufficient to increase the activity of Nrf2.
17. A method of treating a disease or disorder in a subject having said disease or disorder, the method comprising:
administering to the subject a pharmaceutically effective amount of a compound of claim 1 sufficient to treat the disease or disorder,
wherein the disease or disorder is an autoimmune disease or an inflammatory disease.
18. The method of claim 17 , wherein the disease or disorder is psoriasis or multiple sclerosis.
19. The compound of claim 1 , wherein the compound is compound of formula (Ib):
(Ib) wherein X a is aminoacyl.