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 (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:
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.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. 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.
18. 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.
19. The method of claim 18 , wherein the disease or disorder is psoriasis or multiple sclerosis.