Fumarate analogs and uses thereof
Aspects of the present disclosure include compounds that find use for the treatment of a variety of autoimmune and inflammatory diseases and disorders. 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 method of treating a disease or disorder in a subject in need thereof, the method comprising:
administering to the subject a pharmaceutically effective amount of a compound of formula (A):
wherein either:
Y 1 is X a and Y 2 is hydrogen, or Y 2 is X a and Y 1 is hydrogen;
wherein X a is selected from carboxylic acid, carboxyl ester, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; and
R 1 is 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 (A);
or a salt or stereoisomer thereof,
wherein the administering is sufficient to treat the disease or disorder, and
wherein the disease or disorder is psoriasis or multiple sclerosis.
2. The method of claim 1 , wherein the compound is of formula (Ia) or (Ib):
wherein R 15 comprises a linking group and a compound of formula (Ia) or (Ib).
3. The method of claim 1 , wherein X a is a substituted heterocyclyl or a substituted heteroaryl, wherein the substituent on X a is X 1 , wherein X 1 is C 1-6 alkyl or a progroup.
4. The method of claim 1 , wherein the compound is a compound of formula (IIa) or (IIb):
wherein
R 1 is 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 (IIa) or (IIb); and
X 1 is hydrogen, C 1-6 alkyl or a progroup;
or a salt or stereoisomer thereof.
5. The method of claim 4 , wherein R 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
6. The method of claim 4 , wherein R 1 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl.
7. The method of claim 6 , wherein R 1 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, 4-tetrahydropyranyl, —CH 2 CH 2 OCH 3 , —CH 2 OCH 3 , —CH 2 C(O)OCH 3 , or —CH 2 CH(CH 3 ) 2 OH.
8. The method of claim 3 , wherein X 1 is C 1-6 alkyl.
9. The method of claim 7 , wherein X 1 is methyl or tert-butyl.
10. The method of claim 3 , wherein X 1 is a progroup of the formula:
wherein
L 1 is a linking group;
X 2 is optional and selected from O, N and S;
R 2 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aminoacyl, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
R 3 and R 4 are each independently optional and selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, oxo, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R 2 together with X 2 and either R 3 or R 4 form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl.
11. The method of claim 10 , wherein X 1 is selected from:
wherein
L 1 is a C 1-6 alkyl or substituted C 1-6 alkyl;
R 5 and R 6 are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R 5 and R 6 together with the nitrogen to which they are attached form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; and
R 7 is 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 —OR 14 where R 14 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
12. The method of claim 11 , wherein X 1 is selected from:
wherein
R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen, alkyl and substituted alkyl.
13. The method of claim 12 , wherein R 8 and R 9 are each independently selected from hydrogen and C 1-6 alkyl.
14. The method of claim 13 , wherein R 8 and R 9 are each hydrogen.
15. The method of claim 13 , wherein R 8 is hydrogen and R 9 is C 1-6 alkyl.
16. The method of claim 12 , wherein R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen and C 1-6 alkyl.
17. The method of claim 16 , wherein R 10 , R 11 , R 12 and R 13 are each hydrogen.
18. The method of claim 16 , wherein one of R 10 , R 11 , R 12 and R 13 is methyl and the remaining are hydrogen.
19. The method of claim 16 , wherein two of R 10 , R 11 , R 12 and R 13 are methyl and the remaining are hydrogen.
20. The method of claim 1 , wherein the linking group is —(CH 2 ) n —Z y —(CH 2 ) m —,
wherein
n is an integer from 1 to 6;
m is 0 or an integer from 1 to 6;
y is 0 or 1; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—.
21. The method of claim 20 , wherein the compound has one of the following formulae:
wherein
X 1a and X 1b are each independently selected from C 1-6 alkyl and a progroup; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—.
22. The method of claim 1 , wherein R 1 is:
wherein X 1b is selected from C 1-6 alkyl and a progroup.
23. The method of claim 22 , wherein the compound has one of the following formulae:
wherein X 1 and X 1b are each independently selected from C 1-6 alkyl and a progroup.
24. The method of claim 23 , wherein X 1 and X 1b are each independently a C 1-6 alkyl.
25. The method of claim 24 , wherein the compound has the structure:
26. The method of claim 1 , wherein the compound is selected from:
27. The method of claim 1 , wherein the compound is selected from:
wherein X 1 is a progroup.