Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
Phenoxy acetic acids and phenyl propionic acids and their use in improving mitochondrial energy output in a subject are provided herein. The present compounds are activators of PPARδ and may be useful for treating conditions mediated by the same.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein is a double bond, with either E or Z substitution;
X 1 is C 1-6 alkyl substituted with morpholino;
X 2 is phenylene;
X 3 is phenyl substituted with one or more halogens;
Ar is phenylene optionally substituted with methyl;
Y 1 is O;
Y 2 is O;
Z is CH 2 ;
R 1 is hydrogen; and
R 2 is C 1-6 -alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is morpholin-4-ylmethyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl or ethyl.
4. A pharmaceutically acceptable salt of a compound of formula (I):
wherein is a double bond, with either E or Z substitution;
X 1 is C 1-6 alkyl substituted with morpholino;
X 2 is phenylene;
X 3 is phenyl substituted with one or more halogens;
Ar is phenylene optionally substituted with methyl;
Y 1 is O;
Y 2 is O;
Z is CH 2 ;
R 1 is hydrogen; and
R 2 is C 1-6 -alkyl.
5. The pharmaceutically acceptable salt of claim 4 , wherein X 1 is morpholin-4-ylmethyl.
6. The pharmaceutically acceptable salt of claim 5 , wherein R 2 is methyl or ethyl.
7. The pharmaceutically acceptable salt of claim 1 , wherein the pharmaceutically acceptable salt is an acid addition salt.
8. The pharmaceutically acceptable salt of claim 1 , wherein the pharmaceutically acceptable salt is an hydrochloric acid addition salt.
9. A compound that is:
methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate; or
methyl (Z)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate;
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound is methyl (Z)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate, or a pharmaceutically acceptable salt thereof.