Apelin receptor agonists and methods of use thereof
Provided herein are agonists of the apelin receptor for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.
1. A method of treating an apelin mediated disease or disorder in a subject, comprising administering to the subject a compound of structural Formula II:
or a pharmaceutically acceptable salt or tautomer thereof; wherein:
X is selected from the group consisting of S, O and NR 9 ;
A is selected from the group consisting of, substituted phenoxy, optionally substituted aniline, and substituted 5- or 6-membered heteroaryl or heteroaryl-oxy;
B is selected from the group consisting of H, optionally substituted aryl, optionally substituted alkoxy, optionally substituted phenoxy, optionally substituted amino, optionally substituted aniline, and optionally substituted 5- or 6-membered heteroaryl or heteroaryl-oxy;
wherein the optionally substituted aniline of A or B is attached to the parent molecule through a nitrogen atom;
Y 1 is CR 14 ;
each Y 2 —Y 9 are independently selected from the group consisting of N and CR 14 ;
each R 14 is independently selected from the group consisting of hydrogen, halogen, —CN, —CONR 15 R 16 , —COOR 17 , —SO 2 R 18 , optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
R 9 is hydrogen or optionally substituted alkyl;
each R 15 -R 18 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; and
Z is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.
2. The method of claim 1 , wherein X is S.
3. The method of claim 1 , wherein X is O or S.
4. The method of claim 1 , wherein each of Y 1 , Y 2 , Y 3 , and Y 4 is independently CR 14 .
5. The method of claim 1 , wherein each of Y 5 , Y 6 , Y 7 , Y 8 , and Y 9 is independently CR 14 .
6. The method of claim 1 , wherein each of Y 1 -Y 9 is independently CR 14 .
7. The method of claim 6 , wherein Y 1 is CH.
8. The method of claim 6 , wherein each of Y 2 and Y 3 is CR 14 , wherein in each instance, R 14 is optionally substituted alkoxy.
9. The method of claim 8 , wherein each of Y 2 and Y 3 is CR 14 , wherein in each instance, R 14 is-OCH 3 .
10. The method of claim 6 , wherein Y 4 is CH.
11. The method of claim 6 , wherein each of Y 5 , Y 6 , Y 8 , and Y 9 is CH.
12. The method of claim 6 , wherein Y 7 is CR 14 , and R 14 is-CN, —CONR 15 R 16 ,-COOR 17 , or —SO 2 R 18 ; wherein each R 15 , R 16 , R 17 , and R 18 is optionally substituted alkyl.
13. The method of claim 12 , wherein Y 7 is CR 14 , and R 14 is-CN.
14. The method of claim 12 , wherein Y 7 is CR 14 , and R 14 is —CN or —SO 2 R 18 ; and R 18 is optionally substituted alkyl.
15. The method of claim 1 , wherein A is substituted phenoxy.
16. The method of claim 15 , wherein A is para-substituted phenoxy.
17. The method of claim 1 , wherein the apelin mediated disease or disorder is a cardiovascular disease or disorder, pulmonary hypertension, portal hypertension, systolic hypertension, or any combination thereof.
18. The method of claim 17 , wherein the apelin mediated disease or disorder is pulmonary hypertension, portal hypertension, systolic hypertension, or any combination thereof.
19. The method of claim 18 , wherein the apelin mediated disease or disorder is pulmonary hypertension.