Composition and methods for inhibiting mammalian sterile 20-like kinase 1
Disclosed herein are compounds, compositions, and methods of their use for the treatment of diabetes.
1. A method of liver regeneration in a subject by binding MST1 comprising administering to the subject a compound of Formula (I) having the structure:
wherein:
is a single bond;
X is —O—;
R 1 and R 2 are each independently C 1-6 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;
R 3 is C 1-6 alkyl;
each R 4 is independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or —CN;
R 5 is aryl or heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl;
R 6 is H or C 1-6 alkyl;
n is 0, 1, 2, or 3; and
p is 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof.
2. The method of claim 1 , wherein p is 1.
3. The method of claim 2 , wherein n is 1 or 2.
4. The method of claim 3 , wherein each R 4 is independently halogen or C 1-6 alkyl.
5. The method of claim 4 having the structure of Formula (Ia) or Formula (Ib):
6. The method of claim 5 , wherein R 1 and R 2 are each independently C 1-6 alkyl.
7. The method of claim 6 , wherein R 1 and R 2 are each —CH 3 .
8. The method of claim 7 , wherein R 5 is heteroaryl and wherein heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.
9. The method of claim 8 , wherein R 5 is unsubstituted pyridyl.
10. The method of claim 8 , wherein R 5 is pyridyl substituted by one substituent selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.
11. The method of claim 10 , wherein R 5 is pyridyl substituted by C 1-6 alkyl.
12. The method of claim 11 , wherein R 5 is pyridyl substituted by —CH 3 .
13. The method of claim 7 , wherein R 5 is aryl and wherein aryl is unsubstituted or substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.
14. The method of claim 13 , wherein R 5 is unsubstituted phenyl.
15. The method of claim 13 , wherein R 5 is phenyl and wherein phenyl is substituted by one substituent selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.
16. The method of claim 1 , wherein R 4 is halogen.
17. The method of claim 16 , wherein R 4 is —Cl.
18. The method of claim 1 , wherein n is 1.
19. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt or solvate thereof.