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 treating diabetes mellitus in a subject 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; n is 1 or 2; and each R 4 is independently halogen or C 1-6 alkyl.
3. The method of claim 2 having the structure of Formula (Ia) or Formula (Ib):
4. The method of claim 3 , wherein R 1 and R 2 are each —CH 3 and 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.
5. The method of claim 4 , wherein R 5 is unsubstituted pyridyl.
6. The method of claim 4 , 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.
7. The method of claim 6 , wherein R 5 is pyridyl substituted by —CH 3 .
8. The method of claim 3 , 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.
9. The method of claim 8 , wherein R 5 is unsubstituted phenyl.
10. The method of claim 8 , 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.
11. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt or solvate thereof.
12. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
13. The compound of claim 12 that is:
or a pharmaceutically acceptable salt or solvate thereof.
14. The compound of claim 12 that is:
or a pharmaceutically acceptable salt or solvate thereof.
15. The compound of claim 12 that is:
or a pharmaceutically acceptable salt or solvate thereof.
16. The compound of claim 12 that is:
or a pharmaceutically acceptable salt or solvate thereof.