Substituted imidazoles as GLP-1 receptor agonists
The application relates to a compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of GLP-1 receptor, a pharmaceutical composition comprising a compound of Formula (I), and a method of treating or preventing a disease in which GLP-1 receptor plays a role.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
L is —CR 5 R 6 —;
R 1 is phenyl, wherein the phenyl is optionally substituted with 1 or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, OC 1 -C 6 haloalkyl, and C 3 -C 6 cycloalkyl;
R 2 is heteroaryl;
wherein the heteroaryl comprises 1 or 2 5- or 6-membered rings;
wherein the heteroaryl comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;
wherein the heteroaryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, and OC 1 -C 6 haloalkyl; and
wherein each C 1 -C 6 alkyl substituent of the heteroaryl is optionally and independently substituted with 1 or more independently selected OC 1 -C 6 alkyl substituents;
each R 3 is independently halogen, C 3 -C 10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl;
wherein each C 3 -C 10 cycloalkyl is independently a monocyclic, bridged, or spirocyclic cycloalkyl;
wherein each heterocyclyl independently comprises 1 or 2 3- to 6-membered rings;
wherein each heteroaryl independently comprises 1 or 2 5- or 6-membered rings;
wherein each heterocyclyl or heteroaryl independently comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein each C 3 -C 10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, and OC 1 -C 6 haloalkyl;
R 4 is CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OC 1 -C 6 alkyl, or OC 1 -C 6 haloalkyl;
R 5 and R 6 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, OC 1 -C 6 alkyl, and OC 1 -C 6 haloalkyl; and
T is heteroaryl;
wherein the heteroaryl comprises 1 5- or 6-membered ring;
wherein the heteroaryl comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;
wherein the heteroaryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, OC 1 -C 6 alkyl, and OC 1 -C 6 haloalkyl; and
wherein each C 1 -C 6 alkyl substituent of the heteroaryl is optionally and independently substituted with 1 or more independently selected OC 1 -C 6 alkyl substituents;
with the proviso that at least 1 R 3 is C 3 -C 10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is phenyl,
wherein the phenyl is optionally substituted with 1 or more substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is heteroaryl;
wherein the heteroaryl comprises 2 5- or 6-membered rings;
wherein the heteroaryl comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and
wherein the heteroaryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halogen and C 1 -C 6 alkyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is indazolyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 4 is straight-chain C 1 -C 6 alkyl or branched C 3 -C 6 alkyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 4 is CH 3 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 5 and R 6 , together with the carbon atom to which they are attached, form a cyclopropyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein T is oxadiazolyl substituted with OH.
12. The compound of claim 1 , wherein the compound is of Formula (Ib1), Formula (Ib2), Formula (Ib3), Formula (Ib4), Formula (Ib5), Formula (Ib6), Formula (Ib7), Formula (Ib8), Formula (Ib9), Formula (Ib10), or Formula (Ib11):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
each R 7 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, OC 1 -C 6 alkyl, or OC 1 -C 6 haloalkyl; and
each R 11 is independently halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, OC 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl.
13. The compound of claim 12 , wherein the compound is of Formula (Ib9):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
14. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, or tautomer thereof.
15. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof.
16. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof.
17. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.
18. A pharmaceutical composition comprising the compound of claim 16 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.
19. A pharmaceutical composition comprising the compound of claim 14 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.
20. A method for modulating glucagon-like peptide-1 receptor activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
21. The method of claim 20 , wherein the subject has a glucagon-like peptide-1 receptor-mediated condition, disease, or disorder selected from the group consisting of Alzheimer's disease, atherosclerosis, a cardiac arrhythmia, congestive heart failure, coronary heart disease, dementia, diabetes, diabetic kidney disease, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, a liver disease, obesity, Parkinson's disease, and stroke.
22. A method for modulating glucagon-like peptide-1 receptor activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 16 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
23. The method of claim 22 , wherein the subject has a glucagon-like peptide-1 receptor-mediated condition, disease, or disorder selected from the group consisting of Alzheimer's disease, atherosclerosis, a cardiac arrhythmia, congestive heart failure, coronary heart disease, dementia, diabetes, diabetic kidney disease, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, a liver disease, obesity, Parkinson's disease, and stroke.
24. A method for modulating glucagon-like peptide-1 receptor activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 14 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
25. The method of claim 24 , wherein the subject has a glucagon-like peptide-1 receptor-mediated condition, disease, or disorder selected from the group consisting of Alzheimer's disease, atherosclerosis, a cardiac arrhythmia, congestive heart failure, coronary heart disease, dementia, diabetes, diabetic kidney disease, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, a liver disease, obesity, Parkinson's disease, and stroke.