GLP-1R agonists and uses thereof
The present disclosure provides compounds of Formula (III) and pharmaceutical compositions thereof, for use in, e.g. treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.
1. A compound represented by structural formula (III):
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; wherein
X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from N and CH; wherein no more than three of X 1 , X 2 , X 3 , X 4 , and X 5 are N and wherein ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;
ring B is 6 membered heteroaryl or phenyl, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from N or CH; wherein there are no more than 3 nitrogen ring atoms in ring B and ring B does not contain 3 nitrogen ring atoms at 3 contiguous positions;
T 6 , T 7 , and T 8 are each independently selected from N and CR 4 ;
EE is —COOH or a carboxylic group surrogate, optionally, the carboxylic group surrogate is:
R b is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 5′ R 6′ , 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated or partially saturated cycloalkyl and 3-7 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6 alkyl or C 1 -C 6 alkoxy represented by R b is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C 3 -C 6 saturated or partially saturated cycloalkyl; and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R b or in the group represented by R b is optionally substituted with one or more groups selected from halogen, oxo (when R b is non-aromatic), CN, OH, C 1 -C 3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and C 1 -C 3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and NR 5′ R 6′ ;
each R 1 is independently selected from H, deuterium, halogen, —CN, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 5′ R 6′ , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl represented by R 1 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , and saturated or partially saturated C 3 -C 6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ); and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R 1 or in the group represented by R 1 is optionally substituted with one or more groups selected from halogen, oxo (when R 1 is non-aromatic), CN, OH, C 1 -C 3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and C 1 -C 3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH 3 ), and NR 5′ R 6′ ;
each R 2 is independently selected from deuterium, halogen, —CN, OH, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 alkoxy;
each R 3 is independently selected from halogen, CN, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and NR 5′ R 6′ ;
each R 4 is independently selected from H, F, C 1 , methyl, and methoxy;
R 5′ and R 6′ are each independently selected from hydrogen and C 1 -C 6 alkyl;
m is an integer selected from 0, 1, 2, 3, and 4;
n is an integer selected from 0, 1, 2, 3, and 4; and
o is an integer selected from 0, 1, 2, 3, and 4.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
wherein n is an integer selected from 0, 1, 2, and 3.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
each R 1 is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, —NH 2 , —NHC 1 -C 4 alkyl, —N(C 1 -C 4 alkyl) 2 ; and m is an integer selected from 0, 1, and 2.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R b is
each of which is optionally substituted with 1 or 2 groups selected from halogen, oxo (when R b is non-aromatic), CN, NR 5 ′R 6 ′, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy, wherein the C 1 -C 3 alkyl or C 1 -C 3 alkoxy in the group represented by R b is optionally substituted with 1 or 2 groups selected from F, OH, and OCH 3 .
5. The compound according to claim 4 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
6. The compound according to claim 5 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
ring A is
each R 1 is independently selected from halogen, OH, CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 hydroxyalkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy, C 1 -C 2 hydroxyalkoxy, and C 2 -C 4 alkynyl; and m is an integer selected from 0, 1, and 2.
7. The compound according to claim 6 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
8. The compound according to claim 7 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 2 is independently selected from halogen and deuterium; and n is an integer selected from 0, 1, and 2, provided that when R 2 is deuterium, ring B is fully substituted with deuterium.
9. The compound according to claim 8 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 3 is F, Cl or CH 3 ; and o is 0, 1, or 2.
10. The compound according to claim 9 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
11. The compound according to claim 10 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
12. The compound according to claim 11 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
13. A method of treating cardiometabolic and associated diseases comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the disease is Type 1 diabetes, Type 2 diabetes mellitus, pre-diabetes, idiopathic Type 1b, latent autoimmune diabetes in adults, early-onset Type 2 diabetes mellitus, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity, eating disorders, excessive sugar craving, dyslipidemia, hyperinsulinemia, nonalcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome Crohn's disease, colitis, irritable bowel syndrome, treatment of Polycystic Ovary Syndrome and treatment of addiction.
14. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, and a pharmaceutically acceptable excipient.
15. The compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein
16. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein ring A is
17. The compound according to claim 16 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is F or CH 3 ; and o is 2.
18. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein ring A is
19. A pharmaceutical composition comprising the compound of claim 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
20. A pharmaceutical composition comprising the compound of claim 18 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
21. A method of treating Type 2 diabetes mellitus in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 17 , or a pharmaceutically acceptable salt thereof.
22. A method of treating hyperglycemia in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 17 , or a pharmaceutically acceptable salt thereof.
23. A method of treating non-alcoholic steatohepatitis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 17 , or a pharmaceutically acceptable salt thereof.
24. A method of treating obesity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 17 , or a pharmaceutically acceptable salt thereof.
25. A method of treating Type 2 diabetes mellitus in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt thereof.
26. A method of treating hyperglycemia in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt thereof.
27. A method of treating non-alcoholic steatohepatitis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt thereof.
28. A method of treating obesity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt thereof.