GLP-1R agonists and uses thereof
The invention described herein provides compounds of Formula (I) 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 or a pharmaceutically acceptable salt thereof; wherein the compound is represented by the following structure:
2. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is represented by the following structure:
3. A compound represented by the structural formula (I′):
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; or a pharmaceutical composition comprising the compound, the pharmaceutically acceptable salt, the stereoisomer, the solvate, or the hydrate thereof, and a pharmaceutically acceptable excipient; wherein
indicates a single bond or a double bond;
X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from N, C, and CH; wherein no more than three of X 1 , X 2 , X 3 , X 4 , and X 5 are N and ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;
W is selected from O, NH and CH 2 ;
Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from N, NH, C, CH, and CH 2 ;
Y 2 and Y 6 are each independently selected from N, C, or CH;
wherein there is no more than 3 nitrogen ring atoms in ring B and wherein 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 ; and no more than 2 of T 6 , T 7 , and T 8 are selected from N;
EE is —COOH,
R a is hydrogen;
R b is 5-6 membered heteroaryl or 4-7 membered saturated or partially saturated heterocyclyl, wherein the heteroaryl or saturated or partially saturated heterocyclyl represented by R b is optionally substituted with one or more groups selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxy alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkoxy;
R c is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
each R 1 is independently 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′ , phenyl, 5-6 membered heteroaryl, 4-6 membered saturated or partially saturated cycloalkyl and 3-7 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, CN, OH, and C 3 -C 6 cycloalkyl; 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, CN, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxy alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 hydroxy alkoxy, and NR 5′ R 6′ ;
each R 2 is independently selected from halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and NR 5′ R 6′ ;
R 3 is independently halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;
each R 4 is independently H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more groups selected from halogen;
R 5 and R 6 are each independently selected from hydrogen and C 1 -C 6 alkyl;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; and
o is 0, 1, or 2.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
wherein R 2 is halogen; n is 0, 1, or 2.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
wherein R 4 is H or halogen.
6. The compound according to claim 5 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein EE is —COOH, —(C(O)NHOH, —C(O)NHSO 2 CH 3 , —C(O)NHSO 2 CF 3
7. The compound according to claim 6 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R b is
each of which is optionally substituted with one or more groups selected from C 1 -C 3 alkyl; and R c is H or C 1 -C 3 alkyl.
8. The compound according to claim 7 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
9. The compound according to claim 8 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
10. The compound according to claim 9 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
ring A is
each R 1 is independently selected from halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 2 -C 4 alkynyl optionally substituted with cyclopropyl, 5-6 membered heteroaryl wherein the hereroaryl comprises nitrogen as hetero ring atom and is optionally substituted with C 1 -C 4 alkyl; and
m is 0, 1, 2, or 3.
11. The compound according to claim 10 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein W is O.
12. The compound according to claim 11 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
each R 1 is independently selected from halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, imidazolyl, triazolyl, pyridyl, and C 2 -C 4 alkynyl optionally substituted with cyclopropyl; and m is 0, 1, or 2.
13. The compound according to claim 12 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R 1 is selected from halogen and CN.
14. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following structure:
15. The compound according to claim 3 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
wherein R 2 is halogen; n is 0, 1, or 2.
16. The compound according to claim 15 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
wherein R 4 is H or halogen.
17. The compound according to claim 16 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein EE is —COOH, —(C(O)NHOH,
—C(O)NHSQ 2 CH 3 , —C(O)NHSO 2 CF 3 ,
18. The compound according to claim 17 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, where R b is
each of which is optionally substituted with one or more groups selected from C 1 -C 3 alkyl; and R c is H or C 1 -C 3 alkyl.
19. The compound according to claim 18 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
20. The compound according to claim 19 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
is
21. The compound according to claim 20 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein
ring A is
each R 1 is independently selected from halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 2 -C 4 alkynyl optionally substituted with cyclopropyl, 5-6 membered heteroaryl wherein the hereroaryl comprises nitrogen as hetero ring atom and is optionally substituted with C 1 -C 4 alkyl; and
m is 0, 1, 2, or 3.
22. The compound according to claim 21 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein W is O.
23. The compound according to claim 22 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is
each R 1 is independently selected from halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, imidazolyl, triazolyl, pyridyl, and C 2 -C 4 alkynyl optionally substituted with cyclopropyl; and m is 0, 1, or 2.
24. The compound according to claim 23 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R 1 is selected from halogen and CN.
25. 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 3 or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the disease is T1D, T2DM, pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, 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, weight gain from use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, 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, prevention or treatment of Polycystic Ovary Syndrome and treatment of addiction.
26. The method of claim 25 , wherein the disease is type 1 diabetes (T1D) or type 2 diabetes mellitus (T2DM).
27. The method of claim 25 , wherein the disease is obesity.
28. The method of claim 25 , wherein the disease is a cardiovascular disease.
29. The method of claim 25 , wherein disease is non-alcoholic steatohepatitis (NASH).
30. The method of claim 25 , wherein the disease is Alzheimer's Disease.
31. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, and a compound represented by the following structure:
or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, and a compound represented by the following structure:
or a pharmaceutically acceptable salt thereof.