Aryl ether-substituted heterocyclic compounds as glpir agonists
A novel aryl ether substituted heterocyclic compound has GLP1R agonist activity. Specifically, the compound of formula (I) can be used as a GLP1R agonist. The pharmaceutically acceptable salt, solvate, hydrate, isotope substituent or isomer of the compound are also provided. A method for preventing and/or treating diseases related to the GLP1/GLP1R signaling pathway includes the step of administering to a patient a preventive or therapeutically effective amount the compound, a pharmaceutically acceptable salt, or an enantiomer thereof.
1 . A compound of Formula (IE), pharmaceutically acceptable salts, or enantiomers thereof,
wherein,
=represents a single bond;
X represents —O—;
X′ represents —C(R d1 )(R d2 )—;
L represents —O—;
X 1 represents —N—;
X 3 represents —N—;
X 8 represents —CR 5 — or —N—;
R is 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated heterocyclyl, or 3- to 8-membered saturated or partially saturated cycloalkyl, and wherein the heteroaryl, heterocyclyl, and cycloalkyl are optionally substituted with one to multiple substituent groups independently selected from methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl, and hexyl;
each R 1 is the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, and —COOH;
each R 4 is the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, and C 1-10 alkoxy;
R 5 is selected from hydrogen, deuterium, halogen, CN, C 1-10 alkyl, C 2-10 alkynyl, and C 1-10 alkoxy;
each R 6 is the same or different and is independently selected from hydrogen, deuterium, halogen, CN, C 1-10 alkyl, C 2-10 alkynyl, and C 1-10 alkoxy;
R d1 and R d2 are independently selected from hydrogen, deuterium, halogen, and C 1-10 alkyl;
m is an integer selected from 1 and 2;
n is an integer selected from 0, 1 and 2; and
q is an integer selected from 0, 1 and 2.
2 . The compound according to claim 1 , pharmaceutically acceptable salts, or enantiomers thereof, wherein R is oxetanyl or imidazolyl, wherein the oxetanyl or imidazolyl is optionally substituted with methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl, or hexyl.
3 . The compound according to claim 1 , pharmaceutically acceptable salts, or enantiomers thereof, wherein,
each R 1 is the same or different and is independently selected from the group consisting of hydrogen, F and —COOH;
each R 4 is the same or different and is independently selected from the group consisting of hydrogen, deuterium, F and methyl;
R 5 is selected from the group consisting of hydrogen, deuterium and F;
each R 6 is the same or different and is independently selected from the group consisting of hydrogen, deuterium, halogen, ethynyl and CN.
4 . The compound according to claim 1 , pharmaceutically acceptable salts, or enantiomers thereof, wherein, m is 1; n is 0; q is 2.
5 . A compound selected from the following compounds, or
pharmaceutically acceptable salts, or enantiomers thereof:
Number
Structure
Compound 1
Compound 2
Compound 3
Compound 4
Compound 43
Compound 44
Compound 45
Compound 46
Compound C3
Compound C5
Compound C6
Compound C14
Compound C19
Compound C31
Compound C33
Compound C45
Compound C56
Compound C57
Compound C58
Compound C59
6 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 .
7 . A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 1 , wherein the disease is overweight, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, weight gain due to use of other drugs, dyslipidemia, NAFLD, cardiovascular disease, atherosclerosis sclerosis, or peripheral vascular disease.
8 . A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt or enantiomer thereof, wherein the disease is overweight, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, weight gain due to use of other drugs, dyslipidemia, NAFLD, cardiovascular disease, atherosclerosis sclerosis, or peripheral vascular disease.
9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 .
10 . The method of claim 7 , wherein the disease is overweight or obesity.
11 . The method of claim 7 , wherein the disease is diabetes.
12 . The method of claim 8 , wherein the disease is overweight or obesity.
13 . The method of claim 8 , wherein the disease is diabetes.