Benzimidazolone GLP-1 receptor agonist and use thereof

1 . A compound of Formula I-2:

or a pharmaceutically acceptable salt thereof,

wherein:

X is selected from the group consisting of carbonyl, methylphosphoryl, and sulfonyl;

denotes the absence of a bond;

W 1 is selected from CH 2 , O or NH;

Y 1 is selected from CH or N;

Y 2 is selected from CH, N or C;

Y 3 is N;

Z 1 , Z 2 and Z 3 are each independently selected from CH or N;

R 1 is selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 8-membered aryl, 5- to 8-membered heteroaryl, —NH 2 , —NH—C 1-6 alkyl, —NH—C 1-6 alkoxy, —NH—C 1-6 cycloalkoxy, —NH—C 2-6 alkenyl, —NH—C 2-6 alkynyl, —NH—C 3-8 cycloalkyl, —NH-3- to 8-membered heterocyclyl, —NH-6- to 8-membered aryl, and —NH-5- to 8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl in R 1 may be optionally substituted 1-3 times by a substituent(s) independently selected from R x ;

R 2 is independently selected from the group consisting of hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 1-6 alkoxy, —C 1-6 cycloalkoxy, —CN, 3- to 8-membered heterocyclyl, aryl, 5- to 8-membered heteroaryl, or —CO—R 1 , wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, heterocyclyl, aryl and heteroaryl in R 2 may be optionally substituted 1-3 times by a substituent(s) independently selected from R x ;

R 4 is independently selected from the group consisting of hydrogen, halogen, —C 1-3 alkyl, —C 1-3 haloalkyl, —C 1-3 alkoxy, cyano, hydroxy, amino, amido, sulfonyl, and sulfonamido;

R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, —CN, —C 1-3 alkyl, —C 1-3 alkoxy, and —C 1-3 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl in R 5 may be optionally substituted 1-3 times by a halogen atom(s), if valency permits;

R 6 is selected from the group consisting of —R z , —O—R z , —S—R z , —C 1-3 alkyl, —C 1-3 alkylene-R z , —C 0-3 alkylene-amino-R z , —C 0-3 alkylene-carbonyl-R z , —C 0-3 alkylene-amido-R z , —C 0-3 alkylene-sulfonyl-R z , —C 0-3 alkylene-phosphoryl-R z , and —C 0-3 alkylene-sulfonamido-R z , wherein the alkyl, amino, sulfonyl and sulfonamido in R 6 may be optionally substituted 1-3 times by a halogen atom(s) or one time by R w , if valency permits;

n is an integer selected from 0, 1, 2, or 3;

o is an integer selected from 0, 1, 2, 3, or 4;

p is an integer selected from 0, or 1;

when o is not 0 and p is not 0, any R 4 and R 5 may be further cyclized into a 5- to 8-membered ring which may be optionally substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, or C 1-3 alkoxy, if valency permits;

R w is independently selected from the group consisting of —CN, —CH 2 CN, —C 1-3 alkyl, —OH, —C 1-3 alkoxy, amido, sulfonyl, sulfonamido, —NH 2 , and —NH—C 1-3 alkyl, wherein the alkyl in R w may be optionally substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, or C 1-3 alkoxy, if valency permits;

R x is independently selected from the group consisting of hydrogen, halogen, oxo, C 1-6 alkoxy, cyano, hydroxyl, carboxyl, amino, amido, sulfonyl, sulfonamido, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 8-membered aryl, and 5- to 8-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl in R x may be optionally substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, or C 1-3 alkoxy, if valency permits;

R y is independently selected from the group consisting of hydrogen, halogen, oxo, —C 1-3 alkoxy, cyano, hydroxyl, amino, carboxyl, amido, sulfonyl, sulfonamido, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, amino, amido, alkoxy, cycloalkyl, heterocyclyl and heteroaryl in R y may be optionally substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, or C 1-3 alkoxy, if valency permits;

R z is independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, and 5- to 6-membered heteroaryl, wherein R z may be optionally substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, or 3- to 6-membered heterocyclyl, if valency permits.

2 . The compound according to claim 1 , wherein the R 1 may be selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, —NH 2 , —NHCH 3 , —pyridine, pyrimidine, hexahydropyridine, pyrrole, pyrazole, and imidazole, wherein the R 1 may be optionally substituted 1-3 times by halogen;

and/or

wherein the R 2 may be selected from the group consisting of halogen, —CN, —C 1-3 alkyl, —C 1-3 alkoxy, wherein the alkyl and alkoxy in R 2 may be optionally substituted 1-3 times by a F atom(s), if valency permits;

and/or

wherein the R 5 may be selected from —F, —Cl, —CN, —CH 3 , —CH 2 CH 3 , —CF 3 , —CH 2 OH, isopropyl or cyclopropyl.

3 . The compound according to claim 1 , wherein the R z may be selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, and ethoxy.

4 . The compound according to claim 1 , wherein n is 1 or 2; and/or, wherein o is 0 or 1.

5 . The compound according to claim 1 , wherein W 1 is selected from O or NH; and/or, wherein Z 1 and Z 2 are each independently CH.

6 . The compound according to claim 1 , wherein the compound is selected from the following compounds:

and pharmaceutically acceptable salts thereof.

7 . A pharmaceutical composition, comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable pharmaceutical carrier.

8 . The compound according to claim 1 , wherein:

X is carbonyl;

W 1 is O;

Z 1 , Z 2 and Z 3 are each CH; and

o is 1.

9 . The compound according to claim 1 , wherein Y 2 is CH.

10 . The compound according to claim 1 , wherein Y 2 is N.

11 . A compound selected from:

or a pharmaceutically acceptable salt thereof.

12 . The compound according to claim 1 , wherein the R 2 is —F, —Cl, —CN, —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —COCH 3 , —CONH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CH 2 F, cyclopropyl, or —O— cyclopropyl.

13 . The compound according to claim 1 , wherein W 1 is O.

14 . A method for preventing and/or treating GLP-1 mediated diseases, comprising administering to a subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

15 . The method of claim 14 , wherein the GLP-1 mediated diseases are selected from diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, and hyperinsulinemia.