US 10,864,211 B2Granted

Hydroxy isoxazole compounds useful as GPR120 agonists

AssigneeMerck Sharp & Dohme Corp.

InventorsJohn S. Debenham, Jason M. Cox, Ping Lan, Zhongxiang Sun, Zhe Feng, Chunrui Sun, W. Michael Seganish, Zhong Lai, Cheng Zhu, Thomas Bara, Murali Rajagopalan, Qun Dang, Hyunjin M. Kim, Bin Hu, Jinglai Hao

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Abstract

The present invention relates to a compound represented by formula (I): and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing diabetes, hyperlipidemia, obesity, NASH, inflammation related disorders, and related diseases and conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR120. Pharmaceutical compositions and methods of treatment are also included.

A compound according to the formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
(1) aryl and
(2) heteroaryl,
wherein each aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Ra;
B is selected from:
(1) aryl,
(2) —O-aryl,
(3) —(CH2)p—O-aryl,
(4) —O—(CH2)p-aryl,
(5) heteroaryl,
(6) —O-heteroaryl,
(7) —(CH2)p—O-heteroaryl,
(8) —O—(CH2)p-heteroaryl,
(9) —C3-10cycloalkyl,
(10) —(CH2)p—O—C3-10cycloalkyl,
(11) —O—(CH2)p—C3-10cycloalkyl,
(12) —C2-10cycloheteroalkyl,
(13) —(CH2)p—O—C2-10cycloheteroalkyl, and
(14) —O—(CH2)p—C3-10cycloheteroalkyl,
wherein each —CH2, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is unsubstituted or substituted with 1, 2 or 3 or 4 substituents selected from Rb;
R1 is selected from:
(1) hydrogen, and
(2) halogen;
R2 is selected from:
(1) halogen,
(2) —C1-6alkyl,
(3) —C2-6alkenyl,
(4) —C2-6alkynyl, and
(5) —CN,
wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents selected from:
halogen, OH, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2 and —OC1-6alkyl;
each Ra is independently selected from:
(1) halogen, and
(2) —C1-6alkyl,
wherein each alkyl is unsubstituted or substituted with 1-3 substituents selected from:
—C1-6alkyl and halogen;
each Rb is independently selected from:
(1) halogen,
(2) —CN,
(3) —OH,
(4) —C1-6alkyl,
(5) —C2-6alkenyl,
(6) —C2-6alkynyl,
(7) —O—C1-6alkyl,
(8) —O—C2-6alkenyl,
(9) —O—C2-6alkynyl,
(10) —C3-10 cycloalkyl,
(11) —C3-10cycloalkenyl,
(12) aryl,
(13) heteroaryl,
(14) —OC3-10cycloalkyl,
(15) —OC3-6cycloheteroalkyl,
(16) —O-aryl,
(17) —O-heteroaryl,
(18) —NH2,
(19) —NHC1-6alkyl,
(20) —N(C1-6alkyl)2,
(21) —SC1-6alkyl,
(22) —SOC1-6alkyl, and
(23) —SO2C1-6alkyl,
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from:
—C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, and halogen;
n is 1 or 2;
m is 0, 1, or 2;
p is 1, 2, or 3;
and
q is 0 or 1.

65 more elements

Facts

Application

16/462,344Filed 11 Dec 2017

Priority

CN PCT/CN2016/11005415 Dec 2016

Published

US 2019/0269679 A15 Sep 2019

Granted

15 Dec 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/497
Non-condensed pyrazines: containing further heterocyclic rings
A61K 9/0053
Galenical forms characterised by the site of application: mouth and digestive tract, i.e. intraoral and peroral administration
A61K 9/4858
Filling excipients; Inactive ingredients: organic compounds
A61K 31/42
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxazoles

Abstract

Claims14