Hydroxy isoxazole compounds useful as GPR120 agonists

Patent metadata

Field	Value
Publication number	US-10864211-B2
Application number	US-201716462344-A
Country	US
Kind code	B2
Filing date	Dec 11, 2017
Priority date	Dec 15, 2016
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

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.

First claim

What is claimed is:

1. 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 R a ;
B is selected from:
(1) aryl,
(2) —O-aryl,
(3) —(CH 2 ) p —O-aryl,
(4) —O—(CH 2 ) p -aryl,
(5) heteroaryl,
(6) —O-heteroaryl,
(7) —(CH 2 ) p —O-heteroaryl,
(8) —O—(CH 2 ) p -heteroaryl,
(9) —C 3-10 cycloalkyl,
(10) —(CH 2 ) p —O—C 3-10 cycloalkyl,
(11) —O—(CH 2 ) p —C 3-10 cycloalkyl,
(12) —C 2-10 cycloheteroalkyl,
(13) —(CH 2 ) p —O—C 2-10 cycloheteroalkyl, and
(14) —O—(CH 2 ) p —C 3-10 cycloheteroalkyl,

wherein each —CH 2 , cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is unsubstituted or substituted with 1, 2 or 3 or 4 substituents selected from R b ;
R 1 is selected from:
(1) hydrogen, and
(2) halogen;

R 2 is selected from:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —C 2-6 alkenyl,
(4) —C 2-6 alkynyl, and
(5) —CN,

wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents selected from: halogen, OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 and —OC 1-6 alkyl;
each R a is independently selected from:
(1) halogen, and
(2) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with 1-3 substituents selected from: —C 1-6 alkyl and halogen;
each R b is independently selected from:
(1) halogen,
(2) —CN,
(3) —OH,
(4) —C 1-6 alkyl,
(5) —C 2-6 alkenyl,
(6) —C 2-6 alkynyl,
(7) —O—C 1-6 alkyl,
(8) —O—C 2-6 alkenyl,
(9) —O—C 2-6 alkynyl,
(10) —C 3-10 cycloalkyl,
(11) —C 3-10 cycloalkenyl,
(12) aryl,
(13) heteroaryl,
(14) —OC 3-10 cycloalkyl,
(15) —OC 3-6 cycloheteroalkyl,
(16) —O-aryl,
(17) —O-heteroaryl,
(18) —NH 2 ,
(19) —NHC 1-6 alkyl,
(20) —N(C 1-6 alkyl) 2 ,
(21) —SC 1-6 alkyl,
(22) —SOC 1-6 alkyl, and
(23) —SO 2 C 1-6 alkyl,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: —C 1-6 alkyl, —OC 1-6 alkyl, —CF 3 , —OCF 3 , 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.

2. The compound of claim 1 wherein A is aryl, wherein aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein A is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein B is selected from:
(1) aryl,
(2) —O-aryl,
(3) —(CH 2 ) p —O-aryl,
(4) —O—(CH 2 ) p -aryl,
(5) heteroaryl,
(6) —O-heteroaryl,
(7) —O—(CH 2 ) p -heteroaryl,
(8) —C 3-10 cycloalkyl, and
(9) —O—(CH 2 ) p —C 3-10 cycloalkyl,

wherein B is unsubstituted or substituted with 1, 2 or 3 or 4 substituents selected from R b ;
or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein B is selected from:
(1) aryl,
(2) —O-aryl,
(3) —O—(CH 2 ) p -aryl, and
(4) heteroaryl,
wherein B is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 1 is halogen; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein R 1 is hydrogen; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein R 2 is selected from:
(1) halogen, and
(2) —C 1-6 alkyl,
wherein each alkyl is unsubstituted or substituted with 1-3 substituents selected from: halogen, OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 and —OC 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein R 2 is halogen; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 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 R a ;
B is selected from:
(1) aryl,
(2) —O-aryl,
(3) —(CH 2 ) p —O-aryl,
(4) —O—(CH 2 ) p -aryl,
(5) heteroaryl,
(6) —O-heteroaryl,
(7) —O—(CH 2 ) p -heteroaryl,
(8) —C 3-10 cycloalkyl, and
(9) —O—(CH 2 ) p —C 3-10 cycloalkyl,

wherein B is unsubstituted or substituted with 1, 2 or 3 or 4 substituents selected from R b ;
R 1 is selected from:
(1) hydrogen, and
(2) halogen;

R 2 is selected from:
(1) halogen, and
(2) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with 1-3 substituents selected from:
halogen, OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 and —OC 1-6 alkyl;
n is 1 or 2;
m is 0, 1, or 2;
p is 1, 2, or 3; and
q is 0 or 1;
or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 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 R a ;
B is selected from:
(1) aryl,
(2) —O-aryl,
(3) —O—(CH 2 ) p -aryl, and
(4) heteroaryl,

wherein B is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ;
R 1 is hydrogen;
R 2 is halogen;
n is 1;
m is 0, or 1;
p is 1, 2, or 3; and
q is 0 or 1;
or a pharmaceutically acceptable salt thereof.

12. A compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

14. A method for the treatment of a condition selected from the group consisting of diabetes, hyperlipidemia, obesity, and inflammation related disorders comprising administering to an individual a pharmaceutical composition comprising the compound of claim 1 .

Assignees

• Merck Sharp & Dohme

Inventors

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

Classifications

• C07D261/12

  Oxygen atoms · CPC title

• A61P3/10 Primary

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K9/4858

  Organic compounds · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title