GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent

Patent metadata

Field	Value
Publication number	US-9988379-B2
Application number	US-201314441591-A
Country	US
Kind code	B2
Filing date	Nov 8, 2013
Priority date	Nov 9, 2012
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

The present invention relates to a novel compound having GPR40 receptor agonist activity that promotes insulin secretion and inhibits blood sugar rise after glucose loading, and is thereby useful for the treatment of diabetes and complications thereof, the preparation method thereof and pharmaceutical composition containing them as an active ingredient.

First claim

The invention claimed is:

1. A compound of Formula (1), or a pharmaceutically acceptable salt or stereoisomer thereof:

wherein,
Q represents O, or NH,
R1 represents H, alkyl, heteroalkyl, heterocycle, or heterocycle-alkyl,
R2 represents H, alkyl, heteroalkyl, or halogen,
R3 represents H, alkyl, or halogen,
R4 represents H, alkyl, or halogen, or represents O, when R4 is connected with R5,
R5 represents alkoxy, CN, heterocycle, or C≡C-Me, or
R4 and R5 can be connected together to form 5- or 6-membered ring,
R6 represents H, or alkyl, or
R5 and R6 can be connected together to form 3-membered ring,
wherein the structure of

 is selected from the following structures:

wherein, E represents H, alkyl or halogen, and G represents alkyl, heteroalkyl or halogen,
wherein if the structure is

 R2 is absent.

2. A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of the following compounds
3-{4-[(1-isopropyl-1H-indol-6-ylmethyl)-amino-phenyl}-propanoic acid,
3-{4-[(1-benzyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid,
3-{4-[(1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid,
3-{4-[(1-phenethyl-1H-indol-6-ylmethyl)-aminol]-phenyl}-propanoic acid,
3-{4-[(1-benzyl-3-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid,
3-{4-[(1-benzyl-2,3-dichloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid,
3-{4-[(1-benzyl-7-chloro-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid,
3-{4-[(7-chloro-1-thiophen-3-yl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid,
3-(4-{[7-chloro-1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid,
3-(4-{[1-(4-fluoro-phenyl)-1H-indol-6-ylmethyl]-amino}-phenyl)-propanoic acid,
3-{4-[(7-chloro-1-cyclohexyl methyl-1H-indol-6-ylmethyl)-amino]-phenyl}-propanoic acid,
[6-(1-benzyl-3-chloro-1H-indol-6-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid,
3-[4-(1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid,
3-{4-[1-(4-fluoro-phenyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid,
3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid,
3-[4-(7-methyl-1-thiophen-3-yl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid,
3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-propanoic acid,
3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid,
3-[4-(1-cyclohexyl methyl-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid,
3-[4-(3-benzyl-1-methyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid,
3-[4-(1-methyl-3-o-tolyl-1H-indol-5-ylmethoxy)-phenyl]-propanoic acid,
3-{4-[3-chloro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid,
3-{4-[5-fluoro-1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy)-phenyl]-propanoic acid,
{6-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid,
(S)-3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(4-methanesulfonyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(4-methoxy-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[7-methyl-1-(4-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(3-methoxymethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-{4-[1-(4-fluoro-2-methyl-phenyl)-1H-indol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(2,6-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-benzyl-2-(2-methoxy-ethyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(3-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[7-methyl-1-(2-methyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(2-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(2-chloro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(2,6-dimethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(1-benzyl-7-chloro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(1-benzyl-5-fluoro-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-{4-[1-(3-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[7-methyl-1-(3-trifluoromethyl-benzyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[7-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(4-methanesulfonylmethyl-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl }-hex-4-ynoic acid,
(S)-3-{4-[1-(6-chloro-pyridin-3-ylmethyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(2-benzyl-2H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(1-benzyl-1H-indazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(1-benzyl-5-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-{4-[1-(4-fluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(3,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(3,5-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(2,4-difluoro-benzyl)-7-methyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
3-[4-(1-benzyl-1H-indol-4-ylmethoxy)-2-fluoro-phenyl]-propanoic acid,
3-[4-(1-benzyl-7-methyl-1H-indol-6-ylmethoxy)-2-fluoro-phenyl]-propanoic acid,
(S)-3-[4-(7-methyl-1-thiazol-4-ylmethyl-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[7-methyl-1-(2-methyl-thiazol-4-ylmethyl)-1H-indol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(2-benzyl-2H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(7-methyl-1-pyrazin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(7-methyl-1-pyrimidin-4-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(1-benzyl-3-fluoro-7-methyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-{4-[7-methyl-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
(S)-3-[4-(7-methyl-1-pyrimidin-2-ylmethyl-1H-indol-6-ylmethoxy)-phenyl]-hex-4-ynoic acid,
3-[4-(1-benzyl-1H-indazol-6-ylmethoxy)-phenyl]-3-(4,5-dihydro-isoxazol-3-yl)-propanoic acid,
(S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(1-pyrimidin-2-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(2-pyrimidin-2-ylmethyl-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(1-pyrazin-2-ylmethyl-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(4-fluoro-benzyl)-1H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[2-(4-fluoro-benzyl)-2H-indazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[1-(5-methyl-pyrazin-2-ylmethyl)-1H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-{4-[2-(5-methyl-pyrazin-2-ylmethyl)-2H-indazol-6-ylmethoxy]-phenyl}-hex-4-ynoic acid,
(S)-3-[4-(1-pyrimidin-4-ylmethyl-1H-indazol-6-ylmethoxy)-phenyl]-hex-4-ynoic

Assignees

• Lg Chemical Ltd

Inventors

• Lee Sung Bae
• Paek Seung Yup
• Yoon Sook Kyung
• Yoon Seung Hyun
• Choi Jeung Soon

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title