Heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-10011609-B2
Application number	US-201415034661-A
Country	US
Kind code	B2
Filing date	Nov 3, 2014
Priority date	Nov 14, 2013
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

The present invention relates to novel GPR 40 agonists of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

First claim

The invention claimed is:

1. A compound of general Formula (I′)

a tautomeric form thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 and R 4 at each occurrence independently represents H, halogen, hydroxyl, CN, NO 2 , CHO, COOH, CO, alkyl, alkoxy, thiol, sulphoxide, sulphone, acyl, NH 2 , NHCO-linear or branched (C 1 -C 6 )alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetererocyclylalkyl, heteroaryl, or heteroaralkyl or a group OR, C(O)OR, C(O)R, or SO 2 R wherein R at each occurrence is independently selected from H, linear or branched (C 1 -C 6 )alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetrerocyclylalkyl, heteroaryl, and heteroaralkyl groups;
A is selected from 5 or 6 membered heteroaromatic rings which may further have one or more heteroatoms selected from O, S, and N;
each of E and D independently represents either nitrogen or carbon;
F is selected from C, N and O; and
each of n, r, and s independently represents an integer ranging from 0 to 6.

2. The compound as claimed in claim 1 , wherein the heterocycle representing

is selected from the group consisting of

3. The compound as claimed in claim 1 , wherein the COOH is replaced wherever possible with bioisosteric replacements selected from the group consisting of

4. The compound according to claim 1 selected from the group consisting of
(S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-methyl-6,7-dihydrothienazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((1-(tert-butoxycarbonyl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl) methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl) hex-4-ynoic acid;
(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methylbenzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5 (4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
(S)-3-(4-((3-((2-(Difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
Calcium (S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoate;
(S)-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl) hex-4-ynoic acid;
(S)-3-(4-((3-((1-Methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl) hex-4-ynoic acid;
(S)-3-(4-((3-((5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((4H-Thieno[2,3-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
6-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-ium formate;
(S)-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-5-(3-((4-(1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4, 5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid;
3-cyclopropyl-3-(3-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)propanoic acid;
(S)-3-(4-((3-((1-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
Calcium (S)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoate;
(S)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-isopropylpyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl oxy)phenyl)hex-4-ynoic acid;
S)-3-(4-((3-((2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((1-isopropylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid compound with formic acid;
(R)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
(R)-3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((6,7-Dihydro-[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
3-(4-((3-((2-Methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
Calcium (S)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoate;
(S)-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-(pyrrolidine-1-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-acetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
Calcium (S)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoate;
(S)-3-(4-((3-((2-Nitro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
(S)-3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
(S)-3-(4-((3-((2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
(S)-3

Assignees

• Cadila Healthcare Ltd

Inventors

• Desai Ranjit C
• Srivastava Brijeshkumar

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P9/12

  Antihypertensives · 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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title