Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes

Patent metadata

Field	Value
Publication number	US-10131648-B2
Application number	US-201715697867-A
Country	US
Kind code	B2
Filing date	Sep 7, 2017
Priority date	Oct 8, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

Disclosed are compounds, compositions and methods for treating of disorders that are affected by the modulation of the GPR40 receptor. Such compounds are represented by Formula (I) as follows:

wherein R 1 , R 2 , R 3 , R 5 , R 6 , W, and A are defined herein.

First claim

We claim:

1. A compound of Formula (I)

wherein
ring W is phenyl;
A is —CH 2 O— or —OCH 2 —;
Z is CH;
R 6 is hydrogen;
R 1 is selected from hydrogen or methylacetylenyl; or R 1 and R 6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
R 2 is selected from hydrogen or methyl;
R 3 is a substituent selected from the group consisting of piperidin-4-yl, and piperidin-4-ylmethyl;
R 5 is methyl, methoxy, bromo, chloro, C 1-6 alkoxy-C 1-6 alkoxyl, C 1-6 alkylsulfonyl, or trifluoromethyl;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt forms thereof.

2. The compound of claim 1 wherein A is —CH 2 O—.

3. The compound of claim 1 wherein A is —OCH 2 —.

4. The compound of claim 1 wherein Z is CH, R 6 is hydrogen and R 1 is (S)-methylacetylenyl; or R 1 and R 6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl.

5. The compound of claim 1 wherein R 2 is hydrogen.

6. The compound of claim 1 wherein R 3 is piperidin-4-yl.

7. A compound of Formula (I)

wherein
ring W is phenyl;
A is —CH 2 O— or —OCH 2 —;
Z is CH;
R 6 is hydrogen;
R 1 is selected from hydrogen or methylacetylenyl; or R 1 and R 6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
R 2 is hydrogen;
R 3 is a substituent selected from the group consisting of piperidin-4-yl, and piperidin-4-ylmethyl;
R 5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

8. The compound of claim 7 wherein when Z is CH, R 6 is hydrogen and R 1 is (S)-methylacetylenyl; or R 1 and R 6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl or R 1 and R 6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused cyclobut-3-one-yl.

9. A compound of Formula (I)

wherein
ring W is phenyl;
A is —CH 2 O— or —OCH 2 —;
Z is CH, R 6 is hydrogen and R 1 is (S)-methylacetylenyl; or R 1 and R 6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
R 2 is hydrogen;
R 3 is piperidin-4-yl, or piperidin-4-ylmethyl;
R 5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

10. A compound selected from the group consisting of
Cpd 95, (3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid; and
Cpd 96, (3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;

or a pharmaceutically acceptable salt forms thereof.

11. A pharmaceutical composition comprising a compound of claim 1 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

12. The pharmaceutical composition of claim 11 , wherein the composition is a solid oral dosage form.

13. The pharmaceutical composition of claim 11 , wherein the composition is a syrup, an elixir or a suspension.

14. A pharmaceutical composition comprising the compound of claim 10 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Huang Hui
• Kuo Gee-Hong
• Player Mark R
• Yang Shyh-Ming
• Zhang Yue-Mei

Classifications

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title