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

Patent metadata

Field	Value
Publication number	US-9790198-B2
Application number	US-201514877972-A
Country	US
Kind code	B2
Filing date	Oct 8, 2015
Priority date	Oct 8, 2014
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

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 hydrogen, chloro, or a substituent selected from the group consisting of C 1-3 akyl, hydroxy C 1-3 alkylsulfonyl, C 1-3 alkylsulfonylamino, and —OR 4 ;
wherein R 4 is
i) C 1-8 alkyl optionally independently substituted with one or two C 1-3 alkoxy or hydroxy sub stituents;
ii) C 3-7 cycloalkyl;
iii) C 1-3 alkylsulfonylpropyl;
iv) 2-(1-hydroxycyclopropyl)ethyl;
v) (1 -C 3-6 cycloalkyl-1-ol) methyl; or
vi) 2-(C 3-7 cycloalkyl)-2-hydroxyethyl;
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 form 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 R 2 is hydrogen.

5. The compound of claim 1
wherein R 4 is
i) C 1-8 alkyl optionally independently substituted with one or two C 1-3 alkoxy or hydroxy substituents;
ii) C 3-7 cycloalkyl;
iv) C 1-3 alkylsulfonylpropyl; or
v) 2-(1-hydroxycyclopropyl)ethyl.

6. The compound of claim 1 wherein R 3 is hydrogen or a substituent that is —OR 4 ;
wherein R 4 is
i) C 1 -4alkyl optionally independently substituted with one or two hydroxy or
C 1-3 alkoxy substituents; or
C 1-3 alkylsulfonylpropyl.

7. The compound of claim 1 wherein R 3 is selected from the group consisting of hydrogen; methyl; hydroxy; chloro; 4-(3-methylsulfonylpropoxy;
(1-hydroxycyclopropyl)ethoxy; 3-hydroxy-3-methylbutoxy; 2,3-dihydroxypropoxy; -methoxyethoxy; (3-(methylsulfonyl)propoxy; methylsulfonyl; and methylsulfonamido.

8. The compound of claim 1 wherein R 5 is methyl, methoxy, chloro, 2-methoxyethoxy, methanesulfonyl, or trifluoromethyl.

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;
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 hydrogen, chloro, or a substituent selected from the group consisting of C 1-3 alkyl, hydroxy, C 1-3 alkylsulfonyl, C 1-3 alkylsulfonylamino, and —OR 4 ;

wherein R 4 is
i) C 1-8 alkyl optionally independently substituted with one or two C 1-3 alkoxy or hydroxy substituents;
ii) C 3-7 cycloalkyl;
iii) C 1-3 alkylsulfonylpropyl; or
iv) 2-(1-hydroxycyclopropyl)ethyl;
R 5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;

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

10. The compound of claim 9 wherein 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.

11. 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 (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 hydrogen or —OR 4 ;

wherein R 4 is
i) C 1-4 alkyl optionally independently substituted with one or two hydroxy or C 1-3 alkoxy substituents; or
ii) C 1-3 alkylsulfonylpropyl;
R 5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;

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

12. A compound of Formula (I)

wherein
ring W is phenyl;
A is —CH 2 —;
Z is CH;
R 6 is hydrogen;
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 hydrogen or a substituent that is —OR 4 ;

wherein R 4 is
i) C 1-4 alkyl optionally independently substituted with one or two hydroxyl or C 1-3 alkoxy substituents; or
ii) C 1-3 alkylsulfonylpropyl;
R 5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;

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

13. 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 selected from the group consisting of hydrogen; methyl; methoxy; hydroxy; chloro; -4-(3-methylsulfonylpropoxy; -(1-hydroxycycl opropyl)ethoxy; 3 -hydroxy-3 -methylbutoxy; 2,3-dihydroxypropoxy; -methoxyethoxy; methyl sulfonyl; methyl sul fonami do; and 3-hydroxy-3-methylbutoxy;
R 5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;

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

14. The compound of claim 13 wherein
A is —CH 2 —;
R 1 is (S)-methylacetylenyl;
R 2 is hydrogen;
R 3 is hydrogen;
R 5 is methyl;

or pharmaceutically acceptable salt form thereof.

15. A compound selected from the group consisting of
Cpd 1, 3-[4-[[3- (2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]propanoic acid;
Cpd 2, (3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
Cpd 4, (3S)-3-[4-[[3-[2-Methyl-4-(3-methylsulfonylpropoxy)phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
Cpd 7, (3S)-3-[4-[[3-(4-Hydroxy-2-methyl-phenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
Cpd 10, (3S)-3-[4-[[3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
Cpd 11, (3S)-3-(4-((3-(4-(2-(1-Hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
Cpd 12, (3S)-3-(4((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
Cpd 13, (3S)-3-(4((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
Cpd 16, (3S)-3-(4-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
Cpd 19, (3S)-3-(4((3-(2-Chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
Cpd 20, (3S)-3-(4((3-(2-Bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
Cpd 21, (3S)-3-(4((3-(2-(Trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
Cpd 23, (3S)-3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
Cpd 24, (3S)-3-(4-(((3-(2-Methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
Cpd 27, (3S)-3-(4-(((3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)h

Assignees

• Janssen Pharmaceutica Nv

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

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

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title