GPR40 agonists for the treatment of type II diabetes

Patent metadata

Field	Value
Publication number	US-9920040-B2
Application number	US-201615228026-A
Country	US
Kind code	B2
Filing date	Aug 4, 2016
Priority date	Aug 12, 2015
Publication date	Mar 20, 2018
Grant date	Mar 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 4 , W, X, Y, and G, are defined herein.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
X is S or O; provided that when X is O, Y is N;
Y is C(R 3 ) or N;
R 3 is hydrogen or methyl; or when X is S, R 3 is hydrogen, methyl, or chloro;
W is CH or N;
L is —CH 2 O—, —CH═CH—, or —(CH 2 ) 1-2 —;
R 1 is selected from the group consisting of phenyl, pyridin-4-yl, thienyl, benzothiophenyl, benzofuranyl, and indolyl; wherein said benzothiophenyl, benzofuranyl, and indolyl are attached to the core (X)-(Y) containing ring via its benzo ring; and wherein R 1 is optionally independently substituted with one or two substituents selected from C 1-4 alkyl, methoxy, fluoro, cyano, di(C 1-4 alkyl) amino, or trifluoromethyl;
R 2 is C 3-5 cycloalkyl, C 1-6 alkyl, or cyano;
R 4 is hydrogen or chloro;
G is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, phenyl, unsubstituted C 3-7 cycloalkyl, unsubstituted C 3-7 cycloalkoxy, unsubstituted C 3-7 cycloalkyl-methoxy, C 2-6 alk-1-en-1-yl, 3,3,3-trifluoropropoxy, 2,2,2-trifluoro-1-methyl-ethyl, (C 1-6 alkyl)thien-2-yl, and a substituent selected from g1 to g6;

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

2. The compound of claim 1 wherein X is S.

3. The compound of claim 1 wherein X is O and Y is N.

4. The compound of claim 1 wherein L is —CH 2 O—, —CH═CH—, or —(CH 2 ) 2 —.

5. The compound of claim 4 wherein L is —CH 2 O—.

6. The compound of claim 1 wherein R 1 is selected from the group consisting of phenyl, pyridin-4-yl, thienyl, benzothiophenyl, benzofuranyl, and indolyl; wherein said benzothiophenyl, benzofuranyl, and indolyl are attached to the core (X)-(Y) containing ring via its benzo ring; and wherein R 1 is optionally independently substituted with one or two substituents selected from methyl, methoxy, or fluoro.

7. The compound of claim 6 wherein R 1 is selected from the group consisting of phenyl, pyridin-4-yl, and thienyl; wherein R 1 is optionally independently substituted with one or two substituents selected from methyl, methoxy, or fluoro.

8. The compound of claim 1 wherein R 1 is selected from the group consisting of 2-fluoro-5-methoxy-phenyl, 5-fluoro-2-methoxy-pyrid-4-yl, 6-methoxybenzothiophen-4-yl, thien-3-yl, 3-(dimethylamino)phenyl, 2-fluoro-4-methoxy-phenyl, phenyl, 2-fluorophenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 1H—indol-4-yl, benzofuran-4-yl, 3-methoxyphenyl, 5-methoxypyrid-3-yl, 2-methoxypyrid-4-yl, and 5-cyano-2-fluoro-phenyl.

9. The compound of claim 1 wherein R 2 is C 3-5 cycloalkyl.

10. The compound of claim 9 wherein R 2 is cyclopropyl.

11. The compound of claim 1 wherein G is selected from the group consisting of C 1-6 alkoxy, phenyl, unsubstituted C 3-7 cycloalkyl, unsubstituted C 3-7 cycloalkoxy, unsubstituted C 3-7 cycloalkyl-methoxy, C 2-6 alk-1-en-1-yl, 3,3,3-trifluoropropoxy, (C 1-4 alkyl)thien-2-yl, and a substituent selected from g1 to g6

12. The compound of claim 11 wherein G is selected from the group consisting of C 1-4 alkoxy, unsubstituted C 3-7 cycloalkyl, unsubstituted C 3-7 cycloalkoxy, unsubstituted C 3-7 cycloalkyl-methoxy, C 2-6 alk-1-en-1-yl, 5-(C 1-4 alkyl)thien-2-yl, and a substituent selected from g1 to g5;

13. The compound of claim 12 wherein G is selected from the group consisting of C 1-4 alkoxy, unsubstituted C 3-7 cycloalkyl, unsubstituted C 3-7 cycloalkoxy, unsubstituted C 3-7 cycloalkyl-methoxy, C 2-6 alk-1-en-1-yl, 5-(C 1-4 alkyl)thien-2-yl and a substituent selected from g2, g4, or g5;

14. The compound of claim 1 wherein G is selected from the group consisting of 2-methyl-propyl, ethoxy, isopropyloxy, 2-methyl-propyloxy, cyclopropyl, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-methyl-prop-1-en-1-yl, phenyl, 5-(methyl)thien-2-yl, 5-(t-butyl)thien-2-yl, 3-(methyl)thien-2-yl, 2,2,2-trifluoro-1-methyl-ethyl, 3,3,3-trifluoropropyloxy, and a substituent selected from g1 to g5;

15. A compound of Formula (I)

wherein
X is S or O; provided that when X is O, Y is N;
Y is C(R 3 ) or N;
R 3 is hydrogen or methyl; or when X is S, R 3 is hydrogen, methyl, or chloro;
W is CH or N;
L is —CH 2 O—, —CH═CH—, or —(CH 2 ) 2 —;
R 1 is selected from the group consisting of phenyl, pyridin-4-yl, and thienyl; wherein R 1 is optionally independently substituted with one or two
substituents selected from methyl, methoxy, or fluoro;
R 2 is C 3-5 cycloalkyl;
R 4 is hydrogen or chloro;
G is selected from the group consisting of C 1-6 alkoxy, phenyl, unsubstituted C 3-7 cycloalkyl, unsubstituted C 3-7 cycloalkoxy, unsubstituted C 3-7 cycloalkyl-methoxy, C 2-6 alk-1-en-1-yl, 5-(C 1-4 alkyl)thien-2-yl, and a substituent selected from g1 to g6;

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

16. A compound of Formula (I)

wherein
X is O;
Y is N;
W is CH or N;
L is —CH 2 O—, —CH═CH—, or —(CH 2 ) 2 —;
R 1 is selected from the group consisting of phenyl, pyridin-4-yl, or thienyl; wherein R 1 is optionally independently substituted with one or two substituents selected from methyl, methoxy, or fluoro;
R 2 is C 3-5 cycloalkyl;
R 4 is hydrogen or chloro;
G is selected from the group consisting of C 1-4 alkoxy, unsubstituted C 3-7 cycloalkyl, unsubstituted C 3-7 cycloalkoxy, unsubstituted C 3-7 cycloalkyl-methoxy, C 2-6 alk-1-en-1-yl, 5-(C 1-4 alkyl)thien-2-yl, and a substituent selected from g1 to g5;

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

17. A compound of Formula (I)

wherein
X is O;
Y is N;
W is CH or N;
L is —CH 2 O—, —CH═CH—, or —(CH 2 ) 2 —;
R 1 is selected from the group consisting of phenyl, pyridin-4-yl, and thienyl; wherein R 1 is optionally independently substituted with one or two substituents selected from methyl, methoxy, or fluoro;
R 2 is cyclopropyl;
R 4 is hydrogen or chloro;
G is selected from the group consisting of C 1-4 alkoxy, unsubstituted C 3-7 cycloalkyl, unsubstituted C 3-7 cycloalkoxy, unsubstituted C 3 -7 cycloalkyl-methoxy, C 2-6 alk-1-en-1-yl, 5-(C 1-4 alkyl)thien-2-yl and a substituent selected from g2, g4, or g5;

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

18. A compound of Formula (I)

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Huang Hui
• Meegalla Sanath
• Player Mark R

Classifications

• C07D261/12

  Oxygen atoms · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D413/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D333/24

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D261/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title