Substituted pyrazines as GPR40 agonists

Patent metadata

Field	Value
Publication number	US-9688642-B2
Application number	US-201514794907-A
Country	US
Kind code	B2
Filing date	Jul 9, 2015
Priority date	Jul 9, 2014
Publication date	Jun 27, 2017
Grant date	Jun 27, 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 , G, and R 2 are defined herein.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
R 1 is selected from the group consisting of phenyl, pyridin-4-yl, and thiophenyl; wherein R 1 is optionally and independently substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, methoxy, fluoro, cyano, and trifluoromethyl; provided that phenyl of R 1 is substituted with no more than one methoxy substituent;
G is selected from the group consisting of C 1-6 alkyl; C 1-6 alkoxy; C 3-7 cycloalkyl; 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yloxy; oxetan-3-yloxy; C 2-6 alk-1-en-1-yl; 3,3,3-trifluoropropyloxy; 1,1,1-trifluoroprop-2-yl; (C 1-6 alkyl)thiophen-2-yl; phenyl optionally substituted with one or two C 1-4 alkyl substituents; (C 1-6 alkyl)amino; di(C 1-6 alkyl)amino; N-containing heterocyclyl wherein said N-containing heterocyclyl is attached to the core pyrazine ring via a nitrogen atom and said N-containing heterocyclyl is optionally spirofused to a C 3-7 cycloalkyl group; ring g1

 C 3-7 cycloalkyloxy; and C 3-7 cycloalkyl-methoxy;
wherein C 3-7 cycloalkyloxy and the C 3-7 cycloalkyl portion of C 3-7 cycloalkyl-methoxy are optionally substituted with one to four methyl substituents; and
R 2 is C 3-5 cycloalkyl, C 1-6 alkyl, or cyano;

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

2. The compound of claim 1 , wherein G is selected from the group consisting of C 1-6 alkyl; C 1-6 alkoxy; 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yloxy; C 2-6 alk-1-en-1-yl; 3,3,3-trifluoropropyloxy; (C 1-6 alkyl)thiophen-2-yl; phenyl optionally substituted with one or two C 1-4 alkyl substituents; N-containing heterocyclyl wherein said N-containing heterocyclyl is attached to the core pyrazine ring via a nitrogen atom and said N-containing heterocyclyl is optionally spirofused to a C 3-7 cycloalkyl group; ring g1

C 3-7 cycloalkyloxy; and C 3-7 cycloalkyl-methoxy;
wherein said C 3-7 cycloalkyloxy and the C 3-7 cycloalkyl portion of C 3-7 cycloalkyl-methoxy are optionally substituted with one to four methyl substituents.

3. The compound of claim 2 , wherein G is selected from the group consisting of C 1-6 alkyl; C 1-6 alkoxy; 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yloxy; C 2-4 alk-1-en-1-yl; 3,3,3-trifluoropropyloxy; (methyl)thiophen-2-yl; phenyl optionally substituted with one or two C 1-4 alkyl substituents; N-containing heterocyclyl wherein said N-containing heterocyclyl is selected from the group consisting of piperidin-1-yl and azetidin-1-yl and said N-containing heterocyclyl is optionally spirofused to a C 3-7 cycloalkyl;
ring g1

C 3-7 cycloalkyloxy; and C 3-7 cycloalkyl-methoxy;
wherein said C 3-7 cycloalkyloxy and the C 3-7 cycloalkyl portion of C 3-7 cycloalkyl-methoxy are optionally substituted with one to four methyl substituents.

4. The compound of claim 1 , wherein R 1 is selected from the group consisting of phenyl and pyridin-4-yl; wherein R 1 is independently substituted with one or two substituents selected from the group consisting of methoxy and fluoro; provided that phenyl of R 1 is substituted with no more than one methoxy substituent.

5. The compound of claim 4 , wherein R 1 is 2-fluoro-5-methoxyphenyl or 5-fluoro-2-methoxypyridin-4-yl.

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

7. The compound of claim 6 , wherein R 2 is cyclopropyl.

8. A compound selected from the group consisting of:
Cpd 1, (3S)-3-cyclopropyl-3-[3-[[6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 2, (3S)-3-cyclopropyl-3-[3-[[5-(5-fluoro-2-methoxy-4-pyridyl)-6-isobutyl-pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 3, (3S)-3-[3-[[6-butyl-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]-3-cyclopropyl-propanoic acid;
Cpd 4, (3S)-3-cyclopropyl-3-[3-[[6-(2,2-dimethylpropoxy)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 5, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-isobutyl-pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 6, (3S)-3-[3-[(6-[2-azaspiro[3.3]heptan-2-yl]-5-(2-fluoro-5-methoxyphenyl)pyrazin-2-yl)methoxy]phenyl]-3-cyclopropylpropanoic acid;
Cpd 7, (3S)-3-[3-[[6-(cyclohexoxy)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]-3-cyclopropyl-propanoic acid;
Cpd 8, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-(2-methylprop-1-enyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 9, (3S)-3-[3-[[6-(cyclohexoxy)-5-(5-fluoro-2-methoxy-4-pyridyl)pyrazin-2-yl]methoxy]phenyl]-3-cyclopropyl-propanoic acid;
Cpd 10, (3S)-3-cyclopropyl-3-[3-[[6-(3,5-dimethylphenyl)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 11, (3S)-3-cyclopropyl-3-[3-[[5-(5-fluoro-2-methoxy-4-pyridyl)-6-(2-methylprop-1-enyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 12, (3S)-3-cyclopropyl-3-[3-[[5-(5-fluoro-2-methoxy-4-pyridyl)-6-isobutoxy-pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 13, (3S)-3-[3-[[6-(cyclopentoxy)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]-3-cyclopropyl-propanoic acid;
Cpd 14, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-isobutoxy-pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 15, (3S)-3-cyclopropyl-3-[3-[[6-(5,5-dimethylcyclopenten-1-yl)-5-(5-fluoro-2-methoxy-4-pyridyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 16, (3S)-3-[3-[[6-(cyclopentoxy)-5-(5-fluoro-2-methoxy-4-pyridyl)pyrazin-2-yl]methoxy]phenyl]-3-cyclopropyl-propanoic acid;
Cpd 17, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 18, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-phenyl-pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 19, (3S)-3-[3-[[6-(cyclobutoxy)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]-3-cyclopropyl-propanoic acid;
Cpd 20, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-(m-tolyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 21, (3S)-3-cyclopropyl-3-[3-[[6-(cyclopropylmethoxy)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 22, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-(1-piperidyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 23, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-(3-isopropylphenyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 24, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-(3,3,5,5-tetramethylcyclohexoxy)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 25, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-(4-isopropylphenyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 26, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-(2,2,6,6-tetramethyltetrahydropyran-4-yl)oxy-pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 27, (3S)-3-[3-[[6-(cycloheptoxy)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]-3-cyclopropyl-propanoic acid;
Cpd 28, (3S)-3-cyclopropyl-3-[3-[[5-(5-fluoro-2-methoxy-4-pyridyl)-6-(5-methyl-2-thienyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 29, (3S)-3-cyclopropyl-3-[3-[[5-(2-fluoro-5-methoxy-phenyl)-6-isopropoxy-pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cpd 30, (3S)-3-cyclopropyl-3-[3-[[6-(5,5-dimethylcyclopenten-1-yl)-5-(2-fluoro-5-methoxy-phenyl)pyrazin-2-yl]methoxy]phenyl]propanoic acid;
Cp

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Meegalla Sanath
• Huang Hui
• Player Mark R

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

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

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title