Pyrazine derivatives as CB2 receptor agonists

Patent metadata

Field	Value
Publication number	US-9512141-B2
Application number	US-201314648399-A
Country	US
Kind code	B2
Filing date	Dec 4, 2013
Priority date	Dec 7, 2012
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The invention relates to a compound of formula (I) wherein R 1 to R 4 are defined as in the description and in the claims. The compound of formula (I) is a CB2 receptor agonist for use in the treatment of several disorders, such as pain, atherosclerosis and glaucoma.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is cycloalkylalkoxy or haloalkoxy;
R 2 is cycloalkyl or haloazetidinyl;
R 3 and R 4 are independently selected from alkyl, alkoxy, alkoxyalkyl and alkoxycarbonylalkyl;
or R 3 and R 4 together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is pyrrolidinyl, morpholinyl, oxomorpholinyl, 2-oxo-5-aza-bicyclo[2.2.1]heptyl, 7-oxa-4-aza-spiro [2.5]octyl, piperazinyl, 2-oxa-6-aza-spiro[3.4]octyl, piperidinyl, or thiomorpholinyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to four substituents independently selected from alkyl, halogen, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, alkylthiocarbamoyl, and alkylcarbonyloxy;
or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1 , wherein R 1 is cycloalkylalkoxy.

3. A compound according to claim 1 , wherein R 1 is cyclopropylmethoxy.

4. A compound according to claim 1 , wherein R 2 is cyclopropyl or difluoroazetidinyl.

5. A compound according to claim 1 , wherein R 3 and R 4 are independently selected from alkyl, alkoxy and alkoxyalkyl, or wherein R 3 and R 4 together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is pyrrolidinyl, or morpholinyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to three substituents independently selected from alkyl, halogen and aminocarbonyl.

6. A compound according to claim 1 , wherein R 3 and R 4 are independently selected from methyl, tert-butyl, methoxyethyl or methoxybutyl, or wherein R 3 and R 4 together with the nitrogen atom to which they are attached form dimethylmorpholinyl, dimethylpyrrolidinyl, (aminocarbonyl)(difluoro)pyrrolidinyl, or (aminocarbonyl)(dimethyl)pyrrolidinyl.

7. A compound according to claim 1 selected from
(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazin-2-yl)-((R)-2-methyl-pyrrolidin-1-yl)-methanone;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-((R)-2-methyl-pyrrolidin-1-yl)-methanone;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid tert-butyl-(2-methoxy-ethyl)-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-((S)-2-methyl-pyrrolidin-1-yl)-methanone;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid tert-butyl-methyl-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(3,3-difluoro-pyrrolidin-1-yl)-methanone;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ethyl-isopropyl-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(7-oxa-4-aza-spiro[2.5]oct-4-yl)-methanone;
{tert-Butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-acetic acid ethyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide;
(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;
(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester;
(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazin-2-yl)-(7-oxa-4-aza-spiro[2.5]oct-4-yl)-methanone;
(S)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;
(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;
(R)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester;
4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-morpholin-2-one;
(R)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-pyrrolidine-2-carbothioic acid dimethylamide;
Acetic acid 1-(5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-3-methyl-pyrrolidin-3-yl ester;
(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazin-2-yl)-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-methanone;
Acetic acid (S)-1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-pyrrolidin-3-yl ester;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-methanone;
Acetic acid 1-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-3-methyl-pyrrolidin-3-yl ester;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-methanone;
5-(3,3-Difluoro-azetidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid tert-butyl-methyl-amide;
[5-(3,3-Difluoro-azetidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrazin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;
1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-piperidine-2-carboxylic acid amide;
1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;
1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide;
(−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-piperidine-2-carboxylic acid amide;
(−)-4-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-thiomorpholine-3-carboxylic acid amide;
(−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide; and
(−)-1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide.

8. A compound according to claim 1 selected from
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid tert-butyl-(2-methoxy-ethyl)-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid tert-butyl-methyl-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide;
(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazin-2-yl)-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;
(S)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;
1-(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide; and
(−)-1-[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid amide.

9. A process for the preparation of a compound according to claim 1 comprising the reaction of a compound of formula (II)

Assignees

• Hoffmann La Roche

Inventors

• Dhurwasulu Baledi
• Grether Uwe
• Nettekoven Matthias
• Roever Stephan
• Rogers-Evans Mark
• Schulz-Gasch Tanja

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title