Pyridine-2-amides useful as CB2 agonists

Patent metadata

Field	Value
Publication number	US-9303012-B2
Application number	US-201314648418-A
Country	US
Kind code	B2
Filing date	Dec 4, 2013
Priority date	Dec 7, 2012
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The invention relates to CB2 agonists of formula (I) wherein R 1 to R 4 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is cycloalkylalkoxy, halophenyl, tetrahydrofuranylalkoxy, halophenylalkyl, haloalkyloxy, alkylsulfonyl, tetrahydropyranylalkoxy or halogen;
R 2 is alkyl, pyrrolidinyl, cycloalkyl, haloazetidinyl, haloalkyl, cycloalkylalkoxy, haloalkyloxy, halocycloalkyl, hydroxycycloalkyl or halooxetanyl;
one of R 3 and R 4 is alkyl, cycloalkyl, haloalkyl or hydroxyalkyl and the other one is alkyl, alkyloxyalkyl, (haloazetidinyl)(cycloalkyloxy)pyridinylcarbonyloxyalkyl, haloalkylcycloalkyl, hydroxyalkyl, phenylalkyl, alkoxycarbonylalkyl, carboxyalkyl, alkylaminocarbonylalkyl, (alkyloxadiazolyl)(cycloalkylalkyl)alkyl, (alkyloxadiazolyl)(cycloalkyl)alkyl, pyridazinylalkyl, aminocarbonylalkyl, alkyloxadiazolylalkyl, alkyltetrazolylalkyl, formyl, phenyl, dialkylpyrazolyl, alkylcarbonylpiperidinyl or cycloalkylalkyl;
or R 3 and R 4 together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl;
wherein heterocyclyl is 6-oxa-1-aza-spiro[3.3]heptyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 2-oxa-5-aza-spiro[3.4]octyl, piperidinyl, 6-aza-bicyclo[3.2.1.]octyl, imidazolidinyl, 4-aza-spiro[2.4]heptyl, 2-aza-bicyclo[2.2.1]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, hexahydro-furo[2,3-c]pyrrolyl, 2-thia-6-aza-spiro[3.3]heptyl, 1,8-diaza-spiro[4.5]decyl, 1-oxa-7-aza-spiro[4.4]nonyl, 5-oxa-2-aza-spiro[3.4]octyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3-oxa-8-aza-bicyclo[3.2.1]octyl, thiomorpholinyl, thiazolidinyl, 5-aza-spiro[3.4]octyl, azetidinyl, 5-aza-spiro[2.4]heptyl, 3-aza-bicyclo[3.1.0]hexyl or 5-aza-spiro[2.4]heptyl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl; and
wherein substituted heterocyclyl is heterocyclyl substituted with one to four substituents independently selected from alkyl, oxo, hydroxyl, carboxyl, alkylcarbonylamino, alkyloxyalkyl, hydroxyalkyl, aminocarbonyl, halogen, phenylalkyl, phenyl, alkoxycarbonyl, cycloalkylalkyl, phenylalkoxycarbonyl, cycloalkyl, halohydroxyalkyl and haloalkyl;
provided that R 3 and R 4 together with the nitrogen atom to which they are attached don't form unsubstituted piperidinyl, unsubstituted thiomorpholinyl or hydroxyalkylpyrrolidinyl;
or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1 , wherein R 1 is cycloalkylalkoxy, tetrahydrofuranylalkoxy, alkylsulfonyl or halophenylalkyl.

3. A compound according to claim 1 , wherein R 1 is cyclopropylmethoxy, tetrahydrofuranylmethoxy, isobutylsulfonyl or fluorophenylmethyl.

4. A compound according to claim 1 , wherein R 2 is haloazetidinyl, cycloalkyl or halocycloalkyl.

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

6. A compound according to claim 1 , wherein one of R 3 and R 4 is alkyl and the other one is alkyl or haloalkylcycloalkyl.

7. A compound according to claim 1 , wherein one of R 3 and R 4 is methyl and the other one is tert.-butyl or trifluoromethylcyclopropyl.

8. A compound according to claim 1 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolidinyl or 5-aza-spiro[2.4]heptyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to three substituents independently selected from alkyl, hydroxyalkyl, halogen, aminocarbonyl, alkoxycarbonyl, oxo or hydroxyl.

9. A compound according to claim 1 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is oxazolidinyl, morpholinyl, pyrrolidinyl, 6-aza-bicyclo[3.2.1.]octyl, 4-aza-spiro[2.4]heptyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, 5-aza-spiro[3.4]octyl, 5-aza-spiro[2.4]heptyl, 1,8-diaza-spiro[4.5]decyl, thiazolidinyl or 5-aza-spiro[2.4]heptyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to three substituents independently selected from methyl, hydroxymethyl, fluoro, aminocarbonyl, tert.-butoxycarbonyl, oxo or hydroxyl.

10. A compound according to claim 1 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form dimethyloxazolidinyl, dimethylmorpholinyl, dimethylpyrrolidinyl, trimethyl-6-aza-bicyclo[3.2.1.]octyl, (hydroxymethyl)(difluoro)pyrrolidinyl, 4-aza-spiro[2.4]heptyl, (aminocarbonyl)(difluoro)pyrrolidinyl, 2-thia-5-aza-bicyclo[2.2.1]heptyl, (aminocarbonyl)(dimethyl)pyrrolidinyl, 5-aza-spiro[3.4]octyl, difluoro-5-aza-spiro[2.4]heptyl, 5-aza-spiro[2.4]heptyl, tert.-butoxycarbonyl-1,8-diaza-spiro[4.5]decyl, aminocarbonyl-1,1-dioxo-1λ6-thiazolidinyl, aminocarbonyl-1,1-dioxo-1,3-thiazolidinyl, (aminocarbonyl)(methyl)(hydroxyl)pyrrolidinyl or (aminocarbonyl)-5-aza-spiro[2.4]heptyl.

11. A compound according to claim 1 selected from
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid dimethylamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butyl-methyl-amide;
5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-ethyl-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid diisopropylamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-methanone;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid 2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-methyl-amino}-2-methyl-propyl ester;
5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid tert-butyl-methyl-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(4,4-dimethyl-oxazolidin-3-yl)-methanone;
6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid methyl-(1-trifluoromethyl-cyclopropyl)-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(3,3-dimethyl-morpholin-4-yl)-methanone;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-(2,2-dimethyl-pyrrolidin-1-yl)-methanone;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-(2-methoxy-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butyl-(2-methoxy-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ethyl-(1-trifluoromethyl-cyclopropyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid benzyl-(1-trifluoromethyl-cyclopropyl)-amide;
{tert-Butyl-[6-cyclopropylmeth

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Bendels Stefanie
• Grether Uwe
• Kimbara Atsushi
• Nettekoven Matthias
• Roever Stephan
• Rogers-Evans Mark
• Schaffter Ernst
• Schulz-Gasch Tanja

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P9/04

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

• A61P37/06

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