Pyridine and pyrazine derivatives as preferential cannabinoid 2 agonists

Patent metadata

Field	Value
Publication number	US-11655243-B2
Application number	US-202017125647-A
Country	US
Kind code	B2
Filing date	Dec 17, 2020
Priority date	Jun 27, 2018
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

The invention relates to a compound of formula (I)

wherein A 1 , A 2 and R 1 -R 5 are as defined 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
A 1 is —CH— or nitrogen;
A 2 is —CH 2 — or carbonyl;
R 1 is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, haloalkoxyalkyl, hydroxyalkylcycloalkyl, oxetanyl, haloalkoxyalkyloxetanyl, hydroxyalkyloxetanyl, haloalkyloxetanyl, 1-fluoroethyl, 1-fluoro-prop-2-yl, fluoro-tert.-butyl, cyclopropylfluoromethyl, fluorocyclopropyl, halooxanyl, halotetrahydrofuranyl, phenylalkoxyalkylcycloalkyl, 1-fluoro-1,1-dideuteroprop-2-yl, fluorodideuteromethyl, fluorodideuteromethyloxyalkylcycloalkyl, 2-fluoro-2,2-dideuteroethyloxyalkylcycloalkyl, fluorodideuteromethylcycloalkyl, fluorodideuteromethyloxyalkyl, fluorodideuteromethylalkyl, fluorodideuteromethyloxyalkyloxetanyl, 2-fluoro-2,2-dideuteroethyloxyalkyloxetanyl, 3-fluoro-3,3-dideuteropropyloxyalkyloxetanyl or fluorodideuteromethyloxetanyl;

R 2 is alkoxyazetidinyl, haloazetidinyl, dihaloazetidinyl, pyrrolidinyl or alkylphenylsulfonyloxyazetidinyl;
R 3 and R 4 are independently selected from hydrogen, alkyl, alkenyl and deuterioalkyl;
R 5 is hydrogen, alkyl, haloalkyl, deuterioalkyl, alkylphenylsulfonyloxyalkyl, alkylphenylsulfonyloxydeuterioalkyl or hydroxyalkyl; and
X is oxygen or —NH—;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein A 1 is —CH—.

3. The compound of claim 1 , wherein A 2 is carbonyl.

4. The compound of claim 1 , wherein R 1 is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl or hydroxyalkylcycloalkyl.

5. The compound of claim 4 , wherein R 1 is fluoromethoxymethylcyclopropyl, fluoromethylcyclopropyl or hydroxmethylcyclopropyl.

6. The compound of claim 1 , wherein R 2 is alkoxyazetidinyl or haloazetidinyl.

7. The compound of claim 6 , wherein R 2 is methoxyazetidinyl or fluoroazetidinyl.

8. The compound of claim 1 , wherein R 3 and R 4 are both alkyl at the same time or both deuterioalkyl at the same time.

9. The compound claim 8 , wherein R 3 and R 4 are both ethyl at the same time or both dideuterioethyl at the same time.

10. The compound of claim 1 , wherein R 5 is alkyl, haloalkyl or halodeuterioalkyl.

11. The compound of claim 10 , wherein R 5 is ethyl, fluoromethyl, fluoropropyl, fluorobutyl or fluorohexadeuteriopropyl.

12. The compound of claim 1 , wherein X is oxygen.

13. The compound of claim 1 selected from the group consisting of:
Ethyl 2-ethyl-2-{[6-({(1S,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-caronyl]amino}butanoate;
Ethyl 2-ethyl-2-{[6({(1S,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
ethyl 2-ethyl-2-{[6-({(1R,2R)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
Ethyl 2-ethyl-2-{[6-{[(1S,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1R,R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
Ethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate and ethyl 2-ethyl-2-{[6-{[(1S,2R)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
Ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
ethyl 2-ethyl-2-{[6({(1S,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
Ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
ethyl 2-ethyl-2-{[6({(1S,2R)-2-[(2-fluoroethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
Ethyl 2-ethyl-2-({6-[3-(fluoromethoxy)-2,2-dimethylpropoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl}amino)butanoate;
(+)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
(−)-trans-Ethyl 2-ethyl-2-{[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
ethyl 2-ethyl-2-{[6-({(1R,2S)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate
ethyl 2-ethyl-2-{[6-({(1S,2R)-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
(−)-trans-Fluoromethyl 2-ethyl-2-{[6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate; (+)-trans-Fluoromethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
(+)-trans-2-Fluoroethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
(−)-trans-2-Fluoroethyl 2-ethyl-2-{[6-{[-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
3-Fuoropropyl 2-ethyl-2-{[6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
3-Fuoropropyl 2-ethyl-2-{[6-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
N-[(2S)-1-(fluoromethoxy)propan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-6-{[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
fluoromethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
2-fluoroethyl 2-ethyl-2-{[6-{[(1R,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate;
3-fluorop

Assignees

• Hoffmann La Roche
• Eidgenoessische Technische Hochschule Zuerich

Inventors

• Ametamey Simon M
• Atz Kenneth
• Gobbi Luca
• Grether Uwe
• Guba Wolfgang
• Kretz Julian

Classifications

• A61P19/00

  Drugs for skeletal disorders · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title