Pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is alkoxyazetidinyl, dihaloazetidinyl or pyrrolidinyl;

R 2 and R 3 are independently selected from hydrogen and alkyl;

A 1 is —CH— or nitrogen;

A 2 is —CH 2 — or carbonyl;

X is halogen;

n is 0 to 3; and

m is 0 or 1;

provided that m and n are not both 0 at the same time.

2. The compound of claim 1 , wherein R 1 is methoxyazetidinyl, difluoroazetidinyl or pyrrolidinyl.

3. The compound of claim 1 , wherein R 2 and R 3 are independently selected from hydrogen, ethyl and butyl.

4. The compound of claim 3 , wherein R 2 and R 3 are both ethyl at the same time, or one of R 2 and R 3 is hydrogen and the other one is butyl.

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

6. The compound of claim 1 , wherein X is fluorine.

7. The compound of claim 1 , wherein n is 1, 2 or 3.

8. The compound of claim 1 selected from the group consisting of:

fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

fluoromethyl N-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

2-fluoroethyl N-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

3-fluoropropyl N-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

fluoromethyl N-[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

2-fluoroethyl N-[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

3-fluoropropyl N-[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

6-(cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2R)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(3-fluoropropoxy)propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-{3-[(fluoromethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-{3-[(2-fluoroethoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-{3-[(3-fluoropropoxy)methyl]pentan-3-yl}-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

fluoromethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyrazine-2-carbonyl]amino}-2-ethylbutanoate;

fluoro(dideuterio)methyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoro(2,2-dideuterio)ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoro(3,3-dideuterio)propyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

fluoro(dideuterio)methyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoro(2,2-dideuterio)ethyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoro(3,3-dideuterio)propyl 2-{[6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoro(3,3-dideuterio)propyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

fluoro(dideuterio)methyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoro(2,2-dideuterio)ethyl 2-{[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideuterio)methyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideuterio)ethyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterio)propyl]oxy}-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideuterio)methyl]oxy}1-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideuterio)ethyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterio)propyl]oxy}-3-methylbutan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideuterio)methyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideuterio)ethyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterio)propyl]oxy}propan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideuterio)methyl]oxy}1-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideuterio)ethyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterio)propyl]oxy}-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[fluoro(dideuterio)methyl]oxy}1-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideuterio)ethyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterio)propyl]oxy}-3-methylbutan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[2-fluoro(2,2-dideuterio)ethyl]oxy}propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-{[3-fluoro(3,3-dideuterio)propyl]oxy}propan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[3-({[fluoro(dideuterio)methyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[3-({[2-fluoro(2,2-dideuterio)ethyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[3-({[3-fluoro(3,3-dideuterio)propyl]oxy}methyl)pentan-3-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[3-({[fluoro(dideuterio)methyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[3-({[2-fluoro(2,2-dideuterio)ethyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[3-({[3-fluoro(3,3-dideuterio)propyl]oxy}methyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluoro(4,4-dideuterio)butanoate;

ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluoro(4,4-dideuterio)butanoate;

6-(cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)-N-(3-(3-fluoropropylcarbamoyl)pentan-3-yl)picolinamide;

ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluorobutanoate;

ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-3-fluorobutanoate;

ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-4-fluorobutanoate; and

ethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl-3-fluorobutanoate;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 selected from the group consisting of:

2-fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethyl butanoate;

3-fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoroethyl N-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

2-fluoroethyl N-[6-(cyclopropylmethoxy)-5-(pyrrolidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

6-(cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]pyridine-2-carboxamide; and

6-(cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

11. A compound selected from the group consisting of:

2-fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

3-fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate;

2-fluoroethyl N-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucinate;

6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;

6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide; and

6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;

or a pharmaceutical acceptable salt thereof.

12. A compound of claim 11 , wherein the compound is 2-fluoroethyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate, or a pharmaceutical acceptable salt thereof.

13. A compound of claim 11 , wherein the compound is 3-fluoropropyl 2-{[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}-2-ethylbutanoate, or a pharmaceutical acceptable salt thereof.

14. A compound of claim 11 , wherein the compound is 2-fluoroethyl N-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-L-leucinate, or a pharmaceutical acceptable salt thereof.

15. A compound of claim 11 , wherein the compound is 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide, or a pharmaceutical acceptable salt thereof.

16. A compound of claim 11 , wherein the compound is 6-(Cyclopropylmethoxy)-N-[(2S)-1-(2-fluoroethoxy)-4-methylpentan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide, or a pharmaceutical acceptable salt thereof.

17. A compound of claim 11 , wherein the compound is 6-(Cyclopropylmethoxy)-N-[(2S)-1-(fluoromethoxy)-4-methylpentan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide, or a pharmaceutical acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.