Methods of treatment using 4-(3-cyanophenyl)-6-pyridinylpyrimidine mGlu5 modulators
The disclosures herein relate to novel compounds of formula wherein R 1 , R 2 , R 3 and R 4 and n are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of inflammation, neurological or psychiatric disorders associated with modulating mGlu5 receptor function.
1. A method for the treatment of a disorder selected from migraine, dystonia, depression, anxiety, or amyotrophic lateral sclerosis (ALS) comprising administering an effective amount of a compound of formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof:
wherein
R 1 is halogen, optionally substituted C 1 -C 3 alkyl, cyclopropyl, optionally substituted C 1 -C 3 alkoxy, cyano, hydroxyl, nitro or NH 2 ;
R 2 is H or F; and
Q is an optionally substituted pyridyl or pyrazyl group.
2. The method according to claim 1 , wherein the disorder is migraine.
3. The method according to claim 1 , wherein the disorder is dystonia.
4. The method according to claim 1 , wherein the disorder is depression.
5. The method according to claim 1 , wherein the disorder is anxiety.
6. The method according to claim 1 , wherein the disorder is amyotrophic lateral sclerosis (ALS).
7. The method according to claim 4 , wherein the depression is treatment-resistant depression.
8. The method according to claim 1 , wherein the compound is a compound of formula 3:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is halogen, optionally substituted C 1 -C 3 alkyl, cyclopropyl, optionally substituted C 1 -C 3 alkoxy, cyano, hydroxyl, nitro or NH 2 ;
R 2 is H or F;
R 3 is H, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy or cyano; and
R 4 is H, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy or cyano; and
n is 0-3.
9. The method according to claim 1 , wherein the compound is a compound of formula 4:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is halogen, optionally substituted C 1 -C 3 alkyl, cyclopropyl, optionally substituted C 1 -C 3 alkoxy, cyano, hydroxyl, nitro or NH 2 ;
R 2 is H or F; and
R 3 is H, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy or cyano.
10. The method according to claim 1 , wherein the compound is a compound of formula 5:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is halogen, optionally substituted C 1 -C 3 alkyl, cyclopropyl, optionally substituted C 1 -C 3 alkoxy, cyano, hydroxyl, nitro or NH 2 ;
R 2 is H or F;
R 5 is H, D, halogen, optionally substituted C 1 -C 3 alkyl or cyano; and
R 6 is H, D, halogen, optionally substituted C 1 -C 3 alkyl or cyano.
11. The method according to claim 1 , wherein R 1 is F, Cl, OMe, CH 2 OMe, Me, fluoromethyl or cyano.
12. The method according to claim 1 , wherein R 1 is F, Cl or cyano.
13. The method according to claim 8 , wherein R 3 is H, Me, F, Cl or cyano.
14. The method according to claim 8 , wherein n is 0 or 1.
15. The method according to claim 10 , wherein R 5 and R 6 are independently H, D or F.
16. The method according to claim 1 , wherein the compound is selected from the group consisting of:
3-chloro-4-fluoro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile;
6-[6-(3-chloro-5-cyanophenyl)pyrimidin-4-yl]pyridine-3-carbonitrile;
3-methyl-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile;
3-methyl-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-4-fluoro-5-[4-(1H-pyrazol-1-yl)pyridin-2-yl]benzonitrile;
3-chloro-4-fluoro-5-[2-(1H-pyrazol-1-yl)pyridin-4-yl]benzonitrile;
3-chloro-4-fluoro-5-[6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-methyl-5-{6-[( 2 H 3 )-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;
3-chloro-5-{6-[( 2 H 3 )-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;
3-chloro-4-fluoro-5-{6-[( 2 H 3 )-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;
3-(fluoromethyl)-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile;
5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile;
3-chloro-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-5-[6-(5-chloropyridin-2-yl)pyrimidin-4-yl]benzonitrile;
5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzene-1,3-dicarbonitrile;
3-chloro-4-fluoro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile;
3-methyl-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitrile;
3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-(methoxymethyl)benzonitrile; and
3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-methoxybenzonitrile;
or a pharmaceutically acceptable salt thereof.
17. The method according to claim 1 , wherein the compound is selected from the group consisting of:
3-methyl-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-chloro-4-fluoro-5-[4-(1H-pyrazol-1-yl)pyridin-2-yl]benzonitrile;
3-chloro-4-fluoro-5-[2-(1H-pyrazol-1-yl)pyridin-4-yl]benzonitrile;
3-chloro-4-fluoro-5-[6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
3-methyl-5-{6-[( 2 H 3 )-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;
3-chloro-5-{6-[( 2 H 3 )-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile;
3-chloro-4-fluoro-5-{6-[( 2 H 3 )-1H-pyrazol-1-yl]pyrimidin-4-yl}benzonitrile; and
3-(fluoromethyl)-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile;
or a pharmaceutically acceptable salt thereof.