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US 10,538,491 B2Granted
4,5-substituted picolinamide and picolinonitrile metabotropic glutamate receptor 2 negative allosteric modulators
AssigneeVanderbilt University
InventorsP. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte, Andrew S. Felts, Katrina A. Bollinger
Life of this patent
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Abstract
4,5-Substituted Picolinamide and picolinonitrile compounds of formula (I), where R4 is CONH2 or CN and R1 is an optionally substituted aryl or heteroaryl, are negative allosteric modulators of the metabotropic glutamate receptor 2 (mGlu2). The compounds and pharmaceutical compositions including the compounds may be useful for treating depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer's disease, or autism spectrum disorders in a subject.
Claims21
A compound of formula (I)
- or a pharmaceutically acceptable salt thereof, wherein
- R1 is substituted or unsubstituted phenyl;
- R2a and R2b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
- Y is selected from a bond, CR5eR5f, O and NR7;
- R5a, R5b, R5c, R5d, R5e and R5f, at each occurrence in R3, are independently selected from hydrogen and C1-C4 alkyl;
- R6a and R6b together with the nitrogen atom to which they attach form a heterocycle optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl;
- R7 at each occurrence is independently selected from hydrogen and C1-C4 alkyl;
- and
- A is aryl, heteroaryl, or heterocycle;
- wherein said aryl, heteroaryl or heterocycle in A is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, cyano, alkyl, alkoxy, and haloalkyl;
- R4 is —CONH2 or cyano.
8 more elements
A compound selected from the group consisting of:
- 5-((2,2-dimethylmorpholino)methyl)-4-(4-fluorophenyl)picolinamide;
- 5-(((cis)-2,6-dimethylmorpholino)methyl)-4-(4-fluorophenyl)picolinamide;
- 5-((3-cyanobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((3,5-difluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((3,5-difluorobenzyl)oxy)-4-(2-fluoro-4-methoxyphenyl)picolinamide;
- 5-((3-cyano-5-fluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((5-cyano-2-fluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((3-cyano-4-fluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((3-cyano-2-fluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((2-cyanobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((4-bromobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((3-bromobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((2-bromobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((5-bromo-2-fluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((3-bromo-5-fluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 5-((3-bromo-2-fluorobenzyl)oxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-(pyridin-3-ylmethoxy)picolinamide;
- 4-(2-fluoro-4-methoxyphenyl)-5-(pyridin-3-ylmethoxy)picolinamide;
- 5-((5-cyanopyridin-3-yl)methoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-((6-methylpyridin-3-yl)methoxy)picolinamide;
- 4-(2-fluoro-4-methoxyphenyl)-5-((6-methylpyridin-3-yl)methoxy)picolinamide;
- 4-(4-fluorophenyl)-5-((6-methoxypyridin-3-yl)methoxy)picolinamide;
- 5-((6-chloropyridin-3-yl)methoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)picolinamide;
- 4-(2-fluoro-4-methoxyphenyl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(pyridin-4-ylmethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide;
- 4-(2-fluoro-4-methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide;
- 4-(4-fluorophenyl)-5-((2-methoxypyridin-4-yl)methoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(1-(pyridin-3-yl)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(1-(pyridin-4-yl)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(pyridazin-3-ylmethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-ylmethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(thiazol-5-ylmethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide;
- 4-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-4-yl)methoxy)picolinamide;
- 5-((3,5-difluorophenoxy)methyl)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)picolinamide;
- 4-(4-fluorophenyl)-5-(((6-methylpyridin-3-yl)oxy)methyl)picolinamide;
- 4-(4-fluorophenyl)-5-((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)picolinamide;
- 4-(4-fluorophenyl)-5-(2-morpholinoethoxy)picolinamide;
- 5-(2-((cis)-2,6-dimethylmorpholino)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(3-(4,4-difluoropiperidin-1-yl)propoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-(3-(2-methylmorpholino)propoxy)picolinamide;
- 5-(3-(2,2-dimethylmorpholino)propoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(3-((cis)-2,6-dimethylmorpholino)propoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-(3-morpholinopropoxy)picolinamide;
- 5-(2-((3-cyanophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((3-cyano-5-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((3-cyano-4-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((3-cyano-2-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((5-cyano-2-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((5-bromo-2-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((3-bromo-5-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((3-bromo-4-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-((3-bromo-2-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-(2-bromophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-(3-bromophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-(4-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-(3-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-(2-fluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 5-(2-(3,5-difluorophenoxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(pyridin-3-yloxy)ethoxy)picolinamide;
- 5-(2-((5-bromopyridin-3-yl)oxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(5-fluoropyridin-3-yl)oxy)ethoxy)picolinamide;
- 5-(2-((5-cyanopyridin-3-yl)oxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(6-fluoropyridin-3-yl)oxy)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(6-methylpyridin-3-yl)oxy)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(6-(trifluoromethyl)pyridin-3-yl)oxy)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(2-(trifluoromethyl)pyridin-4-yl)oxy)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-((2-fluoropyridin-4-yl)oxy)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-((2-methylpyridin-4-yl)oxy)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-((2-methylpyrimidin-5-yl)oxy)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(1-(2-(trifluoromethyl)pyridin-4-yl)oxy)propan-2-yl)oxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-((6-methylpyridin-3-yl)oxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-((2-methylpyrimidin-5-yl)oxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(pyridin-3-yloxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(2-(trifluoromethyl)pyridin-4-yl)oxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(2-(methyl(2-(trifluoromethyl)pyridin-4-yl)amino)ethoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(3-((2-methylpyrimidin-5-yl)oxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(3-(6-(trifluoromethyl)pyridin-3-yl)oxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(3-(2-(trifluoromethyl)pyridin-4-yl)oxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(3-(pyridin-3-yloxy)propoxy)picolinamide;
- 4-(4-fluorophenyl)-5-(3-((6-methylpyridin-3-yl)oxy)propoxy)picolinamide;
- 5-(2-(benzyloxy)ethoxy)-4-(4-fluorophenyl)picolinamide;
- 4-(4-fluorophenyl)-5-((2-((5-fluoropyridin-3-yl)methoxy)ethyl)(methyl)amino)picolinamide;
- 4-(4-fluorophenyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)picolinamide;
- 4-(4-fluorophenyl)-5-((2-morpholinoethyl)amino)picolinamide;
- 4-(4-fluorophenyl)-5-((1-morpholinopropan-2-yl)amino)picolinamide;
- 4-(4-fluorophenyl)-5-((2-morpholinopropyl)amino)picolinamide;
- 4-(4-fluorophenyl)-5-(methyl(2-morpholinoethyl)amino)picolinamide;
- 4-(4-fluorophenyl)-5-((3-morpholinopropyl)amino)picolinamide;
- 4-(4-fluorophenyl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(pyridin-3-ylmethoxy)picolinonitrile;
- 5-((3-cyanobenzyl)oxy)-4-(4-fluorophenyl)picolinonitrile;
- 5-((3,5-difluorobenzyl)oxy)-4-(4-fluorophenyl)picolinonitrile;
- 5-((5-chloropyridin-3-yl)methoxy)-4-(4-fluorophenyl)picolinonitrile;
- 4-(4-fluorophenyl)-5-((6-methylpyridin-3-yl)methoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-((6-methoxypyridin-3-yl)methoxy)picolinonitrile;
- 5-((6-chloropyridin-3-yl)methoxy)-4-(4-fluorophenyl)picolinonitrile;
- 4-(4-fluorophenyl)-5-(1-(pyridin-3-yl)ethoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(pyridin-4-ylmethoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(1-(pyridin-4-yl)ethoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-((2-(trifluoromethyl)pyridin-4-yl)methoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-ylmethoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(2-(pyridin-3-yl)ethoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(2-morpholinoethoxy)picolinonitrile;
- 5-(2-((cis)-2,6-dimethylmorpholino)ethoxy)-4-(4-fluorophenyl)picolinonitrile;
- 4-(4-fluorophenyl)-5-(3-morpholinopropoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(3-(2-methylmorpholino)propoxy)picolinonitrile;
- 5-(3-(2,2-dimethylmorpholino)propoxy)-4-(4-fluorophenyl)picolinonitrile;
- 5-(3-(4,4-difluoropiperidin-1-yl)propoxy)-4-(4-fluorophenyl)picolinonitrile;
- 4-(4-fluorophenyl)-5-(2-(pyridin-3-yloxy)ethoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(2-((2-methylpyrimidin-5-yl)oxy)ethoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(2-((6-methylpyridin-3-yl)oxy)propoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(2-(2-(trifluoromethyl)pyridin-4-yl)oxy)propoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(3-((2-methylpyrimidin-5-yl)oxy)propoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(3-(pyridin-3-yloxy)propoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)propoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(3-((2-(trifluoromethyl)pyridin-4-yl)oxy)propoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-(3-((6-methylpyridin-3-yl)oxy)propoxy)picolinonitrile;
- 4-(4-fluorophenyl)-5-((2-((5-fluoropyridin-3-yl)methoxy)ethyl)(methyl)amino)picolinonitrile;
- 5-(2-(benzyloxy)ethoxy)-4-(4-fluorophenyl)picolinonitrile;
- 4-(4-fluorophenyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)picolinonitrile;
- 4-(4-fluorophenyl)-5-((2-morpholinoethyl)amino)picolinonitrile;
- 4-(4-fluorophenyl)-5-(methyl(2-morpholinoethyl)amino)picolinonitrile;
- 4-(4-fluorophenyl)-5-((1-morpholinopropan-2-yl)amino)picolinonitrile;
- 4-(4-fluorophenyl)-5-((2-morpholinopropyl)amino)picolinonitrile;
- 4-(4-fluorophenyl)-5-((3-morpholinopropyl)amino)picolinonitrile;
- 5-((2,2-dimethylmorpholino)methyl)-4-(4-fluorophenyl)picolinonitrile;
- 4-(4-fluorophenyl)-5-((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)picolinonitrile;
- and
- 4-(4-fluorophenyl)-5-(2-((2-(trifluoromethyl)pyridin-4-yl)oxy)ethoxy)picolinonitrile;
- or
- a pharmaceutically acceptable salt thereof.
134 more elements
Dependencies are inferred from the claim text.