Substituted pyrazolo-pyrazines and their use as glun2b receptor modulators

A compound selected from the group consisting of:

• 1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]butan-2-one;
• 2-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-cyclopropyl-ethanone;
• N,N-Dimethyl-2-[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
• N,N-Dimethyl-2-[6-(m-tolyl)pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
• 2-[6-(4-Chloro-3-fluoro-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-(3-Fluoro-4-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-(4-Chloro-3-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-(3-Chloro-4-methoxy-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[4-(Difluoromethoxy)-3-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-(3,5-Difluoro-4-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 2-[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• N,N-Dimethyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
• N,N-Dimethyl-2-[6-(2,3,4-trifluorophenyl)pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
• 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 1-(Azetidin-1-yl)-2-[6-[4-chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 1-(Azetidin-1-yl)-2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 1-(Azetidin-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl)ethanone;
• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl)ethanone;
• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
• 2-[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl)ethanone;
• 2-[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
• 2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl)ethanone;
• 2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
• 2-[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-morpholino-ethanone;
• 2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;
• 2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;
• 5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]-3-methyl-isoxazole;
• 6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[3,4-b]pyrazine;
• 1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazine;
• 6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[3,4-b]pyrazine;
• 5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]pyridine-3-carbonitrile;
• 5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]methyl]pyridine-3-carbonitrile;
• and
• 1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazine;
• 2-(6-(4-Chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-N,N-dimethylacetamide;
• N,N-Dimethyl-2-(6-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)acetamide;
• 2-(6-(2,5-Difluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-N,N-dimethylacetamide;
• 5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)oxazolidin-2-one;
• 6-(3-(Difluoromethoxy)-4-fluorophenyl)-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine;
• 2-(6-(4-(1,1-Difluoroethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-N,N-dimethylacetamide;
• and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof.

A compound selected from the group consisting of:

• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N,N-dimethyl-acetamide;
• 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
• 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
• and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof.

A pharmaceutical composition comprising:

• (A) an effective amount of at least one compound selected from compounds of Formula (I):
• and pharmaceutically acceptable salts, solvates, stereoisomers, Isotopic vanants, and N-oxides thereof,
• wherein
• R1 is H or halo;
• Ar1 is selected from the group consisting of:
• (a) phenyl substituted with one, two or three members each independently selected from the group consisting of:
• halo, C1-6alkyl, C1-6perhaloalkyl, OC1-6alkyl, and OC1-6perhaloalkyl;
• and
• (b) thienyl substituted with CF3;
• and
• R2 is selected from the group consisting of:
• (c)
• wherein R is selected from the group consisting of:
• H, halo, and C1-6alkyl;
• wherein Rb is C1-6alkyl, and Rc is C1-6alkyl;
• (d)
• wherein Rd is C1-6alkyl, or C3-6cycloalkyl;
• and
• (e)
• wherein Re is selected from the group consisting of:
• halo, OC1-6alkyl, and CN;
• and
• (B) at least one pharmaceutically acceptable excipient.

A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from compounds of Formula (I):

• and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof,
• wherein
• R1 is H or halo;
• Ar1 is selected from the group consisting of:
• (a) phenyl substituted with one, two or three members each independently selected from the group consisting of:
• halo, C1-6alkyl, C1-6perhaloalkyl, OC1-6alkyl, and OC1-6perhaloalkyl;
• and
• (b) thienyl substituted with CF3;
• and
• R2 is selected from the group consisting of:
• (c)
• wherein Ra is selected from the group consisting of:
• H, halo, and C1-6alkyl;
• wherein Rb is C1-6alkyl, and Rc is C1-6alkyl;
• (d)
• wherein Rd is C1-6alkyl, or C3-6cycloalkyl;
• and
• (e)
• wherein R is selected from the group consisting of:
• halo, OC1-6alkyl, and CN.