Substituted pyrazolo-pyrazines and their use as GluN2B receptor modulators

A pharmaceutical composition comprising (A) 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 thereof;
• and (B) at least one pharmaceutically acceptable excipient.

A pharmaceutical composition comprising (A) 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 thereof;
• and (B) at least one pharmaceutically acceptable excipient.

A pharmaceutical composition comprising:

• (A) 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;
• Ar1 is 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
• R2 is selected from the group consisting of:
• wherein Ra is selected from the group consisting of:
• H, halo, and C1-6alkyl;
• wherein Rb is C1-6alkyl and Rc is C1-6alkyl;
• 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;
• Ar1 is 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
• R2 is selected from the group consisting of:
• wherein Ra is selected from the group consisting of:
• H, halo, and C1-6alkyl;
• wherein Rb is C1-6alkyl and Rc is C1-6alkyl;
• wherein the disorder, disease or medical condition mediated by GluN2B receptor activity is selected from the group consisting of:
• bipolar disorder, major depressive disorder, treatment-resistant depression, post-partum depression, seasonal affective disorder, Alzheimer's disease, Parkinson's disease, Huntington's chorea, multiple sclerosis, cognitive impairment, head injury, spinal cord injury, stroke, epilepsy, dyskinesias, amyotrophic lateral sclerosis, neurodegeneration associated with bacterial or chronic infections, pain, diabetic neuropathy, migraine, cerebral ischemia, schizophrenia, encephalitis, autism and autism spectrum disorders, memory and learning disorders, obsessive compulsive disorder, attention deficit hyperactivity disorder (ADHD) and an addictive illness.