Substituted [1,2,4]triazolo[1,5-a]pyrimidin-7-yl compounds as PDE2 inhibitors
The invention provides a chemical entity of Formula (I): wherein R 1 , R 2 , X, Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods as disclosed herein, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive treatments; modulating and treating disorders mediated by PDE2 activity; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training, including animal skill training protocols; and treating peripheral disorders, including hematological, cardiovascular, gastroenterological, and dermatological disorders.
1. A compound, which is (2S)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine, or a pharmaceutically acceptable salt thereof.
2. A compound, which is (2S)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine, or a pharmaceutically acceptable salt thereof.
3. A compound, which is (2S)-4-(3-Bromo-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a pharmaceutically acceptable excipient; and the compound of claim 1 or a pharmaceutically acceptable salt thereof.
5. A method of inhibiting PDE2 activity, comprising exposing PDE2 to an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein the inhibition of PDE2 activity is in a subject suffering from or diagnosed with a disorder that is treated by inhibiting PDE2 activity.
7. The method of claim 6 , wherein the disorder that is treated by inhibiting PDE2 activity is a neurological disorder selected from the group consisting of a central nervous system (CNS) disorder, a developmental disorder; a schizophrenia spectrum or psychotic disorder; a depressive disorder; an anxiety disorder; an obsessive-compulsive disorder; a dissociative disorder; a disruptive, impulse-control, or conduct disorder; a trauma- or stressor-related disorder; a feeding or eating disorder; a sleep-wake disorder; a sexual disorder; a substance-related or addictive disorder; a personality disorder; delirium; dementia; an age-associated cognitive deficit; a trauma-dependent loss of function; and a cognitive impairment due to chemotherapy.
8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient; and the compound of claim 2 or a pharmaceutically acceptable salt thereof.
9. A method of inhibiting PDE2 activity, comprising exposing PDE2 to an effective amount of the compound of claim 2 or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein the inhibition of PDE2 activity is in a subject suffering from or diagnosed with a disorder that is treated by inhibiting PDE2 activity.
11. The method of claim 10 , wherein the disorder that is treated by inhibiting PDE2 activity is a neurological disorder selected from the group consisting of a central nervous system (CNS) disorder, a developmental disorder; a schizophrenia spectrum or psychotic disorder; a depressive disorder; an anxiety disorder; an obsessive-compulsive disorder; a dissociative disorder; a disruptive, impulse-control, or conduct disorder; a trauma- or stressor-related disorder; a feeding or eating disorder; a sleep-wake disorder; a sexual disorder; a substance-related or addictive disorder; a personality disorder; delirium; dementia; an age-associated cognitive deficit; a trauma-dependent loss of function; and a cognitive impairment due to chemotherapy.
12. A pharmaceutical composition comprising a pharmaceutically acceptable excipient; and the compound of claim 3 or a pharmaceutically acceptable salt thereof.
13. A method of inhibiting PDE2 activity, comprising exposing PDE2 to an effective amount of the compound of claim 3 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the inhibition of PDE2 activity is in a subject suffering from or diagnosed with a disorder that is treated by inhibiting PDE2 activity.
15. The method of claim 14 , wherein the disorder that is treated by inhibiting PDE2 activity is a neurological disorder selected from the group consisting of a central nervous system (CNS) disorder, a developmental disorder; a schizophrenia spectrum or psychotic disorder; a depressive disorder; an anxiety disorder; an obsessive-compulsive disorder; a dissociative disorder; a disruptive, impulse-control, or conduct disorder; a trauma- or stressor-related disorder; a feeding or eating disorder; a sleep-wake disorder; a sexual disorder; a substance-related or addictive disorder; a personality disorder; delirium; dementia; an age-associated cognitive deficit; a trauma-dependent loss of function; and a cognitive impairment due to chemotherapy.
16. The method of claim 7 , wherein the neurological disorder is a psychotic disorder.
17. The method of claim 11 , wherein the neurological disorder is a psychotic disorder.
18. The method of claim 11 , wherein the neurological disorder is dementia.
19. The method of claim 11 , wherein the neurological disorder is dementia due to a neurodegenerative disease.
20. The method of claim 19 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body disease, Pick's disease, a prion disease, Amyotrophic lateral sclerosis (ALS), multiple sclerosis, frontotemporal lobar degeneration, and corticobasal degeneration.