# US 11,999,738 B2 · Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,999,738 B2 - Document ID: US11999738B2 - Status: Granted - Kind: B2 - Application number: 17/232,015 - Filed: 2021-04-15 - Published: 2021-11-04 - Granted: 2024-06-04 - Earliest claimed: 2016-12-28 - Assignees: Dart NeuroScience, LLC - Applicants: Dart Neuroscience, LLC - Inventors: Laurent Gomez; William Francois Vernier - Web page: https://patentgrep.com/patent/US11999738B2 ## CPC - C07D 487/04: Ortho-condensed systems - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/22: Anxiolytics - A61P 25/24: Antidepressants - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract A chemical entity of Formula (I): wherein V, W, 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, 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, cognitive disorders, neurodegenerative diseases, and trauma-dependent losses of function; enhancing the efficiency of cognitive and motor training, including in stroke or TBI rehabilitation; and treating peripheral disorders, including hematological, cardiovascular, gastroenterological, dermatological, inflammatory, and pain disorders. ## Claims ### Claim 1 A compound having the Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein, R1 is —C1-6haloalkyl; X1 and X2 are both CH, X1 is CH and X2 is N (nitrogen), or X1 is N (nitrogen) and X2 is CH; Y is —C1-3alkyl; and Z is —C1-6alkyl, —C1-6haloalkyl, or —C1-6alkoxy. ### Claim 2 (depends on 1) The compound, or a pharmaceutically acceptable salt thereof, of claim 1, wherein Y is —C1-3alkyl. ### Claim 3 (depends on 2) The compound, or a pharmaceutically acceptable salt thereof, of claim 2, wherein Y is —CH3 or —CH2CH3. ### Claim 4 (depends on 2) The compound, or a pharmaceutically acceptable salt thereof, of claim 2, wherein Y is —CH3. ### Claim 5 (depends on 1) The compound, or a pharmaceutically acceptable salt thereof, of claim 1, wherein Z is —CH3 or —CH2CH3. ### Claim 6 (depends on 2) The compound, or a pharmaceutically acceptable salt thereof, of claim 2, wherein Z is —CH2CH3. ### Claim 7 (depends on 1) The compound, or a pharmaceutically acceptable salt thereof, of claim 1, wherein R1 is —CF3. ### Claim 8 A compound selected from the group consisting of: 3-cyclopropyl-6-methyl-1-{1-[6-(trifluoromethyl)pyridin-3-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-{1-[5-(trifluoromethyl)pyridin-2-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-{1-[4-(trifluoromethyl)phenyl]ethyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-{1-[5-(trifluoromethyl)pyridin-2-yl]ethyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-{1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1S)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1S)-1-[6-(trifluoromethyl)pyridin-3-yl]propyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]propyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1S)-1-[5-(trifluoromethyl)pyridin-2-yl]propyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1R)-1-[5-(trifluoromethyl)pyridin-2-yl]propyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1S)-1-[5-(trifluoromethyl)pyridin-2-yl]ethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1R)-1-[5-(trifluoromethyl)pyridin-2-yl]ethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-(2,2,2-trifluoroethyl)-1-(1-(5-(trifluoromethyl)pyridin-2-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; and 3-cyclopropyl-6-(trifluoromethyl)-1-(1-(5-(trifluoromethyl)pyridin-2-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one, or a pharmaceutically acceptable salt thereof. ### Claim 9 A compound selected from the group consisting of: 3-cyclopropyl-6-methyl-1-{1-[6-(trifluoromethyl)pyridin-3-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-{(1S)-1-[6-(trifluoromethyl)pyridin-3-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-{(1S)-1-[5-(trifluoromethyl)pyridin-2-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-[(1S)-1-[5-(trifluoromethyl)pyridin-2-yl]ethyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-cyclopropyl-6-methyl-1-{1-[5-(trifluoromethyl)pyridin-2-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; and 3-cyclopropyl-6-methyl-1-{1-[4-(trifluoromethyl)phenyl]ethyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one; or a pharmaceutically acceptable salt thereof. ### Claim 10 (depends on 9) The compound of claim 9, which is 3-cyclopropyl-6-methyl-1-{1-[6-(trifluoromethyl)pyridin-3-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. ### Claim 11 (depends on 9) The compound of claim 9, which is 3-cyclopropyl-6-methyl-1-{1-[5-(trifluoromethyl)pyridin-2-yl]propyl}-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. ### Claim 12 (depends on 9) The compound of claim 9, which is 3-cyclopropyl-6-methyl-1-[(1S)-1-[6-(trifluoromethyl)pyridin-3-yl]propyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. ### Claim 13 (depends on 9) The compound of claim 9, which is 3-cyclopropyl-6-methyl-1-[(1S)-1-[5-(trifluoromethyl)pyridin-2-yl]propyl]-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. ### Claim 14 (depends on 1) A composition, comprising: (a) a compound, or a pharmaceutically acceptable salt thereof, of claim 1; and (b) a pharmaceutically acceptable carrier. ### Claim 15 (depends on 1) A method of treating a subject suffering from or diagnosed with a disorder mediated by PDE2 activity, comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of claim 1. ### Claim 16 (depends on 1) A method of modulating PDE2 activity, comprising exposing a subject to an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of claim 1. ### Claim 17 (depends on 16) The method of claim 16, wherein the PDE2 activity is modulated in a human subject. ### Claim 18 (depends on 1) A method of treating a neurological disorder, comprising administering to a subject suffering from or diagnosed with the disorder an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of claim 1, wherein the neurological disorder is selected from the group consisting of a central nervous system (CNS) disorder; a developmental disorder; a schizophrenia spectrum or psychotic disorder; a bipolar 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; and a neurodegenerative disorder. ### Claim 19 (depends on 18) The method of claim 18, wherein the neurological disorder is associated with cognitive deficit. ### Claim 20 (depends on 1) A method of treating a cognitive disorder, comprising administering to a subject in need thereof suffering from or diagnosed with the disorder an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of claim 1. ### Claim 21 (depends on 1) A method of treating a cardiovascular disease, comprising administering to a subject suffering from or diagnosed with the disease an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of claim 1. ### Claim 22 (depends on 21) The method of claim 21, wherein the cardiovascular disease is selected from the group consisting of: a congestive heart failure, a myocardial infarction, an ischemic disease, an atrial arrhythmia, a ventricular arrhythmia, a hypertensive vascular disease, and atherosclerosis.