Substituted [1,2,4]triazolo[1,5-a]pyrimidin-7-yl compounds as PDE2 inhibitors

Inventors

Breitenbucher, James • Freestone, Graeme • Gomez, Laurent • Lemus, Robert • Ly, Kiev • McCarrick, Margaret • Vernier, William • VICKERS, Troy

Assignees

Dart Neuroscience LLC

Abstract

The invention provides a chemical entity of Formula (I): wherein R1, R2, 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.

Core Innovation

The disclosure provides substituted [1,2,4]triazolo[1,5-a]pyrimidin-7-yl chemical entities as phosphodiesterase 2 (PDE2) inhibitors. The entities include variable substituents and cover compounds and related forms, including pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, isotopically labeled compounds, solvates, hydrates, polymorphs, and conformers.

The document describes stereodefined morpholine-containing compounds, including specific (2S)-configured examples with a 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl core and substituted benzoyl or carbonyl-linked aryl groups. The examples and claims repeatedly identify 3,5-dichlorophenyl, 3-bromo-4-(trifluoromethyl)benzoyl, and 3-bromo-4,5-difluorobenzoyl substitution patterns, together with pharmaceutical composition embodiments containing a pharmaceutically acceptable excipient and an effective amount of the compound.

The disclosure further links the compounds to biological utility focused on PDE2 inhibition by exposing PDE2 to an effective amount of the claimed compound. It additionally states therapeutic concepts for treating PDE2-mediated disorders, including broad peripheral disorders, and mentions cognitive and motor training, neuronal plasticity, and related behavioral assay contexts.

Claims Coverage

The independent claims cover three specific (2S)-configured morpholine-containing compounds built on a 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl scaffold. Dependent claim coverage further includes pharmaceutical compositions with a pharmaceutically acceptable excipient and an effective amount, and a method of inhibiting PDE2 activity by exposing PDE2 to an effective amount. In total, three inventive compound features are identifiable across the independent claims.

The claim coverage centers on three specifically defined (2S)-configured morpholine compounds with distinct benzoyl or carbonyl aryl substitution patterns on a 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl framework. The dependent claims further tie these compounds to pharmaceutical compositions and to PDE2 inhibition by exposing PDE2 to an effective amount of the claimed compound.

Stated Advantages

Documented Applications