Substituted pyrazolopyrimidinone compounds as PDE2 inhibitors
Inventors
Gomez, Laurent • Vernier, William Francois
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10981916-B2
Publication Date
2021-04-20
Expiration Date
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, dermatoiogical, inflammatory, and pain disorders.
Core Innovation
The invention relates to substituted pyrazolopyrimidinone compounds and substituted pyrazolo[3,4-d]pyrimidin-4-one derivatives that inhibit PDE2 (phosphodiesterase 2). The compounds are defined by Formula (I), Formula (Ia), and Formula (Ib), and by selected structures bearing cycloalkyl groups, pyridine and aryl substituents, and substituted pyrazolo[3,4-d]pyrimidin-4-one cores.
The disclosed scaffold incorporates variable substituents including V/W/Y/Z, R1, X1, and X2, with permitted classes including cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl, haloalkyl, alkoxy, and halogen/halo substituents. The compounds include enantiomerically pure compounds obtained by chiral separation of racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, pharmaceutically active metabolites, and isotopically labeled compounds.
The disclosure also includes isotopically labeled compounds for metabolic and reaction kinetics studies and for detection and imaging, including PET and SPECT, as well as tissue distribution and radioactive treatments. The therapeutic theme is the use of PDE2 inhibitors for treating PDE2-mediated disorders, including neurological and CNS-related indications, enhancing neuronal plasticity and augmenting cognitive and motor training and rehabilitation, and peripheral inflammatory disorders and pain disorders.
Claims Coverage
The provided claims cover two structural claim groups and related dependent claims. Across the set, the inventive features center on specific substituted pyrazolopyrimidinone and pyrazolo[3,4-d]pyrimidin-4-one scaffolds, constrained substituent patterns, stereochemical variants, and downstream pharmaceutical composition and method-of-use limitations, with a total of 11 inventive features identified.
Formula (Ia) compound with constrained substituents
A compound of Formula (Ia) wherein R1 is C1-6 haloalkyl; X1 and X2 are both CH, or X1 is CH and X2 is N, or X1 is N and X2 is CH; Y is C1-6 alkyl; and Z is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -(CH2)n aryl, or -(CH2)n heteroaryl, including pharmaceutically acceptable salts thereof.
Z as a (CH2)n-linked aryl or heteroaryl with limited optional substitution
A compound or pharmaceutically acceptable salt wherein Z is -(CH2)n aryl or -(CH2)n heteroaryl, with the aryl or heteroaryl optionally substituted with up to 3 members selected from the specified substituent group.
Fixed Z substituent selection
A compound or pharmaceutically acceptable salt in which Z is CH3 or CH2CH3.
R1 as a specific haloalkyl substituent
A compound or pharmaceutically acceptable salt in which R1 is CF3.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
Method of treating neurological disorders by administering effective amount
A method for treating a neurological disorder by administering an effective amount of a compound or pharmaceutically acceptable salt thereof to a subject, where the disorder is selected from listed neurological disorder categories, including CNS, developmental, and neurodegenerative disorders.
Selected substituted pyrazolo[3,4-d]pyrimidin-4-one compounds
A compound selected from the group consisting of substituted pyrazolo[3,4-d]pyrimidin-4-one derivatives, including pharmaceutically acceptable salts thereof.
Cycloalkyl substitution on the pyrazolo[3,4-d]pyrimidin-4-one core
Selected compounds include variants having a cycloalkyl group at the 3-position, including 3-cyclopropyl, 3-cyclobutyl, 3-cyclopentyl, and 3-cyclohexyl.
Substituted pyridine/aryl side chain containing trifluoromethyl
Selected compounds include side-chain substituents with pyridine and/or phenyl patterns bearing trifluoromethyl, including 6-(trifluoromethyl)pyridin-3-yl and related trifluoromethylpyridinyl and phenyl variants.
Variable linker and optional pyridine substituents
Selected compounds include variations in the linker segment, including propyl versus ethyl, and optional pyridine substituents such as 5-methoxypyridin-2-yl and 5-fluoropyridin-2-yl.
Stereodefined (1S)/(1R) variants
Selected compounds include stereodefined variants specified as (1S) and (1R) where the chiral center is indicated in the substituent segment.
Overall, the claim coverage is centered on substituted pyrazolopyrimidinone and pyrazolo[3,4-d]pyrimidin-4-one compounds with defined substituent constraints, specific aryl and heteroaryl substitution patterns, stereochemical variants, and associated pharmaceutical composition and treatment claims.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
Interested in licensing this patent?