Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

Inventors

Mekonnen, Belew • Butera, John A. • Huang, Jianxing • Patel, Hemantbhai • Jiang, Qin • Herr, Robert Jason • FREEMAN, Emily Elizabeth • Mayhew, Nicholas James

Assignees

Hager Biosciences LLC • Agenebio Inc

Abstract

This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with CNS disorders. It also relates to the use of an α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) in treating cognitive impairment associated with CNS disorders in a subject in need or at risk thereof, including age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI, Age-Associated Memory Impairment, Age Related Cognitive Decline, dementia, Alzheimer's Disease (AD), prodromal AD, PTSD, schizophrenia, bipolar disorder, ALS, cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. It also relates to the use of an α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) in treating brain cancers (including brain tumors, e.g., medulloblastomas), and cognitive impairment associated therewith.

Core Innovation

The invention describes compounds of formula XI and formula XI-a, or pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, defined by a common polycyclic heteroaromatic scaffold with multiple nitrogen atoms. The chemical scope is expressed through variable substituent positions including R2, R8, R3, R9, R10, R6, and, in some variants, R7, together with independently substituted positions R1, R4, and R5 and explicit substitution-count limits. The scope is controlled by integer ranges and substitution-count limits, including independently substituted 0-5 R' and defined ranges for m, n, and p.

R2 is defined by options including OR8, SR8, (CH2)nOR8, (CH2)nO(CH2)nR8, (CH2)pR8, and (CH2)nN(R)R10, with R2 independently substituted with 0-5 R'. R8 is defined as H, alkyl, cycloalkyl, aryl, heteroaryl, or alkyl-heteroaryl combinations, with further optional substitution in the disclosed embodiments. R3 is defined as C≡C-R9, where R9 is selected from 5- to 10-membered heteroaryl or alkyl-heteroaryl motifs and is independently substituted with 0-5 R11.

The substituent definitions also include permitted meanings for R1, R4, and R5 such as halogen, CN, CF3, OCF3, NO2, NCS, SiR3, N(R)2, and multiple carbonyl- and heteroatom-containing groups. R10 is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl options with defined substitution limits, and R6 is independently H or (C1-C6)alkyl. The disclosure includes specific compound depictions that illustrate a common fused polycyclic heteroaromatic scaffold with variable halogen, alkoxy, aryl, and heteroaryl substituents.

Claims Coverage

The independent claims cover compound families defined by formula XI, formula XI-a, and a structure-defined compound, with extensive substituent-variable constraints and pharmaceutically acceptable salt, hydrate, isomer, or combination forms. The claim coverage is driven by the defined substituent sets and substitution-count limits for R2, m, n, p, R1, R4, R5, R8, R3/R9, R10, R6, and in some claim variants R7.

Across the independent claims, the invention is a set of structurally defined compounds centered on formula XI and formula XI-a, plus a structure-defined compound, with broad but bounded substituent options and explicit substitution-count limits. The main inventive features are the formula-based scaffold definitions and the constrained selections for R2, R8, R3/R9, R10, R6, and in some variants R7.

Stated Advantages

Documented Applications