Formula I Compounds Modulating Integrated Stress Response
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Solution Overview
Problem
There is a continuing need for new compounds that effectively modulate the integrated stress response pathway with improved pharmacokinetic properties, such as activity, solubility, selectivity, and reduced side effects, for the treatment of related diseases.
Innovation Solution
Development of specific compounds of formula (I) or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers, which are designed to target the integrated stress response pathway, including phenyl or aromatic heterocyclyl derivatives with specific substituents to enhance therapeutic efficacy while minimizing adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds are used to modulate the integrated stress response pathway, then therapeutic effects can be achieved, but pharmacokinetic properties such as solubility, selectivity, and side effects are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structure parameters of compounds to optimize their pharmacokinetic properties. Specific substitutions at defined positions (R1-R6) alter solubility, selectivity, and metabolic stability while maintaining eIF2B modulator activity, thereby reducing side effects while preserving therapeutic efficacy
Solution Approach 2:
The patent implements local quality by introducing specific functional groups and substituents at particular positions within the molecular structure. These localized modifications (e.g., aromatic heterocyclyl derivatives with specific substituents) enhance therapeutic efficacy and selectivity for the integrated stress response pathway without broadly increasing toxicity
2Reliability
If existing compounds are used to modulate the integrated stress response pathway, then therapeutic effects can be achieved, but solubility and pharmacokinetic properties are insufficient
Solution Approach 1:
The patent modifies chemical parameters including the introduction of polar groups, aromatic heterocyclyl moieties, and specific substituent patterns that enhance aqueous solubility while maintaining pharmacological activity. These parameter changes address the solubility deficiency of existing compounds without compromising therapeutic efficacy
3Reliability
If existing compounds are used to modulate the integrated stress response pathway, then therapeutic effects can be achieved, but selectivity is insufficient
Solution Approach 1:
The patent enhances selectivity through localized structural features including specific aromatic heterocyclyl derivatives and substituent patterns at defined positions. These local structural qualities enable preferential binding to eIF2B while minimizing off-target effects, thereby improving selectivity for the integrated stress response pathway
Solution Approach 2:
The patent employs asymmetric molecular structures with specific chiral centers and non-symmetric substituent arrangements that enhance selectivity for the target pathway. The asymmetric design allows for more specific molecular recognition and interaction with eIF2B, reducing cross-reactivity with other cellular pathways
Data Source
AI summary
The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R1, R2, R2a, R3, R4, R4a, R4b, R4c, R4d, R4e, R4f, R5, R6 have the meaning as indicated in the description and claims The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating or preventing of one or more diseases or disorders associated with integrated stress response.