Alkynyl Quinazoline Inhibitors for Variable ErbB Mutant Response
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Solution Overview
Problem
Existing ErbB inhibitors fail to satisfactorily address the variable responsiveness of cancer patients, particularly those with oncogenic mutants of ErbB receptors, leading to ineffective treatments for cancers like glioblastoma and non-small cell lung cancer.
Innovation Solution
Development of new alkynyl quinazoline compounds that inhibit receptor tyrosine kinases, specifically targeting oncogenic mutants of ErbB receptors, including allosteric mutants with mutations outside the ATP-binding site, to prevent or treat cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ErbB inhibitors are used to treat cancer patients with oncogenic mutants, then treatment is provided, but variable responsiveness leads to ineffective treatment outcomes
Solution Approach 1:
The patent modifies the chemical structure of quinazoline compounds by introducing specific substituents at defined positions (e.g., R1, R2, R3, R4, R5, R6 groups) to change the binding parameters of the inhibitor, thereby improving its effectiveness against variable ErbB mutants while maintaining reliable treatment outcomes
Solution Approach 2:
The invention creates composite chemical structures by combining quinazoline core with various substituent groups (aryl, heteroaryl, alkyl, halo substituents) to develop a family of compounds with enhanced and consistent activity across different ErbB mutant types, resolving the variability issue
2Reliability
If new alkynyl quinazoline compounds are developed to target oncogenic mutants, then treatment effectiveness improves, but compound complexity increases
Solution Approach 1:
The patent segments the quinazoline compound into distinct functional regions (core quinazoline structure, N-substituent, C-substituent, and various R-groups at defined positions), allowing systematic optimization of each segment to achieve effective inhibition while managing overall molecular complexity through modular design
Data Source
AI summary
The present disclosure relates to compounds of Formula (I'): and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans.