Quinoline Carboxamide Kinase Inhibitors for FGFR Selectivity
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Solution Overview
Problem
Current protein kinase inhibitors, such as those disclosed in WO2006/000420, WO03/023004, WO02/102972, and WO05/118580, while considered active, have limitations in selectively blocking aberrant constitutive receptor protein tyrosine kinase activity, particularly FGFR activity, necessitating the development of novel, highly affine and selective compounds for treating proliferative diseases associated with protein tyrosine kinase-related disorders.
Innovation Solution
Development of quinoline/quinoxaline-carboxamide derivatives, specifically compounds of formula (I), which inhibit protein tyrosine kinases like FGFR, VEGFR2, PDGFR, cKIT, LCK, cAbl, and RET, offering pharmacological properties that inhibit various protein kinases and demonstrate antitumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing protein kinase inhibitors are used, then some kinase activity is inhibited, but selectivity for FGFR and affinity are insufficient
Solution Approach 1:
The patent applies local quality by introducing specific substituent patterns at defined positions on the quinoline/quinoxaline core structure. Different substituents (R1-R6) are placed at specific locations to optimize interactions with the FGFR binding site, thereby achieving high selectivity and affinity for this specific kinase while maintaining broad kinase inhibitory activity.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent types, positions, and configurations on the quinoline/quinoxaline scaffold. This includes modifying electronic properties, steric bulk, and hydrogen bonding capabilities of substituents to optimize the balance between selectivity for FGFR and overall kinase inhibitory potency.
2Measurement precision
If novel quinoline/quinoxaline derivatives are developed, then selectivity and affinity for FGFR improve, but molecular complexity increases
Solution Approach 1:
The patent applies universality by designing a quinoline/quinoxaline core structure that can serve multiple functions: it provides a flat aromatic surface for stacking interactions, contains nitrogen atoms for hydrogen bonding, and offers multiple substitution positions for optimizing binding. This multi-functional core achieves high binding affinity while maintaining a relatively simple and synthetically accessible molecular framework.
Data Source
AI summary
The invention relates to compounds of Formula (I), wherein the substituens are as defined in the specification, in free form or in the form of a pharmaceutically acceptable salt, solvate, ester, N-oxide thereof; processes for the preparation thereof; to pharmaceuticals containing such compounds, in particular for the use in one or more Protein tyrosine kinase mediated diseases.