Macrocyclic imidazo [1,2-b] pyridazine derivative, preparation method therefor, and use thereof
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Solution Overview
Problem
Current TRK inhibitors face challenges in overcoming acquired resistance mutations, such as solvent-front and gatekeeper mutations, and have limited ability to penetrate the blood-brain barrier, necessitating the development of new TRK inhibitors that can effectively target TRK fusion-related tumors, including those in the brain.
Innovation Solution
A macrocyclic imidazo[1,2-b]pyridazine derivative and its pharmaceutically acceptable salts are developed as TRK kinase inhibitors, designed to overcome drug resistance mutations and enhance brain penetration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current TRK inhibitors are used to target TRK fusion-related tumors, then TRK kinase activity is inhibited, but acquired resistance mutations (solvent-front and gatekeeper mutations) develop and blood-brain barrier penetration is limited
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of TRK inhibitors to create a new macrocyclic imidazo[1,2-b]pyridazine derivative with altered molecular properties. This structural modification changes key parameters including macrocyclization to form a cyclic structure with specific ring size, substitution patterns at defined positions, and stereochemical configurations, enabling the inhibitor to overcome resistance mutations and improve blood-brain barrier penetration while maintaining TRK kinase inhibition effectiveness
Solution Approach 2:
The patent creates a composite molecular structure by combining multiple functional moieties into a single macrocyclic inhibitor molecule. The compound integrates the imidazo[1,2-b]pyridazine core with additional structural elements including substituted groups at specific positions, forming a composite structure that simultaneously achieves high TRK binding affinity, resistance to mutations, and enhanced brain penetration capabilities
Data Source
AI summary
A macrocyclic imidazo[1,2-b]pyridazine compound represented by formula (I) or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer, a tautomer thereof or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutical composition of the derivative are disclosed. The macrocyclic imidazo[1,2-b]pyridazine compound represented by formula I or the pharmaceutical composition can be used as a TRK kinase inhibitor for treating or preventing diseases or symptoms mediated by TRK or TRK mutation.