Pyrazolo[1,5-a]Pyridine Derivatives for Selective RET Inhibition

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current small-molecule kinase inhibitors targeting RET protein kinase lack selectivity, leading to pharmacodynamics and pharmacovigilance issues, limiting their effectiveness in treating RET-related neoplastic diseases.

Innovation Solution

Development of pyrazolo[1,5-a]pyridine derivatives that selectively inhibit RET kinase, formulated as pharmaceutical compounds and compositions for targeted cancer treatment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small-molecule kinase inhibitors are used to target RET protein kinase, then RET kinase inhibition activity is achieved, but selectivity for RET protein is insufficient leading to pharmacodynamics and pharmacovigilance problems

Engineering Contradiction:

ImproveRET kinase inhibition activityVSAvoidlack of selectivity causing pharmacodynamics issues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific substituent groups at particular positions on the pyrazolo[1,5-a]pyridine core structure. Different substituents (R1-R6, L1-L5, A1-A6) are strategically placed to optimize both RET kinase binding affinity and selectivity, creating localized interactions that differentiate RET from other kinases while maintaining inhibition activity.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying chemical parameters including substituent types, ring structures, and molecular configurations of the pyrazolo[1,5-a]pyridine derivatives. These parameter modifications enable fine-tuning of the compound's pharmacological properties to achieve high RET selectivity while maintaining potent inhibition activity.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If broad-spectrum kinase inhibitors are used, then multiple kinase targets are covered, but selectivity for RET protein decreases causing side effects

Engineering Contradiction:

Improvemulti-kinase coverageVSAvoidpharmacovigilance problems due to low selectivity

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies segmentation by dividing the kinase inhibitor market into specific target classes. The pyrazolo[1,5-a]pyridine derivatives are designed to selectively target the RET kinase family (including RET, TRK A/B/C, and NTRK1/2/3) while sparing other kinase families, achieving segmented coverage that reduces off-target effects.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies universality by designing a core pyrazolo[1,5-a]pyridine structure that can bind to multiple RET-related kinases (RET, TRKs, NTRKs) with high affinity and selectivity. This multi-functional capability allows a single compound class to address multiple targets within the RET family while maintaining selectivity through optimized structural features.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS12516054B2Pyrazolo[1,5-a]pyridine derivatives, preparation method therefor and use thereof

Publication Date: 2026.01.06 SHANGHAI DAIDAI INVESTMENT CONSULTING CO LTD

AI summary

A pyrazolo[1,5-a]pyridine derivative, and a preparation method and medical use thereof are provided. The pyrazolo[1,5-a]pyridine derivative shown in general formula (I), a preparation method of the derivative, a pharmaceutically acceptable salt of the derivative, and use of the derivative or salt as a therapeutic agent, especially as a rearranged during transfection (RET) inhibitor, are provided.