Pyrazolopyrimidine mTOR Inhibitors for Dual Complex Blockade

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is a need for small-molecule compounds with desirable physicochemical properties that can effectively inhibit both mTORC1 and mTORC2 to treat cancer and other disorders associated with deregulated mTOR activity, as current inhibitors primarily target mTORC1, offering limited spectrum antitumor activity.

Innovation Solution

Development of pyrazolo[1,5-a]pyrimidine compounds that act as inhibitors of mammalian Target Of Rapamycin (mTOR) kinase, capable of blocking signaling through both mTORC1 and mTORC2, providing a broader spectrum of antitumor activity and improved efficacy in treating cancer and other disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If current mTOR inhibitors are used, then mTORC1 inhibition is achieved, but mTORC2 inhibition is not achieved, resulting in limited spectrum antitumor activity

Engineering Contradiction:

Improvespectrum of antitumor activityVSAvoidinhibition efficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The pyrazolo[1,5-a]pyrimidine compound is designed to perform multiple functions by simultaneously inhibiting both mTORC1 and mTORC2 complexes. The molecular structure (Formula I) incorporates specific substituents (R1-R6, M1-M2) that enable dual binding affinity to both mTOR complexes, transforming a single-function inhibitor into a multi-functional agent that addresses the full spectrum of mTOR-driven tumor pathways.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention optimizes molecular parameters of the pyrazolo[1,5-a]pyrimidine core structure, including substituent positions (R1-R6), heteroatom configurations (M1-M2), and stereochemical arrangements, to achieve balanced inhibition of both mTORC1 and mTORC2. By systematically varying these structural parameters, the compound achieves simultaneous high-affinity binding to both complexes, expanding therapeutic spectrum while maintaining efficacy.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If small-molecule inhibitors are developed to target both mTORC1 and mTORC2, then broader spectrum activity is achieved, but compound design complexity increases

Engineering Contradiction:

Improvedual complex inhibition capabilityVSAvoidmolecular structure complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The pyrazolo[1,5-a]pyrimidine molecule is segmented into distinct functional regions: the core bicyclic structure provides foundational binding, while separate substituent positions (R1-R6 at specific ring positions) independently contribute to mTORC1 and mTORC2 recognition. This segmentation allows each region to be optimized for specific complex interactions, achieving dual inhibition through modular design rather than monolithic complexity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The pyrazolo[1,5-a]pyrimidine core acts as an intermediary structure that mediates between the requirements of mTORC1 and mTORC2 binding. Specific substituents serve as intermediary elements that facilitate simultaneous interaction with both complexes - for example, certain R-group configurations mediate hydrogen bonding networks that are compatible with both mTOR isoforms, simplifying the design of dual-specificity inhibitors.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentEP2608669B1NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS

Publication Date: 2016.06.22 MERCK SHARP & DOHME CORP

AI summary

The present invention relates to certain pyrazolo[1,5-a]pyrimidine compounds of Formula (I) as inhibitors of mammalian Target Of Rapamycin (mTOR) kinase, which is also known as FRAP, RAFT, RAPT or SEP. The compounds may be used in the treatment of cancer and other disorders where mTOR is deregulated. The present invention further provides pharmaceutical compositions comprising the pyrazolo[1,5-a]pyrimidine compounds.