Fused Ring Ras Inhibitors for K-Ras G12C Targeting
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Solution Overview
Problem
Mutant Ras proteins, particularly K-Ras G12C, are associated with prolonged activation leading to cancer due to reduced GTPase activity, promoting uncontrolled cell growth and division, and existing inhibitors like substituted 5,6,7,8-tetrahydropyrido(3,4-d)pyrimidine compounds have limitations in effectively targeting these mutations.
Innovation Solution
Development of fused ring compounds, such as those described by Formula (II), which inhibit Ras proteins by targeting the K-Ras G12C mutation, including specific substitutions and configurations to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional methods (Steglich coupling, Suzuki coupling, etc.) are used to synthesize fused ring compounds, then the synthesis process requires multiple steps and specialized reagents, but this leads to increased process complexity and reduced efficiency
Solution Approach 1:
The patent changes the chemical parameters of the reaction system by introducing a specific catalyst system (metal complex with ligands) and controlling reaction conditions (temperature, solvent type, additive concentration) to enable direct coupling of aryl halides with terminal alkynes to form fused ring compounds in one step, eliminating the need for multiple conventional coupling steps
Solution Approach 2:
The patent extracts and eliminates unnecessary intermediate steps and specialized reagents from the conventional synthesis pathway by using a direct coupling method that proceeds from aryl halide and terminal alkyne directly to the fused ring compound through catalytic action, removing the need for separate coupling, cyclization, and purification steps
2Ease of manufacture
If conventional coupling methods are used, then the synthesis requires specific reagents and conditions, but this increases the cost and reduces scalability
Solution Approach 1:
The patent develops a universal catalytic system that can accommodate different aryl halide and alkyne substrates through a single reaction protocol, allowing the same catalyst system to produce various fused ring compounds (benzofuran, benzothiophene, indole, etc.) by simply changing the substrates without requiring different reagents or conditions for each compound type
Solution Approach 2:
The patent employs a catalytic system that can be easily removed from the reaction mixture and reused, replacing the need for stoichiometric amounts of expensive and difficult-to-remove reagents in conventional methods, thereby reducing material costs and simplifying purification
3Loss of time
If conventional synthesis methods are used, then the process requires multiple steps, but this increases the time consumption and reduces throughput
Solution Approach 1:
The patent enables continuous one-pot synthesis where aryl halide and terminal alkyne are coupled and cyclized simultaneously in a single reaction vessel without requiring isolation of intermediates, allowing for continuous processing and immediate formation of the fused ring compound through catalytic action throughout the reaction period
Data Source
AI summary
Provided are fused ring compounds of Formula (I), Formula (II), or Formula (III), as further detailed herein, which are used for the inhibition of Ras proteins, as well as compositions comprising these compounds and methods treatment by their administration.