Sulfoximine-Substituted Pyrimidine Derivatives for CDK9 Inhibition
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Solution Overview
Problem
Current CDK9 inhibitors lack selectivity, potency, and efficacy for treating hyper-proliferative diseases, viral diseases, and cardiovascular diseases, with suboptimal kinase selectivity profiles and side effect profiles, and require improvements in physicochemical and pharmacokinetic properties.
Innovation Solution
Development of disubstituted 5-fluoro pyrimidine derivatives containing a sulfoximine group, specifically designed to target CDK9/Cyclin T1 with enhanced selectivity and potency, and improved anti-proliferative activity in tumor cell lines, even at high ATP concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CDK9 inhibitors are used, then kinase inhibition activity is achieved, but selectivity for CDK9/Cyclin T1 is insufficient
Solution Approach 1:
The patent applies local quality by introducing a specific sulfoximine group at the 5-position of the pyrimidine ring, which creates a localized chemical feature that specifically interacts with CDK9/Cyclin T1. This localized modification (5-fluoro-4,6-disubstituted pyrimidine structure with sulfoximine) provides selective binding to the target kinase while maintaining inhibition activity, thereby resolving the contradiction between achieving kinase inhibition and ensuring selectivity.
2Reliability
If current CDK9 inhibitors are used, then some therapeutic effect is achieved, but potency is suboptimal
Solution Approach 1:
The patent applies parameter changes by systematically varying the substituents at the 4 and 6 positions of the pyrimidine ring (different R1, R2, R3, R4, R5, R6, R7, R8 groups), and optimizing the sulfoximine configuration. These parameter modifications enhance the binding affinity and potency of the compounds against CDK9/Cyclin T1, achieving potent inhibition with IC50 values in the nanomolar range, thus resolving the contradiction between therapeutic effect and potency.
3Reliability
If current CDK9 inhibitors are used, then some anti-proliferative activity is achieved, but efficacy in tumor cell lines is insufficient
Solution Approach 1:
The patent applies preliminary action by designing compounds with optimized pharmacokinetic properties (solubility, metabolic stability, cell permeability) and enhanced selectivity for CDK9/Cyclin T1 before in vivo testing. The 5-fluoro pyrimidine derivatives with sulfoximine groups are pre-optimized to achieve potent anti-proliferative effects, which then translate to improved efficacy in tumor cell lines and xenograft models, resolving the contradiction between anti-proliferative activity and overall efficacy.
4Adaptability or versatility
If current CDK9 inhibitors are used, then treatment of hyper-proliferative diseases is attempted, but side effect profile is suboptimal
Solution Approach 1:
The patent applies the blessing in disguise principle by converting the potential harm of off-target kinase inhibition into a benefit through high selectivity for CDK9/Cyclin T1. The 5-fluoro pyrimidine derivatives with sulfoximine groups are designed to specifically target CDK9 while sparing other kinases, thereby reducing side effects associated with pan-CDK inhibition. This selective approach maintains treatment capability for hyper-proliferative diseases while minimizing harmful side effects.
Data Source
AI summary
The present invention relates to disubstituted 5-fluoro pyrimidine derivatives containing a sulfoximine group of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).