Facile Preparation of 3-Substituted-2,6-difluoropyridines and Application to the Synthesis of 2,3,6-Trisubstituted Pyridines for PKCθ Inhibitors

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  • 2,3,6-三置換ピリジン誘導体の簡便合成法開発とPKCθ阻害剤の合成研究への応用
  • 2,3,6-サン チカン ピリジン ユウドウタイ ノ カンベン ゴウセイホウ カイハツ ト PKCthソガイザイ ノ ゴウセイ ケンキュウ エ ノ オウヨウ

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Abstract

<p>2,3,6-Trisubstituted pyridine is attractive in drug discovery since a wide variety of medicines and biologically active compounds include the scaffold. Therefore, the development of a facile methodology for synthesizing 2,3,6-trisubstituted pyridines contributes not only to easy preparation of drug candidates but to design of an original scaffold in medicinal chemistry. 3-Substituted-2,6-difluoropyridines play an important role in the synthesis of 2,3,6-trisubstituted pyridines because they have two distinguishable carbon-fluorine bonds susceptible to a tandem nucleophilic aromatic substitutions (SNAr). Herein, this article describes facile preparation of 3-substituted-2,6-difluoropyridines derived from 3-substituted-2,6-dichloropyridines by using cesium fluoride (CsF) and dimethyl sulfoxide (DMSO) and its application to the synthesis of 2,3,6-trisubstituted pyridines for potent and novel Protein Kinase C theta (PKCθ) inhibitors. Studying on the Structure-Activity Relationship (SAR) of 2,3-dihydroquinazolin-4(1H)-ones, PKCθ inhibitors, identified that filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity. Strong PKCθ inhibition was observed with 2,3,6-trisubstituted pyridines having lipophilic substituents. The report presents an easier method for preparing 2,3,6-trisubstituted pyridines and practical application to drug discovery.</p>

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