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  • Other N substituted carboxamide oxy pyridine derivatives


    Other N-substituted-6-carboxamide-3-oxy-pyridine derivatives 52a, 52h, 52i, and 53h were synthesized using an alternative route. The Pd-catalyzed Heck aminocarbonylation of 44 or 45 with (PPh3)2PdCl2 catalyst in the presence of Et3N under CO atmosphere successfully provided various N-substituted-6-carboxamide-3-oxy-pyridine derivatives 48h–i, 49h. Transformation of the ethyl ester moiety of 48h–i, 49h to a carboxamide group by an analogous method to that shown in Scheme 3 afforded the desired compounds 52h–i and 53h. N-Substituted-6-amino-3-oxy-pyridine derivatives 52a–c were synthesized using ethyl ester intermediate 44. The Pd-Catalyzed Buchwald–Hartwig amination42, 43 of 44 and diphenylmethanimine with Pd2(dba)3 and t-BuXPhos afforded 48j in 47% yield. Hydrolysis of 48j with aqueous NaOH achieved double hydrolysis of both the ethyl ester and the imine group to afford 6-amino-3-oxy-pyridine compound 50a. Transformation of the carboxylic CA074 group of 50a to a carboxamide group in a manner similar to Scheme 3 provided 52a, which was in turn acetylated to provide 6-acetylamino-3-oxy-pyridine derivative 52c. On the other hand, conducting the analogous Pd-Catalyzed Buchwald–Hartwig amidation43, 44 of 44 with N-methylcyclopropylamide with Pd2(dba)3 and t-BuXPhos afforded 48k in low yield (20%). Subsequent transformation of the ethyl ester moiety of 48k to a carboxamide in a similar manner to that described above afforded 50k. The hydrolysis of N-methy-N-cyclopropylamide group (50k) afforded 6-methylamino-3-oxy-pyridine derivative 52b.
    Results and discussion
    Conclusion We designed and developed CDK8/19 dual inhibitors bearing a novel 4,5-dihydrothieno[3′,4′:3,4]benzo[1,2-d]isothiazole scaffold utilizing structure-based drug design techniques based on docking models of our lead compound, 4,5-dihydroimidazolo[3′,4′:3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. To improve physicochemical properties and kinase selectivity, we introduced a substituted 3-pyridyloxy group into the 8-position of the scaffold in the front pocket region. The resulting optimized compound 52h showed excellent in vitro potency, physicochemical properties, and kinase selectivity. Based on our docking model of 52h bound to CDK8, we could explain the highly specific kinase activity profile found for this compound, based on the interaction of the pyridyl ether sidechain of 52h interacting with Met174 of the DMG activation loop of CDK8. In vitro pharmacological evaluation CA074 of 52h revealed potent suppression of phosphorylated STAT1 in various cancer cells. The high oral bioavailability found for this compound enabled in vivo studies, in which we demonstrated a mechanism-based in vivo PD effect as well as tumor growth suppression in an RPMI8226 human hematopoietic and lymphoid xenograft model in mice. These results suggested that inhibition of CDK8/19 may provide strong antitumor efficacy and that 52h is a promising candidate for the treatment of various human cancers. Further pharmacological evaluation of this compound and of CDK8/19 inhibition is in progress and will be reported in due course.
    Acknowledgements The authors thank Takashi Motoyaji and Akiyoshi Tani for target identification studies of compound 16. We also would like to express our appreciation to Tsuneo Yasuma, Akira Mori, Hitoaki Nishikawa, Yoshihiro Banno, Jun Fujimoto, Abhijit Nayek, and Goutam Saha for their helpful advice and support in organic synthesis. We also thank Yukio Toyoda for his assistance in cell Western blotting assay development, and Tsuyoshi Ishii for his useful discussion about in vitro assay development. We are also grateful to Hiroshi Miyake, Hikichi Yuichi, and Tomoyasu Ishikawa for helpful discussion and guidance in the overall execution of this research.