title: Practical application of 3-substituted-2,6-difluoropyridines in drug discovery: Facile synthesis of novel protein kinase C theta inhibitors.
abstract: We previously reported a facile preparation method of 3-substituted-2,6-difluoropyridines, which were easily converted to 2,3,6-trisubstituted pyridines by nucleophilic aromatic substitution with good regioselectivity and yield. In this study, we demonstrate the synthetic utility of 3-substituted-2,6-difluoropyridines in drug discovery via their application in the synthesis of various 2,3,6-trisubstituted pyridines, including macrocyclic derivatives, as novel protein kinase C theta inhibitors in a moderate to good yield. This synthetic approach is useful for the preparation of 2,3,6-trisubstituted pyridines, which are a popular scaffold for drug candidates and biologically attractive compounds.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: taisuke.katoh@takeda.com.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Katoh
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tomata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Setoh
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Takai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Yoshitomi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yukawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakada
mesh_terms: D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: C518916:2,6-difluoropyridine; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
keywords: 2,3,6-Trisubstituted pyridine; 3-Substituted-2,6-difluoropyridine; Drug design; Macrocyclic derivatives; PKCθ inhibitor