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      A General One-Pot Synthesis of 2H -Indazoles Using an Organophosphorus-Silane System

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          Pot economy and one-pot synthesis

          This review describes the importance and usefulness of pot-economy and one-pot reactions in current synthetic organic chemistry.
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            Cobalt(III)-Catalyzed Synthesis of Indazoles and Furans by C–H Bond Functionalization/Addition/Cyclization Cascades

            The development of operationally straightforward and cost-effective routes for the assembly of heterocycles from simple inputs is important for many scientific endeavors, including pharmaceutical, agrochemical, and materials research. In this article we describe the development of a new air-stable cationic Co(III) catalyst for convergent, one-step benchtop syntheses of N-aryl-2H-indazoles and furans by C–H bond additions to aldehydes followed by in situ cyclization and aromatization. Only a substoichiometric amount of AcOH is required as an additive that is both low-cost and convenient to handle. The syntheses of these heterocycles are the first examples of Co(III)-catalyzed additions to aldehydes, and reactions are demonstrated for a variety of aromatic, heteroaromatic, and aliphatic derivatives. The syntheses of both N-aryl-2H-indazoles and furans have been performed on 20 mmol scales and should be readily applicable to larger scales. The reported heterocycle syntheses also demonstrate the use of directing groups that have not previously been applied to Co(III)-catalyzed C–H bond functionalizations. Additionally, the synthesis of furans demonstrates the first example of Co(III)-catalyzed functionalization of alkenyl C–H bonds.
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              Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.

              We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
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                Author and article information

                Journal
                Chemistry - A European Journal
                Chem. Eur. J.
                Wiley
                09476539
                June 26 2018
                June 26 2018
                June 06 2018
                : 24
                : 36
                : 9090-9100
                Affiliations
                [1 ]Departments of Chemical Biology and Structural Biology; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch; Robert-Roessle-Str. 10 13125 Berlin Germany
                [2 ]Institut für Chemie und Biochemie, Organische Chemie; Freie Universität Berlin; Takustrasse. 3 14195 Berlin Germany
                [3 ]Berlin Institute of Health (BIH); Anna-Louisa-Karsch-Str. 2, 10178 Kapelle-Ufer 2 10117 Berlin Germany
                Article
                10.1002/chem.201800763
                b460ca14-05cb-4467-ac94-9763050b535a
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

                http://onlinelibrary.wiley.com/termsAndConditions#vor

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