Synthesis and biological evaluation of benzo[4,5]imidazo[1,2-c]pyrimidine and benzo[4,5]imidazo[1,2-a]pyrazine derivatives as anaplastic lymphoma kinase inhibitors |
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| Affiliation: | 1. Université de Lyon, Laboratoire Chimie Organique 2-Glycochimie, ICBMS, UMR-5246, CNRS-Université Claude Bernard Lyon 1, Bât. 308 CPE Lyon, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France;2. University of Milano-Bicocca, Department of Health Sciences, Via Cadore 48, 20052 Monza, Italy;3. University of Geneva, School of Pharmaceutical Sciences, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland;1. School of Chemistry and Biochemistry, Parker H. Petit for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA;2. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA;3. Department of Chemistry and Biomedical Engineering, Northwestern University, 2145 Sheridan Rd, Evanston, IL 60208-3113, USA;1. School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China;2. Department of Medicinal Chemistry and The Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA;3. Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA;4. School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China;1. Department of Chemistry, Payame Noor University, PO Box,19395-3697, Tehran, Iran;2. Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran;3. Ghadr Institute of Higher Education, Department of Pharmaceutical Chemistry, Koochesfahan, Guilan, Iran;1. Department of Chemistry, Kurukshetra University, Kurukshetra 136119, Haryana, India;2. Departamento de Química Orgánica y Bio-orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain;3. Departamento de Química Inorgánica I and CAI de Difracción de Rayos-X, Facultad de Ciencias Químicas, Universidad Complutense de Madrid (UCM), E-28040 Madrid, Spain |
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| Abstract: | ![]()
Chromosomal translocations involving anaplastic lymphoma kinase (ALK) are the driving mutations for a range of cancers and ALK is thus considered an attractive therapeutic target. We synthesized a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines and benzo[4,5]imidazo[1,2-a]pyrazines by an aza-Graebe–Ullman reaction, followed by palladium-catalyzed cross-coupling reactions. A sequential regioselective cross-coupling route is reported for the synthesis of unsymmetrically disubstituted benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of ALK was evaluated and compound 19 in particular showed good activity against both the wild type and crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells. |
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| Keywords: | Anaplastic lymphoma kinase Kinase inhibitors Aza-Graebe–Ullman Regioselective cross coupling Palladium catalyzed coupling |
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