2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2014 Feb 15;22(4):1303-12. doi: 10.1016/j.bmc.2014.01.007.
Sébastien Tardy 1,  Alexandre Orsato 1,  Luca Mologni 2,  William H Bisson 3,  Carla Donadoni 2,  Carlo Gambacorti-Passerini 2,  Leonardo Scapozza 3,  David Gueyrard 1,  Peter G Goekjian 4
Affiliations

Affiliations

  • 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.
  • 4 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. Electronic address: goekjian@univ-lyon1.fr.
PMID: 24468632 DOI: 10.1016/j.bmc.2014.01.007
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.

Keywords

Anaplastic lymphoma kinase; Aza-Graebe–Ullman; Kinase inhibitors; Palladium catalyzed coupling; Regioselective cross coupling.

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