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.

S Tardy (1, 2) , A Orsato (1) , L Mologni , Wh Bisson , C Donadoni , C Gambacorti-Passerini , L Scapozza , D Gueyrard (3) , Pg. Goekjian (3)

1 ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires
2 ICOA - Institut de Chimie Organique et Analytique
3 CO2GLYCO - Chimie Organique 2-Glycochimie

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; Kinase inhibitors; Aza-Graebe–Ullman; Regioselective cross coupling; Palladium catalyzed coupling

Domains: Organic chemistry

S Tardy, A Orsato, L Mologni, Wh Bisson, C Donadoni, et al.. 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.. Bioorganic and Medicinal Chemistry, 2014, 22 (4), pp.1303-1312. ⟨10.1016/j.bmc.2014.01.007⟩. ⟨hal-01147409⟩