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

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 4; pp. 1303 - 1312
• Main Authors: Tardy, Sébastien, Orsato, Alexandre, Mologni, Luca, Bisson, William H., Donadoni, Carla, Gambacorti-Passerini, Carlo, Scapozza, Leonardo, Gueyrard, David, Goekjian, Peter G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-02-2014; Elsevier
• Subjects: Anaplastic lymphoma kinase; Animals; Aza-Graebe–Ullman; Binding Sites; Catalysis; Catalytic Domain; Cell Line; Chemical Sciences; Enzyme Activation - drug effects; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - metabolism; Kinase inhibitors; Mice; Molecular Docking Simulation; Organic chemistry; Palladium; Palladium catalyzed coupling; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - metabolism; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Regioselective cross coupling; Stereoisomerism; Aza-Graebe–Ullman; Palladium catalyzed coupling; Regioselective cross coupling; Kinase inhibitors; Anaplastic lymphoma kinase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.01.007

Novel fused tricyclic heterocycles were prepared as inhibitors of oncogenic fusion proteins of the ALK tyrosine kinase. The best compound was active against wt ALK and the crizotinib-resistant mutant L1196M in vitro and in BaF3 cells.
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.