Synthesis and fungicidal activity of tubulin polymerisation promoters, Part 1: pyrido[2,3-b]pyrazines

BACKGROUND: The excellent fungicidal activity of [1,2,4]triazolo[1,5-a]pyrimidines suggested the search for further analogues with improved properties. RESULTS: A series of novel trisubstituted pyrido[2,3-b]pyrazines has been designed and prepared as 6,6-biheterocyclic analogues of related 5,6-bicyclic [1,2,4]triazolo[1,5-a]pyrimidines. Their fungicidal activity was evaluated against the plant pathogens Puccinia recondita Rob. ex Desm. f. sp. tritici (Eriks.) CO Johnston (wheat brown rust), Mycosphaerella graminicola (Fuckel) Schroter (Septoria tritici Rob., leaf spot of wheat) and Magnaporthe grisea (Hebert) Barr (Pyricularia oryzae Cav., rice blast). Structure-activity relationship studies revealed the advantage of a fluoro substituent in position 6 and of a secondary amine in position 8. CONCLUSION: 8-Amino-7-aryl-6-halogen-substituted pyrido[2,3-b]pyrazines have been prepared as 6,6-biheterocyclic analogues of similarly substituted triazolopyrimidine fungicides. A concise four-step synthesis route has been worked out to prepare these novel compounds from commercially available starting materials. [(R)-(1,2-Dimethylpropyl)]-[6-fluoro-7-(2,4,6-trifluorophenyl)pyrido[2,3-b]pyrazin-8-yl]amine showed excellent activity against three economically important phytopathogens. (C) 2009 Society of Chemical Industry