ABSTRACT
A time-dependent, divergent synthesis of highly functionalized [1,2,3]triazolo[1,5-a]pyrazin-4(5H)-one (reaction time: 12 h) or 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazin-4(5H)-one (reaction time: 2 h) scaffolds via a cascade azide-alkyne cycloaddition/hydroamination protocol is reported. The transformation features good functional group compatibility, broad substrate scope, high atom economy and avoidance of the use of transition-metal catalysts.
ABSTRACT
Rearranged during transfection (RET) is a promising target for antitumor drug development. Multikinase inhibitors (MKI) have been developed for RET-driven cancers but displayed limited efficacy in disease control. Two selective RET inhibitors were approved by FDA in 2020 and proved potent clinical efficacy. However, the discovery of novel RET inhibitors with high target selectivity and improved safety is still highly desirable. Herein, we reported a class of 3,5-diaryl-1H-pyrazol-based ureas as new RET inhibitors. The representative compounds 17a/b displayed high selectivity to other kinases, and potently inhibited isogenic BaF3-CCDC6-RET cells harboring wild-type, or gatekeeper mutation (V804M). They also displayed moderate potency against BaF3-CCDC6-RET-G810C with solvent-front mutation. Compound 17b showed better pharmacokinetics properties and demonstrated promising oral in vivo antitumor efficacy in a BaF3-CCDC6-RET-V804M xenograft model. It may be utilized as a new lead compound for further development.
Subject(s)
Antineoplastic Agents , Lung Neoplasms , Neoplasms , Humans , Urea/therapeutic use , Proto-Oncogene Proteins c-ret/genetics , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Lung Neoplasms/drug therapyABSTRACT
A base-promoted tandem SNAr/Boulton-Katritzky rearrangement is developed. It offers a simple and straightforward method for the formation of functionalized [1,2,4]triazolo[1,5-a]pyridines from 1,2,4-oxadiazol-3-amines or 3-aminoisoxazoles with 2-fluoropyridines.
