Design and synthesis of dihydroindazolo(5,4-a)pyrrolo(3,4-c)carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases.

摘要

Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.