Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors

The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor.

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► Synthesis of pyrazolo-quinazolines as MPS1 kinase inhibitors.
► High selectivity towards other kinases achieved.
► Antiproliferative activity in A2780 tumor cell line obtained.
► NMS-715 showed good oral bioavailability.
► Efficacy in A2780 xenograft mouse model demonstrated.