Discovery of a Series of 7‑Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement

Optimization
of a series of azabenzimidazoles identified from screening
hit 2 and the information gained from a co-crystal structure
of the azabenzimidazole-based lead 6 bound to CDK9 led
to the discovery of azaindoles as highly potent and selective CDK9
inhibitors. With the goal of discovering a highly selective and potent
CDK9 inhibitor administrated intravenously that would enable transient
target engagement of CDK9 for the treatment of hematological malignancies,
further optimization focusing on physicochemical and pharmacokinetic
properties led to azaindoles 38 and 39.
These compounds are highly potent and selective CDK9 inhibitors having
short half-lives in rodents, suitable physical properties for intravenous
administration, and the potential to achieve profound but transient
inhibition of CDK9 in vivo.