Balancing Properties with Carboxylates: A Lead Optimization Campaign for Selective and Orally Active CDK9 Inhibitors

Abstract

Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as 14 and 16. These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.

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

“…While this project was ongoing, other groups disclosed the discovery of azaindoles bearing a substituted 2-methoxyphenyl at C-4 . We decided to look for alternative groups at the C-4 position (Table ).…”

“…Chloro­(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)­[2-(2′-amino-1,1′-biphenyl)]­palladium­(II) (0.337 g, 0.430 mmol) and cesium carbonate (2.93 g, 9.00 mmol) were added to a reaction mixture containing (4-fluoro-2-methoxyphenyl)­boronic acid (0.984 g, 5.79 mmol), tert -butyl (4-(4-chloro-1 H -pyrrolo­[2,3- b ]­pyridin-2-yl)­cyclohexyl)­carbamate ( 48 , 1.5 g, 4.3 mmol), dioxane (35 mL), and water (7.2 mL) that had been degassed with nitrogen. The mixture was immersed in an oil bath that had been preheated to 85 °C.…”

“…Regioselective Suzuki coupling of previously described azaindole 44 with boronic ester 45 , followed by another Suzuki coupling with 2-methoxy-4-fluorophenylboronic acid afforded compound 7 after 2-trimethylsilylethyoxymethyl (SEM) protection with trifluoroacetic acid (TFA). Compound 8 (previously described in refs , ) was obtained from previously described intermediate 46 after hydrogenation and amine deprotection. Compound 9 was obtained from Suzuki coupling of previously described intermediate 47 with boronic ester 42 , followed by amine deprotection.…”

“…Compounds 10 and 11 were made according to Scheme . Previously described compound 48 was subjected to Suzuki coupling with 2-methoxy-4-fluorophenylboronic acid. Separation of trans ( 49 ) and the cis diastereoisomers, followed by an amine deprotection/acetylation sequence, afforded compound 10 .…”

“…Compounds 13 , 15 , 16 , and 18 and compounds 14 , 17 , and 19 were, respectively, made from compounds 8 and 9 via standard derivatization of the piperidine group (Scheme ).…”