Synthesis of BI 1584142 and BI 1810631 (Zongertinib), Two Potent HER2 Inhibitors, Labeled With Carbon‐14 and With Deuterium

ABSTRACT BI 1584142 (1) and BI 1810631 (2, zongertinib) are potent and selective HER2 tyrosine kinase inhibitors being developed for the treatment of non–small cell lung cancer. Carbon‐14–labeled versions of these drug candidates were needed to study their absorption, distribution, metabolism, and excretion in animals and in humans. BI 1584142 and BI 1810631 differ in two moieties; the former contains a piperazine and the latter a 4‐aminopiperidine. Therefore, a common carbon‐14–labeled intermediate like the sulfoxide [ 14 C]‐8 was prepared in four radioactive steps and used to provide [ 14 C]‐1 and [ 14 C]‐2 in two and three extra steps, respectively. Deuterium‐labeled 1 and 2 were also synthesized as internal standards, using piperazine‐ d 8 and 4‐aminopiperidine‐ d 9 for bioanalytical studies and other studies.