Synthesis of the Substituted 7-Azaindazole Core of TEAD Inhibitor GDC-8025 via Gould–Jacobs Cyclization and Halogen Dance Routes

Abstract Herein we report our efforts to identify a convergent and efficient route to the highly substituted 7-azaindazole core of GDC-8025, a potent pan-TEAD inhibitor. We investigated two orthogonal routes to access the requisite 4-iodo-1-aryl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile intermediate. The first of these featured a one-flask halogen dance rearrangement/acylation to enable construction of the pyrazole ring around a pyridine starting material. The second route relied on elaboration of a highly substituted aminopyrazole to a Meldrum’s acid derivative, which then engaged in a Gould–Jacobs cyclization to form the pyridine ring. Both routes were found to be effective and efficient means of accessing the target GDC-8025 precursor in 6 steps from economical starting materials.