Process Development toward DHODH Inhibitor JNJ-6665.

JNJ-6665 is a dihydroorotate dehydrogenase (DHODH) inhibitor progressed for first-in-human studies. We developed a convergent, chromatography-free manufacturing route leveraging a regioselective SNAr coupling of triazolone 5 and isoquinolone 10. Triazolone 5 was prepared through a safe three-step telescoped process using catalytic TBD to deliver very high purity material in 83% overall yield. Isoquinolone 10 was accessed via an elegant Pd-catalyzed α-arylation, followed by a telescoped hydrolysis/amination. Coupling of 5 and 10 was performed using a phase-transfer catalyst, affording JNJ-6665 in 91-92% isolated yield and 99.2-99.6 area% purity after final debenzylation, enabling robust GMP campaigns to support GLP toxicology and FIH clinical studies.