Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

The development of a regio- and stereoselective deoxyfluorination process for the manufacture of belzutifan (MK-6482) was challenging because of a combination of particular reaction and engineering sensitivities. These aspects were addressed through a series of mechanistic, range-finding, and mixing studies that enabled a robust process to be established. In particular, mixing studies led to the discovery of a second phase of perfluoro-1-butanesulfonyl fluoride in the reaction at cryogenic temperature, requiring the liquid–liquid dispersion to be controlled sufficiently to minimize the formation of side products. The changes implemented as a result of these investigations culminated in a process executed successfully on the pilot and commercial scales.

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The mechanism of the aza-Diels−Alder reaction catalyzed by tetraalkylammonium or trialkylsulfonium salts is explored with density functional theory. Favorable electrostatic interactions between the dienophile and the charged catalyst stabilize the highly polar transition state, leading to lower free energy barriers and higher dipole moments. Endo selectivity is predicted for both uncatalyzed and catalyzed systems. We also computationally evaluate the effects of oriented external electric fields (EEFs) on the same aza-Diels−Alder reaction, demonstrating that very strong EEFs would be needed to achieve the catalytic strength of these cationic catalysts.

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