BACKGROUND OF THE INVENTION

As researchers continue to explore immune checkpoints as targets for anticancer and other treatment therapies, the indoleamine 2,3-dioxygenase (IDO) pathway has emerged as a contender to yield the next batch of new drugs in the field. The IDO protein, or indoleamine 2,3-dioxygenase, has been identified as a checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. The enzyme has two isoforms, IDO1 and IDO2, which act as the first step in the metabolic pathway that breaks down the essential amino acid tryptophan. Tryptophan 2,3-dioxygenase (TDO) is a biologically significant enzyme that catalyzes the first and committing step of L-Trp degradation in the kynurenine pathway. The kynurenine pathway constitutes the major route of de novo biosynthesis of nicotinamide adenine dinucleotide (NAD), which is one of the essential redox cofactors in all living systems. Excessive accumulation of many of the intermediate metabolites of this pathway can lead to numerous physiological and pathological conditions, including cataract formation, cerebral malaria, Alzheimer's disease, HIV infection, Huntington's disease, depression, and ischemic brain injury. Both IDO and TDO triggered by the immune challenge can catalzye L-tryptophan to kynurenine and then start the kynurenine pathway.

Thus, there remains a need to provide new inhibitors of IDO and/or TDO to treat IDO- and TDO-mediated disease, including chemo-resistant cancer and diseases of the brain.

BRIEF SUMMARY OF THE INVENTION

The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:


in which W1, W2, W3, and W4, X, Y, Z1, Z2, and R1-7are described herein. It is envisioned that a compound of formula (I) is desirable for treating diseases associated with the enzymes IDO and/or TDO, such as cancer, due at least in part, because of the compound's ability to inhibit one or preferably both of these enzymes

Thus, the invention further provides a method of treating an IDO- and/or TDO-mediated disease in a subject, such as cancer, a neurological and/or brain disorder, an eye disorder, or HIV infection. The method comprises administering to a subject in need of such treatment a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Also provided is a method of inhibiting an IDO and/or TDO enzyme in a cell comprising contacting an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a cell in need of such inhibition.

