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Potential Cancer Treatment by Agonists of the Stimulator of Interferon Genes.

Title. Aza-Benzothiophene Compounds as Sting Agonists Patent Application Number. WO 2019/195063 Publication Date. October 10, 2019 Priority Application. US 62/651,968 Priority Date. April 3, 2018 Inventors. (for U.S. only): Altman, M. D., Cash, B. D. Cumming, J. N. Demong, D. E. Haidle, A. M. Jewell, J. P. Larsen, M. A. Lu, M.; Otte, R. D.; Taoka, B. M.; Trotter, B. W.; Truong, Q. T. Assignee Company. Merck Sharp & Dohme Corp., 126 East Lincoln Avenue, Rahway, New Jersey 07065-0907, United States Disease Area. Cancer Biological Target. Stimulator of Interferon Genes (STING) Summary.The invention in this patent application relates to heterocyclic compounds represented generally by formula I. These compounds are stimulator of interferon genes (STING) agonists that activate the STING pathway and may provide a useful treatment for cell proliferation disorders, such as cancer. The human immune system is classified into adaptive and innate types. Both types function to defend and maintain the homeostasis of the body against different types of threats. The adaptive immune system recognizes foreign antigens and then mounts an anti-antigen response through the coordinated actions of many leukocyte subsets. It is a slow-acting system that requires time to generate a full-blown response, but it maintains a memory of theses encountered antigen to provide a longlasting immunity against them. This specific and long-lasting effect is critical to the health and survival of the host. The innate immune system is designed to be fast acting to compensate for the slow-acting adaptive system by acting quickly against different insults or danger signals. While it does not have the adaptive system specificity, it can provide the first line defense against infectious threats such as bacteria, viruses, and parasites. In addition, it responds strongly to certain danger signals associated with cellular or tissue damage. The innate system responds to threats through a variety of mechanisms including opsonization, phagocytosis, activation of the complement system, and production of soluble bioactive molecules such as cytokines or chemokines. The innate system is capable of providing broad protection against multiple threats by sensing and responding to certain damage-associated molecular patterns (DAMPs) or pathogenassociated molecular patterns (P-AMPs) such as free cytosolic DNA and RNA. Recent studies have determined that the enzyme cyclic GMP-AMP synthase (cGAS) is the main sensor that recognizes cytosolic DNA. When cGAS senses cytosolic DNA, it catalyzes the formation of a cyclic-dinucleotide known as 2′3′-cGAMP. This dinucleotide is a second messenger that binds to an endoplasmic reticulum (ER)-transmembrane adaptor protein named stimulator of interferon genes (STING). This binding activates STING, which in turn induces the activation of the critical transcription factors interferon regulatory transcription factor 3 (IRF-3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ΚB). This leads to a strong induction of type I interferons and production of pro-inflammatory cytokines such as interferon gamma (IFNγ), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFα). Type I interferons and pro-inflammatory cytokines can increase the activities of T-cells by enhancing the capabilities of dendritic cells and macrophages to uptake, process, present, and cross-present antigens to T-cells. The enhancement of these antigen-presenting cells is attained by the up-regulation of critical costimulatory molecules, such as CD80 or CD86. Type I interferons can significantly contribute to the activation of adaptive immune cell by rapidly engaging their cognate receptors to trigger the activation of interferon-responsive genes. Type I interferons can directly inhibit the replication of human hepatitis B and C viruses, and they can stimulate the immune responses to virally infected cells. In addition, compounds that can induce the production of type I interferon