Novel Phosphorylpurinone Compounds for Treating Cancer

Abstract

USA Disease Area. Cancer Biological Target. TLR7 Summary. Although immune checkpoint inhibitors have change the treatment landscape of many tumors, durable responses are limited. Immunological treatment of cold tumors is a great challenge, as no adaptive immune response has been set up or maintained. Cold tumors can, however, contain a substantial number of myeloid cells, including macrophages, different subsets of dendritic cells, and myeloid-derived suppressor cells.Toll-like receptors (TLRs) detect highly conserved, pathogenic danger signals, resulting in a strong inflammatory response. TLRs detect a wide range of conserved pathogen-associated molecular patterns (PAMPs). There are 10 known members of the TLT family in humans. Within this family, TLR3, TLR7, TLR8, and TLR9 are located within endosomes. Systemic administration of TLR agonists leads to strong systemic activation of different immune cells, and eventually immune cells within the tumor microenvironment are activated to achieve an antitumor effect.The present application describes a series of novel phosphorylpurinone compounds as TLR7 inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.Definitions. R 1 = C 1−6 alkyl; R 2 = C 1−6 alkyl; and R 3 = pyridinyl substituted by ((C 1−6 alkyl) 2 amino)C 1−6 alkoxy, ((C 1−6 alkyl) 2 amino)C 1−6 alkylamino, ((C 1−6 alkyl) 2 amino)-C 1−6 alkylpyrrolidinyl, (C 1−6 alkyl) 2 piperazinyl, (C 1−6 alkylamino) C 1−6 alkylamino, (C 1−6 alkylpyrrolidinyl)amino, 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrolyl, 2,5-diazabicyclo[2.2.2]octanyl, aminopyrrolidinyl, C 1−6 alkyl-1-oxa-4,9-diazaspiro[5.