Cyclic di-nucleotide compounds and methods of use

Inventors

Zhong, Boyu • Shi, Heping • DAI, Yuanwei • Wei, Qi • Chen, Chuo • Chen, Zhijian • Sun, Lijun

Assignees

University of Texas System • Immunesensor Therapeutics Inc

Abstract

Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.

Core Innovation

The invention relates to cGAMP analogs of Formula I and Formula Ic, including phosphodiester-containing bicyclic sugar core structures and cyclic di-nucleotide compounds that activate STING (Stimulator of Interferon Genes). The compounds are characterized by defined ring atom identities at Z12, Z13, Z14, Z15, Z16, and Z17 and by variable substituent sets including R3, R4, R7, R8, R9, and R10, with examples spanning phosphoramidate/phosphate, phosphonate/phosphorothioate, and related linker or protecting-group variants.

In Formula Ic, Z12 and Z15 are N, while Z13, Z14, Z16, and Z17 are independently CH or N, or in some embodiments Z13 and Z16 are CH with Z14 and Z17 independently CH or N. R3 is defined as alkyl functionalized with one or more selected groups including halogen, thiol, hydroxyl, carboxyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, or azido, and R4 is hydroxyl. R9 and R10 are independently hydroxyl, thiol, C1-6 alkyl, functionalized C1-6 alkyl or alkoxy, C3-5 alkenyl-O, C3-5 alkynyl-O, oligo(ethylene glycol), poly(ethylene glycol), borano, or NR7R8, with additional definitions for R7 and R8.

The disclosed embodiments further include pharmaceutically acceptable salts, optional oxygen-to-sulfur or selenium substitutions, and structural variants that are presented as example compounds and stereoisomeric forms. Therapeutic context is described through pharmaceutical compositions, immunogenic compositions comprising an antigen or immunogen together with the compound, and combination therapy with immune checkpoint inhibitors, radiation including SBRT, and chemotherapeutic agents, with stated use in diseases including cancer and immune disorders such as autoimmune and autoinflammatory conditions.

Claims Coverage

The independent claims cover compounds of Formula Ic with defined Z atom patterns and selected substituents, including pharmaceutically acceptable salts. Across the independent claims, the inventive features center on the Z12/Z15 assignments, the allowed CH/N patterns at Z13/Z14/Z16/Z17, and the permitted substituent definitions for R3, R4, R9, and R10, with some claims also defining R7 and R8.

Overall, the claim coverage is directed to Formula Ic compounds with fixed Z12 and Z15 as N, claim-specific CH/N assignments at the remaining Z positions, and defined functionalization of R3, R4, R9, and R10. The independent claims differ mainly in the breadth of allowable substituents, while all include pharmaceutically acceptable salt forms.

Stated Advantages

Documented Applications