Compounds, compositions, and methods for the treatment of disease
Inventors
Iyer, Radhakrishnan P. • Meher, Geeta • Challa, Sreerupa • Zhou, Shenghua
Assignees
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Publication Number
US-12291548-B2
Publication Date
2025-05-06
Expiration Date
Abstract
Disclosed are compounds and compositions for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.
Core Innovation
The invention concerns Formula (I) small-molecule compounds, including pharmaceutically acceptable salts, stereoisomers, and compounds selected from a defined group of numbered structures with a pharmaceutically acceptable cation. The disclosed compounds include stereodefined nucleoside-like scaffolds with fluorinated carbohydrate-like rings, a fused bicyclic sugar system, natural purinyl and/or natural pyrimidinyl nucleobase moieties, and phosphorothioate/phosphate motifs or organophosphonate/phosphate-like functionality.
The Formula (I) framework defines variable heteroatom assignments in the phosphorus-linked portion, including Z as S or O, X1 and X2 as independently O or S, and Y1 and Y2 as independently O, S, or NR5. The compounds also include variable linker presence and linkage types through L1 and L2, together with substituent variability at R1 through R9, including aryl and heteroaryl substituent patterns and optional substitution on alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
The compounds are described as activating innate immune pattern recognition receptors, including STING and RIG-I/MDA5, and as inducing PRR expression and downstream interferon and NF-kB signaling. The disclosure also links the compounds to cancer treatment, microbial infections, vaccine formulations, and vaccine adjuvants.
Claims Coverage
The consolidated claim coverage centers on Formula (I) compounds with multiple structural-variable definitions and includes a therapeutic-use claim for improving cancer symptoms, together with a claim selecting listed compound numbers with pharmaceutically acceptable cations or salts. The covered inventive features are the shared Formula (I) scaffold, the defined substitution patterns, the phosphorothioate/phosphate-related linkage features, and the therapeutic method.
Formula (I) scaffold with defined structural variables
A compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer, with Z either S or O; B1 and B2 selected from natural purinyl and natural pyrimidinyl nucleobases in the allowed combinations; X1 and X2 independently O or S; Y1 and Y2 independently O, S, or NR5.
Linkage substituents L1 and L2 constraints
L1 is absent, C1-C6 alkyl, or C1-C6 heteroalkyl and L2 is C1-C6 alkyl or C1-C6 heteroalkyl, each optionally substituted with R6, or L1 is C1-C6 alkyl or C1-C6 heteroalkyl and L2 is absent, C1-C6 alkyl, or C1-C6 heteroalkyl, each optionally substituted with R6.
Core substitution pattern R1-R9 with optional substitution
R1 and R2 are independently hydrogen, halo, CN, C1-C20 alkyl, or OR7; R3 and R4 are independently hydrogen, C1-C20 alkyl, C1-C20 heteroalkyl, OC(O)C1-C20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more R8; R5 is hydrogen or C1-C20 alkyl; R6 is halo, CN, C1-C20 alkyl, OR7, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more R9; R7 is hydrogen, C1-C20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more R9; and R8 and R9 are defined with the allowed substituent categories and optional substitution rules.
Phosphorothioate and thiophosphate linkage features
The Formula (I) structures include nucleoside-like fluorinated sugar rings and paired phosphate/phosphorothioate linkages, with aryl substituents bearing S/P(O)(OH)-type phosphorus/sulfur functionalities as described in the input.
Therapeutic method for improving cancer symptoms
A method for improving at least one cancer symptom in a subject by administering a therapeutically effective amount of a compound of Formula (I) as defined in the claims.
Selected compound group with pharmaceutically acceptable cation salts
A compound selected from a group consisting of listed Compound No. structures, wherein X+ is a pharmaceutically acceptable cation, or a pharmaceutically acceptable salt thereof.
The claims are directed to Formula (I) compounds defined by multiple structural-choice variables, including nucleobases, heteroatom positions, linkage substituents, and broad substituent classes, with additional coverage for specific Compound No. selections. The claim set also includes a therapeutic-use method directed to improving at least one cancer symptom by administering a therapeutically effective amount of the claimed compound.
Stated Advantages
STING agonists show therapeutic effects in cryo-ablation models.
STING or STING-pathway defects reduce spontaneous tumor T-cell priming and tumor rejection in mouse models.
Failed STING activation can be associated with prognostic or predictive biomarker potential.
Increased PRR expression and IFN/ISG/cytokine production are connected to enhanced cross-priming and anti-tumor activity.
Documented Applications
Treating cancer, including improving at least one cancer symptom in a subject by administering a therapeutically effective amount of a Formula (I) compound.
Treating microbial infections, including viral, bacterial, fungal, and parasitic microbial infections.
Vaccine formulations and vaccine adjuvants containing the Formula (I) compounds.
Therapeutic effects in cryo-ablation models.
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