Substituted-3H-imidazo [4,5-c] pyridine and 1H-pyrrolo[2,3-c]pyridine series of novel ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) and stimulator for interferon genes (STING) modulators as cancer immunotherapeutics

Inventors

Vankayalapati, Hariprasad • Liu, Xiaohui • Ramamoorthy, Gurusankar • Sharma, Sunil • Kaadige, Mohan Rao • Weston, Alexis • Thode, Trason

Assignees

University of Utah • Stingray Therapeutics Inc

Abstract

Substituted-3H-imidazo[4,5-c]pyridine and 1H-pyrrolo[2,3-c]pyridine series of novel Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) and related compounds, which are useful as inhibitors of ENPP1; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds and compositions to treat disorders associated with dysfunction of the ENPP1.

Core Innovation

The disclosed subject matter concerns a class of heteroaryl thio/amide analogs featuring an imidazo[4,5-c]pyridine scaffold, including cyclized imidazo[4,5-c]pyridine-2-thiols, S-alkylation to form acetamide derivatives, and related benzo[d]thiazole-acetamide analogs. The shared heteroaromatic core is linked via a thioether to an amide-bearing substituted phenyl group, with structural variants retaining this core linkage while varying substituents on the phenyl group.

The disclosed structures include substituted imidazo[4,5-c]pyridine/1H-pyrrolo[2,3-c]pyridine compounds of Formula I and pharmaceutically acceptable salts thereof as ENPP1 inhibitors. The series includes compounds defined as chemical structures and as pharmaceutically acceptable salts, with additional variants including isotopically labeled versions, prodrugs, solvates and hydrates, and tautomeric and polymorphic forms.

The document further describes diversity in the aryl portion and in the imidazo scaffold, including substituents such as methoxy, fluoro, hydroxy, trifluoromethoxy, methyl, cyano, fluorine, and difluoro/trifluoro-like motifs. The disclosed compounds are positioned to inhibit ENPP1 activity and to address ENPP1 dysfunction disorders, with therapeutic and immunotherapeutic use associated with cyclic dinucleotide pathways, STING-dependent responses, and interferon genes/IFN-β.

Claims Coverage

The provided claim sets center on structurally defined compounds, or pharmaceutically acceptable salts thereof, and include pharmaceutical compositions and therapeutic administration methods. Four inventive feature categories are present across the consolidated items: the defined compound, the pharmaceutical composition, treatment of disorders characterized by uncontrolled cellular proliferation, and treatment of cancer in a mammal.

Overall, the claims cover compounds defined by the specified structure, including pharmaceutically acceptable salts, and extend to pharmaceutical compositions containing a therapeutically effective amount with a pharmaceutically acceptable carrier. The claim set also covers therapeutic methods administering an effective amount for disorders of uncontrolled cellular proliferation and for cancer in a mammal; one set specifically identifies Formula I ENPP1 inhibitor compounds.

Stated Advantages

Documented Applications