Compounds and compositions for treating conditions associated with APJ receptor activity

Inventors

Tang, Haifeng • Hanson, Michael • Boyce, Sarah • Nie, Zhe

Assignees

Structure Therapeutics Inc • Schroedinger LLC • Annapurna Bio Inc

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor, gene symbol APLNR). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and/or symptoms and/or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular non-limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.

Core Innovation

The disclosure provides substituted imidazo[4,5-b]pyrazine derivatives and related fused heteroaryl compounds with 2,6-dimethoxyphenyl and 6-ethoxypyridin-2-yl substituents, together with sulfonamide, methanesulfonamide, and related sulfonamide groups. The compounds are presented as specific named structures and analogs, including heteroaryl, cycloalkyl, and stereochemically defined variants, and include pharmaceutically acceptable salts.

The compounds also include APJ receptor (APLNR) agonist, partial agonist and ligand-biased chemical entities, and the disclosure characterizes pharmacological behavior in terms of full agonism versus partial agonism and G-protein signaling versus β-arrestin recruitment. The disclosed chemistry is also described as preparation and characterization of substituted imidazo[4,5-b]pyrazine derivatives, with LC-MS and 1H NMR data reported for examples and intermediates.

The disclosure further presents structural definitions for Formula (I) analogs and related sub-formulas, including variable substituents, linker options, and allowed sulfonamide-linked substituents. The described embodiments encompass multiple enumerated compound families, including imidazo[4,5-b]pyrazine and related heteroaromatic scaffolds, as well as pharmaceutical salt forms.

Claims Coverage

The consolidated independent-claim coverage centers on structurally defined compounds and pharmaceutically acceptable salts, with several excerpts also directed to pharmaceutical compositions comprising the claimed compound or salt and pharmaceutically acceptable excipients. Across the provided items, the inventive features repeatedly focus on the substituted imidazo[4,5-b]pyrazine scaffold, enumerated sulfonamide variants, and composition claims.

The claim coverage in the supplied items is dominated by two recurring themes: specific substituted imidazo[4,5-b]pyrazine sulfonamide compounds with pharmaceutically acceptable salts, and pharmaceutical compositions containing those compounds with pharmaceutically acceptable excipients. A separate claim family covers APJ receptor-modulating compounds defined by Formula (I) and related structural variants.

Stated Advantages

Documented Applications