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 relates to imidazo[4,5-b]pyrazine-based sulfonamide compounds bearing a 2,6-dimethoxyphenyl group and a 6-ethoxypyridin-2-yl substituent. The compounds include methanesulfonamide and related sulfonamide variants, with multiple N-substituted sulfonamide groups, heteroaryl variants, and cyclic sulfonamide groups described in the examples and structural definitions.

The document provides detailed substituent definitions for Formula (I) and related sub-formulas, including variable groups such as R1, R2, R3, R4, L4, A1, X1-X4, and Rc′, together with allowable aryl, heteroaryl, alkoxy, haloalkoxy, halo, OH, NO2, carbonyl-containing groups, NH2, sulfonamide-linked motifs, heteroatom-containing linkers, and stereochemical variants. The provided content is predominantly structural definition content and includes representative compound structures and pharmaceutically acceptable salts.

The compounds are described in methods for treating fibrosis, including fibrosis associated with lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joint, and a reproductive organ, and in a specific embodiment idiopathic pulmonary fibrosis (IPF). The claims and examples center on administering an effective amount of the selected imidazo[4,5-b]pyrazine sulfonamide compound or a pharmaceutically acceptable salt thereof.

Claims Coverage

The provided claim set includes two independent method-of-treatment themes: broad fibrosis treatment associated with specified organs or tissues, and treatment of idiopathic pulmonary fibrosis (IPF). Across the independent claims, the inventive features revolve around administering an effective amount of a selected imidazo[4,5-b]pyrazine sulfonamide compound, including methanesulfonamide and related sulfonamide variants, or a pharmaceutically acceptable salt thereof.

The independent claims cover methods of treating fibrosis, including IPF, by administering an effective amount of enumerated imidazo[4,5-b]pyrazine sulfonamide compounds with a shared 2,6-dimethoxyphenyl and 6-ethoxypyridin-2-yl core, together with methanesulfonamide and related sulfonamide N-substituent variants.

Stated Advantages

Documented Applications