Modulators of cystic fibrosis transmembrane conductance regulator
Inventors
McCartney, Jason • Abela, Alexander Russell • Abraham, Sunny • Anderson, Corey Don • Arumugam, Vijayalaksmi • Chau, Jaclyn • Clemens, Jeremy • Cleveland, Thomas • DWIGHT, Timothy A. • Frieman, Bryan A. • Grootenhuis, Peter • Hadida Ruah, Sara Sabina • Ishihara, Yoshihiro • Krenitsky, Paul • Miller, Mark Thomas • Pierre, Fabrice • Silina, Alina • Zhou, Jinglan
Assignees
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Publication Number
US-12612416-B2
Publication Date
2026-04-28
Expiration Date
Abstract
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, combination therapies, and processes and intermediates for making such modulators.
Core Innovation
The disclosure provides a broad genus of sulfonamide-linked heteroaryl Formula I compounds, tautomers thereof, deuterated derivatives, and pharmaceutically acceptable salts. The claimed compounds define Ring A and Ring B selected from aryl, cycloalkyl, heterocyclyl, and heteroaryl groups, alongside defined structural options for Ring C, variable positions, and linkers. The compounds are identified as CFTR correctors for use in pharmaceutical compositions, encompassing cyclic sulfonamides and spiro-substituted fused thia-tetrazatricyclic sulfone derivatives.
The description characterizes specific Formula I analogues, analytical characterization, intermediate synthesis, and evaluation of CFTR-modulating activity [procedural detail omitted for safety]. Assessments report CFTR modulation in human bronchial epithelial cells, F508del-expressing NIH 3T3 cells, and human intestinal enteroids alone or in combination with CFTR potentiators such as ivacaftor. Explicit statements of the problem addressed are not included in the provided patent content.
Claims Coverage
The claim text identifies one independent claim directed to the Formula I compound genus and specified related forms, defined across two inventive features.
Formula I compound genus and related forms
Claim 1 covers a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
Defined structural and substituent choices
The claim defines Ring A and Ring B selected from aryl, cycloalkyl, heterocyclyl, and heteroaryl groups, alongside specified structural choices for Ring C, variable positions V, W1, W2, X, Y, and Z, linkers, and permitted substituent groups.
The independent claim defines the Formula I compound genus, tautomers, deuterated derivatives, and pharmaceutically acceptable salts, with dependent claims covering narrower subgenera, pharmaceutical compositions, and methods of treating cystic fibrosis.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of cystic fibrosis using a Formula I compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof.
Combination treatment of cystic fibrosis by administering a claimed compound or related form in combination with a CFTR potentiator compound, such as ivacaftor, and a CFTR corrector compound.
Pharmaceutical compositions comprising a claimed compound or related form and a pharmaceutically acceptable carrier, including compositions comprising additional therapeutic agents such as tezacaftor, ivacaftor, deutivacaftor, or lumacaftor.
Evaluation of CFTR corrector and CFTR-modulating activity using membrane-potential assays or short-circuit current measurements in human bronchial epithelial cells, F508del-expressing NIH 3T3 cells, and human intestinal enteroids.
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