Modulators of cystic fibrosis transmembrane conductance regulator
Inventors
Clemens, Jeremy J. • Bechara, William Schulz • Bookser, Brett C. • Cleveland, Thomas • Coon, Timothy R. • Gallant, Michel • Grootenhuis, Peter • Hadida Ruah, Sara Sabina • Laterreur, Julie • Miller, Mark Thomas • Paraselli, Prasuna • Ramtohul, Yeeman K. • Reddy, Thumkunta Jagadeeswar • Sturino, Claudio • Valdez, Lino • Zhou, Jinglan • Baek, Minson
Assignees
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Publication Number
US-12324802-B2
Publication Date
2025-06-10
Expiration Date
Abstract
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.
Core Innovation
The invention relates to compounds of Formula I and deuterated derivatives thereof, or pharmaceutically acceptable salts of the foregoing, with extensive structural selection rules for X, Ring A, Ring B, Ring C, Z, and multiple substituent variables. Ring A and Ring B are selected from defined heterocyclyl, heteroaryl, cycloalkyl, aryl, and related classes, with additional substitution patterns and integer parameters n and m. The disclosed scope also includes selected compounds from specified tables or lists, preserving inclusion of deuterated derivatives and salts.
The disclosure further includes a process for preparing a compound of Formula 7-7 by converting a compound of Formula 7-6 into a compound of Formula 7-7. The process is constrained by defined selections for R, RX1, RX2, Y, Y1, RYN, RY, RY1, Ring B, Q, R1, R2, m, a, and b, and specifies that PG1 or PG is selected from suitable oxygen protecting groups. The claimed subject matter therefore combines compound-definition coverage with a defined conversion process between formula-defined intermediates.
The document also includes pharmaceutical composition and treatment embodiments for CFTR-mediated disease, including cystic fibrosis, using the disclosed compounds, deuterated derivatives, or pharmaceutically acceptable salts. In addition, the disclosure describes stereochemical variants and solid-form refinements, including crystalline and amorphous forms, polymorph and solvate characterization, and analytical descriptions supporting preparation and characterization of fluorinated, polycyclic, heterocycle-containing, bicyclic, tetraazatetracyclic, spiro-tetrazatricyclic, and oxadiazole-containing compounds within the disclosed scope.
Claims Coverage
The consolidated claim coverage centers on multiple independent claim families: a broad Formula I compound claim, a claim selecting compounds from a specified list or table, a process claim converting Formula 7-6 into Formula 7-7, and a separate formula-defined compound claim, with dependent coverage for pharmaceutical compositions and cystic fibrosis treatment. Across these families, the core inventive features are the constrained chemical scaffolds, inclusion of deuterated derivatives and pharmaceutically acceptable salts, the table-based compound selection, and the defined formula-to-formula conversion process.
Formula I compound with deuterated derivative and pharmaceutically acceptable salt
A compound of Formula I and a deuterated derivative thereof, or a pharmaceutically acceptable salt of the foregoing, with X, Ring A, Ring B, Ring C or Z, and substituent variables defined by extensive selection rules, and with integer parameters n and m selected from the stated sets.
Selected compounds from a specified list or table
A compound selected from a specified list or table of compound numbers or structures, including a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.
Conversion of Formula 7-6 into Formula 7-7
A process for preparing a compound of Formula 7-7 by converting a compound of Formula 7-6 into a compound of Formula 7-7, with constrained selections for R, RX1, RX2, Y, Y1, RYN, RY, RY1, Ring B, Q, R1, R2, m, a, b, and PG1 or PG.
Pharmaceutical composition and cystic fibrosis treatment
A pharmaceutical composition including a specified compound, deuterated derivative, or pharmaceutically acceptable salt with a pharmaceutically acceptable carrier, and a method for treating cystic fibrosis by administering an effective amount, optionally with one or more additional therapeutic agents.
Overall, the claim coverage is directed to structurally defined compounds and selected listed compounds, all extending to deuterated derivatives and pharmaceutically acceptable salts, together with a constrained preparation process for Formula 7-7 and dependent pharmaceutical composition and cystic fibrosis treatment coverage.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of cystic fibrosis by administering an effective amount of the specified compound, deuterated derivative, or pharmaceutically acceptable salt, optionally with one or more additional therapeutic agents.
Pharmaceutical composition including the specified compound with a pharmaceutically acceptable carrier.
Solid-state characterization of crystalline and amorphous forms using XRPD, TGA, DSC, and single-crystal X-ray diffraction.
Separation and characterization of stereoisomeric forms using chiral SFC.
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