BCKDK inhibitors and/or degraders
Inventors
Buzon, Leanne Marie • Cameron, Kimberly O'Keefe • DEBOYACE, Kevin Francis • Filipski, Kevin James • Griffith, David Andrew • Kormos, Bethany Lyn • Liu, Shenping • MARTINEZ ALSINA, Luis Angel • Reese, Matthew Richard • Roth Flach, Rachel Jane • Zhang, Yuan
Assignees
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Publication Number
US-12466803-B2
Publication Date
2025-11-11
Expiration Date
Abstract
Described herein are compounds of Formula I, wherein the variables are defined herein, their use as branched-chain alpha keto acid dehydrogenase kinase inhibitors and/or degraders, pharmaceutical compositions containing such compounds and their use to treat, for example, diabetes, kidney disease, NASH and heart failure.
Core Innovation
The patent describes substituted benzothiophene-2-carboxylic acid derivatives according to a Formula I compound in which Z is S and R2 is fluoro. The scaffold includes a carboxylic acid group and multiple substituent options at R1, R3, R4, R5, R6, R7, R8, R9, R10, and R11, with at least one of R5, R6, R7, R10, and R11 being other than H, or the compound being a pharmaceutically acceptable salt.
The document provides specific example embodiments, including fluorinated benzothiophene-2-carboxylic acid derivatives, benzofuran analogs, enantiomeric forms labeled ENANT-1 and ENANT-2, and additional named benzothiophene-2-carboxylic acid derivatives. The examples include characterization data such as 1H NMR and LCMS m/z values, with noted solvent conditions, sodium adducts, chlorine isotope patterns, and analytical characterization for multiple examples and intermediates.
The document also includes claims and description relating to solid-state forms, including crystalline compounds defined by X-ray powder diffractogram peak positions and alternative amorphous forms. It identifies specific atropisomeric embodiments, including ATROP-1 and ATROP-2, and in a separate portion of the record the compounds are associated with BCKDK-directed activity, pharmaceutical compositions, prodrugs, and therapeutic use in fatty liver disease and related human conditions.
Claims Coverage
The consolidated claim coverage includes independent features centered on a Formula I compound family of substituted benzothiophene-2-carboxylic acid derivatives, with Z = S, fluoro at R2, and a requirement that at least one of R5, R6, R7, R10, and R11 is other than H, together with pharmaceutically acceptable salts. The claim set also includes solid-state definitions for crystalline and amorphous forms, and pharmaceutical composition coverage.
Formula I benzothiophene-2-carboxylic acid derivatives with Z is S and R2 fluoro
A compound of Formula I wherein Z is S, R2 is fluoro, each of R1, R3, and R4 is independently selected from H, each of R5, R6, R7, R8, R9, and R11 is independently selected from H, halo, hydroxyl, amino, cyano, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, (C1-C4) fluoroalkyl, (C3-C6) fluorocycloalkyl, (C1-C4) fluoroalkoxy, or (C1-C4) alkyl-(C1-C4) alkoxy, and R10 is H, fluoro, chloro, cyano, or (C1-C4) alkyl, wherein at least one of R5, R6, R7, R10, and R11 is other than H, or a pharmaceutically acceptable salt thereof.
Crystalline form defined by XRPD diffraction peaks
A compound, or a pharmaceutically acceptable salt thereof, in crystalline form defined by specified X-ray powder diffractogram diffraction peak positions.
Amorphous form of the compound
A specified compound, or a pharmaceutically acceptable salt thereof, in amorphous form.
Pharmaceutical composition with a therapeutically effective amount
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to the Formula I claim, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, vehicle, or diluent.
The claims focus on Formula I substituted benzothiophene-2-carboxylic acid compounds with Z = S and fluoro at R2, together with salt coverage and a requirement that at least one of R5, R6, R7, R10, and R11 is other than H. The consolidated coverage also includes crystalline and amorphous solid-state forms and a pharmaceutical composition claim.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating fatty liver disease and related conditions in a human, including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and hepatocellular carcinoma.
A pharmaceutical composition containing a therapeutically effective amount of a compound of claim 1 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, vehicle, or diluent.
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