Compounds for the activation of AMPK
Inventors
Aspnes, Gary Erik • BUTLER, Christopher Ryan • CALABRESE, MATTHEW FRANK PAUL • Cameron, Kimberly O'Keefe • CURTO, JOHN MARION • Green, Michael Eric • Hou, Xinjun • Liu, Shenping • McClendon, Christopher Lee • Murray, John Charles • PANCHAGNULA, ADVAITA • ROSE, Colin Richard • TARANTINO, KYLE THOMAS • Tu, Meihua Mike • Unwalla, Rayomand Jal • Warmus, Joseph Scott • Xiao, Jun • YANG, Qingyi • Zhang, Lei
Assignees
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Publication Number
US-12637461-B2
Publication Date
2026-05-26
Expiration Date
Abstract
Described herein are compounds of Formula I,wherein the variables are defined herein, their use as activators from AMPK, pharmaceutical compositions containing such compounds and their use to treat, for example, heart failure or peripheral vascular disease.
Core Innovation
The disclosure provides Formula I small-molecule AMPKγ3 activators and their pharmaceutically acceptable salts, including substituted 3,4-dihydro-2,7-naphthyridin-1(2H)-ones and deuterated analogs. The compounds possess variable ring systems and substituents, including heteroaryl, phenyl, and azetidine moieties, and are evaluated for cellular activation of human AMPK α1β2γ3. The disclosure specifically identifies the fluorinated compound (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-6-({1-[(1S,2S)-2-fluorocyclopropane-1-carbonyl]azetidin-3-yl}amino)-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one.
The disclosure describes intermediate preparation, stereochemical characterization including single-crystal X-ray analysis, and separation of enantiomers or diastereomers. It further describes crystalline forms characterized by powder X-ray diffraction profiles, as well as formulation approaches including solid amorphous dispersions and pharmaceutical combinations with anti-heart-failure agents for treating cardiovascular conditions such as heart failure and peripheral artery disease.
Claims Coverage
The provided claims identify three independent claims covering three inventive features: a Formula I compound genus, a specifically named fluorinated naphthyridinone compound, and a crystal comprising a compound having a recited structure.
Formula I compound genus and pharmaceutically acceptable salts
Independent claim 1 covers a compound of Formula I, wherein Ar is (C2-C9)heteroaryl or phenyl, with X1, X2, R1–R12, m, and n defined by recited alternatives, or a pharmaceutically acceptable salt thereof.
Specifically named fluorinated naphthyridinone compound
Independent claim 15 covers (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-6-({1-[(1S,2S)-2-fluorocyclopropane-1-carbonyl]azetidin-3-yl}amino)-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-3,4-dihydro-2,7-naphthyridin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
Crystal comprising a compound having a recited structure
Independent claim 18 covers a crystal comprising a compound having the recited structure, with related claims characterizing the crystal by specified powder X-ray diffraction profiles.
The independent claims cover the defined Formula I compound genus, a specifically named fluorinated naphthyridinone compound, each including pharmaceutically acceptable salts, and a crystal form comprising a compound having the recited structure.
Stated Advantages
The described deuterated analogs are predicted as potentially providing increased metabolic stability, exposure benefits, and increased in vivo half-life, with these effects noted as predicted rather than demonstrated.
Documented Applications
Methods directed to treating heart failure, peripheral artery disease, and other cardiovascular and metabolic conditions, including obesity and diabetes.
Pharmaceutical compositions and combination therapy comprising a Formula I compound or pharmaceutically acceptable salt, an anti-heart failure treatment agent, and a pharmaceutical carrier, vehicle, or diluent.
Solid-form characterization of a crystal form of a specific compound using powder X-ray diffraction profiles.
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