3-((1R,3s,5S)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl) propanenitrile as a JAK kinase inhibitor
Inventors
Hudson, Ryan • Kozak, Jennifer • Fatheree, Paul R. • Podesto, Dante D. • Brandt, Gary E. L. • Fleury, Melissa • Beausoleil, Anne-Marie
Assignees
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Publication Number
US-12358931-B2
Publication Date
2025-07-15
Expiration Date
Abstract
Disclosed is a compound of the formula: or a pharmaceutically-acceptable salt thereof. Also disclosed is a method of inhibiting a Janus kinase enzyme in a mammal using the compound.
Core Innovation
The document discloses substituted naphthyridine-pyrazole compounds, specifically substituted 1,6-naphthyridine-5,7-diamine compounds bearing 5-methylpyrazolyl and chiral azabicyclic groups, as inhibitors of Janus kinase family enzymes including JAK1, JAK2, JAK3, and TYK2. The compounds show cellular potency against cytokine-induced STAT6 phosphorylation, with variations in azabicyclic nitrogen and naphthyridine ring substituents supported by mass-spectrometric data. The independent claim recites a compound of a stated formula, though the formula structure is omitted from the supplied claim text.
The compounds provide gastrointestinal- and colon-focused exposure with low systemic exposure for addressing gastrointestinal inflammatory conditions, including ulcerative colitis and Crohn's disease. Preclinical oxazolone colitis evaluations demonstrate reduced disease activity and minimal systemic immunosuppression, while human clinical evaluations indicate low plasma exposure and high stool drug concentration. The document also describes crystalline Form I freebase and Form II solvate, with Form I characterized by powder X-ray diffraction, low hygroscopicity, and stability during storage.
Claims Coverage
The supplied claims identify one independent claim reciting a compound of a stated formula, encompassing four inventive features across the independent and dependent claims.
Compound of a stated formula
Independent claim 1 recites a compound of a stated formula, though the specific chemical structure is not provided in the supplied claim text.
Janus kinase inhibition
A dependent claim describes inhibiting a Janus kinase enzyme in a mammal by administering a therapeutically effective amount of the claimed compound.
Treatment of ulcerative colitis or Crohn's disease in a human
Dependent claims specify that the mammal has ulcerative colitis or Crohn's disease and further specify that the mammal is a human patient.
Administration of additional therapeutic agents
A dependent claim specifies administering one or more additional therapeutic agents to the mammal in need thereof.
The claim coverage centers on a compound of a stated formula alongside dependent method limitations directed to Janus kinase inhibition, treatment of ulcerative colitis or Crohn's disease in a human, and co-administration of additional therapeutic agents.
Stated Advantages
Crystalline Form I is characterized by low hygroscopicity, thermal properties, and stability, maintaining HPLC purity of about 99.75-99.79% through three months of storage.
Selected compounds exhibit gastrointestinal- and colon-focused exposure with little systemic exposure and low systemic absorption, showing reduced disease activity in oxazolone colitis models and minimal systemic immunosuppression without reducing splenic natural killer-cell counts, supporting a functional therapeutic index above 100.
Human study results indicate low plasma drug exposure accompanied by high stool drug concentration.
Documented Applications
Inhibition of Janus kinase family enzymes, including JAK1, JAK2, JAK3, and TYK2, in a mammal.
Treatment of gastrointestinal inflammatory disease, specifically ulcerative colitis and Crohn's disease, in a human patient.
Administration of the claimed compound in combination with one or more additional therapeutic agents to a mammal in need thereof.
Preclinical evaluation in an oxazolone-induced colitis model and human clinical study evaluations.
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