Imidazolo indazole compounds as JAK inhibitors
Inventors
McKinnell, Robert Murray • LAM, TOM M. • Smith, Cameron • GERKEN, Philip • Allegretti, Paul • DOLGONOS, Gabrielle Elaine • Owens, Christina
Assignees
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Publication Number
US-12384761-B2
Publication Date
2025-08-12
Expiration Date
Abstract
Provided herein are compounds of formula (I): and pharmaceutically-acceptable salts thereof, where A, W, X, Y and Z are defined in the specification. The compounds of formula (I) and pharmaceutically-acceptable salts thereof are Janus kinase (JAK) inhibitors. Also provided herein are pharmaceutical compositions comprising such compounds; and methods of using such compounds to treat, e.g., inflammatory and fibrotic diseases, including respiratory diseases.
Core Innovation
The invention relates to pan-JAK inhibitor compounds of formula (I) and formula (II), or pharmaceutically acceptable salts thereof, for conditions associated with cytokine signaling through JAK/JAK-STAT pathways. The chemical structures feature a hydroxyethyl-substituted biaryl fused nitrogen-heteroaromatic scaffold linked to an unsaturated 4- to 7-membered monocyclic heterocyclic group A having a double bond. Disclosed exemplars encompass structural variants differing in fluorination, ring substituents, side chains, and stereochemistry, with reported molecular masses ranging from approximately 386 to 551 Da.
The compounds provide lung-directed therapy, including inhaled administration, to treat respiratory inflammation while limiting systemic exposure and immunosuppression. Biological evaluations demonstrate enzymatic inhibition across JAK1, JAK2, JAK3, and TYK2, accompanied by inhibition of IL-13-induced STAT6 phosphorylation in BEAS-2B cells and lung tissue. Preclinical characterization in animal models reports high local lung exposure alongside low systemic plasma exposure and measurable lung-to-plasma AUC ratios.
Claims Coverage
The claims identify two independent claims defining two inventive features directed to a broad compound genus and a selection of depicted chemical structures.
Compound of formula (I) and pharmaceutically acceptable salts
Claim 1 covers a compound of formula (I), or a pharmaceutically acceptable salt thereof, defining choices for W, X, Y, and Z and an unsaturated 4- to 7-membered monocyclic heterocyclic group A having a double bond, including specified optional substituents and optional fused or bridged cycloalkyl or heterocyclic rings.
Compounds selected from depicted structures
Claim 15 covers a compound selected from depicted chemical structures, or a pharmaceutically acceptable salt thereof, comprising a hydroxyethyl-substituted biaryl fused nitrogen heteroaryl core linked to an unsaturated nitrogen-containing heterocycle.
The two independent claims define a formula (I) chemical genus and a discrete selection of depicted compounds, each encompassing pharmaceutically acceptable salts, with dependent claims directed to pharmaceutical compositions and treatment methods.
Stated Advantages
Lung-directed administration treats respiratory inflammation while limiting systemic exposure and immunosuppression.
Preclinical findings demonstrate high lung exposure and low plasma exposure, alongside potent inhibition of JAK1, JAK2, JAK3, and TYK2 and inhibition of IL-13-induced STAT6 phosphorylation in lung tissue.
Documented Applications
Inhaled administration, lung-delivery formulations, and treatment of Janus kinase-modulated respiratory diseases and related conditions, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, COVID-19, pulmonary arterial hypertension, and chronic rhinosinusitis with or without nasal polyps.
Treatment of lung transplant rejection, chronic lung allograft dysfunction, and lung graft-versus-host disease.
Treatment of gastrointestinal inflammatory diseases, including ulcerative colitis and Crohn's disease.
Treatment of dermal, ocular, autoimmune, inflammatory, and cancer indications, including atopic dermatitis, uveitis, diabetic retinopathy, and dry eye disease, via topical and ocular administration embodiments.
Pharmaceutical compositions comprising a claimed compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, as well as combination therapies.
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