Dimethyl amino azetidine amides as JAK inhibitors
Inventors
Long, Daniel D. • Smith, Cameron • Thompson, Corbin
Assignees
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Publication Number
US-12398135-B2
Publication Date
2025-08-26
Expiration Date
Abstract
The invention provides compounds of formula (I): where the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are useful as JAK kinase inhibitors. The invention also provides pharmaceutical compositions comprising such compounds and methods of using such compounds to treat respiratory diseases.
Core Innovation
The disclosure describes substituted indazole-imidazopyridine compounds and dimethylamino-azetidine amides of formula (I) as potent inhibitors of JAK1, JAK2, JAK3, and TYK2. It also describes pharmaceutical compositions comprising these compounds and a pharmaceutically acceptable carrier. Tested compounds combine cellular cytokine signaling inhibition with lung retention, low plasma absorption, and inhibition of IL-13-induced lung STAT6 phosphorylation in vivo.
The disclosed approach provides inhaled, lung-directed treatment of respiratory diseases with the stated aim of limiting systemic immunosuppression. Compounds 1–6 demonstrate lower sulfation metabolism and enhanced human lung S9 metabolic stability relative to comparative analogs. Furthermore, an exocyclic amide interaction with Arg879 observed in a JAK1 co-crystal structure supports improved kinome selectivity.
Claims Coverage
The claims include two independent claims directed to pharmaceutical compositions, presenting two inventive features.
Compound or salt with a pharmaceutically acceptable carrier
Claim 1 covers a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Dependent claims specify administration by inhalation, including using a nebulizer inhaler.
Compound with a pharmaceutically acceptable carrier
Claim 4 covers a pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier. Dependent claims specify administration by inhalation, including using a nebulizer inhaler.
The independent claims cover pharmaceutical compositions containing a compound of formula 1 with a pharmaceutically acceptable carrier, with claim 1 also covering a pharmaceutically acceptable salt thereof. Dependent claims specify inhalation and use of a nebulizer inhaler.
Stated Advantages
Compounds 1–6 combine cellular activity with lung retention, substantial lung exposure, and low plasma absorption.
The compounds inhibit IL-13-induced STAT6 phosphorylation in vivo and inhibit cellular cytokine signaling.
Compounds 1–6 show lower sulfation metabolism and greater human lung S9 metabolic stability than comparative analogs.
Inhaled, lung-directed treatment is intended to limit systemic immunosuppression.
The JAK1 co-crystal structure supports the proposed basis for improved JAK1 kinome selectivity.
Documented Applications
Inhaled, lung-directed treatment of asthma.
Inhaled, lung-directed treatment of chronic obstructive pulmonary disease (COPD).
Inhaled, lung-directed treatment of chronic lung allograft dysfunction (CLAD).
Pharmaceutical compositions for inhalation, including administration using a nebulizer inhaler.
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