5 to 7 membered heterocyclic amides as JAK inhibitors
Inventors
Long, Daniel D. • Smith, Cameron • Thompson, Corbin
Assignees
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Publication Number
US-11713315-B2
Publication Date
2023-08-01
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 disclosed subject matter provides indazole–imidazopyridine carboxylic acid derivatives, amide analogues, and 5–7-membered heterocyclic amide compounds of formulas (I)–(IV), including substituted imidazo[4,5-c]pyridine carboxylic-acid compounds bearing a 6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl group, N-alkyl variants, piperazine or bicyclic-amine amides, and corresponding 5-fluoro analogs. These compounds and their pharmaceutically acceptable salts act as inhibitors of JAK1, JAK2, JAK3, and Tyk2. The disclosure further provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a specified compound or pharmaceutically acceptable salt thereof.
The described compounds provide cellular inhibition of IL-2-stimulated STAT5 and TSLP-induced TARC release while limiting lung-to-plasma absorption and sulfation metabolism. These pharmaceutical compositions are configured for inhaled lung delivery. Reported preclinical findings demonstrate lung retention, low plasma exposure, and inhibition of IL-13-induced STAT6 phosphorylation in mouse lung tissue.
Claims Coverage
The claims identify one independent claim comprising one inventive feature directed to a pharmaceutical composition.
Pharmaceutical composition comprising a carrier and a specified compound
The independent claim recites a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the specified group, or a pharmaceutically acceptable salt thereof.
The independent claim covers a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a selected compound or a pharmaceutically acceptable salt thereof.
Stated Advantages
The compounds show potent biochemical inhibition of JAK1, JAK2, JAK3, and Tyk2, as well as cellular inhibition of IL-2-stimulated STAT5 and TSLP-induced TARC release.
Compounds 1–6 demonstrate high lung-to-plasma exposure and reduced lung sulfation relative to compounds C-1 to C-6, retaining potent cellular JAK inhibition while limiting lung-to-plasma absorption and sulfation metabolism.
Reported preclinical findings include lung retention, low plasma exposure, and inhibition of IL-13-induced STAT6 phosphorylation in mouse lung tissue.
Documented Applications
The compositions are proposed for respiratory diseases, including asthma and chronic lung allograft dysfunction (CLAD), particularly through inhaled lung delivery.
The compositions are suitable for inhaled administration, including delivery using a dry powder inhaler, metered-dose inhaler, or nebulizer inhaler, configured as solutions, suspensions, or dry-powder forms.
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