Fused pyrimidine pyridinone compounds as JAK inhibitors
Inventors
McKinnell, Robert Murray • FENSTER, Erik • LAM, TOM M. • WANG, DIANA JIN • PALERMO, ANTHONY FRANCESCO • BORALSKY, Luke • FRAGA, BREENA
Assignees
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Publication Number
US-11697648-B2
Publication Date
2023-07-11
Expiration Date
Abstract
The disclosure provides compounds of formula (I): or a pharmaceutically-acceptable salt thereof, wherein the variables are defined in the specification, that are inhibitors of JAK kinases, particularly JAK3. The disclosure also provides pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat gastrointestinal inflammatory diseases.
Core Innovation
The disclosure describes formula (I) compounds and pharmaceutically acceptable salts thereof, including pyrido[2,3-d]pyrimidin-7-one and 1,6-naphthyridinone derivatives wherein X is CH or N. These compounds bear azetidine-linked acrylamide, piperazine, or pyrazole substituents, alongside defined alternatives for substituent groups. They act as selective JAK3 inhibitors demonstrating stronger activity against JAK3 than JAK1, JAK2, or TYK2, with cellular potency and potential covalent bonding to JAK3 Cys909.
Reduced permeability and low systemic exposure provide oral gastrointestinal targeting, with compounds exhibiting colon-to-plasma ratios above 100 or 1,000 compared with 2.8 for PF-06651600. Multiple identified compounds significantly reduce the combined stool score in an oxazolone-induced colitis model. The compounds are provided for pharmaceutical compositions and the treatment of gastrointestinal inflammatory diseases, though the specific problem being solved is not explicitly described in the patent.
Claims Coverage
The relevant claim set identifies one independent claim, claim 1, directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, encompassing two inventive features.
Formula (I) compounds and pharmaceutically acceptable salts
Claim 1 covers a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is selected as CH or N.
Defined substituent alternatives
Claim 1 defines structural alternatives for R1, Ra, Rb, Rc, R2, R, R3, and R4 groups selected from specified alkyl, aryl, heterocyclic, cycloalkyl, and substituted groups, subject to permitted ring groups and substitution limits.
The independent claim covers a structurally defined genus of formula (I) compounds and pharmaceutically acceptable salts, with scope determined by the stated alternatives and substitution limits for X and the substituent groups.
Stated Advantages
Selective JAK3 inhibition, with potential covalent bonding to JAK3 Cys909 and stronger activity against JAK3 than JAK1, JAK2, or TYK2.
Reduced permeability and low systemic exposure supporting gastrointestinal targeting with minimal systemic exposure.
Colon-to-plasma ratios above 100 or 1,000 for numerous compounds, compared with 2.8 for PF-06651600.
Significant reduction of the combined stool score in an oxazolone-induced colitis model.
Documented Applications
Treatment in a mammal of gastrointestinal inflammatory diseases, including ulcerative colitis, Crohn's disease, celiac disease, immune checkpoint inhibitor-induced colitis, CTLA-4 inhibitor-induced colitis, graft-versus-host disease-related colitis, collagenous colitis, lymphocytic colitis, Behcet's disease, ileitis, eosinophilic esophagitis, and infectious colitis.
Treatment of skin, respiratory, and ocular inflammatory disorders.
Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, as well as combination therapies.
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