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Publication Number
US-12747228-B2
Publication Date
2026-09-29
Expiration Date
Abstract
The disclosure relates to compounds that act as inhibitors of interleukin 1 (IL-1) receptor-associated kinase 4 (IRAK4); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
Core Innovation
The invention provides pyrazole-based compounds of Formula (I), including Formula (I-a) variants, Formula (I-a5), and Formula (Ia3), and pharmaceutically acceptable salts thereof. Formula (Ia3) compounds feature a pyridinyl substituent C and a defined group A consisting of cycloalkyl or heterocyclyl moieties. The compounds selectively inhibit IRAK4, exhibiting 2- to 30-fold selectivity over IRAK1, with certain embodiments demonstrating at least tenfold greater inhibitory activity against IRAK4 than IRAK1.
The disclosure reports IRAK4 enzymatic inhibition alongside pharmaceutical compositions and methods of inhibiting IRAK4 or treating proliferative diseases, cancers, autoimmune, inflammatory, and kinase-mediated disorders. Documented conditions include AML, MDS, lymphoma, diffuse large B-cell lymphoma, Waldenström macroglobulinemia, triple-negative breast cancer, septic response, and myocardial dysfunction. Furthermore, compound 015 exhibits lower ED50 values than reference inhibitors across tested cell lines, while the problem being solved is not explicitly described in patent.
Claims Coverage
The relevant claims identify one independent claim, claim 1, directed to a compound of Formula (Ia3) or a pharmaceutically acceptable salt thereof, comprising three inventive features.
Formula (Ia3) compound
A compound of Formula (Ia3), or a pharmaceutically acceptable salt thereof.
Defined A and C groups
A is C3-10 cycloalkyl or 4- to 10-membered heterocyclyl, unsubstituted or substituted with one, two, or three R1; and C is pyridinyl, unsubstituted or substituted with one, two, or three R3.
Defined substituent alternatives
R2a is selected from H, C1-4 alkyl, cyclopropyl, cyclobutyl, —CF3, —CHF2, —CH2F, C1-4 alkoxy, halo, or —CN; RA2 is H; subject to defined substituent alternatives for R1, R3, R4, X, R5, and R6 and provisos.
The independent claim defines the Formula (Ia3) compound genus and permitted substituent alternatives, including pharmaceutically acceptable salts thereof, while dependent claims recite pharmaceutical compositions with a carrier and methods of inhibiting IRAK4.
Stated Advantages
The compounds selectively inhibit IRAK4, showing an asserted 2- to 30-fold selectivity over IRAK1, with certain embodiments exhibiting at least tenfold greater inhibitory activity against IRAK4 than IRAK1.
Compound 015 exhibits lower ED50 values compared to CA-4948 and PF06650833 in most tested cell lines.
Documented Applications
Methods of inhibiting IRAK4 by administering a therapeutically effective amount of a claim 1 compound or its pharmaceutically acceptable salt.
Treatment of proliferative, inflammatory, autoimmune, and kinase-mediated diseases, including AML, MDS, lymphoma, diffuse large B-cell lymphoma, Waldenström macroglobulinemia, triple-negative breast cancer, septic response, myocardial dysfunction, and other cancers.
A pharmaceutical composition comprising a claim 1 compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, including optional combination use with kinase inhibitors such as BTK inhibitors.
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