Potent and selective irreversible inhibitors of IRAK1
Inventors
Assignees
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Publication Number
US-12709607-B2
Publication Date
2026-08-18
Expiration Date
Abstract
The disclosure relates to compounds that act as irreversible inhibitors interleukin 1 (IL-1) receptor-associated kinases (IRAKs); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
Core Innovation
The independent claim covers a compound of Formula I or a pharmaceutically acceptable salt thereof, characterized by defined heterocyclic scaffolds and substituents including piperidinyl, pyrazole, or isoxazole groups. The disclosure describes synthesized Formula I picolinamide compounds and related structural variants featuring acrylamide-bearing substituents and diverse heterocyclic rings. These compounds function as potent and selective irreversible IRAK inhibitors.
The disclosure provides IRAK1 and IRAK4 screening results for the evaluated compounds, demonstrating greater potency against IRAK1 compared to IRAK4. Reported IRAK1 inhibitory values range from 6.37 to 1,190 nM, whereas IRAK4 values range from 722 to greater than 10,000 nM. The described subject matter includes pharmaceutical compositions and methods for combination treatment with a second agent such as a BTK inhibitor.
Claims Coverage
The claim coverage comprises six inventive features directed to Formula I compounds, compositions, and therapeutic methods.
Formula I compound or salt
The independent claim covers a compound of Formula I or a pharmaceutically acceptable salt thereof.
Defined heterocyclic scaffolds and substituents
The claim defines structural variables including piperidinyl at A, CH at C, N at D, CH or CR5 at B, pyrazole or isoxazole at R1, and defined classes for R3, R4, R5, R8, and R9 with defined values for n and p.
IRAK1 inhibition
A dependent claim covers inhibiting IRAK1 in a subject by administering a therapeutically effective amount of the compound or its pharmaceutically acceptable salt.
Pharmaceutical composition
A dependent claim covers a pharmaceutical composition comprising the Formula I compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
Treatment of proliferative disease
Dependent claims cover methods of treating proliferative diseases, including conditions associated with IRAK1 or IRAK4 overexpression, such as leukemia, lymphoma, breast cancer, myelodysplastic syndrome, and Waldenström macroglobulinemia.
Combination treatment
Dependent claims cover methods comprising administration of a second pharmaceutical agent, specifically identified as a BTK inhibitor.
The independent claim defines Formula I compounds and salts with specified structural groups, while dependent claims cover pharmaceutical compositions, IRAK1 inhibition, proliferative disease treatments, and combination therapy with a BTK inhibitor.
Stated Advantages
The Formula I compounds are described as potent, selective irreversible IRAK inhibitors.
Documented Applications
Methods for inhibiting IRAK1 and IRAK4 in a subject.
Treatment or prevention of proliferative, inflammatory, autoimmune, and other kinase-mediated disorders, including cancers such as myelodysplastic syndrome, acute myeloid leukemia, breast cancer, Waldenström macroglobulinemia, leukemia, and lymphoma.
Combination treatment with a second pharmaceutical agent, specifically including a BTK inhibitor.
Pharmaceutical compositions comprising a Formula I compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
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