Compounds and methods for the targeted degradation of Interleukin-1 receptor-associated kinase 4 polypeptides
Inventors
Crew, Andrew P. • Araujo, Erika
Assignees
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Publication Number
US-12036209-B2
Publication Date
2024-07-16
Expiration Date
Abstract
The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
Core Innovation
The invention defines extensive structural variability for compound linkers and related moieties connecting PTM and ULM frameworks. The linker (L) is expressed through selectable ring systems, variable linkage definitions, PEG-like alkylene glycol/ethylene glycol linker options, and additional linker groups comprising multiple covalently connected structural units, with variable length parameters and attachment-point logic reflected in the structural definitions.
The disclosure also describes structural definitions for ULM, PTM, ILM, CLM, and MLM moieties, including heteroaryl, heterocycle, aryl, and fused ring systems, together with variable substituent sets and covalent attachment through selected R groups or linker positions. Bifunctional compounds are described in PTM-L-ULM, ULM-L-PTM, and related architectures, with representative chemical structures illustrating selectable moieties and linker connectivity.
In addition, the document presents specific scaffold families and example compound series, including triazole-containing PTM-X scaffolds, nicotinamide-type PTM-IV scaffolds, ILM scaffold families based on IAP ligand scaffolds, and quinazoline-carbonitrile and benzimidazole-based chemical series. The described structures include pharmaceutically acceptable salts and, where stated, stereoisomers, tautomers, solvates, polymorphs, prodrugs, analogues, derivatives, and deuterated forms.
Claims Coverage
The provided claim summaries consistently describe one independent claim directed to a compound selected from a set of chemical structures, with coverage extending to pharmaceutically acceptable salts. Across the items, the inventive coverage is centered on selection of the covered compound from the depicted or defined structural set and the maintained salt coverage.
Compound selected from chemical structures with pharmaceutically acceptable salt coverage
A compound selected from a set of chemical structures, or a pharmaceutically acceptable salt thereof.
Depicted chemical structure coverage
The covered compound corresponds to the depicted chemical structure while retaining pharmaceutically acceptable salt coverage.
Specific depicted compound definition
The compound is defined as the specific depicted chemical structure, with pharmaceutically acceptable salt coverage.
Overall, the claims are consolidated around a compound selected from the disclosed chemical-structure set and the inclusion of pharmaceutically acceptable salts, with dependent claims narrowing the covered member to the depicted chemical structure(s).
Stated Advantages
Documented Applications
Treatment or use in connection with tau aggregation-associated neurodegenerative disease, inflammatory disease, and cancer indications.
Therapeutic compositions and treatment methods targeting diseases associated with IRAK-4 protein dysregulation, including therapeutic use in cancer and inflammatory, neurodegenerative, and cardiovascular diseases.
Listed indication examples include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, leukemias, lymphomas, melanoma, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis.
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