IRAK inhibitors and method for making and using
Inventors
Li, Hui • Heckrodt, Thilo • Chen, Yan • Kelley, Ryan • McMurtrie, Darren • Tso, Kin • Taylor, Vanessa • Singh, Rajinder • Yen, Rose • Maung, Jack
Assignees
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Publication Number
US-11993594-B2
Publication Date
2024-05-28
Expiration Date
Abstract
Disclosed embodiments concern interleukin receptor associated kinases (IRAK) inhibitors, such as oxazole compounds, and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.
Core Innovation
The invention relates to compounds, or salts thereof, having formula 1 in which at least one of R1 and R2 is a nitrogen-containing heteroaryl and the remaining R1 or R2 is selected from H, alkyl, haloalkyl, nitro, cyano, amide, amino, hydroxyl, carboxyl, carboxyl ester, or acyl. R3, R4, and R5 are defined by selected structural classes, and ring A is a heterocyclic ring.
The disclosure extends the compound definition through further formulae, including formula 2 to 7, with additional variable R6, Z positions, and substituent categories that constrain the placement and allowed types of heteroatoms and substituents. The document also includes oxazole-bearing species, heteroaryl examples such as pyridinyl, pyrimidinyl, pyrazinyl, and pyrazolyl, and exclusions of certain not oxazole-carboxamide compound structures.
Beyond the compound structures, the disclosure includes pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable excipient, as well as methods involving administration of a therapeutically effective amount to a subject to treat a disease or condition or to inhibit IRAK. The described applications include auto-immune disease, inflammatory disorder, ALS, systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, and psoriasis.
Claims Coverage
The claim set covers at least three inventive feature groupings: the Formula 1 compound definition, additional dependent-claim variable constraints and formula refinements, and therapeutic administration claims for treatment and IRAK inhibition.
Formula 1 heterocyclic ring compound and salt definition
A compound having formula 1 or a salt thereof, wherein at least one of R1 and R2 is a nitrogen-containing heteroaryl and the remaining R1 or R2 is selected from H, alkyl, haloalkyl, nitro, cyano, amide, amino, hydroxyl, carboxyl, carboxyl ester, or acyl; R3 is H, aliphatic, heteroaliphatic, heterocyclyl, amide, aromatic, or araliphatic; R4 is H, aliphatic, heteroaliphatic, or one of R1 or R2 together with R4 and the atoms to which they are attached form a heterocyclic ring; R5 is H or alkyl; and ring A is a heterocyclic ring.
Formula refinements with Z positions and R6/R10 constraints
Additional dependent claims refine the structural scope using further formulae, including Formula 7, with specified substituent definitions for Z1, Z2, Z3, Z4 and each R6 and R10 under the claimed categories and variable constraints.
Nitrogen-count constraint across Z2 to Z4
Z1 is N, and none or only one of Z2, Z3, and Z4 is N.
Therapeutic treatment by administering a therapeutically effective amount
A method of treating a disease or condition by administering a therapeutically effective amount of a compound, or a composition containing the compound, to a subject.
IRAK inhibition by therapeutic administration
A method of inhibiting IRAK in a subject by administering a therapeutically effective amount of a compound, or a composition containing the compound, as defined for the compound.
Overall, the claims cover Formula 1 compounds or salts with nitrogen-containing heteroaryl substitution at at least one of R1 or R2, defined R3, R4, R5, and heterocyclic ring A constraints, further narrowed by formula-specific variable definitions and nitrogen-count restrictions, and extended to pharmaceutical compositions and therapeutic methods involving treatment and IRAK inhibition.
Stated Advantages
IRAK inhibition with EC50 ranges, including values down to less than 1 μM in typical examples.
Therapeutic benefit and prophylactic benefit via pharmaceutical delivery systems for oxazole compounds.
Toxicity and therapeutic index considerations are included.
Documented Applications
Pharmaceutical compositions comprising the compound and pharmaceutically acceptable excipient.
Methods of treating a disease or condition by administering a therapeutically effective amount of the compound or a composition containing the compound to a subject.
Methods of inhibiting IRAK in a subject by administering a therapeutically effective amount of the compound or a composition containing the compound.
Treatment of auto-immune disease and inflammatory disorder, with examples including ALS, systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, and psoriasis.
Combination therapies and pharmaceutical formulations for targeting disease areas via IRAK-pathway inhibition.
Formulation and dosing concepts for oxazole compounds using delivery vehicles such as liposomes and emulsions, with pack/dispenser options including blister pack and instructions for administration.
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