Benzazole compounds and methods for making and using the compounds
Inventors
Yen, Rose • Chen, Yan • Singh, Rajinder • Taylor, Vanessa
Assignees
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Publication Number
US-12043620-B2
Publication Date
2024-07-23
Expiration Date
Abstract
Disclosed are novel benzazole compounds and compositions comprising the compounds. The compounds are useful as kinase inhibitors including interleukin receptor associated kinases (IRAK) 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 a compound having formula I, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or prodrug thereof. The compound is defined by heteroatom selections within the core such that X is O or S, Y is S, and Z is N, and by a Het-1 substituent with variable substituents R1, R2, R8, R10, R23, R, and R′.
Het-1 is defined by R1 and R2, where R1 and R2 are independently selected from H, aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, and combinations that together with the nitrogen form a heterocyclic ring. The substituent set includes R8 independently selected from aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, or haloalkyl, and R10 and R23 independently selected from a similar set including hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl.
The compound framework also specifies that R and R′ are each independently aliphatic, or together with the nitrogen attached thereto form a heterocyclic ring. The compounds are presented as kinase inhibitors, particularly IRAK inhibitors, and the disclosure also includes pharmaceutical formulations, dosing concepts, and synthetic examples and characterization information for benzazole-related compounds.
Claims Coverage
The consolidated claim coverage centers on formula I compounds defined by X, Y, Z heteroatom assignments, a Het-1 group defined by R1/R2 with a heterocyclic ring option, and broad lists of substituent classes for R8 and for R10/R23, together with an option for R/R′ to form a heterocyclic ring with the attached nitrogen. The independent claim identifies five inventive features.
Heteroatom-defined core for formula-based compound
A compound having formula I or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or prodrug thereof, wherein X is O or S, Y is S, and Z is N.
Het-1 substituent defined by R1 and R2 with heterocyclic ring option
Het-1 is defined by R1 and R2, wherein R1 and R2 independently are H, aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, or together with the nitrogen to which they are attached, form a heterocyclic ring.
Variable substituent class scope for R8 and R10/R23
Each R8 independently is aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl; and R10 and R23 are selected from H, aliphatic, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl.
R and R′ with nitrogen heterocyclic ring formation option
R and R′ are each independently aliphatic, or R and R′ together with the nitrogen attached thereto form a heterocyclic ring.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition is provided that includes a compound according to claim 1 along with a pharmaceutically acceptable excipient.
Overall, the claims coverage is centered on formula I compounds defined by X, Y, Z heteroatom assignments, a Het-1 group defined by R1/R2 with a heterocyclic ring option, and broad lists of substituent classes for R8 and for R10/R23, together with an option for R/R′ to form a heterocyclic ring with the attached nitrogen; additional dependent claim scope includes a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
Stated Advantages
Inhibit or modulate IRAK signaling.
Treat or prevent IRAK-associated diseases or conditions.
Delivery of benzazole compounds using delivery vehicles such as liposomes and emulsions.
Potential prophylactic benefit and therapeutic benefit for allergy, asthma, and hypersensitivity contexts.
Dosing considerations based on potency (EC50/IC50 from in vitro assays) and serum concentration.
Use of therapeutic index considerations by comparing toxicity and therapeutic benefit.
Documented Applications
Contacting IRAK protein with an effective amount to inhibit or modulate IRAK signaling.
Treating or preventing IRAK-associated diseases or conditions.
Use in relation to allergy, asthma, and hypersensitivity contexts with prophylactic benefit and therapeutic benefit.
Evaluation in animal models and reference to in vitro assays, including EC50/IC50 measurements linked to therapeutic benefit.
IL-23p19 EC50 assessment of example compounds (I-1 through I-55) in THP1-IFNγ primed LPS and dendritic/LPS formats, supported by Table 1.
Biological assay framework for Example 9–11 using IL-23p19 measurement (p19) and associated readouts including a toxicity readout framework.
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