Compounds and methods for treating cancer, viral infections, and allergic conditions
Inventors
Janetka, James W. • Damalanka, Vishnu
Assignees
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Publication Number
US-12590123-B2
Publication Date
2026-03-31
Expiration Date
Abstract
The present invention generally relates to compounds that are useful for inhibiting one or more trypsin-like S1 serine proteases, HGFA, matriptase, hepsin, KLK5 and/or TMPRSS2 as well as cysteine proteases including trypsin-like cysteine proteases (e.g. Cathepsin B). The present invention also relates to various methods of using the inhibitor compounds to treat or prevent viral infections, including those caused by coronaviruses and influenza, conditions associated with KLK5, various malignancies, pre-malignant conditions, and cancer.
Core Innovation
The invention relates to compounds of Formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), or (IIH), including salts and stereoisomers, with substituent variables n, P3, X, Y, x, R, Z, and related R1-R6 constraints. The compounds are characterized by P3 as hydrogen or a side chain of a natural or unnatural amino acid, X as hydrogen or methyl, and Y as hydrogen or specified protecting-group and substituted moieties, with additional ring-compatible residue definitions.
The disclosed framework further constrains R to C1 to C6 alkyl, C3 to C6 cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkylheterocycle, aralkyl, or aryl. Z is defined through R1-R6 and ring-forming possibilities, including R4 as hydrogen, an alkyl group, or a residue of an amino acid, with R3 and R4 able to form a piperazine or piperidine ring, R5 able to form a ring, and R6 restricted to aryl.
The disclosure also describes dependent selections that enumerate Y protecting groups and P3 amino-acid side-chain identities, specify depicted heteroaromatic Z-core structures, and define A as O or NH with R11 selected from H, methyl, benzyl, optionally substituted alkyl, optionally substituted aryl, heterocycle, or a residue of an alpha-amino acid. Representative compounds and examples are provided across the Formula (IIA)- (IIH) scaffold, including specific compound embodiments and example chemical structures.
Claims Coverage
The consolidated claim coverage centers on compounds of Formula (IIA)-(IIH), including salts and stereoisomers, with multiple structural variables constrained across at least six inventive feature groups: P3, Y, X, x, R, and Z/R1-R6. Dependent claims further refine these constraints by enumerating Y and P3 selections, restricting R4 and allowing piperazine or piperidine ring formation, limiting R6 to aryl, specifying Z-core options with A and R11, and adding a pharmaceutical composition embodiment.
Compounds of Formula (IIA)-(IIH) with constrained substituents
A compound of Formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), or (IIH), a salt thereof, or a stereoisomer thereof, wherein n is independently 1 or 2; P3 is independently hydrogen or a side chain of a natural or unnatural amino acid; X is independently hydrogen or methyl; Y is independently hydrogen or one of the enumerated moiety classes; x is independently 0, 1, or 2; R is independently C1 to C6 alkyl, C3 to C6 cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkylheterocycle, aralkyl, or aryl; and Z is independently defined through R1-R6 and ring-forming constraints.
Enumerated Y protecting groups and P3 side-chain identities
Each Y is independently hydrogen or one of the listed protecting-group moieties, including acetyl, Boc, Cbz, Fmoc, benzyl, C(O)R, SOOR, COOR, C(O)NHR, and substituted or unsubstituted (CH2)x aryl, heteroaryl, cycloalkyl, or heterocycle options; each P3 is independently chosen from an enumerated set of amino-acid side-chain identities and combinations thereof.
R4 selection and R3/R4 ring formation
R4 is hydrogen, an alkyl group, or a residue of an amino acid, or R3 and R4 form a piperazine ring or a piperidine ring.
Aryl restriction on R6
Each R6 substituent is aryl.
Z-core structural options and A/R11 pairing
Each Z independently takes one of several depicted heteroaromatic core structures, and A is O or NH with R11 selected from H, methyl, benzyl, optionally substituted alkyl, optionally substituted aryl, heterocycle, or a residue of an alpha-amino acid.
Pharmaceutical composition comprising a claim 1 compound
A pharmaceutical composition including a therapeutically effective amount of at least one compound of claim 1, or a salt thereof.
Overall, the claims cover Formula (IIA)-(IIH) compounds (including salts and stereoisomers) through constrained substituent classes and ring-forming options, with dependent claims narrowing Y and P3, imposing R4 and R3/R4 ring constraints, restricting R6 to aryl, specifying Z-core heteroaromatic structures with A and R11 selection, and extending the scope to pharmaceutical compositions.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Enzyme inhibition assays targeting HGFA, matriptase, hepsin, Factor Xa, and thrombin.
Cancer detection using radiolabeled compounds including PET and SPECT, and fluorescent compound imaging.
Treatment or prevention of cancers including breast cancer and ovarian cancer.
Treatment or prevention of allergic conditions including eosinophilic esophagitis.
Treatment or prevention of skin disorders including Netherton syndrome.
Pharmaceutical composition and administration concepts are referenced.
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