Inhibitors of ARG1 and/or ARG2
Inventors
BEATTY, Joel • NEWCOMB, Eric Thomas • Powers, Jay Patrick • Rosen, Brandon Reid • Su, Yongli • TRAN, Anh Thu • FOLEY, Corinne Nicole • GRANGE, Rebecca Louise • Guney, Tezcan • JACOB, Steven Donald • Kalisiak, Jaroslaw • Leleti, Manmohan Reddy • LINDSEY, Erick Allen • MANDAL, Debashis
Assignees
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Publication Number
US-12226425-B2
Publication Date
2025-02-18
Expiration Date
Abstract
Compounds that are inhibitors of at least one of ARG1 and ARG2, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by ARG1 and ARG2 are also described herein.
Core Innovation
The invention provides compounds having Formula (I) or pharmaceutically acceptable salts, hydrates, or solvates thereof. The compounds are defined by a detailed set of structural variables including X, R1, R2, R3, R4a, R4b, R4c, and R4d, with additional variables Ra, Rb, Rc, X1, Y, and Rd. The definitions allow broad substituent variability, including ring-formation options, linking groups, and selected classes such as halogen, CN, OH, NH2, CO2H, alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl.
The Formula (I) definitions further incorporate X1 as a bond, —O—, C1-6 alkylene, or —O—C1-6 alkylene with optional substitution and 0 or 1 oxo. Y is independently phenyl, a 5- or 6-membered heteroaryl, a 3- to 7-membered heterocycloalkyl, or C3-6 cycloalkyl, each unsubstituted or substituted with from 1 to 3 Rd. The described structures also include exemplified boronic acid and carboxylic acid motifs, as well as substituted aromatic or heterocyclic rings bearing amino and halogen substituents.
Claims Coverage
The provided claim coverage centers on one independent claim defining a broad Formula (I) compound family with extensive substituent and ring/linking variability, including pharmaceutically acceptable salt, hydrate, or solvate forms. Additional claim coverage includes combination and pharmaceutical composition embodiments, as well as dependent refinements to specific substituent choices and structural parameters.
Formula (I) compound with variable substituents and linkers
A compound having Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is N or CR4a, R1 is independently H or C1-8 alkyl, R2 is H or CH3, each R3 is independently H or C1-8 alkyl or two R3 groups are joined to form a 5 or 6-membered ring with defined substitution limits, and R4a, R4b, R4c, and R4d are independently selected from specified groups including H, halogen, CN, C1-8 alkyl, C1-8 alkoxy, C1-8 hydroxyalkyl, C1-8 haloalkyl, C1-8 haloalkoxy, -X1-Y, -X1—SO2R5a, and -X1—NR5bR5c.
Permitted substitution classes for ring and aryl/heteroaryl groups
The claim specifies that ring, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are unsubstituted or substituted with defined numbers of substituents, and that X1 is a bond, —O—, C1-6 alkylene, or —O—C1-6 alkylene with optional substitution and oxo limits.
Y and Rd substituent variability
Y is independently phenyl, a 5- or 6-membered heteroaryl, a 3- to 7-membered heterocycloalkyl, or C3-6 cycloalkyl, each unsubstituted or substituted with from 1 to 3 Rd, and each Rd is independently halogen, C1-4 alkyl, amino, aminoC1-4 alkyl, C1-4 haloalkyl, OH, or C1-4 hydroxyalkyl.
Combination with at least one additional therapeutic agent
A combination comprising the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with at least one additional therapeutic agent.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.
Overall, the claims define a broad Formula (I) compound family through extensive variability across X, R-groups, X1, Y, and Rd, while expressly including pharmaceutically acceptable salts, hydrates, and solvates. The claim set also includes combination and composition embodiments.
Stated Advantages
Improvement of PK/PD/tox profile via deuteration modifications.
Half-life extension approaches are described.
Documented Applications
Arginase (ARG1/ARG2) inhibition as therapy for cancer and immune dysfunction, including impairment in the tumor microenvironment involving T-cell impairment and myeloid-derived suppressor cells (MDSC).
Treatment and prevention of immune- and inflammation-related and infectious disorders.
Therapeutic and prophylactic uses of arginase inhibitors across cancer/oncology, including contexts involving immune/inflammatory disorders and microbial infections.
Use cases for arginase inhibitors include modulation of arginase-mediated immunosuppression associated with T-cell depletion and immune checkpoints.
Combination administration with immune checkpoint inhibitors, chemotherapeutic agents, radiation, signal transduction inhibitors, immunomodulators, anti-infectives, and vaccines.
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