Bicyclic HPK1 inhibitors
Inventors
Mevellec, Laurence Anne • Vialard, Jorge Eduardo • Coupa, Sophie • ADELINET, Christophe Denis Pascal • Wroblowski, Berthold • Edwards, James Patrick
Assignees
Janssen Pharmaceutica NV • Janssen Cilag SAS • Janssen Research and Development LLC
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12486264-B2
Publication Date
2025-12-02
Expiration Date
Abstract
The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as HPK1 inhibitors, useful for treating diseases such as cancer.
Core Innovation
The invention provides a compound of Formula (I), or a tautomer or a stereoisomeric form thereof, including a pharmaceutically acceptable addition salt or an N-oxide thereof. The Formula (I) defines a fused or non-fused aromatic heterocyclyl or fully saturated heterocyclyl framework through constraints on A1-A6 and on R1a, R1b, R4a, and R4b, including an optional dotted bond configuration when R1b and R4b are taken together.
The heterocyclyl groups are further defined by ring size, aromatic versus fully saturated character, heteroatom count and selection, and optional substituents on carbon atoms and optional additional nitrogen atoms. The substitution pattern includes groups selected from -OH, CN, halo, -O-R7, -S(=O)2-R7, -C(=O)-R7, -NR6cR6d, and -C(=O)-NR6aR6b, together with Hetc, Hetf, and Hetg substituents as defined heterocyclyl groups.
The disclosure also states that the compounds inhibit HPK1 kinase/activity and enhance immune responses and T-cell activity, including TCR protein recruitment, SLP76 and GADS involvement. The invention concerns HPK1 (MAP4K1) inhibitor pharmaceutical agents for immune-cell signaling and anti-tumor immunity, and the partial content further describes example compound embodiments prepared from named intermediates with supporting characterization and pharmacological assay results.
Claims Coverage
The provided material supports one broad independent compound claim for Formula (I) and additional dependent coverage for therapeutic use, pharmaceutical composition, and selected embodiments. In total, the coverage centers on a structural Formula (I) scaffold with detailed heterocyclyl formation and substitution rules, plus use and composition limitations.
Compound of Formula (I) with defined heterocyclyl formation and substituent rules
A compound of Formula (I) or a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or an N-oxide thereof, wherein the dotted bond towards R1b is optional and, when R1b and R4b are taken together, allows formation of a monocyclic or bicyclic aromatic heterocyclyl or a fully saturated heterocyclyl as defined, with constraints for A1-A6 and specified meanings of R1a, R1b, R4a, and R4b, including allowed substituents and sulfur-oxidation patterns.
Pharmaceutical composition including the claimed compound
A pharmaceutical composition that includes the compound of Formula (I) together with a pharmaceutically acceptable carrier or diluent.
Therapeutic use for preventing or treating cancer and viral infection
The compound as defined is provided for preventing or treating cancer and viral infections, including chronic viral infection.
Cancer subtypes within prevention or treatment scope
The prevention or treatment scope explicitly includes lung cancer, melanoma, head and neck cancer, esophageal cancer, bladder and urothelial cancer, liver cancer, kidney cancer, prostate cancer, and hematopoietic cancer.
Selected compound embodiments
The compound of Formula (I) is selected from specified chemical compounds, including indicated tautomers, stereoisomeric forms, pharmaceutically acceptable addition salts, and N-oxides.
The claim coverage is anchored by a broad Formula (I) definition that constrains heterocyclyl formation, aromaticity or saturation, heteroatom selection, sulfur oxidation patterns, and substituent options, and it is further narrowed to therapeutic use, pharmaceutical composition form, and selected compound embodiments.
Stated Advantages
Enhances immune responses and T-cell activity via HPK1 kinase/activity inhibition.
Provides therapeutic indications for cancer.
Provides therapeutic indications for chronic viral infection.
Documented Applications
Use as medicaments and in pharmaceutical compositions for prevention or treatment of cancer and viral infections.
Prevention or treatment of cancer including lung cancer, melanoma, head and neck cancer, esophageal cancer, bladder and urothelial cancer, liver cancer, kidney cancer, prostate cancer, and hematopoietic cancers.
Prevention or treatment where the disorder treated is a chronic viral infection.
Use in combination regimens, including with immune checkpoint inhibitors (PD1/PDL1 immune checkpoint inhibitors), as described in the document context.
Imaging/assays using isotopically labeled compounds including radiolabeled variants for PET radiotracers, including target-specific PET radiotracers associated with biomarkers [procedural detail omitted for safety].
Formulating the compound into a pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Pharmacological evaluation includes Hpk1 biochemical kinase inhibition and cellular SLP76 pS376 phosphorylation.
Interested in licensing this patent?