Heterocyclic RIP1 kinase inhibitors
Inventors
Shaw, Simon • Bhamidipati, Somasekhar • Taylor, Vanessa • Defrees, Kyle
Assignees
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Publication Number
US-12156880-B2
Publication Date
2024-12-03
Expiration Date
Abstract
Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.
Core Innovation
The disclosure characterizes chiral (S)-picolinamide compounds built on a tetrahydrobenzo[b][1,4]oxazepin core and related tetrahydro-1H-benzo[b]azepin or benzo[b][1,4]oxazepin scaffold variants. The compounds are defined with varied substitution at the picolinamide portion, including pyridinylmethyl, pyridyloxy, fluoropyridinyl, thiazolylmethyl, pyrazolyl, and isoxazolyl motifs, together with ethynyl-linked moieties attached to the fused-ring core.
The variable substituent scope includes fluorinated, cyano, trifluoromethyl, and difluoro or CF3 pyridyl variants, as well as tetrahydro-2H-pyran-4-yl, oxetan-3-yl, hydroxyoxetan-3-yl, cyclobutyl, and hydroxy-substituted alkynyl motifs. The disclosure also states broader variable group definitions for Formula I, including stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, prodrugs, linker variations, and alternative structural series.
The compound scope is organized around a shared (S)-configured multi-ring scaffold with alternative ring attachments and substitution patterns across the picolinamide and ethynyl-linked portions. The described exemplars include numbered compounds and structural embodiments supported by NMR, LCMS, mass spectrometry, and purity data.
Claims Coverage
The consolidated claim coverage includes independent claim content directed to a chiral (S)-picolinamide family with a multi-ring tetrahydrobenzo[b][1,4]oxazepin or related benzo[b][1,4]oxazepin scaffold. Across the inputs, the inventive features center on the scaffold, the stereochemical designation, the variable picolinamide substitution, and the alternative ethynyl-linked moieties; one dependent claim also places the compound in a pharmaceutical composition context.
Chiral (S)-picolinamide multi-ring scaffold
An (S)-configured picolinamide compound defined by a tetrahydrobenzo[b][1,4]oxazepin or related benzo[b][1,4]oxazepin core with a 4-oxo arrangement and a 7-substituted ethynyl-linked moiety.
Variable pyridinyl, pyridyloxy, and pyridinylmethyl substitution at the picolinamide position
The picolinamide 4-position is substituted with fluoropyridinyl, pyridyloxy, pyridinylmethyl, and related heteroaryl variants, including fluorinated, cyano, trifluoromethyl, and methyl-substituted pyridines, and thiazolylmethyl examples.
Alternative ethynyl-linked cyclic and hydroxyl-substituted moieties
The 7-position ethynyl-linked substituent includes tetrahydro-2H-pyran-4-yl, oxetan-3-yl, hydroxyoxetan-3-yl, cyclobutyl, and hydroxy-substituted but-1-yn-1-yl variants.
Additional heteroaryl and functional group variants within the compound set
The compound set includes alternative heteroaryl motifs such as thiazole, pyrazole, isoxazole, and furan, together with allowed Formula I variants such as stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, prodrugs, and amino-acid-derived -OC(O)-R8 substituents.
Pharmaceutical composition comprising the claim-1 compound
A pharmaceutical composition comprising the compound according to claim 1, further comprising an excipient, therapeutic agent, or a combination thereof.
The claim coverage is centered on an (S)-configured picolinamide scaffold built on a tetrahydrobenzo[b][1,4]oxazepin or related benzo[b][1,4]oxazepin core, with broad alternatives for the picolinamide substituent and the ethynyl-linked moiety. The consolidated set also includes a dependent pharmaceutical composition claim incorporating the claim-1 compound with excipient and/or therapeutic agent.
Stated Advantages
Biochemical activity against RIPK1 is reported through kinase biochemical ADP-Glo assay results and RIPK1 IC50 values.
Cell-based necroptosis assay results are reported for L929 and U937 cells with zVAD-fmk and TNFα, including IC50 values for human and murine RIP1.
In vivo TNFα-induced hypothermia inhibition is reported, together with brain penetration metrics (Bu/Pu ratios) and MDR1 permeability criteria.
Documented Applications
Biochemical evaluation of the compounds against RIPK1 using a kinase biochemical ADP-Glo assay.
Cell-based necroptosis assay evaluation using L929 and U937 cells with zVAD-fmk and TNFα.
In vivo acute hypothermia model for TNFα-induced hypothermia inhibition.
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