Bicyclic ketone compounds and methods of use thereof
Inventors
Patel, Snahel • Hamilton, Gregory • Zhao, Guiling • Chen, Huifen • Daniels, Blake • Stivala, Craig
Assignees
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Publication Number
US-12344612-B2
Publication Date
2025-07-01
Expiration Date
Abstract
Some embodiments of the invention provide compounds having the general formula I: wherein R1, R2, R3a and R3b are as described herein, pharmaceutical compositions including the compounds, and methods of using the compounds.
Core Innovation
The patent relates to bicyclic ketone compounds described as RIP1 kinase inhibitors. The compounds are presented within defined structural frameworks, including fluorinated cyclopropyl or bicyclic pyrrolo[1,2-b][1,2,4]triazole methanone structures, with substituted variants such as hydroxy, difluoromethoxy, nitrile-containing, and other aryl or heteroaryl members. The disclosure includes stereodefined and racemic variants and pharmaceutically acceptable salts thereof.
The disclosed examples include specific compound members within the formula I compound set, together with reported analytical characterization and potency-related measurements such as Ki values. The material also describes stereoisomer separation, including chiral SFC separation, and presents LC-MS/NMR data for selected compounds. The overall contribution is a set of defined RIP1 kinase inhibitor compounds and related pharmaceutical use language.
The patent ties RIP1 kinase inhibition to neurodegenerative/necroptosis-related diseases, inflammatory diseases, inflammation, and cell death or necroptosis. It also includes formulation concepts such as pharmaceutical compositions, oral formulation, therapeutically inert carrier, and blood-brain barrier context using free brain/plasma ratio (Bu/Pu).
Claims Coverage
The independent claim recites a compound selected from a defined list of fluorinated cyclopropyl or bicyclic ketone structures, including stereodefined and racemic variants, and pharmaceutically acceptable salts thereof. A dependent claim further recites a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, formulated with a therapeutically inert carrier. The inventive features are the specific scaffold selections and the formulation claim.
Selected bicyclic ketone RIP1 kinase inhibitor compounds
A compound selected from cyclopropyl (7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone; (2,2-dimethyl-3-oxabicyclo[3.1.0]hexan-1-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; 3-hydroxy-2,2-dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one; 3-(difluoromethoxy)-2,2-dimethyl-1-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one; 1-[rac-(5S,7S)-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propan-1-one; 1-(3-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbonyl) azetidin-1-yl) ethan-1-one; 3-[rac-(5S,7S)-2-(cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile; cyclopropyl-[rac-(5S,7S)-5-(3-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl-[rac-(7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; cyclopropyl ((5S,7S)-7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone; and cyclopropyl ((5R,7R)-7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methanone, or pharmaceutically acceptable salts thereof.
Pharmaceutical composition with a therapeutically inert carrier
A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, formulated with a therapeutically inert carrier.
Overall, the claim coverage centers on a defined set of fluorinated cyclopropyl or bicyclic ketone structures described as RIP1 kinase inhibitors, with explicit selection from enumerated stereochemical or racemic members and inclusion of pharmaceutically acceptable salts. Formulation coverage is indicated via the pharmaceutical composition claim with a therapeutically inert carrier.
Stated Advantages
Inhibition of RIP1 kinase activity.
Inhibition of RIP1 kinase for treating diseases associated with inflammation, cell death or necroptosis, and extensive neurodegenerative and inflammatory disorders.
Oral formulation is described.
Blood-brain barrier penetration is discussed using free brain/plasma ratio (Bu/Pu).
Documented Applications
RIP1 kinase inhibition for neurodegenerative/necroptosis-related diseases, including synucleopathies, taupathies, and demyelination.
RIP1 kinase inhibition for inflammatory diseases, including IBD, Crohn's, ulcerative colitis, psoriasis, and arthritis.
Treatment of conditions involving cell death or necroptosis.
Treatment of neurodegenerative diseases including Parkinson's, Alzheimer's, Huntington's, ALS, and SMA.
Pharmaceutical compositions and use for administration/formulation, including oral formulation, are described.
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