RIP1K inhibitors
Inventors
Bhamidipati, Somasekhar • Shaw, Simon • Darwish, Ihab • Yu, Jiaxin • Kolluri, Rao • Taylor, Vanessa • Masuda, Esteban • Irving, Mark
Assignees
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Publication Number
US-12297202-B2
Publication Date
2025-05-13
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 invention provides a method of treating a RIP1K associated condition in a subject by administering a therapeutically effective amount of a compound of formula. The compounds are selective RIP1 inhibitory kinase compounds represented by Formula I and related structural embodiments, with extensive variable substituent positions defining heteroaryl/aryl portions, ring B, W, L, and R-group substituents. The scaffold includes multiring heteroaryl-linked amide/urea-like motifs and permissible stereoisomers, N-oxides, tautomers, hydrates/solvates, and prodrugs.
The formula permits variable atom and ring substitutions including X, Y1, Y2, Y3, Z, R^c, R^z, and a linker-R^6 group, together with ring constraints in which ring B is a 5- to 10-membered heteroaryl and W is a 5- to 10-membered aryl or 5- to 10-membered heteroaryl substituted by p R4. The disclosed examples include halogen-substituted analogs such as chloro and fluoro, along with hydroxyl, methoxy/alkoxy, oxygen- and nitrogen-containing rings, and sulfur-containing groups.
The disclosed compounds are characterized by 1H NMR and 13C NMR and by ESI-MS, including calculated versus found [M+H]+ values. The structural content specifies fused benzo[b]tetrazolo cores linked to a triazole-carboxamide motif and includes substituted benzyl, aromatic, alkynyl, fluorinated, and heteroaryl/aryl substituents.
Claims Coverage
The claim coverage consists of independent claims directed to administering a therapeutically effective amount of a structurally defined compound to treat a RIP1K associated condition, with extensive variable atom, linker, and heterocycle definitions. Across the provided items, the inventive features center on the therapeutic method, the variable scaffold, and the disease limitations to Parkinson's disease, Alzheimer's disease, or multiple sclerosis.
Treatment of a RIP1K-associated condition
A method of treating a RIP1K associated condition in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula.
Variable compound scaffold
The compound formula defines X, R^a, Y^1, Y^2, Y^3, Z, R^c, R^z, ring B, L, W, R^1, R^2, R^3, R^d, R^e, R^f, m, n, and p, including ring B as a 5- to 10-membered heteroaryl and W as a 5- to 10-membered aryl or 5- to 10-membered heteroaryl substituted by p R4.
Linker and substituent architecture
R^1 is a linker-R^6 group; the linker is a bond, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl; R^6 is R^e, —C(R^f)3, or —C(R^f)=C(R^f)2; and the remaining substituents are defined by the claim's substitution rules.
Parkinson's disease, Alzheimer's disease, or multiple sclerosis
The RIP1K associated condition is Parkinson's disease, Alzheimer's disease, or multiple sclerosis.
Claim coverage centers on administering a therapeutically effective amount of a broad formula-defined compound to treat a RIP1K associated condition, with dependent claims limiting the condition to Parkinson's disease, Alzheimer's disease, or multiple sclerosis.
Stated Advantages
Selective RIP1 inhibitory kinase compounds are provided.
The compounds are directed to treatment or prevention of RIP1-associated kinase conditions.
RIP1-mediated signaling is associated with programmed cell death and necroptotic cell death.
In vivo acute hypothermia model results demonstrate TNF-β1 signaling inhibition potential.
Biochemical RIPK1 inhibition is evaluated with ADP-Glo IC50 values.
Functional whole-cell necroptosis assay results are reported using U937 and L929 cells with IC50 values.
Documented Applications
Treating a RIP1K associated condition in a subject, wherein the RIP1K associated condition is Parkinson's disease.
Treating a RIP1K associated condition in a subject, wherein the RIP1K associated condition is Alzheimer's disease.
Treating a RIP1K associated condition in a subject, wherein the RIP1K associated condition is multiple sclerosis.
Biochemical evaluation of RIPK1 inhibition using ADP-Glo with IC50 values.
Functional whole-cell necroptosis assay evaluation using U937 and L929 cells with IC50 values.
In vivo acute hypothermia mouse model demonstrating TNF-β1 signaling inhibition potential in C57BL/6 mice.
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