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Publication Number
US-12043629-B2
Publication Date
2024-07-23
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 relates to receptor-interacting protein-1 (RIP1) kinase inhibitor compounds and their use in treating or preventing diseases involving receptor-interacting protein-1 (RIP1) kinase. It describes the role of RIP1 in inflammatory and necroptotic cell death and frames selective inhibition of RIP1 over related kinases as a key objective.
The document defines a general Formula I scaffold for selective RIP1 inhibition. Within Formula I, ring B is a 5-membered or 6-membered heteroaryl, X is CH2 or O, L is a heteroatom or Ra with Ra not hydrogen, and Z is C1-10 aliphatic, aryl, or heteroaryl optionally substituted with one or more R5.
The Formula I substituent scheme defines extensive options for R1 through Re, including C≡CH or a -linker-R6 group, where the linker is a divalent C1-10 aliphatic or C1-10 cycloaliphatic and R6 is Rb, C(Rf)3, or -C(Rf)2. The disclosure also covers compound forms including hydrates, solvates, stereoisomers, N-oxides, tautomers, and prodrugs, and links the Formula I compounds and pharmaceutical compositions to treating or preventing RIP1-associated diseases.
Claims Coverage
The provided data includes three independent claims. Across these independent claims, the inventive coverage centers on administering therapeutically effective amounts of a Formula I compound or pharmaceutical composition for RIP1-kinase-involved diseases, and on inhibiting RIP1 kinase in a subject using the same Formula I structural definition.
Treating a RIP1-kinase-involved disease with a formula I compound
A method for treating a disease in a subject comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutical composition comprising the compound of Formula I and one or more pharmaceutically acceptable excipients, wherein the subject has, or is suspected of having or developing, a disease involving receptor-interacting protein-1 (RIP1) kinase, and wherein the disease is amyotrophic lateral sclerosis (ALS), type I diabetes, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, asthma, or leukemia.
Formula I structural definition for RIP1-kinase treatment
Using the compound of Formula I with structural scope defining ring B as a 5-membered or 6-membered heteroaryl; X as CH2 or O; L as a heteroatom or Ra provided that Ra is not hydrogen; and Z as C1-10 aliphatic, aryl, or heteroaryl optionally substituted with one or more R5, with the remaining substituent definitions and constraints for R1 through R6 and m and n as recited.
Inhibiting RIP1 kinase with a formula I compound
A method of inhibiting receptor-interacting protein-1 (RIP1) kinase in a subject comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutical composition comprising the compound of Formula I and one or more pharmaceutically acceptable excipients, wherein the compound of Formula I is defined by the specified ring/linker/substituent constraints and the parameters m and n.
Across the independent claims, the core claim coverage is for administering Formula I compounds or pharmaceutical compositions to treat or prevent diseases involving RIP1 kinase, and for inhibiting RIP1 kinase in a subject, with the compound structure constrained to the extensive Formula I ring and substituent definitions.
Stated Advantages
Selective RIP1 inhibition over related kinases.
Treating or preventing RIP1-associated diseases.
Documented Applications
Treating amyotrophic lateral sclerosis (ALS).
Treating type I diabetes.
Treating rheumatoid arthritis.
Treating Crohn's disease.
Treating ulcerative colitis.
Treating multiple sclerosis.
Treating asthma.
Treating leukemia.
Inhibiting receptor-interacting protein-1 (RIP1) kinase in a subject.
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