Compounds
Inventors
Rabbitts, Terrence • QUEVEDO, Camilo • CRUZ, Abimael • Phillips, Simon • Fallon, Philip Spencer • DUNN, Jonathan Neil • FREEM, Joshua Robert • LEE, Lydia Yuen-Wah • TRAORE, Tenin • Williams, Sophie Caroline
Assignees
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Publication Number
US-12024506-B2
Publication Date
2024-07-02
Expiration Date
Abstract
The present invention relates to compounds of Formula I as defined herein, and salts and solvates thereof. (I) The present invention also relates to pharmaceutical compositions comprising compounds of Formula (I), and to compounds of Formula (I) for use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which inhibition of a RAS-effector protein-protein interaction is implicated.
Core Innovation
The invention relates to compounds of Formula (Ia), or a salt or solvate thereof, and to substituted benzodioxin-containing amide, urea, carbamate, and benzodioxin–pyridine-related compounds. The compounds are defined by extensive structural variability through substituent selections including R5 and Ra, with further constraints provided by Formula II and, where applicable, Formula III.
The structural scope includes benzodioxin- and methoxy-pyridine-containing members, as well as analogs bearing substituted pyridine, amino-derived, carbamoyl, amide, urea, carbamate, and heterocycle-linked side chains. The examples and enumerated structures include compounds such as 2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-6-methoxy-pyridine and related substituted derivatives, including stereochemical forms designated with (R) and (S).
The document further frames the compounds as inhibitors of RAS–effector protein–protein interactions, including RAS–RAF and RAS–PI3K interactions, and describes BRET-based assay context for measuring inhibition of KRAS, NRAS, and HRAS interactions with effector domains. The disclosed compounds are presented in the context of pharmaceutical compositions and treatment of proliferative disorders/cancer.
Claims Coverage
Three independent claim themes are present across the input: a broad Formula (Ia) compound family with Formula II and optionally Formula III constraints, a specifically enumerated set of substituted benzodioxin/pyridine-related compounds, and use/composition claims. The inventive features center on the Formula (Ia) scaffold, defined linkage and ring-system constraints, selected named compounds, and pharmaceutical use formats.
Compounds of Formula (Ia) with variable substituents
A compound of Formula (Ia), or a salt or solvate thereof, wherein R5, Ra, and Rb are selected from the recited substituent sets, including hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, O—C1-6 alkyl, C1-6 alkyl optionally substituted by one or more Ra, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, and carbonyl- or sulfonyl-adjacent groups.
Formula II linkage and scaffold constraints
A Formula (Ia) compound that includes a group of Formula II, defined by (CR e R f )a-J1a-(CR g R h )b-A1a-((CR i R j )c-J1b-(CR l R m )d-A1b)x, with the claimed selections for a, b, c, d, x, J1a, J1b, A1a, and A1b.
Optional Formula III structural framework
A Formula (Ia) compound that further includes a group of Formula III, defined through a similar connectivity framework with J2a, J2b, A2a, and A2b, and the associated variable selections described in the claims.
Enumerated substituted compounds
A compound, or a salt or solvate thereof, selected from a stated group of specific substituted compounds, including benzodioxin and methoxy-pyridine-related structures, stereochemically defined members, and amide, urea, carbamoyl, morpholine, piperidine, piperazine, and related side-chain motifs.
Inhibiting cell proliferation
A method for inhibiting cell proliferation, in vitro or in vivo, by contacting a cell with an effective amount of a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.
Pharmaceutical composition and combination therapy
A pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, and a pharmaceutical combination including the compound together with an additional therapeutically active agent.
Overall, the claims cover a broad Formula (Ia) compound family constrained by Formula II and optionally Formula III, a specific enumerated set of substituted benzodioxin/pyridine-related compounds, and use formats including inhibiting cell proliferation, pharmaceutical compositions, and combination therapy.
Stated Advantages
Inhibits RAS–effector protein–protein interactions, including RAS–RAF and RAS–PI3K interactions.
Dose-dependent inhibition is described in the BRET-based assay context.
Therapeutic use for proliferative disorders/cancer is described.
Documented Applications
Therapeutic treatment of proliferative disorders/cancer using the described compounds.
In vitro and in vivo inhibition of cell proliferation by contacting a cell with an effective amount of the compound.
BRET-based biosensor or BRET2 cell-based assay context for measuring inhibition of KRAS, NRAS, and HRAS interactions with PI3K, CRAF, and RALGDS effector domains.
Pharmaceutical compositions and pharmaceutical combination use with an additional therapeutically active agent.
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