Bicyclic heteroaryl compounds and uses thereof
Inventors
Gill, Adrian L. • BUCKL, Andreas • Koltun, Elena S. • Aay, Naing • Tambo-ong, Arlyn A. • Thompson, Severin • Gliedt, Micah James • Knox, John E. • Cregg, James • Edwards, Anne V. • Liu, Yang • Burnett, G. Leslie
Assignees
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Publication Number
US-12258366-B2
Publication Date
2025-03-25
Expiration Date
Abstract
The present disclosure is directed to modulators of SOS1 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.
Core Innovation
The invention relates to treating a disease by inhibiting the interaction of SOS1 and a RAS-family protein or by inhibiting the interaction of SOS1 and RAC1. The method comprises administering to a subject in need thereof an effective amount of a compound selected from specified pyrido[2,3-d]pyrimidin-7(8H)-one derivatives, including pharmaceutically acceptable salts and stereoisomers. The compounds are described with defined stereochemistry and diverse substituents, including fluorinated aryl groups and cyclic amine or heterocycle side groups.
The disclosed compound sets include substituted pyrido[2,3-d]pyrimidin-7(8H)-one analogs and related small-molecule compounds identified in enumerated lists or tables of structures. The examples and structural depictions include stereochemical variants and substituents such as morpholine-like, tetrahydropyridinyl, thiopyran, tetrahydrothiopyran, oxido, sulfone, and sulfonamide-related motifs. The compounds are positioned as SOS1-targeting agents within the claimed method families.
The claimed subject matter also covers methods of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell. Across the provided material, the same mechanistic characterization is maintained: administration of an effective amount of the selected compounds, or selected compounds from a table, to achieve SOS1 interaction inhibition in disease-treatment or cell-based contexts.
Claims Coverage
The consolidated claim coverage includes 2 biological interaction targets, SOS1 with a RAS-family protein and SOS1 with RAC1, and 4 recurring claim types: treating a disease with enumerated compounds, treating a disease with table-selected compounds, inhibiting SOS1 interaction in a cell with enumerated compounds, and inhibiting SOS1 interaction in a cell with table-selected compounds. The inventive scope is consistently defined by administering an effective amount of specified small-molecule compounds, including pharmaceutically acceptable salts and stereoisomers, or compounds selected from a table of structures.
Treating a disease by inhibiting SOS1 interaction with a RAS-family protein or RAC1
A method of treating a disease characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of specified pyrido[2,3-d]pyrimidin-7(8H)-one or related compounds, or a pharmaceutically acceptable salt or a stereoisomer thereof.
Treating a disease with table-selected SOS1 inhibitors
A method of treating a disease characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, selected from among the compounds in a table of structures.
Inhibiting SOS1 interaction in a cell by administering specified compounds
A method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell an effective amount of a compound selected from the group consisting of specified pyrido[2,3-d]pyrimidin-7(8H)-one or related compounds, or a pharmaceutically acceptable salt or a stereoisomer thereof.
Inhibiting SOS1 interaction in a cell using table-selected compounds
A method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell an effective amount of a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, selected from among the compounds in a table of structures.
Overall, the claims cover administration of defined pyrido[2,3-d]pyrimidin-based compounds, or table-selected compounds, to inhibit SOS1 interaction with either a RAS-family protein or RAC1 in disease-treatment and cell-based methods.
Stated Advantages
Inhibition of the interaction of SOS1 with a RAS-family protein or inhibition of the interaction of SOS1 with RAC1.
Methods of treating a disease characterized by SOS1 interaction inhibition.
Supports disease-scope targeting including cancer and RASopathy, with further refinement to cancers including Ras MUT and/or NF1 LOF mutations.
Documented Applications
Treatment of a disease in a subject by administering an effective amount of an SOS1 interaction inhibitor compound.
Inhibition of SOS1–RAS-family protein interaction or SOS1–RAC1 interaction in a cell by administering an effective amount of a listed compound.
Cancer treatment characterized by SOS1–RAS-family or SOS1–RAC1 interaction inhibition.
RASopathy treatment characterized by SOS1–RAS-family or SOS1–RAC1 interaction inhibition.
Treating hyperproliferative diseases such as cancer by SOS1 inhibition and modulation of SOS1–RAS-family protein and SOS1–RAC1 interactions, including within RASopathies such as NF1 and Noonan Syndrome and related disorders.
Combination therapy and therapeutic regimens are described in connection with administering the disclosed compounds.
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