Compounds and uses thereof
Inventors
Ruppel, Sabine K. • Yang, Zhaoxia • LOWE, Jason T. • Voigt, Johannes H. • Netherton, Matthew
Assignees
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Publication Number
US-12351579-B2
Publication Date
2025-07-08
Expiration Date
Abstract
The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, defined by an A-L-B architecture. Substructure A has the structure of Formula IIc or Formula IlIc, substructure B has the structure of Formula AA0, and linker L has the structure of Formula IIg or Formula Ilg, with bonds between L and A and between B and L. The definitions include variable structural parameters and substituent classes for R4, R5, R6a, R6b, v1, J_A, J, n, o1, E1, E3, and F1/F2.
For A, R4 is -CH3, R5 is H, and R6a and R6b are selected from H, halogen, cyano, or optionally substituted C1-C6 alkyl, with R6b also stated as H or —CH3 in one disclosure. For B, v1 is 0, 1, 2, 3, 4, or 5, J_A is absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and J is absent or selected from optionally substituted carbocyclylene, arylene, heterocyclylene, or heteroarylene classes.
The linker L is defined with each of n and o1 independently 0 or 1. E1 is selected from O, S, NRN, optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, optionally substituted C2-10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkylene; E3 is optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, O, S, or NRN; each R_N is independently H or methyl; and each of F1 and F2 is independently optionally substituted C2-9 heterocyclylene. The disclosed embodiments include multiple exemplified compound structures and pharmaceutically acceptable salts thereof.
Claims Coverage
The claim coverage centers on one Formula I compound family built from three connected structural regions, A, B, and linker L. The main inventive content is the structural definition of A, B, and L together with discrete variable values and selectable substituent classes, including v1, J_A, J, n, o1, E1, E3, and F1/F2. Dependent claims further narrow specific parameter choices and topology constraints.
Formula I compound with A-L-B architecture
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A has the structure of Formula IIc or Formula IlIc, B has the structure of Formula AA0, and L has the structure of Formula IIg or Formula Ilg, with bonds between L and A and between B and L.
A substructure constraints
A is defined with R4 as -CH3, R5 as H, and R6a and R6b limited to H, halogen, cyano, and optionally substituted C1-C6 alkyl, with R6b also stated as H or —CH3 in one disclosure.
B substructure constraints
B is defined with v1 as 0, 1, 2, 3, 4, or 5, J_A as absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and J as absent or selected from optionally substituted carbocyclylene, arylene, heterocyclylene, or heteroarylene classes.
Linker L constraints
L is defined by Formula IIg or Formula Ilg with n and o1 independently 0 or 1, E1 selected from O, S, NRN, optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, optionally substituted C2-10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkylene, and E3 selected from optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, O, S, or NRN.
Heterocyclylene options for F1 and F2
F1 and F2 are each independently optionally substituted C2-9 heterocyclylene.
Dependent narrowing of variable selections
Dependent narrowing includes v1 equal to 0, J_A selected as O or optionally substituted amino, E3 optionally substituted with C1-6 alkylene, O, S, or NRN, and the C2-C9 heterocyclylene of F1 and F2 being monocyclic.
Overall, the claim coverage is directed to Formula I compounds defined by a modular A-L-B framework with explicit structural formulae for A, B, and linker L. The inventive scope is expressed through parameterized variability in the substructures and linker, with additional dependent claims narrowing discrete variables and selected structural classes.
Stated Advantages
Inhibit BRD9 level and/or activity in cells.
Treat BRD9-related disorders.
Treat BAF complex-related disorders.
Treat SS18-SSX fusion protein-related disorders.
May be administered as part of combination therapy.
Documented Applications
Used to inhibit BRD9 level and/or activity in cells, including cancer cells.
Used to treat BRD9-related disorders.
Used in contexts of BAF complex-related disorders, including cancer and viral infection.
Used in contexts of SS18-SSX fusion protein-related disorders, including synovial sarcoma tumors by depletion of the SS18-SSX fusion protein associated with BRD9 depletion.
Administration as part of combination therapy.
BRD9 targeting degraders/depleting agents leveraging BAF involvement in antiviral activities.
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