Compounds and uses thereof
Inventors
Netherton, Matthew • Brucelle, Francois • Deng, Jing • Voigt, Johannes H.
Assignees
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Publication Number
US-12552775-B2
Publication Date
2026-02-17
Expiration Date
Abstract
The present disclosure features compounds and methods useful for the treatment of BAF complex-related disorders.
Core Innovation
The invention relates to compounds having the structure of Formula I, wherein X is halo; X1 is absent, O, or NR1; k is 0, 1, 2, or 3; n is 0, 1, or 2; R1 is H or optionally substituted C1-C6 alkyl; L1 is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, or optionally substituted C2-C6 alkynylene; L2 is absent, optionally substituted C1-C6 alkylene, optionally substituted C1-C20 heteroalkylene, or optionally substituted C2-C9 heterocyclylene; and each L3 is independently selected from optionally substituted C1-C20 heteroalkylene, optionally substituted C3-C10 carbocyclylene, optionally substituted C3-C10 carbocyclylene-C1-C6 alkylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C2-C9 heterocyclylene-C1-C6 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 arylene-C1-C6 alkylene, optionally substituted C2-C6 alkynylene, O, or NR1. The compound includes D as a degradation moiety or a pharmaceutically acceptable salt thereof.
The degradation moiety D is narrowed in dependent coverage to a ubiquitin ligase binding moiety. The ubiquitin ligase binding moiety comprises a Cereblon ligand, an IAP (Inhibitors of Apoptosis) ligand, a mouse double minute 2 homolog (MDM2), or a von Hippel-Lindau ligand, and further dependent coverage constrains D by Formula A and Formula C scaffold definitions with variable rules and connection definitions between the degradation moiety and a linker.
The provided claim set also includes a quantitative BRG1 IC50 to BRM IC50 ratio threshold of at least 5. The description content further states that the compounds modulate or inhibit BAF complex activity by inhibiting BRG1 and optionally BRM, and describes pharmaceutical compositions comprising the compounds and pharmaceutically acceptable excipients, along with treatment contexts for cancers associated with BRG1 loss of function mutation.
Claims Coverage
The independent claims cover a Formula I compound with constrained structural variables and a degradation moiety D, and a separate claim selecting compounds 1-105 in Table 1. The claim framework includes four main inventive features around the degradation moiety and one quantitative performance threshold.
Formula I compound with constrained structural variables
A compound having the structure of Formula I, where X is halo; X1 is absent, O, or NR1; k is 0, 1, 2, or 3; n is 0, 1, or 2; R1 is H or optionally substituted C1-C6 alkyl; L1 is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, or optionally substituted C2-C6 alkynylene; L2 is absent, optionally substituted C1-C6 alkylene, optionally substituted C1-C20 heteroalkylene, or optionally substituted C2-C9 heterocyclylene; each L3 is independently selected from the listed structural classes; and D is a degradation moiety or a pharmaceutically acceptable salt thereof.
Ubiquitin ligase binding degradation moiety
The compound where D is a ubiquitin ligase binding moiety.
Selected ubiquitin ligase ligand options
The ubiquitin ligase binding moiety comprises a Cereblon ligand, an IAP (Inhibitors of Apoptosis) ligand, a mouse double minute 2 homolog (MDM2), or a von Hippel-Lindau ligand.
Degradation moiety constrained by Formula A or Formula C
The degradation moiety has Formula A structure with variable definitions including Y1, RA1-RA5, and RA6-RA8, with A2 as a bond between the degradation moiety and a linker, or has the structure of Formula C with L4 as —N(RB1)(RB2), v2 ranging from 0 to 4, and exactly one of RB1, RB3, and RB6 being A2.
Selected compound set from Table 1
A compound selected from the group consisting of compounds 1-105 in Table 1 and pharmaceutically acceptable salts thereof.
BRG1 IC50 to BRM IC50 ratio threshold
A compound having a BRG1 IC50 to BRM IC50 ratio of at least 5.
The claims are centered on a Formula I scaffold with defined substituent classes and a degradation moiety D, narrowed in dependent claims to a ubiquitin ligase binding moiety with named ligand options, further constrained by Formula A or Formula C degradation-moiety definitions, and supplemented by a BRG1 IC50 to BRM IC50 ratio threshold; a separate claim covers compounds 1-105 in Table 1.
Stated Advantages
Modulate or inhibit BAF complex activity by inhibiting BRG1 and optionally BRM.
Provide BRG1/BRM selectivity using a BRG1 IC50 to BRM IC50 ratio threshold of at least 5.
Treat cancers associated with BRG1 loss of function mutation.
Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable excipients are described.
Documented Applications
Method of treatment for cancers associated with BRG1 loss of function mutation, including non-small cell lung cancer, colorectal cancer, bladder cancer, glioma, melanoma, prostate cancer, breast cancer, renal cell carcinoma, and hematologic cancers.
Reducing tumor growth, metastasis, and/or survival.
Combination-therapy contexts.
Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable excipients.
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