Compounds and uses thereof
Inventors
Anthony, Neville John • Millan, David Simon • Vaswani, Rishi G. • Schiller, Shawn E. R.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12383560-B2
Publication Date
2025-08-12
Expiration Date
Abstract
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
Core Innovation
The disclosed subject matter relates to compounds having the structure of Formula I and pharmaceutically acceptable salts thereof. The Formula I structure is defined by variable substituents including B, A, X, Y, Z, m, n, and multiple substituent groups such as R, R1, R3, R4, R5, R6, and R7, with defined options for aryl, heteroaryl, alkoxy, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, alkenyl, heteroalkenyl, hydroxy, halo, amino, sulfone, sulfonamide, cyano, thiol, and related optionally substituted variants. The disclosed compound family includes ring-fragment options for A and B and variable heteroatom or linkage definitions for X, Y, and Z, which preserve the shared scaffold while permitting chemical diversification.
The disclosure further describes a family of compound embodiments within the Formula I framework, including examples and illustrated structures, such as compounds enumerated in Tables 1, 3, and 4, as well as related structural embodiments and specific compound examples. The examples retain the same core scaffold while varying pendant substituents and stereochemical variants, including compounds with benzamide or urea-like linkages, thiazole-containing heteroaromatic cores, and substituted aromatic or heteroaromatic regions. The document further notes characterization of intermediates and final compounds by LCMS and 1H NMR, and in some excerpts references chiral HPLC and enantiomeric excess.
The document also relates the compounds to modulation of the SWI/SNF (BAF) chromatin remodeling complex and to BRG1 and/or BRM. It describes compounds and methods in the context of BAF-complex-related disorders, cancer, BRG1-loss-of-function cancer, BRM-selective compounds, and BRM/BRG1 dual inhibitors, and states that the compounds can be used alone or with other pharmaceutically active agents.
Claims Coverage
The consolidated claim coverage centers on one broad independent claim family directed to Formula I compounds and pharmaceutically acceptable salts, with the claim set repeatedly defining the same scaffold through variable ring fragments and substituents. Across the provided items, the independent scope includes 1 main inventive feature set for the Formula I scaffold, and dependent limitations further refine substituent choices, add pharmaceutical composition language, and recite cancer-treatment methods with BRM/BRG1 selectivity constraints.
Formula I compound with defined variable substituents
A compound having the structure of Formula I, with B, A, X, Y, Z, m, n, and the R-group positions defined by the recited substituent options, including optionally substituted aryl, heteroaryl, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, alkenyl, heteroalkenyl, hydroxy, halo, amino, and related variants.
A and ring heteroatom selections via X, Y, and Z
A is defined by X being N or CRX and Y being N or CRY, with RX and RY selected from the enumerated substituent classes; Z is S, O, or NRZ, with RZ selected from the listed options.
R6 and R7 substitution and ring formation
R6 and R7 are independently selected from halo, optionally substituted alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkenyl, heteroalkenyl, and amino, and two R7 may combine with the carbons to form a 5- or 6-membered ring.
Pharmaceutically acceptable salts
The Formula I compound is claimed together with a pharmaceutically acceptable salt thereof.
Fixed substituent refinement for R3 and R5
In the dependent claim coverage, R3 and R5 are specified as H.
Pharmaceutical composition with excipient
A pharmaceutical composition includes the Formula I compound together with a pharmaceutically acceptable excipient.
Cancer treatment method using the Formula I compound
A method of treating cancer in a subject by administering an effective amount of the Formula I compound.
BRM-selective compound in cancer treatment
The cancer treatment method is performed using a BRM-selective compound.
BRM over BRG1 selectivity threshold
A BRM-selective compound inhibits BRM level and/or activity at least 10-fold more than it inhibits BRG1, and/or binds to BRM at least 10-fold more than it binds to BRG1.
Specific compounds by structure
An additional independent claim covers a compound having the structure of any one of specific compounds, or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage is dominated by a broad Formula I scaffold with explicitly defined substituent variability, including A, B, X, Y, Z, R-group positions, and salt forms. The dependent and related claim coverage adds narrower substituent selections, pharmaceutical compositions, and cancer-treatment methods, including BRM-selective limitations with an explicit 10-fold comparative inhibition and/or binding threshold versus BRG1.
Stated Advantages
Inhibits BAF (BRG1/BRM) complex activity in cells.
Induces apoptosis.
Enables treatment of BAF-complex-related disorders, including cancer.
Provides target selectivity by inhibiting BRM level and/or activity and/or binding to BRM more than BRG1 using a comparative threshold.
Provides dual BRM/BRG1 inhibition within a comparative threshold.
Shows anti-tumor effects.
Shows growth inhibition of tumor cell models.
Shows anti-proliferative effects across additional cancer cell lines.
Documented Applications
Treating cancer in a subject by administering an effective amount of a Formula I compound.
Using a BRM-selective compound in a cancer treatment method.
Treating or inhibiting BRM and/or BRG1 in the context of BAF-complex-related disorders, including BRG1 loss of function mutation contexts.
Inducing apoptosis in cells as part of therapeutic methods described for cancer and related disorders.
Use with other cancer therapeutics in combination therapy.
Preparation and characterization of specific Formula I-related compounds and intermediates.
In vitro BRM/BRG1 ATPase catalytic activity evaluation.
Growth inhibition evaluation in uveal melanoma and hematologic cancer cell lines.
Comparison of Compound 87 to clinical PKC/MEK inhibitors.
Anti-proliferative evaluation across additional cancer cell lines using Compound B.
Interested in licensing this patent?