Compounds and uses thereof
Inventors
Schiller, Shawn E. R. • NEGRETTI, Solymar • Huang, David S. • Wilson, Kevin J. • UCISIK, Melek Nihan • Caldwell, Richard
Assignees
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Publication Number
US-12139487-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The present disclosure features compounds of Formula I, or pharmaceutically acceptable salts thereof, and formulations containing the same. Methods of treating BAF complex-related disorders, such as cancer, are also disclosed.
Core Innovation
The invention provides compounds and pharmaceutically acceptable salts defined by a structure with multiple variable positions m, n, p; X1, X2; Z1, Z2; and R1 through R10, including R5 through R6, R7/R7A, R8, and R9, together with conditional structural rules. The structure includes X1 being O, NR5, or (C(R5)(R6)), X2 being N or CR8, and L1 and L2 selected from specified bicyclic heterocyclyl/heteroaryl, heteroarylvinyl, heteroaryl-C3-C8-cycloalkyl, heteroarylethynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl classes.
The compound framework includes deuterium and halo substituents and optional formation of a carbonyl from geminal substituents, together with optional formation of ring systems from geminal R7A or vicinal R6/R9 groups. The disclosed compound class is described as a BRG1/BRM inhibitor class associated with modulation of BAF chromatin remodeling complexes, and the compounds decrease BAF complex activity and inhibit BRM/BRG1, including in the context of BRG1 loss-of-function.
The document further relates the compounds to therapeutic use contexts and to biological assay characterization. It references BRG1 IC50 to BRM IC50 ratio thresholds, BRG1/BRM-dependent transcription inhibition, ATPase catalytic activity assays, growth inhibition studies in cancer cell lines, and treatment of BAF complex-related disorders, including cancer.
Claims Coverage
The independent claim defines a broad compound class, or pharmaceutically acceptable salts, through a highly variable structure with conditional rules and broad substituent definitions. Across the provided items, the claim coverage is consistently centered on the same core scaffold variables and substitution patterns, with dependent claims narrowing selected variables and adding BRG1/BRM selectivity thresholds and therapeutic use limitations.
Variable compound scaffold with conditional heteroatom and bridge rules
A compound having the structure where m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X1 is O, NR5, or (C(R5)(R6)); X2 is N or CR8; and each of Z1 and Z2 is independently absent or (C(R9)2) or O, with the condition that if X1 is O then each of Z1 and Z2 is independently absent or (C(R9)2).
Linkage selection through L1 and L2
L1 is optionally substituted 9- or 10-membered bicyclic heterocyclyl, optionally substituted 9- or 10-membered bicyclic heteroaryl, optionally substituted monocyclic 6-membered heteroarylvinyl, optionally substituted monocyclic 6-membered heteroaryl-C3-C8-cycloalkyl, or optionally substituted monocyclic 6-membered heteroarylethynyl; and L2 is absent, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl.
Deuterium, halo, and carbonyl-forming substituent options
Each RX1 is independently deuterium, optionally substituted C1-C6 alkyl, or halo, or two geminal RX1 groups together with the atom to which they are attached combine to form a carbonyl; R5 is hydrogen, deuterium, or optionally substituted C1-C6 alkyl; R6 is hydrogen, deuterium, optionally substituted C1-C6 alkyl, or halo; and each R9 is independently hydrogen, deuterium, optionally substituted C1-C6 alkyl, or halo, with an alternative where R6 and one vicinal R9 together form an optionally substituted C3-C8 cycloalkyl.
Broad R-group substitution framework including ring-forming options
R1 is hydrogen or optionally substituted C1-C6 alkyl; each R2 and each R3 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R4 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl; each R7 is independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, halo, optionally substituted C3-C10 cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, —N(R7A)2, or —OR7A, where each R7A is independently H or one of the listed substituent classes, and two geminal R7A groups can form optionally substituted 5- to 10-membered heteroaryl or optionally substituted 4- to 10-membered heterocyclyl; R8 is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 cycloalkyl; and R10 is hydrogen or halo.
Pharmaceutically acceptable salt coverage
The claim covers the compound and a pharmaceutically acceptable salt thereof.
Dependent claim narrowing by selected variable values
Dependent coverage includes selections such as X2 = CR8, R8 = fluoro, and p = 3.
BRG1/BRM selectivity threshold
Dependent coverage includes a BRG1 IC50 to BRM IC50 ratio of at least 5, with additional ratios referenced in the provided material.
Therapeutic use for BAF complex-related disorders
Dependent coverage includes administering an effective amount of the compound to treat a BAF complex-related disorder in a subject.
Overall, the claims are directed to a broad, conditional, variable compound class with extensive substituent definitions, defined L1/L2 linkage options, deuterium and halo coverage, and pharmaceutically acceptable salts. Dependent claims further narrow the structure and add BRG1/BRM selectivity and therapeutic-use limitations for BAF complex-related disorders.
Stated Advantages
Decreases BAF complex activity.
Inhibits BRM/BRG1, including in the context of BRG1 loss-of-function.
Induces apoptosis.
Reports in vitro ATPase catalytic activity and BRG1/BRM-dependent transcription inhibition using IC50 values and ratios.
Reports growth inhibition in cancer cell lines, including uveal melanoma sensitivity.
Includes chiral SFC results indicating 100% ee for some compounds.
Comparable potency with clinical PKC (LXS196) and MEK (selumetinib) inhibitors, with faster onset.
Dose-dependent tumor regression in a nude mouse uveal melanoma model.
Good tolerability in the reported in vivo model.
Documented Applications
Treatment of BAF complex-related disorders in a subject.
Treatment of cancer, including non-small cell lung cancer, colorectal cancer, uveal melanoma, bladder cancer, glioma, breast cancer, melanoma, prostate cancer, renal cell carcinoma, and hematologic cancers.
Treatment of specified viral infections/disorders associated with Retroviridae, Hepadnaviridae, Flaviviridae, Herpesviridae, Papillomaviridae, Polyomaviridae, Adenoviridae, Parvoviridae, Paramyxoviridae, and Togaviridae.
In vitro BRG/BRM ATPase inhibition and BRG1/BRM-dependent transcription inhibition studies.
Growth inhibition studies in cancer cell lines, including uveal melanoma cell lines.
Uveal melanoma tumor regression in a nude mouse uveal melanoma model for Compound C.
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