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Publication Number
US-11458149-B1
Publication Date
2022-10-04
Expiration Date
Abstract
The present invention provides compounds, compositions thereof, and methods of using the same.
Core Innovation
The disclosed invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof. The compounds are defined by Ring A as optionally substituted phenyl and Ring B optionally substituted with Rw = -L-Y, within a structural framework that includes linker variables L1 and L and substituent variables Y, Re, Q, Z, and R.
L1 is a C1-6 bivalent straight or branched hydrocarbon chain in which one, two, or three methylene units are independently and optionally replaced by heteroatom-containing, carbonyl-containing, thio-, sulfonyl-, sulfone-, thiocarbonyl-, and related functional groups. L is a covalent bond or a bivalent C1-8 saturated or unsaturated straight or branched hydrocarbon chain with optional methylene replacements by corresponding heteroatom- and carbonyl-containing groups, and Q is similarly defined as a covalent bond or a bivalent C1-6 hydrocarbon chain with optional replacements.
Y is hydrogen, a C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur and substituted with 1-4 Re groups. Each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, or a C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, and Z is hydrogen or a C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN.
Claims Coverage
The provided claim coverage centers on one independent claim for a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with dependent refinements. The principal inventive features are the Formula I scaffold, the linker variables L1 and L, and the nested substitution definitions for Ring A, Ring B via Rw = -L-Y, Y, Re, Q, Z, and R.
Formula I compound scaffold with optional pharmaceutically acceptable salts
A compound of Formula I or a pharmaceutically acceptable salt thereof, with Ring A as optionally substituted phenyl and Ring B optionally substituted with Rw = -L-Y.
Linker L1 with optional heteroatom and carbonyl replacements
L1 is a C1-6 bivalent straight or branched hydrocarbon chain in which one, two, or three methylene units are independently and optionally replaced by heteroatom-containing, carbonyl-containing, thio-, sulfonyl-, sulfone-, thiocarbonyl-, and related functional groups.
Ring B substitution as Rw = -L-Y
Ring B is optionally substituted with Rw = -L-Y, where L is a covalent bond or a bivalent C1-8 saturated or unsaturated straight or branched hydrocarbon chain with optional methylene replacements, and Y is defined by the permitted aliphatic or ring classes and Re substitutions.
Y, Re, Q, and Z substituent definitions
Y is hydrogen, a C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms and substituted with 1-4 Re groups; each Re is independently -Q-Z, oxo, NO2, halogen, CN, or a C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN; Q and Z are defined by covalent bond or hydrocarbon chain options with optional replacements.
Pharmaceutical composition with carrier, adjuvant, or vehicle
A pharmaceutical composition including the compound of Formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Overall, the claim coverage is organized around Formula I compounds defined by Ring A and Ring B linked through Rw = -L-Y, with detailed structural constraints on L1, L, Y, Re, Q, Z, and R. Dependent claims narrow these variables by specifying particular Ring A substitution patterns, discrete L1 selections, and a partially unsaturated heterocyclic Y embodiment, and one claim covers a pharmaceutical composition.
Stated Advantages
Inhibiting TEAD via the Hippo signaling pathway.
Modulating YAP/TAZ-TEAD interactions.
Modulating TEAD palmitoylation.
Disrupts YAP/TAZ interaction with TEAD.
Prevents TEAD palmitoylation.
Downregulates YAP-dependent genes in human tumor xenografts after oral dosing.
Produces single-agent tumor growth inhibition at well-tolerated doses.
In vitro growth inhibition is selective in Hippo/NF2 mutant cancer cells.
No detectable impact on differentiated mouse podocytes and no kidney histology impact were reported.
Inhibition of TEAD-family function by binding to TEAD1 and disrupting TEAD1-dependent activity.
Prevention of TEAD1 palmitoylation at the disclosed TEAD1 residues.
Extension of TEAD inhibition to TEAD2, TEAD3, and TEAD4 through binding at respective disclosed residues.
Therapeutic use in treating TEAD-mediated disorders is discussed in the document.
TEAD inhibitors are assayed in vitro and in vivo.
Documented Applications
Pharmaceutical compositions intended to inhibit TEAD via the Hippo signaling pathway, including modulation of YAP/TAZ-TEAD interactions and TEAD palmitoylation.
Use context within broader discussion of Hippo signaling and GPCR/G-protein regulation.
In vitro testing in Hippo/NF2 mutant cancer cells.
Evaluation in differentiated mouse podocytes and kidney histology.
In vivo human tumor xenografts with oral dosing, including H226 mesothelioma xenograft and MSTO-211H mesothelioma xenograft.
TEAD Reporter MCF7 assay with Hippo-pathway activation controls.
Methods of treating TEAD-mediated disorders are discussed, with disease-treatment context including cancer/proliferative disorders.
Therapeutic combination context with other therapeutic agents is discussed.
TEAD inhibitors are assayed in vitro and in vivo.
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