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Publication Number
US-11274082-B2
Publication Date
2022-03-15
Expiration Date
Abstract
The present invention provides compounds, compositions thereof, and methods of using the same.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, defined by specific structural selections for L1, Ring A, R2, R3, R4, and R6. L1 is —NH—CH2— or —NH—C(O)—, Ring A is phenyl optionally substituted by halogen, —CN, —NO2, or C1-6 aliphatic substitution, R2 is an optionally substituted 5-membered heteroaryl ring having 2 nitrogen atoms, R3 is —H, R4 is selected from halogen, —S(O)2N(R)2, —S(O)N(R)2, or —C(O)N(R)2, and R6 is —H or an optionally substituted C1-6 aliphatic group.
The disclosure also provides related Formula II and sub-formulas, including additional generalized compound templates with variables such as R1, R2, R3, R6, R7, and Rw. The scaffold is described in connection with benzenesulfonamide-containing embodiments and multiple specific analog structures, including heteroaromatic sulfonamide/sulfonyl-containing compounds with varying heterocycles and aryl groups.
The document describes TEAD inhibitor compounds of Formula I and their functional behavior, including selective binding to TEAD, disruption of YAP/TAZ—TEAD interaction, downregulation of YAP/TAZ-dependent transcription, and prevention of TEAD palmitoylation. It further links the scaffold-variable substituent choices to TEAD reversible inhibition and Hippo/YAP/TAZ pathway activity.
Claims Coverage
The consolidated claim coverage includes Formula I compound claim frameworks and dependent refinements that narrow linkage, Ring A substitution, R4 form, and related sub-formulas, together with pharmaceutical composition claims. Across the independent claim material, the main inventive features are the Formula I structural variables and formulations including the claimed compound or salt with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Formula I compound structural definition
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein L1 is —NH—CH2— or —NH—C(O)—; Ring A is phenyl optionally substituted 1-2 times by halogen, —CN, —NO2, or by C1-6 aliphatic substitution options; R2 is an optionally substituted 5-membered heteroaryl ring having 2 nitrogen atoms; R3 is —H; R4 is halogen, —S(O)2N(R)2, —S(O)N(R)2, or —C(O)N(R)2; R6 is —H or C1-6 aliphatic substituted 0-6 times by halogen, —CN, or —NO2; and each R is independently —H or optionally substituted C1-6 aliphatic.
L1 fixed to —NH—CH2—
The compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein L1 is —NH—CH2—.
Ring A phenyl substitution constraints
The compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted 1-2 times and further substituted 0-6 times by halogen, with optional C1-6 aliphatic groups substituted 0-6 times by halogen.
R4 selected as —S(O)2NHR
The compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4 is —S(O)2NHR.
Pharmaceutical composition including carrier, adjuvant, or vehicle
A pharmaceutical composition that includes the compound of Formula I, or a pharmaceutically acceptable salt form thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Claim coverage centers on Formula I compounds defined by L1, Ring A, R2, R3, R4, R6, and R substituent constraints, with dependent claims narrowing L1 to —NH—CH2—, limiting Ring A substitution patterns, specifying R4 as —S(O)2NHR, and extending coverage to pharmaceutical compositions containing the compound with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Stated Advantages
Selective binding to TEAD.
Disruption of YAP/TAZ—TEAD interaction.
Downregulation of YAP/TAZ-dependent transcription.
Prevention of TEAD palmitoylation.
Inhibition of TEAD-mediated signaling in the Hippo/YAP/TAZ pathway.
Reversible inhibition of TEAD.
Hippo-pathway-dependent antiproliferative activity in vitro.
Downregulation of YAP-dependent genes in human tumor xenografts after oral dosing.
Inhibition of tumor growth at well-tolerated doses.
Documented Applications
Inhibition of TEAD-mediated signaling in the Hippo/YAP/TAZ pathway for cancer and proliferative disorders, including cellular proliferative disorder.
In vivo use in human tumor xenografts, where the compounds downregulate YAP-dependent genes after oral dosing and inhibit tumor growth.
In vitro assessment of Hippo-pathway-dependent antiproliferative activity.
Example TEAD inhibition assay using a Hippo Pathway TEAD Reporter—MCF7 luciferase system.
Mouse pharmacokinetics (BALB/c) context with LC/MS/MS measurement.
Anti-proliferation assay context and in vivo tumor growth inhibition in NCI-H226 and MSTO-211H.
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