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Publication Number
US-11760728-B2
Publication Date
2023-09-19
Expiration Date
Abstract
The present invention provides compounds, compositions thereof, and methods of using the same.
Core Innovation
The disclosed subject matter relates to compounds of Formula I and their use in a method for treating mesothelioma in a patient by administering a compound of Formula I or a pharmaceutically acceptable salt thereof. Formula I defines the chemical structure through variables including L1, Ring A, R2, R3, R4, R6, and each R, with L1 as —NH—CH2— or —NH—C(O)—, Ring A as phenyl optionally substituted by halogen, —CN, —NO2, or C1-6 aliphatic substitution patterns, and R2 as an optionally substituted 5-membered heteroaryl ring having 2 nitrogen atoms.
The structural definition further includes R3 as —H, R4 selected from halogen, —S(O)2N(R)2, —S(O)N(R)2, or —C(O)N(R)2, and R6 as —H or C1-6 aliphatic substituted 0-6 times by halogen, —CN, or —NO2. Each R is independently —H or optionally substituted C1-6 aliphatic, thereby defining the chemical space for the claimed mesothelioma-treatment compounds.
The document also describes compounds of Formula I as TEAD-pathway inhibitor compounds and provides compound preparation and characterization for substituted benzenesulfonamide and imidazole-containing intermediates and final compounds. The described examples include sulfonamide compounds bearing imidazole or 1-methylimidazol-4-yl moieties, fluorinated pyridyl groups, and other substituted aromatic or heteroaromatic fragments, with structures supported by analytical data such as 1H NMR and ES-LCMS.
Claims Coverage
The consolidated claim coverage centers on one independent method claim for treating mesothelioma by administering a compound of Formula I, or a pharmaceutically acceptable salt. Across the provided items, the inventive features focus on the structural definition of Formula I and dependent narrowing by linker, ring, and substituent selections.
Mesothelioma treatment by administering a Formula I compound
A method for treating mesothelioma in a patient comprising administering to the patient a compound of Formula I or a pharmaceutically acceptable salt thereof.
Formula I substituent-variable framework
Formula I defines L1 as —NH—CH2— or —NH—C(O)—; Ring A as phenyl optionally substituted 1-2 times by halogen, —CN, —NO2, or C1-6 aliphatic groups; R2 as an optionally substituted 5-membered heteroaryl ring having 2 nitrogen atoms; R3 as —H; R4 as halogen, —S(O)2N(R)2, —S(O)N(R)2, or —C(O)N(R)2; R6 as —H or C1-6 aliphatic substituted 0-6 times by halogen, —CN, or —NO2; and each R as independently —H or optionally substituted C1-6 aliphatic.
Narrowing L1 and R4
Dependent claims further specify L1 as —NH—CH2— and R4 as —S(O)2NH—CH3.
Defined substitution pattern on Ring A
Dependent claims constrain Ring A to phenyl with optional substitution by halogen, —CN, —NO2, or C1-6 aliphatic groups, including specified substitution-count limits.
Formula (XIIa-1) and (XIIa-2) embodiments
The method is carried out using a compound of Formula (XIIa-1) or (XIIa-2), with L1 as —NH—CH2— and R as C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F.
Enumerated compound structures
Dependent claims select from listed chemical structures including I-27, I-29, I-31, I-32, I-41, I-42, I-46, I-50, I-51, I-68, and I-74.
Overall, claim coverage is directed to mesothelioma treatment by administering Formula I compounds, with the structural scope defined by L1, Ring A, R2, R3, R4, R6, and R, and narrowed by dependent claims through specific substituent choices, substitution-count constraints, Formula (XIIa) embodiments, and enumerated compound selections.
Stated Advantages
Inhibits TEAD/YAP-TAZ transcriptional activity downstream of the Hippo pathway by modulating YAP/TAZ post-translational regulation.
Prevents TEAD palmitoylation and disrupts YAP/TAZ-TEAD interaction.
Inhibits proliferation of Hippo-pathway-deficient cancer cells.
In vivo tumor xenograft gene downregulation.
Single-agent tumor growth inhibition after oral dosing.
Oral dosing at well-tolerated levels.
Documented Applications
Treating mesothelioma in a patient by administering a compound of Formula I or a pharmaceutically acceptable salt thereof.
Inhibiting proliferation of Hippo-pathway-deficient cancer cells.
Human tumor xenografts with tumor xenograft gene downregulation and single-agent tumor growth inhibition after oral dosing.
Treating TEAD- and YAP/TAZ-mediated cancers and related proliferative disorders.
Use of a Hippo Pathway TEAD Reporter-MCF7 system to report luciferase-based Hippo/TEAD activity readouts in the context of TEAD inhibition.
TEAD selectivity assay concept for assessing TEAD pathway selectivity.
PD analysis described in the document following functional biology evaluation related to the TEAD pathway.
Mouse pharmacokinetics and subsequent in vivo/PD efficacy study references.
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