Bisfluoroalkyl-1,4-benzodiazepinone compounds and methods of use thereof
Inventors
Davis, Matti • FISCHER, BRUCE S. • BAJAJ, Gaurav
Assignees
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Publication Number
US-12281085-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The present invention provides compositions comprising bisfluoroalkyl-1,4-benzodiazepinone compounds, including compounds of Formula (I) or prodrugs thereof; in combination with an additional cancer therapeutic agent, and methods of use thereof for treating diseases and disorders such as cancer.
Core Innovation
The disclosure provides benzodiazepinone compounds, including compounds represented by Formula (I), Formula (IV), Formula (V), and related sub-formulas (II-VI), as well as a Compound (1) structure. It defines chemical substituent variables and structural variations, including Ring A phenyl or pyridinyl, and describes substituted benzodiazepinone derivatives, salts, and prodrugs.
The disclosed compounds are described as Notch inhibitors and/or gamma-secretase inhibitors. The disclosure positions these compounds for treating proliferative diseases and cancer, including adenoid cystic carcinoma (ACC), including cases involving NOTCH-activating mutations.
The disclosure also describes combination compositions and therapeutic use with other anti-cancer agents. A first composition comprising a Compound (1) and/or at least one salt thereof or a Formula (I) compound and/or at least one salt or prodrug is administered together with a CDK 4 and 6 inhibitor, sorafenib, regorafenib, venetoclax, vorinostat, retinoic acid derivatives, or combinations thereof.
Claims Coverage
The consolidated independent claims cover 2 claim sets centered on a Compound (1) composition and specified second therapeutic agents, and on treating ACC by administering two compositions to a subject. Across the claims, the inventive features are the defined Compound (1) and/or salts, the specified partner agents, and the ACC treatment context.
Compound (1) composition with salts
A composition comprising a compound represented by the structure of Compound (1), and/or at least one salt thereof.
Combination with specified therapeutic agents
In combination with a composition comprising a CDK 4 and 6 inhibitor, sorafenib, regorafenib, venetoclax, vorinostat, or a combination thereof.
Treating adenoid cystic carcinoma (ACC) in a subject
Administering a first composition comprising a compound represented by the structure of Compound (1) and/or at least one salt thereof, and a second composition comprising a CDK 4 and 6 inhibitor, sorafenib, regorafenib, venetoclax, vorinostat, or a combination thereof, wherein the subject has adenoid cystic carcinoma (ACC).
The claims require Compound (1) and/or its salts together with specified therapeutic agents, either as a combination composition or in a method for treating, suppressing, or inhibiting ACC in a subject.
Stated Advantages
Tumor growth inhibition and enhanced efficacy in ACC PDX models (ACC×9 and ACC×11).
Documented Applications
Treating, suppressing or inhibiting adenoid cystic carcinoma (ACC) in a subject using a first composition comprising Compound (1) and/or at least one salt, together with a second composition comprising a CDK 4 and 6 inhibitor, sorafenib, regorafenib, venetoclax, or vorinostat.
Treatment of proliferative diseases and cancer as Notch inhibitors and/or gamma-secretase inhibitors, including cases involving NOTCH-activating mutations.
Use in ACC PDX models (ACC×9 and ACC×11) showing tumor growth inhibition and enhanced efficacy when combined with agents such as ABT-199, sorafenib, and ATRA.
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