Compounds which inhibit RNA polymerase

Inventors

Liu, Hester Hui • Barrow, James C. • Laiho, Marikki K. • Nv, Rajesh Kumar • De Leon, Pablo • Dorado, Tony • Begum, Asma • Fan, Wenjun • Stachelek, Gregory

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit RNA polymerase I (Pol I). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) Pol I activity contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

Core Innovation

The invention concerns Formula (I) compounds, including pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, and pharmaceutical compositions containing the compounds. The disclosed structure includes a benzo[h]pyrido[2,1-b]quinazoline-7-oxo-12-carboxamide scaffold and is defined by substituent variables including R1, R2, and an optional L1 linkage, with R2 selected from amine-containing groups, ether-containing groups, or heterocyclyl moieties of 4-12 ring atoms with defined heteroatoms and optional substitution.

In Formula (I), L1 is a bond or C1-6 alkylene optionally substituted with Rc, with a specific constraint when L1 is a bond requiring attachment via a ring carbon atom. The remaining variable groups R3a, R3b, R3c, R4a, R4b, R5a, R5b, R5c, and R5d are independently selected from H, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and OH, with further enumerated options for Ra, Rb, Rd, and the pair R′ and R″.

The patent describes these Formula (I) compounds as RNA Pol I inhibitor chemical entities and states that they destruct RPA194 and inhibit RNA polymerase I. It also recites methods for modulating RNA Pol I activity in mammalian cells and activating upstream p53 pathways in mammalian cells by contacting cells or a population of cells with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Claims Coverage

The consolidated claim coverage includes one independent claim to a Formula (I) compound or pharmaceutically acceptable salt thereof, and a method claim directed to activating upstream p53 pathways in a mammalian cell by contacting the cell with the compound. The inventive features center on the enumerated structural constraints of Formula (I), including specific R2 and L1 definitions and dependent narrowing of substituent choices.

Overall, the claims are directed to Formula (I) compounds defined by enumerated substituent selections, including heterocyclyl R2 and optional L1 linkage, with dependent refinements that narrow R2 to specific ring scaffolds and fix selected substituent positions, and to a method of contacting mammalian cells with the compound to activate upstream p53 pathways.

Stated Advantages

Documented Applications