Phthalazine derivatives as inhibitors of PARP1, PARP2, and/or tubulin useful for the treatment of cancer

Inventors

Peto, Csaba J. • Jablons, David M. • TSANG, Tsze • Lemjabbar-Alaoui, Hassan

Assignees

Atlasmedx Inc • University of California San Diego UCSD

Abstract

The application relates to phthalazine derivatives of formula (I) which are inhibitors of PARP1, PARP2 and/or tubulin and thus useful for the treatment of cancer. Also disclosed are pharmaceutical formulations containing such compounds, as well as combinations of these compounds with at least one additional therapeutic agent.

Core Innovation

The invention relates to compounds, or salts thereof, having a structure according to formula (I). The scaffold includes a benzimidazole core connected to a substituted 4-oxo-3,4-dihydrophthalazin-1-ylmethyl/aryl group, with defined connectivity to the methylene group, the U ring, the T ring, and the NH-Y-Z-R1 segment. The disclosed embodiments include carbamate, urea, sulfonamide, and amide derivatives within this scaffold.

Within formula (I), Y is C(O) or S(O), and Z is O, CH2, NH, or N(CH2R7), wherein R7 is hydrogen or substituted or unsubstituted C1 to C6 alkyl. The structure is further diversified by R1, R2, R5, and R6, where R1 is hydrogen or selected substituted or unsubstituted alkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, and R2, R5, and R6 are hydrogen or halogen or substituted or unsubstituted C1 to C6 alkyl.

The disclosed embodiments include benzimidazole-linked carbamates and ureas, including methyl and ethyl carbamate forms, with specific substitutions such as fluoro, difluoro, chloro, methyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methoxyethoxy, difluoromethoxy, and heteroaryl furan analogs. The retained core is the benzimidazole-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl scaffold.

The compounds are associated with inhibitory activity directed to PARP1 and/or PARP2 and/or tubulin, and with use in cancer treatment where the cancer is deficient in Homologous Recombination (HR)-dependent DNA double strand repair (DSB). Biological evaluation is also described, including PARP1 and PARP2 IC50 determination, PARP trapping on damaged DNA, tubulin polymerization effects, and cell viability assays in multiple solid tumor cell lines.

Claims Coverage

The consolidated claim coverage includes one principal independent claim directed to a compound, or a salt thereof, according to formula (I), with defined scaffold connectivity and multiple substituent variables. The inventive features combine the T/U connectivity, Y and Z linkage options, and the variable sets R1, R2, R5, and R6, with dependent claims further refining substituents and biological uses.

Claim coverage centers on a formula (I) compound class defined by scaffold connectivity, Y and Z linkage choices, and broad but specified substituent ranges for R1, R2, R5, and R6. The dependent coverage also includes benzimidazole/phthalazinone/carbamate and urea embodiments and use features for PARP1/PARP2/tubulin inhibition and cancer treatment in HR-dependent DSB deficiency.

Stated Advantages

Documented Applications