Indolyl-substituted pyrazino[1,2-b]isoquinolines for cancer treatment

摘要

The disclosure describes compounds of formula I,;wherein the wedged bonds, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, X and Y have meanings given in the description, and pharmaceutically-acceptable salts thereof; and methods of using such compounds useful in the treatment of cancer and conditions affected by inhibition of angiogenesis. Also provided, are processes for the preparation of formula I, by reacting formula I with other compounds; and processes for the preparation of a pharmaceutical formulation by bringing into association, a compound of formula I, with therapeutic agents and/or a pharmaceutically-acceptable adjuvant, diluent, or carrier.;

主权项

1. A compound of Formula 1; wherein: X and Y are each independently represented by —O—, or —N(Ra)—; Ra represents H or C1-6 alkyl optionally substituted by one or more fluoro atoms; wherein can have either an R or an S relative configuration, R1 and R2 each independently represent H, C1-6 alkyl optionally substituted by one or more fluoro atoms, —C(O)C1-6 alkyl optionally substituted by one or more fluoro atoms, or —CH2-phenyl wherein the phenyl is optionally substituted by one or more substituents selected from halo and C1-3 alkyl; or R1 and R2 can together represent a C1-2 alkylene linker group; R3, R4, R5, R5a, R6, R7, R8, R9, and R10 each independently represent H, halo, —ORb, —N(Rc)Rd, C1-6 alkyl optionally substituted by one or more fluoro atoms, or —CH2-phenyl wherein the phenyl is optionally substituted by one or more substituents selected from halo and C1-3 alkyl; or any two adjacent R6, R7, R8, and R9 groups can be linked together to form a further 3- to 8-membered ring optionally containing one to three double bonds, optionally containing one to four heteroatoms, and wherein the ring is optionally substituted by one or more substituents selected from halo and C1-4 alkyl optionally substituted by one or more fluoro atoms; Rb represents H, C1-6 alkyl optionally substituted by one or more fluoro atoms, or —C(O)C1-6 alkyl optionally substituted by one or more fluoro atoms; Rc and Rd each independently represent H or C1-6 alkyl optionally substituted by one or more fluoro atoms; R11 and R12 each independently represent H, C1-6 alkyl optionally substituted by one or more fluoro atoms, —C(O)C1-6 alkyl optionally substituted by one or more fluoro atoms, phenyl optionally substituted by one or more substituents selected from halo and C1-3 alkyl, or —CH2-phenyl wherein the phenyl is optionally substituted by one or more substituents selected from halo and C1-3 alkyl; R13 and R14 each independently represent H, C1-6 alkyl optionally substituted by one or more fluoro atoms, or —CH2-phenyl wherein the phenyl is optionally substituted by one or more substituents selected from halo and C1-3 alkyl, or a pharmaceutically-acceptable salt, ester, stereoisomer or tautomer thereof.