Isoquinolin-1(2H)-one derivatives as PARP-1 inhibitors

摘要

There are provided substituted isoquinolin-1(2H)-one derivatives which selectively inhibit the activity of poly (ADP-ribose) polymerase PARP-1 with respect to poly (ADP-ribose) polymerase PARP-2. The compounds of the present invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds. A screening method for the identification of compounds capable of binding several PARP proteins, as well the probes used in such method, are further objects of the invention.

主权项

1. A method for treating breast cancer, ovarian cancer, and pancreatic cancer, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I): wherein L is an optionally substituted linear or branched C2-C6 alkyl, C3-C7 cycloalkyl group or, by including the nitrogen atom to which it is bonded, an optionally substituted heterocyclyl or heterocyclyl C1-C6 alkyl; R and R1 are independently hydrogen atom, an optionally substituted linear or branched C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl or COR5 group or, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl or heteroaryl group; R2 and R3 are independently hydrogen or halogen atom; a cyano, nitro, NHCOR5, COR5, NR6R7, NR6COR5, OR8, SR8, SOR11, SO2R11, NHSOR11, NHSO2R11, R9R10N—C1-C6 alkyl, R9O—C1-C6 alkyl group, or an optionally substituted linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl, or heteroaryl group; R4 is an optionally substituted linear or branched C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, aryl C1-C6 alkyl, aryl C3-C7 cycloalkyl, aryl C2-C6 alkenyl, aryl C2-C6 alkynyl, heterocyclyl, heterocyclyl C1-C6 alkyl, heterocyclyl C3-C7 cycloalkyl, heterocyclyl C2-C6 alkenyl, heterocyclyl C2-C6 alkynyl, heteroaryl, heteroaryl C1-C6 alkyl, heteroaryl C3-C7 cycloalkyl, heteroaryl C2-C6 alkenyl, heteroaryl C2-C6 alkynyl; R5 is hydrogen atom or NR6R8, OR8, SR8, R9R10N—C1-C6 alkyl, R9O—C1-C6 alkyl, or an optionally substituted linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl or heteroaryl group; R6 and R7 are independently hydrogen atom, an optionally substituted linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, R9R10N—C2-C6 alkyl, R9O—C2-C6 alkyl, heterocyclyl, aryl or heteroaryl group, or R6 and R7, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted heterocyclyl group; R8 is hydrogen, a COR6, SOR11, SO2R11, R9R10N—C2-C6 alkyl or R9O—C2-C6 alkyl group, or an optionally substituted linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein R6 is as defined above; R9 and R10 are independently hydrogen, COR5, or an optionally substituted linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl or heteroaryl group, or R9 and R10, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted heterocyclyl group, wherein R5 is as defined above; R11 is hydrogen atom, NR6R7, OR8, R9R10N—C1-C6 alkyl, R9O—C1-C6 alkyl, or an optionally substituted linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein R6, R7, R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt thereof.