Bromodomain inhibitors

摘要

The present invention relates to substituted heterocyclic derivative compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of cancer and neoplastic disease.

主权项

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3; X5 is C—R5 or N; X6 is C—R6 or N; X7 is C—R7 or N; X8 is C—R8 or N; wherein no more than two of X5, X6, X7, or X8 may be N; R5 is hydrogen, halogen, —CN, —NHR61, —N(R61)2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R6 is hydrogen, halogen, —CN, —NHR61, —N(R61)2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R7 is hydrogen, halogen, —CN, —NHR61, —N(R61)2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R8 is hydrogen, halogen, or alkyl; X2 is N or C—R12, wherein R12 is hydrogen, halogen, alkyl, or alkoxy; R13 is —Y—Z; Y is selected from a bond, —CH2—, or —CH(C1-C4 alkyl)-; Z is selected from —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R21, —N(R22)CON(R22)2, —N(R22)COR21, —COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21; X3 is N or C—R14, wherein R14 is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; X4 is N or C—R15, wherein R15 is hydrogen, halogen, alkyl, —CN, or alkoxy; R16 is hydrogen, halogen, —N(H)COX, or —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.