BCL-2/BCL-XL inhibitors and therapeutic methods using the same

摘要

Inhibitors of Bcl-2/Bcl-xL and compositions containing the same are disclosed. Methods of using the Bcl-2/Bcl-xL inhibitors in the treatment of diseases and conditions wherein inhibition of Bcl-2/Bcl-xL provides a benefit, like cancers, also are disclosed.

主权项

1. A compound having a structural formula: wherein the A ring is X is selected from the group consisting of alkylene, alkenylene, cycloalkylene, cycloalkenylene, and heterocycloalkylene; Y is selected from the group consisting of (CH2)n—N(Ra) and Q is selected from the group consisting of O, O(CH2)1-3, NRc, NRc(C1-3alkylene), OC(═O)(C1-3alkylene), C(═O)O, C(═O)O(C1-3 alkylene), NHC(═O)(C1-3alkylene), C(═O)NH, and C(═O)NH(C1-3 alkylene); Z is O or NRc; R1 and R2, independently, are selected from the group consisting of H, CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR′, SR′, NR′R″, COR′, CO2R′, OCOR′, CONR′R″, CONR′SO2R″, NR′COR″, NR′CONR″R′″, NR′C═SNR″R′″, NR′SO2R″, SO2R′, and SO2NR′R″; R3 is selected from a group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR′, NR′R″, OCOR′, CO2R′, COR′, CONR′R″, CONR′SO2R″, C1-3 alkyleneCH(OH)CH2OH, SO2R′, and SO2NR′R″; R′, R″, and R′″, independently, are H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, C1-3 alkyleneheterocycloalkyl, or heterocycloalkyl; R4 is hydrogen, halo, C1-3alkyl, CF3, or CN; R5 is hydrogen, halo, C1-3alkyl, hydroxyalkyl, or alkoxy; R6 is selected from the group consisting of H, CN, NO2, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR′, SR′, NR′R″, CO2R′, OCOR′, CONR′R″, CONR′SO2R″, NR′COR″, NR′CONR″R′″, NR′C═SNR″R′″, NR′SO2R″, SO2R′, and SO2NR′R″; R7 is selected form the group consisting of hydrogen, alkyl, alkenyl, (CH2)0-3cycloalkyl, optionally substituted with —OH(CH2)0-3cycloalkenyl, (CH2)0-3heterocycloalkyl, optionally substituted with —OH(CH2)0-3aryl, and (CH2)0-3heteroaryl; R8 is selected form the group consisting of hydrogen, halo, NO2, CN, CF3SO2, and CF3; Ra is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, hydroxyalkyl, alkoxy, cycloalkyl, cycloalkenyl, and heterocycloalkyl; Rb is hydrogen or alkyl; Rc is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and alkoxy; and n, r, and s, independently, are 1, 2, 3, 4, 5, or 6; or a pharmaceutically acceptable salt of (I), (II), or (III).