Fused tricyclic inhibitors of mammalian target of rapamycin

摘要

This invention relates to novel fused tricyclic compounds that are inhibitors of mammalian Target of Rapamycin (mTOR) kinase, which is also known as FRAP, RAFT, RAPT or SEP, and are useful in the treatment of cellular proliferative diseases, for example cancer and other proliferative disorders.

主权项

1. A compound of the formula: wherein the dotted line between W and X represents an optional double bond; W is CRxRy; X is CRxRy; Y is NR5; R1 is —C(O)R5, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of R4, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, (CRyRz)mORy, (CRyRz)mNRyRz, C(O)Ry, C(O)ORy, SOmRy, C(O)NRyRz, NRyC(O)R3 and NHR4; R2 is hydrogen, halo, cyano, NRyRz, ORy, C1-6 alkyl or C1-6 haloalkyl; R3 is hydrogen, NRyRz, (CRyRz)mORy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, aryl, heteroaryl or heterocyclyl, wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C1-6 alkyl, C1-6 haloalkyl and ORy; R4 is C3-8 cycloalkyl, C3-8 cycloalkenyl, aryl, heteroaryl or heterocyclyl, wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C1-6 alkyl, C1-6 haloalkyl, (CRyRz)mORy, O(C1-6 haloalkyl), C(O)Ry, C(O)ORy, SOmRy and NRyRz; R5 is hydrogen, aryl, heteroaryl, heterocyclyl or heterocyclyl(R6); R6 is not present, (C═O)C1-6 alkyl, (C═O)aryl, (C═O)heteroaryl, (C═O)O(C1-6 alkyl)-R4, wherein said alkyl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and NRyRz; Rx is hydrogen or C1-6 alkyl; Ry is not present, hydrogen, C1-6 alkyl or C1-6 haloalkyl, wherein said alkyl group is optionally substituted with one to three hydroxyl; Rz is hydrogen, C1-6 alkyl or C1-6 haloalkyl, wherein said alkyl group is optionally substituted with one to three hydroxyl; m is an integer from zero to two; or a pharmaceutically acceptable salt thereof.