Fused tricyclic inhibitors of mammalian target of rapamycin
View Patent ↗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.
1. A compound of the formula:
wherein the dotted line between W and X represents an optional double bond;
W is CR x R y ;
X is CR x R y ;
Y is NR 5 ;
R 1 is —C(O)R 5 , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 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 R 4 , halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, (CR y R z ) m OR y , (CR y R z ) m NR y R z , C(O)R y , C(O)OR y , SO m R y , C(O)NR y R z , NR y C(O)R 3 and NHR 4 ;
R 2 is hydrogen, halo, cyano, NR y R z , OR y , C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is hydrogen, NR y R z , (CR y R z ) m OR y , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 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, C 1-6 alkyl, C 1-6 haloalkyl and OR y ;
R 4 is C 3-8 cycloalkyl, C 3-8 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, C 1-6 alkyl, C 1-6 haloalkyl, (CR y R z ) m OR y , O(C 1-6 haloalkyl), C(O)R y , C(O)OR y , SO m R y and NR y R z ;
R 5 is hydrogen, aryl, heteroaryl, heterocyclyl or heterocyclyl(R 6 );
R 6 is not present, (C═O)C 1-6 alkyl, (C═O)aryl, (C═O)heteroaryl, (C═O)O(C 1-6 alkyl)-R 4 , wherein said alkyl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl and NR y R z ;
R x is hydrogen or C 1-6 alkyl;
R y is not present, hydrogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein said alkyl group is optionally substituted with one to three hydroxyl;
R z is hydrogen, C 1-6 alkyl or C 1-6 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.
2. The compound of claim 1 wherein R 2 is hydrogen; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 wherein R 3 is hydrogen; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 wherein R 1 is heteroaryl wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of R 4 , halo and C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 wherein R 1 is pyridinyl or quinolinyl wherein said pyridinyl and quinolinyl groups are optionally substituted with one to three substituents independently selected from the group consisting of R 4 , halo and C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 4 wherein R 4 is aryl or heteroaryl, wherein said heteroaryl group is optionally substituted with C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 that is selected from
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.