BCL-2/BCL-XL inhibitors and therapeutic methods using the same
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.
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 (CH 2 ) n —N(R a ) and
Q is selected from the group consisting of O, O(CH 2 ) 1-3 , NR c , NR c (C 1-3 alkylene), OC(═O)(C 1-3 alkylene), C(═O)O, C(═O)O(C 1-3 alkylene), NHC(═O)(C 1-3 alkylene), C(═O)NH, and C(═O)NH(C 1-3 alkylene);
Z is O or NR c ;
R 1 and R 2 , independently, are selected from the group consisting of H, CN, NO 2 , halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR′, SR′, NR′R″, COR′, CO 2 R′, OCOR′, CONR′R″, CONR′SO 2 R″, NR′COR″, NR′CONR″R′″, NR′C═SNR″R′″, NR′SO 2 R″, SO 2 R′, and SO 2 NR′R″;
R 3 is selected from a group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR′, NR′R″, OCOR′, CO 2 R′, COR′, CONR′R″, CONR′SO 2 R″, C 1-3 alkyleneCH(OH)CH 2 OH, SO 2 R′, and SO 2 NR′R″;
R′, R″, and R′″, independently, are H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, C 1-3 alkyleneheterocycloalkyl, or heterocycloalkyl;
R 4 is hydrogen, halo, C 1-3 alkyl, CF 3 , or CN;
R 5 is hydrogen, halo, C 1-3 alkyl, hydroxyalkyl, or alkoxy;
R 6 is selected from the group consisting of H, CN, NO 2 , halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, OR′, SR′, NR′R″, CO 2 R′, OCOR′, CONR′R″, CONR′SO 2 R″, NR′COR″, NR′CONR″R′″, NR′C═SNR″R′″, NR′SO 2 R″, SO 2 R′, and SO 2 NR′R″;
R 7 is selected form the group consisting of hydrogen, alkyl, alkenyl, (CH 2 ) 0-3 cycloalkyl, optionally substituted with —OH(CH 2 ) 0-3 cycloalkenyl, (CH 2 ) 0-3 heterocycloalkyl, optionally substituted with —OH(CH 2 ) 0-3 aryl, and (CH 2 ) 0-3 heteroaryl;
R 8 is selected form the group consisting of hydrogen, halo, NO 2 , CN, CF 3 SO 2 , and CF 3 ;
R a is selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, hydroxyalkyl, alkoxy, cycloalkyl, cycloalkenyl, and heterocycloalkyl;
R b is hydrogen or alkyl;
R c 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).
2. The compound of claim 1 wherein X is alkylene.
3. The compound of claim 1 wherein Y is
4. The compound of claim 3 wherein n is 1-3.
5. The compound of claim 3 wherein R b is hydrogen or C 1-3 alkyl.
6. The compound of claim 1 wherein Q is O, O(CH 2 ) 1-3 , C(═O)O(CH 2 ) 1-3 , OC(═O)(CH 2 ) 1-3 , or C(═O)O(CH(CH 3 )CH 2 ).
7. The compound of claim 1 wherein Z is O, NH, or N(C 1-3 alkyl).
8. The compound of claim 1 wherein R 1 is SO 2 R′, SO 2 NR′R″, NR′SOR″, H, or alkyl.
9. The compound of claim 1 wherein R 2 is H, C 1-3 alkyl, cycloalkyl, or halo.
10. The compound of claim 1 wherein R 3 is H, C 1-3 alkyl, or cycloalkyl.
11. The compound of claim 1 wherein R 4 is H or halo.
12. The compound of claim 1 wherein R 5 is H, halo, or C 1-3 alkyl.
13. The compound of claim 1 wherein R 6 is H, halo, C 1-3 alkyl, or cycloalkyl.
14. The compound of claim 1 wherein R 7 is (CH 2 ) 0-3 cycloalkyl optionally substituted with —OH or (CH 2 ) 0-3 heterocycloalkyl optionally substituted with —OH.
15. The compound of claim 1 wherein R 8 is CF 3 SO 2 or CF 3 .
16. The compound of claim 1 wherein R b and R c , independently, are H or C 1-3 alkyl.
17. A compound having a structure
18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.