Bcl-2/Bcl-xL inhibitors and therapeutic methods using the same

1. A compound having a structural formula:

wherein A is an optionally substituted 2, 3-1H-pyrrolylene;

B and E individually are optionally substituted phenyl; C is optionally substituted 1,3-phenylene; D is optionally substituted 1,4-phenylene; and

X and Y taken together form

and

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein ring B is selected from the group consisting of

3. The compound of claim 1 wherein ring A is

wherein 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″, 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, CF 3 , aryl, heteroaryl, C 1-3 alkyleneheterocycloalkyl, or heterocycloalkyl;

R′ and R″, or R″ and R″′, can be taken together with the atom to which they are bound to form a 3 to 7 membered ring.

4. The compound of claim 1 wherein the nitrogen atom of ring A is substituted with C 1-6 alkyl, cycloalkyl, —(CH 2 ) 1-3 N(C 1-4 -alkyl) 2 or —(CH 2 ) 1-3 CH(OH)CH 2 OH or the nitrogen atom of the A ring and an adjacent carbon atom of the A ring are taken together to form a five or six membered ring.

5. The compound of claim 1 wherein one to three carbon atoms of ring A are substituted, independently, with CH 3 , C 2 H 5 , C 3 H 7 , CF 3 , NH 2 , Cl, CN, CO 2 H, C(═O)CH 3 , C(═O)C 2 H 5 , C(═O)CF 3 , SO 2 CH 3 , SO 2 C 2 H 5 , SO 2 C 3 H 7 , SO 2 CF 3 , SO 2 N(CH 3 ) 2 , C(═O)NHSO 2 CH 3 , C(═O)NH 2 , C(═O)NHCH 3 , C(═O)NH(CH 2 ) 1-3 N(CH 3 ) 2 , C(═O)NHSO 2 CH 3 ,

6. The compound of claim 1 having a structure:

wherein R 4 and R 5 , independently, are selected from a 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″.

7. The compound of claim 6 having a structure

wherein R 6 , R 7 , R 8 , R 9 and R 10 , 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″, 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″.

8. The compound of claim 1 wherein ring E is substituted at a meta position to the —SO 2 NH— group with NO 2 or SO 2 CF 3 .

9. The compound of claim 1 wherein ring E is substituted at a para position to the —SO 2 NH— group with

wherein R a and R b , individually, are H, methyl, and

or R a and R b are taken together to form

10. The compound of claim 7 having a structure

wherein the A ring is

X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R′, R″, R″′ are defined as above; and

R 11 and R 12 , 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″, CO 2 R′, OCOR′, CONR′R″, CONSO 2 R′R″, NR′COR″, NR′CONR″R″′, NR′C═SNR″R″′, NR′SO 2 R″, SO 2 R′, and SO 2 NR′R″;

or a pharmaceutically acceptable salt thereof.

11. A compound having a structure

12. A composition comprising (a) compound of claim 1 , (b) a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of Bcl-2 or Bcl-xL provides a benefit, and (c) an optional excipient and/or pharmaceutically acceptable carrier.

13. The composition of claim 12 wherein the second therapeutic agent comprises a chemotherapeutic agent useful in the treatment of cancer.

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.

15. A compound having a structure