Inhibitors of the Notch transcriptional activation complex and methods for use of the same

1. A method of inhibiting the Notch transcriptional activation complex (“NTC”) in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the NTC:

wherein

represents a bond that results in the adjacent double bond being in either the E or Z configuration;

n is 0, 1, 2, 3, or 4;

X is O or S;

Y is O, S, NH, or NC 1-3 alkyl;

R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkenyl, C 0-6 alkylene—COR 9 , NH-aryl, NH—(C═O)-aryl, C 0-6 alkylene-cycloalkyl, C 0-6 alkylene-heterocycloalkyl, C 0-6 alkylene-heterocycloalkenyl, C 0-6 alkylene-aryl, C 1-6 alkylene—SO 2 R 5 , C 1-6 alkylene-R 5 , and C 0-6 alkylene-heteroaryl;

R 2 is H or C 1-3 alkyl;

each R 3 is independently selected from the group consisting of OR 4 , COOR 4 , NO 2 , halo, SO 2 R 5 , C 1-6 alkyl, C 1-6 alkenyl, C 0-6 alkylene-cycloalkyl, C 0-6 alkylene-aryl, C 0-6 alkylene-heteroaryl, and (C═O)N(R 7 ) 2 ;

R 4 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 0-6 alkylene-(C═O)R 8 , C 1-6 alkylene-N(R 6 ) 2 , C 1-6 alkylene-CN, C 0-6 alkylene-aryl, C 0-6 alkylene-heteroaryl, C 1-6 alkylene-O-aryl, C 1-6 alkylene-S-aryl, C 1-6 alkylene-NR 6 -aryl, and C 1-6 alkylene-NR 6 -heteroaryl;

R 5 is OH, N(R 6 ) 2 , NH(C═O)C 1-3 alkyl, or NH(C═O)aryl;

each R 6 is independently H, C 1-3 alkyl;

each R 7 is independently H, C 1-3 alkyl, SO 2 H; or SO 2 (C 1-3 alkyl);

R 8 is C 1-6 alkyl, aryl, OC 1-6 alkyl, or N(R 6 ) 2 ; and

R 9 is OH, N(R 6 ) 2 , NHSO 2 R 6 , SO 2 N(R 6 ) 2 .

2. The method of claim 1 , wherein R 2 is H.

3. The method of claim 1 , wherein X is S.

4. The method of claim 1 , wherein Y is: (a) NH or NC 1-3 alkyl; or (b) O.

5. The method of claim 1 , wherein Y is S.

6. The method of claim 1 , wherein the compound comprises Formula (Ia), or a pharmaceutically acceptable salt thereof:

7. The method of claim 1 , wherein R 1 is C 1-6 alkyl, C 1-6 alkenyl, C 0-6 alkylene-COR 9 , C 0-6 alkylene-cycloalkyl, C 0-6 alkylene-heterocycloalkenyl, C 1-6 alkylene-SO 2 R 5 , or C 1-6 alkylene-R 5 .

8. The method of claim 1 , wherein R 1 is NH-aryl, NH—(C═O)-aryl, C 0-6 alkylene-heterocycloalkyl, C 0-6 alkylene-aryl, or C 0-6 alkylene-heteroaryl.

9. The method of claim 1 , wherein R 1 is H.

10. The method of claim 1 , wherein n is 1, 2, or 3.

11. The method of claim 1 , wherein at least one R 3 is OR 4 ; and R 4 optionally is: (a) H, C 1-6 alkyl, C 1-6 alkenyl, or C 1-6 alkynyl; (b) C 1-6 alkylene-(C═O)R 8 ; or (c) C 1-6 alkylene-N(R 6 ) 2 , C 1-6 alkylene-CN, C 0-6 alkylene-cycloalkyl, C 0-6 alkylene-aryl, C 0-6 alkylene-heteroaryl, C 1-6 alkylene-O-aryl, C 1-6 alkylene-S-aryl, C 1-6 alkylene-NR 6 -aryl, or C 1-6 alkylene-NR 6 -heteroaryl; and R 8 optionally is (a) C 1-6 alkyl, or aryl; or (b) OC 1-6 alkyl or N(R 6 ) 2 .

12. The method of claim 1 , wherein at least one R 3 is (a) selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkenyl, C 0-6 alkylene-aryl, and C 0-6 alkylene-heteroaryl; or (b) COOH, NO 2 , SO 2 R 5 , or (C═O)N(R 7 ) 2 .

13. The method of claim 1 , wherein n is 2 or 3, and each R 3 is OR 4 or halo.

14. The method of claim 13 , wherein: (a) one R 3 is OH, and one R 3 is OC 1-6 alkyl or halo; or (b) n is 2, one R 3 is OH, and the other R 3 is OC 1-6 alkyl.

15. The method of claim 1 , wherein the compound comprises Formula (Ib), or a pharmaceutically acceptable salt thereof:

wherein n is 1 or 2; optionally wherein n is 1, R 3 is OC 1-6 alkyl, and R 3 is para to the hydroxyl substituent.

16. A method of inhibiting the Notch transcriptional activation complex (“NTC”) in a cell, comprising contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

or a mixture thereof, in an amount effective to inhibit the NTC.