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

Patent metadata

Field	Value
Publication number	US-10501413-B2
Application number	US-201615560743-A
Country	US
Kind code	B2
Filing date	Mar 23, 2016
Priority date	Mar 23, 2015
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

Disclosed herein are inhibitors of the Notch transcriptional activation complex, and methods for their use in treating or preventing diseases, such as cancer. The inhibitors described herein can include compounds of Formula (I) and pharmaceutically acceptable salts thereof: Formula (I), wherein the substituents are as described.

First claim

We claim:

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:

Assignees

• Univ Miami
• Univ Maryland

Inventors

• Capobianco Anthony J
• Mackerell Jr Alex
• Spyvee Mark

Classifications

• C07D277/36

  Sulfur atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/426

  1,3-Thiazoles · CPC title

• A61K31/4015

  having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide · CPC title

• C07D207/444 Primary

  having two doubly-bound oxygen atoms directly attached in positions 2 and 5 · CPC title