# US 10,501,413 B2 · Inhibitors of the Notch transcriptional activation complex and methods for use of the same

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- Number: US 10,501,413 B2
- Document ID: US10501413B2
- Status: Granted
- Kind: B2
- Application number: 15/560,743
- Filed: 2016-03-23
- Published: 2018-03-29
- Granted: 2019-12-10
- Earliest claimed: 2015-03-23
- Assignees: University of Miami; University of Maryland, Baltimore
- Applicants: University of Miami; University of Maryland, Baltimore
- Inventors: Anthony J. Capobianco; Alex Mackerell, Jr.; Mark Spyvee
- Web page: https://patentgrep.com/patent/US10501413B2

## CPC

- C07D 207/444: having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61K 31/426: 1,3-Thiazoles
- A61P 35/00: Antineoplastic agents
- C07D 277/36: Sulfur atoms
- C07D 277/54: Nitrogen and either oxygen or sulfur atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### 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 NC1-3 alkyl;
R1 is selected from the group consisting of H, C1-6 alkyl, C1-6 alkenyl, C0-6 alkylene—COR9, NH-aryl, NH—(C═O)-aryl, C0-6 alkylene-cycloalkyl, C0-6 alkylene-heterocycloalkyl, C0-6 alkylene-heterocycloalkenyl, C0-6 alkylene-aryl, C1-6 alkylene—SO2R5, C1-6 alkylene-R5, and C0-6 alkylene-heteroaryl;
R2 is H or C1-3 alkyl;
each R3 is independently selected from the group consisting of OR4, COOR4, NO2, halo, SO2R5, C1-6 alkyl, C1-6 alkenyl, C0-6 alkylene-cycloalkyl, C0-6 alkylene-aryl, C0-6 alkylene-heteroaryl, and (C═O)N(R7)2;
R4 is selected from the group consisting of H, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C0-6 alkylene-(C═O)R8, C1-6 alkylene-N(R6)2, C1-6 alkylene-CN, C0-6 alkylene-aryl, C0-6 alkylene-heteroaryl, C1-6 alkylene-O-aryl, C1-6 alkylene-S-aryl, C1-6 alkylene-NR6-aryl, and C1-6 alkylene-NR6-heteroaryl;
R5 is OH, N(R6)2, NH(C═O)C1-3 alkyl, or NH(C═O)aryl;
each R6 is independently H, C1-3 alkyl;
each R7 is independently H, C1-3 alkyl, SO2H; or SO2(C1-3 alkyl);
R8 is C1-6 alkyl, aryl, OC1-6 alkyl, or N(R6)2; and
R9 is OH, N(R6)2, NHSO2R6, SO2N(R6)2.

### Claim 2 (depends on 1)

The method of claim 1, wherein R2 is H.

### Claim 3 (depends on 1)

The method of claim 1, wherein X is S.

### Claim 4 (depends on 1)

The method of claim 1, wherein Y is: (a) NH or NC1-3 alkyl; or (b) O.

### Claim 5 (depends on 1)

The method of claim 1, wherein Y is S.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The method of claim 1, wherein R1 is C1-6 alkyl, C1-6 alkenyl, C0-6 alkylene-COR9, C0-6 alkylene-cycloalkyl, C0-6 alkylene-heterocycloalkenyl, C1-6 alkylene-SO2R5, or C1-6 alkylene-R5.

### Claim 8 (depends on 1)

The method of claim 1, wherein R1 is NH-aryl, NH—(C═O)-aryl, C0-6 alkylene-heterocycloalkyl, C0-6 alkylene-aryl, or C0-6 alkylene-heteroaryl.

### Claim 9 (depends on 1)

The method of claim 1, wherein R1 is H.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

The method of claim 1, wherein at least one R3 is OR4; and R4 optionally is: (a) H, C1-6 alkyl, C1-6 alkenyl, or C1-6 alkynyl; (b) C1-6 alkylene-(C═O)R8; or (c) C1-6 alkylene-N(R6)2, C1-6 alkylene-CN, C0-6 alkylene-cycloalkyl, C0-6 alkylene-aryl, C0-6 alkylene-heteroaryl, C1-6 alkylene-O-aryl, C1-6 alkylene-S-aryl, C1-6 alkylene-NR6-aryl, or C1-6 alkylene-NR6-heteroaryl; and R8 optionally is (a) C1-6 alkyl, or aryl; or (b) OC1-6 alkyl or N(R6)2.

### Claim 12 (depends on 1)

The method of claim 1, wherein at least one R3 is (a) selected from the group consisting of halo, C1-6 alkyl, C1-6 alkenyl, C0-6 alkylene-aryl, and C0-6 alkylene-heteroaryl; or (b) COOH, NO2, SO2R5, or (C═O)N(R7)2.

### Claim 13 (depends on 1)

The method of claim 1, wherein n is 2 or 3, and each R3 is OR4 or halo.

### Claim 14 (depends on 13)

The method of claim 13, wherein: (a) one R3 is OH, and one R3 is OC1-6 alkyl or halo; or (b) n is 2, one R3 is OH, and the other R3 is OC1-6 alkyl.

### Claim 15 (depends on 1)

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, R3 is OC1-6 alkyl, and R3 is para to the hydroxyl substituent.

### Claim 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.