Bromodomain inhibitors to target therapy-resistant cancer

Patent metadata

Field	Value
Publication number	US-12329755-B2
Application number	US-202017639114-A
Country	US
Kind code	B2
Filing date	Aug 28, 2020
Priority date	Aug 29, 2019
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

Abstract

Novel inhibitors of the bromodomain of Brahma-related gene 1 (BRG1) are described. Also described are methods of treating glioblastoma using inhibitors of the BRG1 bromodomain in combination with chemotherapeutics, such as DNA alkylating agents. As described herein, the inhibitors sensitize glioblastoma cells, including chemoresistant glioblastoma cells, to DNA alkylating agents, for example, temozolomide and carmustine.

First claim

What is claimed is:

1. A compound having the structure of Formula (I):

wherein:
represents a single or double bond;
Ar is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R is H, halo, amino, thiol, or hydroxy; and Y is H or halo; or
where R and Y together from a group selected from —N═CH—NH—, —N═N—NH—, and —CH═N—NH—;
R 1 and R 2 are each independently selected from the group consisting of H, cyano, halo, alkyl, substituted alkyl, perhaloalkyl, alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
R 3 , R 4 and R 5 are each H; and
X is O, S, or NH; or
wherein (i) X and R 5 together comprise —N—NH— and/or wherein R 3 and R 4 together form an alkylene group, optionally ethylene or (ii) R 3 and R 5 together form a covalent bond or methylene group;
or a pharmaceutically acceptable salt thereof, subject to the proviso that the compound is not PFI-3.

2. The compound of claim 1 , wherein Ar is selected phenyl or pyridinyl, optionally substituted with one or more aryl group substituents, further optionally wherein the one or more aryl group substituents are selected from halo, alkoxy, and cyano.

3. The compound of claim 1 , wherein the compound of Formula (I) has a structure of Formula (II):

wherein R, Y, X, and R 1 -R 5 are as defined for the compound of Formula (I) and wherein X 1 is CH, C (R 7 ), or N; n is an integer from 0 to 4; and each R 6 and R 7 is independently selected from cyano, halo, amino, alkyl, substituted alkyl, hydroxy, alkoxy, and perhaloalkyl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein n is 0, 1, or 2 and wherein each R 6 is independently selected from fluoro, chloro, methoxy, and cyano.

5. The compound of claim 3 , wherein X is O, X 1 is N and wherein R and Y together form a group selected from —N═CH—NH—, —N═N—NH—, and —CH═N—NH—.

6. The compound of claim 3 , wherein X and R 5 together comprise —N—NH, optionally wherein R is OH and R 2 is H, fluoro, chloro, or bromo.

7. The compound of claim 3 , wherein X is O, R is OH, and R 2 is selected from H, fluoro, chloro, and bromo, optionally wherein R 2 is fluoro or bromo.

8. The compound of claim 7 , wherein R 3 and R 4 together form an ethylene group.

9. The compound of claim 3 , wherein the compound of Formula (II) has a structure of Formula (III):

wherein:
R is selected from H, hydroxy and halo;
Y is H or halo; and
R 1 and R 2 are independently selected from H, cyano and halo, subject to the proviso that when R is hydroxy, Y is halo and/or at least one of R 1 and R 2 is cyano or halo; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein one of R, R 1 , and R 2 is selected from fluoro, chloro, and bromo.

11. The compound of claim 9 , wherein the compound of Formula (III) is selected from:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 3 , wherein the compound is selected from the group consisting of:

13. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound of ene of claim 1 .

14. A method of treating glioblastoma in a subject in need thereof, the method comprising:
(a) administering to the subject a compound of Formula (I)

wherein:
represents a single or double bond;
Ar is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R is H, halo, amino, thiol, or hydroxy and Y is H or halo; or

wherein R and Y together form a group selected from —N═CH—NH—, —N═N—NH—, and —CH═N—NH—;
R 1 and R 2 are each independently selected from the group consisting of H, cyano, halo, alkyl, substituted alkyl, perhaloalkyl, alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
R 3 , R 4 and R 5 are each H; and
X is O, S, or NH; or
wherein (i) X and R 5 together comprise —N—NH— and/or R 3 and R 4 together form an alkylene group, optionally ethylene or (ii) R 3 and R 5 together form a covalent bond or methylene group;
or a pharmaceutically acceptable salt thereof, and optionally wherein the compound of Formula (I) is not PFI-3; and
(b) administering to the subject a chemotherapeutic compound, wherein said chemotherapeutic compound is a DNA alkylating agent.

15. The method of claim 14 , wherein the DNA alkylating agent is temozolomide (TMZ) or carmustine.

16. The method of claim 14 , wherein Ar is selected phenyl or pyridinyl, optionally substituted with one or more aryl group substituents, further optionally wherein the one or more aryl group substituents are selected from halo, alkoxy, and cyano.

17. The method of claim 14 , wherein the compound of Formula (I) has a structure of Formula (II):

wherein R, Y, X, and R 1 -R 5 are as defined for the compound of Formula (I) and wherein X 1 is CH, C (R 7 ), or N; n is an integer from 0 to 4; and each R 6 and R 7 is independently selected from cyano, halo, amino, alkyl, substituted alkyl, hydroxy, alkoxy, and perhaloalkyl; or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 , wherein n is 0, 1, or 2 and wherein each R 6 is independently selected from fluoro, chloro, methoxy, and cyano.

19. The method of claim 17 , wherein X is O, X 1 is N and wherein R and Y together form a group selected from —N═CH—NH—, —N═N—NH—, and —CH═N—NH—.

20. The method of claim 17 , wherein X and R 5 together comprise —N—NH, optionally wherein R is OH and R 2 is H, fluoro, chloro, or bromo.

21. The method of claim 17 , wherein X is O, R is OH, and R 2 is selected from H, fluoro, chloro, and bromo, optionally wherein R 2 is fluoro or bromo.

22. The method of claim 21 , wherein R 3 and R 4 together form an ethylene group.

23. The method of claim 17 , wherein the compound of Formula (II) has a structure of Formula (III):

wherein:
R is selected from H, hydroxy and halo;
Y is H or halo; and
R 1 and R 2 are independently selected from H, cyano and halo, optionally wherein when R is hydroxy, Y is halo and/or at least one of R 1 and R 2 is cyano or halo;

or a pharmaceutically acceptable salt thereof.

24. The method of claim 23 , wherein one of R, R 1 , and R 2 is selected from fluoro, chloro, and bromo.

25. The method of claim 23 , wherein the compound of Formula (III) is selected from:

or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Tennessee Res Found

Inventors

• Miller Duane
• Pfeffer Lawrence M
• He Yali
• Ganguly Debolina

Classifications

• C07D487/08

  Bridged systems · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title

• A61K31/17

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C12Y306/04

  acting on acid anhydrides; involved in cellular and subcellular movement (3.6.4) · CPC title