BET bromodomain inhibitors and therapeutic methods using the same

Patent metadata

Field	Value
Publication number	US-9675697-B2
Application number	US-201414204076-A
Country	US
Kind code	B2
Filing date	Mar 11, 2014
Priority date	Mar 11, 2013
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

Inhibitors of BET bromodomains and compositions containing the same are disclosed. Methods of using the BET bromodomain inhibitors in the treatment of diseases and conditions wherein inhibition of BET bromodomain provides a benefit, like cancers, also are disclosed.

First claim

What is claimed:

1. A compound having a structural formula (I):

wherein:
X is N(R a );
Y 1 and Y 3 , independently, are CH or N;
Y 2 is CH, CR a , or N;
Z is H,

halo, or OH;
A is

each unsubstituted or substituted;
B is aryl, CH(R a )-aryl, C 3-10 cycloalkyl, CH(R a )—C 3-10 cycloalkyl, heteroaryl, CH(R a )-heteroaryl, C 3-10 heterocycloalkyl, or CH(R a )—C 3-10 heterocycloalkyl, each unsubstituted or substituted;
G is N, O, or S;
L is null, H, or C(R d ) 3 ;
R 1 is H, halo, OH, OR a , or N(R a ) 2 ;
R a , independently, is H, C 1-3 alkyl, or benzyl;
R b , independently, is C 1-6 alkyl, halo, aryl, unsubstituted or substituted CH 2 -aryl, unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted CH 2 —C 3-10 cycloalkyl, heteroaryl, unsubstituted or substituted CH 2 -heteroaryl, unsubstituted or substituted C 3-10 heterocycloalkyl, or unsubstituted or substituted CH 2 —C 3-10 heterocycloalkyl, or CHO;
n is an integer 0, 1, 2, or 3; and
R c and R d , each independently, are hydrogen, C 1-6 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted CH 2 -aryl, unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted CH 2 —C 3-10 cycloalkyl, heteroaryl, unsubstituted or substituted CH 2 -heteroaryl, unsubstituted or substituted C 3-10 heterocycloalkyl, or unsubstituted or substituted CH 2 —C 3-10 heterocycloalkyl;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

2. The compound of claim 1 , wherein ring A is:

3. The compound of claim 1 or 2 , wherein R 1 is OCH 3 .

4. The compound of claim 1 , wherein the ring system

5. The compound of claim 1 , wherein Z is

6. The compound of claim 5 , wherein the B ring, substituted or unsubstituted, is selected from the group consisting of:

7. The compound of claim 6 , wherein the B ring is substituted with one to three of methyl, phenyl, fluoro, pyridinyl, chloro, isopropyl, cyclopropyl, or ethyl.

8. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

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

10. A method of reducing or ameliorating breast cancer, leukemia, or prostate cancer, the method comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof.

11. The method of claim 10 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of cancer.

12. The method of claim 11 , wherein the compound of claim 1 and the second therapeutic agent are administered simultaneously.

13. The method of claim 11 , wherein the compound of claim 1 and the second therapeutic agent are administered separately.

14. The method of claim 11 , wherein the second therapeutic agent is one or more of surgery, a chemotherapeutic agent, or radiation.

15. The method of claim 11 , wherein the compound of claim 1 and the second therapeutic agent are administered from a single composition.

16. The method of claim 11 , wherein the compound of claim 1 and the second therapeutic agent are administered from separate compositions.

17. The method of claim 13 , wherein the compound of claim 1 is administered prior to the second therapeutic agent.

18. The method of claim 13 , wherein the compound of claim 1 is administered after the second therapeutic agent.

19. The compound of claim 8 which is:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

20. A method of reducing or ameliorating breast cancer, leukemia, or prostate cancer, the method comprising administering a therapeutically effective amount of a compound of claim 8 to an individual in need thereof.

21. A method of reducing or ameliorating breast cancer, leukemia, or prostate cancer, the method comprising administering a therapeutically effective amount of a compound of claim 19 to an individual in need thereof.

Assignees

• Univ Michigan Regents

Inventors

• Wang Shaomeng
• Ran Xu
• Zhao Yujun
• Yang Chao-Yie
• Liu Liu
• Bai Longchuan
• Mceachern Donna
• Stuckey Jeanne
• Meagher Jennifer Lynn
• Sun Duxin
• Li Xiaoqin
• Zhou Bing
• Karatas Hacer
• Luo Ruijuan
• Chinnaiyan Arul
• Asangani Irfan A

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title