Small molecule regulators of steroid receptor coactivators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10512647-B2
Application number	US-201916361600-A
Country	US
Kind code	B2
Filing date	Mar 22, 2019
Priority date	Apr 8, 2016
Publication date	Dec 24, 2019
Grant date	Dec 24, 2019

Abstract

Small molecule regulators of steroid receptor coactivator (SRC) family proteins are provided, as well as methods for their use in treating or preventing SRC-related diseases. The SRC-related diseases can include cancer, metabolic disorders, human immunodeficiency virus, neurodegenerative disorders, and/or inflammatory diseases. Also provided are methods for regulating SRC family proteins in a cell.

First claim

What is claimed is:

1. A method of treating prostate cancer in a subject, comprising:
administering to the subject an effective amount of a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 , R 4 , R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;
R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
Y 1 and Y 2 are each independently selected from CR and N, wherein R is hydrogen, halogen, cyano, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; and
R 10 and R 12 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl,
wherein at least one of R 4 , R 5 , R 6 , and R 7 is halogen.

2. The method of claim 1 , wherein R, R 10 , and R 12 are each independently selected from hydrogen and halogen.

3. The method of claim 1 , wherein at least one of R 4 , R 5 , R 6 , and R 7 is fluoro.

4. The method of claim 1 , wherein the compound is selected from the group consisting of

5. The method of claim 1 , wherein the compound is a tautomer of the compound.

6. The method of claim 1 , wherein the compound is in a Z-configuration or an E-configuration.

7. The method of claim 1 , wherein the compound is isotopically substituted with a stable isotope.

8. The method of claim 7 , wherein the stable isotope is selected from the group consisting of deuterium, 13 C, 15 N, and 18 O.

9. The method of claim 1 , further comprising administering to the subject a pharmaceutically acceptable carrier.

10. The method of claim 1 , further comprising administering to the subject a second compound or composition comprising the compound and a pharmaceutically acceptable carrier.

11. The method of claim 10 , wherein the second compound or composition comprises a chemotherapeutic agent.

12. The method of claim 11 , wherein the chemotherapeutic agent comprises docetaxel or hormones.

13. The method of claim 1 , wherein the compound is administered in combination with a radiation therapy, an immunotherapy, a gene therapy, a surgery, or a combination thereof.

14. The method of claim 13 , wherein the radiation therapy, the immunotherapy, the gene therapy, or the surgery is performed concomitantly with administering the compound.

15. The method of claim 13 , wherein the radiation therapy, the immunotherapy, the gene therapy, or the surgery is performed simultaneously with administering the compound.

16. The method of claim 13 , wherein the radiation therapy, the immunotherapy, the gene therapy, or the surgery is performed sequentially before or after administering the compound.

17. The method of claim 1 , wherein the compound is orally administered to the subject.

18. A method of treating prostate cancer in a subject, comprising:
administering to the subject an effective amount of a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof.

19. A method of treating prostate cancer in a subject, comprising:
administering to the subject an effective amount of a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is methyl, R 2 is methyl or hydrogen, R 3 is methyl or hydrogen, R 4 is hydrogen, R 5 is fluoro, R 6 is fluoro, R 7 is hydrogen, Y 1 is CH or CF, Y 2 is CH, R 10 is hydrogen, and R 12 is hydrogen,
with the proviso that when R 2 is methyl, then R 3 is hydrogen and when R 2 is hydrogen, then R 3 is methyl.

20. The method of claim 19 , wherein the compound is in a Z-configuration or an E-configuration.

Assignees

• Baylor College Medicine

Inventors

• O'Malley Bert W
• Lonard David Michael
• Wang Jin
• Xu Jianming
• Chen Jianwei

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/18

  for HIV · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title