Cereblon binding compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11634407-B2
Application number	US-202117356370-A
Country	US
Kind code	B2
Filing date	Jun 23, 2021
Priority date	Jun 24, 2020
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

Abstract

Provided herein are piperidine dione compounds having the following structure:wherein RN, R1, R2, R3, R4, RN, L, V, X, a, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.

First claim

What is claimed is:

1. A compound selected from the group consisting of
2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,
2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,
2-((2R,6S)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,
2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,
2-((2R,6S)-4-(3-(trans-4-(3-(5-Chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,
2-((2R,6S)-4-(3-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride,
2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,
2-((R)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide,
2-((2R,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide, and
2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3 dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , and a pharmaceutically acceptable carrier, excipient or vehicle.

3. A method for the treatment of an androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , wherein the androgen mediated disease is prostate cancer.

4. The method of claim 3 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

5. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 2 , wherein the androgen mediated disease is prostate cancer.

6. The method of claim 5 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

7. A compound 2-((2R,6S)-4-(2-((trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 7 , and a pharmaceutically acceptable carrier, excipient or vehicle.

9. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 7 , wherein the androgen mediated disease is prostate cancer.

10. The method of claim 9 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

11. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically amount of the pharmaceutical composition of claim 8 , wherein the androgen mediated disease is prostate cancer.

12. The method of claim 11 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

13. A compound 2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 13 , and a pharmaceutically acceptable carrier, excipient or vehicle.

15. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 13 , wherein the androgen mediated disease is prostate cancer.

16. The method of claim 15 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

17. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 14 , wherein the androgen mediated disease is prostate cancer.

18. The method of claim 17 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

19. A compound 2-((2R,6S)-4-(2-((trans-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 19 , and a pharmaceutically acceptable carrier, excipient or vehicle.

21. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 19 , wherein the androgen mediated disease is prostate cancer.

22. The method of claim 21 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

23. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 20 , wherein the androgen mediated disease is prostate cancer.

24. The method of claim 23 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

25. A compound 2-((2R,6S)-4-(3-(trans-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 25 , and a pharmaceutically acceptable carrier, excipient or vehicle.

27. A method for the treatment of androgen receptor mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 25 , wherein the androgen mediated disease is prostate cancer.

28. The method of claim 27 , wherein the prostate cancer is castration resistant

Assignees

• Celgene Corp

Inventors

• Alexander Matthew D
• Correa Matthew D
• Dalvie Deepak
• Grant Virginia Heather Sharron
• Hansen Joshua
• Harris Iii Roy L
• Horn Evan J
• Huang Dehua
• Mayne Christopher
• Norris Stephen
• Plantevin-Krenitsky Veronique
• Sapienza John J
• Tehrani Lida
• Whitefield Brandon W

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title