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

Patent metadata

Field	Value
Publication number	US-12227490-B2
Application number	US-202318219511-A
Country	US
Kind code	B2
Filing date	Jul 7, 2023
Priority date	Jun 24, 2020
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

Abstract

Provided herein are piperidine dione compounds having the following structure:

wherein R 1 , R 2 , R 3 , R 4 , L, V, X, a and m 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 of formula I

or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, wherein
R 1 is C 1-3 alkyl;
a is 1 or 2;
R 2 and R 3 are each independently selected from H, and C 1-3 alkyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted C 3-6 cycloalkyl;
m is 0-8;
each R 4 is independently substituted or unsubstituted C 1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C 3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
X is CR X ;
R X is hydrogen, halogen, —O(C 1-6 alkyl) or —(C 1-9 alkyl);
L is substituted or unsubstituted —O(C 1-6 alkyl)-, —(C 1-6 alkyl)O—, —O(C 1-6 alkyl)O—, or —(C 1-9 alkyl)-;
V is

wherein
B is N, CH, or CR B ;
each R B is independently selected from halogen, and substituted or unsubstituted C 1-6 alkyl;
R C is halogen, CF 3 or SF 5 ;
R 5 and R 6 are C 1-3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3-6 cycloalkyl or a 3-6 membered heterocyclyl; and
b is 0-2.

2. The compound of claim 1 , wherein R 1 is methyl.

3. The compound of claim 1 , wherein a is 1, and R 2 and R 3 are both H.

4. The compound of claim 1 , wherein each R 4 is independently selected from methyl and CF 3 .

5. The compound of claim 1 , wherein X is N or CR X ; and R X is hydrogen, halogen, —O(C 1-6 alkyl) or —(C 1-9 alkyl).

6. The compound of claim 1 , wherein L is substituted or unsubstituted —O(CH 2 ) p —, —O(CH 2 ) p O— or —(CH 2 ) p —, and p is 1-4.

7. The compound of claim 1 , wherein B is CH or N.

8. The compound of claim 1 , wherein R C is CF 3 , Cl or SF 5 .

9. The compound of claim 1 , wherein R 5 and R 6 are methyl.

10. The compound of claim 1 , having formula II

or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

11. The compound of claim 1 , wherein the compound is selected from
2-((2R,4s,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-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride;
2-((2R,4r,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-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride;
2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridine-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
2-((2R,4s,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-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
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-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide;
or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

12. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

13. A method for the treatment of an androgen receptor mediated disease, the method comprising administering to a subject in need thereof an effective amount of the compound of claim 1 .

14. The method of claim 13 , wherein the androgen mediated disease is prostate cancer.

15. The method of claim 14 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

16. A method for the treatment of an androgen receptor mediated disease, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 12 .

17. The method of claim 16 , wherein the androgen mediated disease is prostate cancer.

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

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/496

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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title