Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11325889-B2
Application number	US-201916719217-A
Country	US
Kind code	B2
Filing date	Dec 18, 2019
Priority date	Dec 19, 2018
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

Provided herein are piperidine dione compounds having the following structure:wherein RN, R1, R2, R3, R4, X, L, V, 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 of formula (I)

or a pharmaceutically acceptable salt thereof,
wherein
R N is H;
each R 1 is independently selected from halogen, CN, and C 1-3 alkyl;
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;
each R 4 is independently selected from substituted or unsubstituted C 1-3 alkyl;
X is CR x ;
R x is H, halogen, or substituted or unsubstituted C 1-3 alkyl;
L is —O—, or —O(CH 2 ) p —;
n is 0-4;
m is 0-8;
p is 1-3;
V is

wherein
A is N, CH, or CR A ;
B is N, CH or CR B ;
each R A is independently selected from halogen, substituted or unsubstituted C 1-6 alkyl, and substituted and unsubstituted C 3-6 cycloalkyl;
each R B is independently selected from halogen, and substituted or unsubstituted C 1-6 alkyl;
R C is halogen or CF 3 ;
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 3-5 cycloalkyl or a 3-5 membered heterocyclyl;
a is 0-3; and
b is 0-2.

2. The compound of claim 1 , wherein each R 1 is independently selected from Cl, F, Br, CN, —CH 3 , and —CH 2 CH 3 .

3. The compound of claim 1 , wherein each R 1 is independently selected from Cl, F, and CN.

4. The compound of claim 1 , wherein n is 0.

5. The compound of claim 1 , wherein n is 1.

6. The compound of claim 1 , wherein R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl, and ethyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl.

7. The compound of claim 1 , wherein R 2 and R 3 are each independently selected from H and methyl, or wherein R 2 and R 3 and the carbon to which they are attached form an unsubstituted cyclopropyl.

8. The compound of claim 1 , wherein R 2 and R 3 are both H or methyl, or wherein R 2 and R 3 and the carbon to which they are attached form an unsubstituted cyclopropyl.

9. The compound of claim 1 , wherein each R 4 is independently selected from substituted or unsubstituted methyl and ethyl.

10. The compound of claim 1 , wherein each R 4 is independently selected from substituted or unsubstituted methyl.

11. The compound of claim 1 , wherein each R 4 is independently selected from methyl and CH 2 OH.

12. The compound of claim 1 , wherein m is 0, 1, 2, 3 or 4.

13. The compound of claim 1 , wherein m is 0, 1, or 2.

14. The compound of claim 1 , wherein R x is H.

15. The compound of claim 1 , wherein R x is CH 3 .

16. The compound of claim 1 , wherein R x is F.

17. The compound of claim 1 , wherein L is —O—, —O(CH 2 )—, or —O(CH 2 (CH 2 )—.

18. The compound of claim 1 , wherein A is CH.

19. The compound of claim 1 , wherein B is CH.

20. The compound of claim 1 , wherein B is N.

21. The compound of claim 1 , wherein a is 0, 1 or 2.

22. The compound of claim 18 , wherein each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH 2 CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH(CH 3 ) 2 , CH 2 C(CH 3 ) 3 , CF 3 , CF 2 CH 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH(CH 3 )OH, CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, cyclopopyl, cyclobutyl, and cyclopentyl.

23. The compound of claim 1 , wherein each R A is independently selected from Cl, F, ethyl, isopropyl, CF 2 CH 3 , and CH 2 CH 2 F.

24. The compound of claim 19 , wherein each R A is independently selected from Cl, F, ethyl, isopropyl, CF 2 CH 3 , and CH 2 CH 2 F.

25. The compound of claim 20 , wherein each R A is independently selected from Cl, ethyl, isopropyl, CF 2 CH 3 and CH 2 CH 2 F.

26. The compound of claim 1 , wherein b is 0.

27. The compound of claim 1 , wherein R C is CF 3 .

28. The compound of claim 1 , wherein R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, tetrahydrofuranyl, or tetrahydropyranyl.

29. The compound of claim 1 , wherein R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a cyclobutyl.

30. A compound
2-(4-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenoxy)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-((4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)ethyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-(2-(2-chloro-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)ethyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-((4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)methyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-((2-chloro-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)methyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)ethyl)piperidin-1-yl)-N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-((2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)methyl)piperidin-1-yl)-N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperidin-1-yl)acetamide,
2-(4-((4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)methyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-ylamino)phenyl)acetamide,
N-(3-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperidin-1-yl)acetamide,
N-(2-chloro-5-(2,6-dioxopiperidin-3-ylamino)phenyl)-2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperidin-1-yl)acetamide,
2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphen

Assignees

• Celgene Corp

Inventors

• Ammirante Massimo
• Bahmanyar Sogole
• Correa Matthew D
• Grant Virginia
• Hansen Joshua
• Horn Evan J
• Kercher Timothy S
• Mayne Christopher
• Nagy Mark A
• Narla Rama Krishna
• Nayak Surendra
• Norris Stephen
• Papa Patrick
• Plantevin-Krenitsky Veronique
• Sapienza John J
• Whitefield Brandon W
• Xu Shuichan

Classifications

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D211/94 Primary

  Oxygen atom, e.g. piperidine N-oxide · CPC title

• C07D211/98

  Nitrogen atom · CPC title