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

Patent metadata

Field	Value
Publication number	US-11873283-B2
Application number	US-202117403742-A
Country	US
Kind code	B2
Filing date	Aug 16, 2021
Priority date	Dec 19, 2018
Publication date	Jan 16, 2024
Grant date	Jan 16, 2024

Abstract

Provided herein are piperidine dione compounds having the following structure:

wherein R N , R 1 , R 2 , R 3 , R 4 , 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, tautomer, or stereoisomer 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 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 N;
L is —O(C 1-6 alkyl)- or —(C 1-9 alkyl)-;
n is 0-4;
m is 0-8;
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 or 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 3-6 cycloalkyl or a 3-6 membered heterocyclyl;
a is 0-3; and
b is 0-2.

2. The compound of claim 1 , wherein L is —O(CH 2 ) p — or —(CH 2 ) p —, and p is 1-3.

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

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

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

6. The compound of claim 1 , wherein n is 1 or 2.

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

8. 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.

9. 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.

10. The compound of claim 1 , wherein each R 4 is independently selected from substituted or unsubstituted methyl and ethyl, or wherein two R 4 groups, together with the same carbon atom to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl.

11. The compound of claim 1 , wherein each R 4 is independently selected from substituted or unsubstituted methyl, or wherein two R 4 groups, together with the same carbon atom to which they are attached, form an unsubstituted cyclopropyl.

12. The compound of claim 1 , wherein each R 4 is independently selected from methyl, CF 3 , and CH 2 OH, or wherein two R 4 groups, together with the same carbon atom to which they are attached, form an unsubstituted cyclopropyl.

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

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

15. The compound of claim 1 , wherein two R 4 groups together with the non-adjacent carbon atoms to which they are attached form an unsubstituted 4-7-membered heterocyclyl.

16. The compound of claim 1 , wherein L is O(CH 2 )(CH 2 )—, —O(CH 2 )(CH(CH 3 ))—, —O(CH 2 )(C(CH 3 ) 2 )—, —O(CH(CH 3 ))(CH 2 )—, —O(C(CH 3 ) 2 )(CH 2 )—, —O(CH(CH 3 ))(CH(CH 3 ))—, —O(CH(CH 3 ))(C(CH 3 ) 2 )—, —O(C(CH 3 ) 2 )(CH(CH 3 ))—, —(CH 2 )—, —(CH 2 )(CH 2 )—, —(CH 2 )(CH 2 )(CH 2 )—, —(C(CH 3 ) 2 )(C(CH 3 ) 2 )—, —(CH(CH 3 ))—, —(C(CH 3 ) 2 )—, —(CH(CH 3 ))(CH(CH 3 ))—, —(CH(CH 3 ))(C(CH 3 ) 2 )—, —(C(CH 3 ) 2 )(CH(CH 3 ))—, —(C(CH 3 ) 2 )(C(CH 3 ) 2 )—, —(CH 3 )(CH 3 )(CH(CH 3 ))—, —(CH 2 )(CH(CH 3 ))(CH 2 )—, —(CH(CH 3 ))(CH 2 )(CH 2 )—, —(CH 2 )(CH 2 )(C(CH 2 ) 2 )—, —(CH 2 )(C(CH 2 ) 2 )(CH 2 )—, —(C(CH 2 ) 2 )(CH 2 )(CH 2 )—, —(CH 2 )(CH(CH 3 ))(CH(CH 3 ))—, —(CH(CH 3 ))(CH(CH 3 ))(CH(CH 3 ))—, —(CH(CH 3 ))(CH(CH 3 ))(CH 2 )—, —(CH(CH 3 ))(CH 2 )(CH(CH 3 ))—, —(CH 2 )(CH(CH 3 ))(C(CH 3 ) 2 )—, —(CH(CH 3 ))(CH 2 )(C(CH 2 ) 2 )—, —(C(CH 3 ) 2 )(CH 2 )(C(CH 3 ) 2 )—, —(CH 2 )(C(CH 3 ) 2 )(C(CH 3 ) 2 )—, —(CH 2 )(C(CH 3 ) 2 )(CH(CH 3 ))—, —(CH(CH 3 )(C(CH 3 ) 2 )(CH 2 )—, —(C(CH 3 ) 2 )(CH 2 )(CH(CH 3 ))—, —(C(CH 3 ) 2 )(CH(CH 3 ))(CH 2 )—, —(C(CH 3 ) 2 )(C(CH 3 ) 2 )(CH 2 )—, —(CH(CH 3 ))(CH(CH 3 ))(C(CH 3 ) 2 )—, —(CH(CH 3 ))(C(CH 3 ) 2 )(C(CH 3 ) 2 )—, —(C(CH 3 ) 2 )(CH(CH 3 ))(C(CH 3 ) 2 )—, —(CH(CH 3 ))(C(CH 3 ) 2 )(CH(CH 3 ))—, —(C(CH 3 ) 2 )(C(CH 3 ) 2 )(CH(CH 3 ))—, —(C(CH 3 ) 2 )(CH(CH 3 ))(CH(CH 3 ))—, and —(C(CH 3 ) 2 )(C(CH 3 ) 2 )(C(CH 3 ) 2 )—.

17. The compound of claim 1 , wherein L is —O(CH 2 )(CH 2 )—, —O(CH 2 )(CH(CH 3 ))—, —O(CH 2 )(C(CH 3 ) 2 )—, —O(CH(CH 3 ))(CH 2 )—, —O(C(CH 3 ) 2 )(CH 2 )—, —(CH 2 )—, —(CH 2 )(CH 2 )—, or —(CH 2 )(CH 2 )(CH 2 )—.

18. The compound of claim 1 , wherein L is —O(CH 2 )(CH 2 )—, —O(CH 2 )(CH(CH 3 ))—, —O(CH(CH 3 ))(CH 2 )—, or —(CH 2 )(CH 2 )(CH 2 )—.

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

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

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

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

23. The compound of claim 19 , 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 , 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, cyclopropyl, cyclobutyl, and cyclopentyl.

24. The compound of claim 1 , wherein each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF 3 , CF 2 CH 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 OH, CH(CH 3 )OH, cyclopropyl, cyclobutyl, and cyclopentyl.

25. The compound of claim 1 , wherein each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF 3 , CF 2 CH 3 , CH 2 CH 2 F, CH 2 CHF 2 , cyclopropyl, cyclobutyl, and cyclopentyl.

26. The compound of claim 1 , wherein each R A is independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF 2 CH 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 OH, CH(CH 3 )OH, cyclopropyl, and cyclobutyl.

27. The compound of claim 1 , wherein b is 0 or 1.

28. The compound of claim 1 , wherein R B is methyl.

29. The compound of claim 1 , wherein R C is CF 3 or Cl.

30. 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, cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl.

31. The compound of cla

Assignees

• Celgene Corp

Inventors

• Ammirante Massimo
• Bahmanyar Sogole
• Correa Matthew D
• Grant Virginia Heather Sharron
• 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

• C07D487/08

  Bridged systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/08

  of the prostate · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title