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

Patent metadata

Field	Value
Publication number	US-12404241-B2
Application number	US-202318521663-A
Country	US
Kind code	B2
Filing date	Nov 28, 2023
Priority date	Dec 19, 2018
Publication date	Sep 2, 2025
Grant date	Sep 2, 2025

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 process of preparing a compound of formula (I)

wherein the process comprises contacting a compound of formula (i)

with a compound of formula (b)

wherein Hal 2 is Br or Cl, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (I); 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, or substituted and 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 process of claim 1 , comprising contacting a compound of formula (h)

with Hal 2 -C(R 2 )(R 3 )COY, wherein Y is OH or Cl, under conditions suitable to provide a compound of formula (i).

3. The process of claim 2 , wherein Y is OH and the contacting is performed in the presence of a coupling agent, and a base, in a solvent.

4. The process of claim 3 , wherein the coupling agent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate (HBTU), 3-{[(ethylimino)methylidene]amino}-N,N-dimethylpropan-1-amine (EDC) or N,N′-dicyclohexylmethanediimine (DCC), optionally in combination with 1H-1,2,3-benzotriazol-1-ol (HOBt).

5. The process of claim 3 , wherein the base is N,N-diisopropylethylamine (DIEA), triethylamine (TEA), or 4-methylmorpholine (NMM).

6. The process of claim 3 , wherein the solvent is dichloromethane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP) or mixtures thereof.

7. The process of claim 1 , wherein the base is DIEA, TEA or NMM.

8. The process of claim 1 , wherein the solvent is DMF or NMP.

9. The process of claim 1 , wherein the contacting is performed at a temperature between about 40° C. and about 60° C.

10. The process of claim 1 , wherein the contacting is performed in the presence of NaI or KI.

11. The process of claim 1 , comprising deprotecting a compound of formula (a)

wherein P N is an amine protecting group, under conditions suitable to provide a compound of formula (b).

12. The process of claim 11 , comprising contacting a compound

with V-L-Hal, wherein Hal is Cl, Br, OMs, or OTs, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (a).

13. The process of claim 12 , wherein the base is CsCO 3 or K 2 CO 3 .

14. The process of claim 12 , wherein the solvent is DMF or NMP.

15. The process of claim 12 , wherein the contacting is performed at a temperature between about 40° C. and about 70° C.

16. The process of claim 12 , wherein Hal is Cl or Br.

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

• C07D233/30

  Oxygen or sulfur atoms · CPC title

• C07D401/12

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

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