Substituted 1-oxo-isoindoline-5-carboxamide compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-12486281-B2
Application number	US-202217690921-A
Country	US
Kind code	B2
Filing date	Mar 9, 2022
Priority date	May 31, 2019
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

Provided herein are 1-oxo-isoindoline-5-carboxamide compounds having the following structure:wherein R1, R2, R3, R4 and n are as defined herein, compositions comprising an effective amount of a 1-oxo-isoindoline-5-carboxamide compound, and methods for treating or preventing disorders.

First claim

What is claimed is:

1 . A process for preparing a compound of Formula (I)

or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, comprising contacting a compound of formula b

wherein X is OH, with NH 2 (CR 1 R 2 R 3 ), in a solvent, in the presence of a coupling agent and a base, wherein
R 1 is C 1-3 alkyl, or C 1-3 fluoroalkyl;
R 2 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted 5-10-membered heteroaryl;
R 3 is H;
R 4 is halogen; and
n is 0-3.

2 . The process of claim 1 , wherein the solvent is DMF, DMA, DCM, THF, or NMP.

3 . The process of claim 1 , wherein the coupling agent is HOBT, EDCI, HATU, or T3P.

4 . The process of claim 1 , wherein the base is DIPEA, TEA, or NMM.

5 . The process of claim 1 , wherein the compound of formula b is obtained by contacting compound c

wherein Hal is Br or I, with carbon monoxide and water in the presence of 1,3-bis(diphenylphosphino)propane, a palladium catalyst and a base in a solvent.

6 . The process of claim 5 , wherein the palladium catalyst comprises palladium acetate.

7 . The process of claim 5 , wherein the solvent is selected from DMF, DMA and NMP.

8 . The process of claim 5 , wherein the base is DIPEA, TEA or NMM.

9 . The process of claim 5 , wherein the compound of formula c is obtained by contacting a benzyl halide of formula

with 3-aminopiperidine-2,6-dione, in a solvent, in the presence of a base, wherein Hal is Br or I.

10 . The process of claim 9 , wherein the solvent is ACN, THF, DCM, DMF, DMA, or NMP.

11 . The process of claim 9 , wherein the base is DIPEA, TEA or NMM.

12 . The process of claim 5 , wherein the compound of formula c is obtained by contacting a benzyl aldehyde of formula

wherein Hal is Br or I, with 3-aminopiperidine-2,6-dione, in the presence of a reducing agent, in a solvent, in the presence of an acid.

13 . The process of claim 12 , wherein the solvent is ACN, MeOH, or EtOH.

14 . The process of claim 12 , wherein the acid is acetic acid or sodium acetate.

15 . The process of claim 12 , wherein the reducing agent is 2-MePyBH 3 , NaBH 4 , NaBH 3 CN, (CH 3 COO) 3 BHNa, or decaborane.

16 . The process of claim 1 , wherein the compound of formula b is obtained by contacting a compound of formula a

wherein Hal is Br or I, with carbon monoxide and water, in the presence of 1,3-bis(diphenylphosphino)propane and a palladium catalyst, in a solvent, in the presence of a base.

17 . The process of claim 16 , wherein the palladium catalyst comprises palladium acetate.

18 . The process of claim 16 , wherein the solvent is selected from DMF, DMA and NMP.

19 . The process of claim 16 , wherein the base is DIPEA, TEA or NMM.

20 . The process of claim 16 , wherein the compound of formula a is obtained by contacting an alkyl benzoate of formula

wherein Hal is Br or I and R is C 1-3 alkyl, with 3 aminopiperidine-2,6-dione in a solvent, in the presence of a base.

21 . The process of claim 20 , wherein the solvent is ACN, THF, DCM, DMF, DMA, or NMP.

22 . The process of claim 20 , wherein the base is DIPEA, TEA or NMM.

23 . A process for preparing a compound of Formula (I)

or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, comprising contacting a compound of formula e

wherein P O is a carboxyl protecting group, with an acid, in a solvent, wherein
R 1 is C 1-3 alkyl, or C 1-3 fluoroalkyl;
R 2 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted 5-10-membered heteroaryl;
R 3 is H;
R 4 is halogen; and
n is 0-3.

24 . The process of claim 23 , wherein the compound of formula e is obtained by contacting a compound of formula d

wherein X is OH, with NH 2 (CR 1 R 2 R 3 ), in a solvent, in the presence of a coupling agent, and a base.

25 . The process of claim 24 , wherein the compound of formula d is obtained by contacting a compound of formula

wherein Hal is Br or I, with carbon monoxide and water, in the presence of dicyclohexyl (3-dicyclohexylphosphaniumylpropyl) phosphonium ditetrafluoroborate and a palladium catalyst, in a solvent, in the presence of a base.

Assignees

• Celgene Corp

Inventors

• Baculi Frans
• Northcote Katherine
• Correa Matthew D
• Hansen Joshua
• Lebrun Laurie A
• Lu Chin-Chun
• Lu Gang
• Nagy Mark A
• Peng Sophie
• Perrin-Ninkovic Sophie

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title