Substituted 1-oxo-isoindoline-5-carboxamide compounds, compositions thereof, and methods of treatment therewith
Provided herein are 1-oxo-isoindoline-5-carboxamide compounds having the following structure: wherein R 1 , R 2 , R 3 , R 4 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.
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.