3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-12570625-B2
Application number	US-202117520857-A
Country	US
Kind code	B2
Filing date	Nov 8, 2021
Priority date	Jul 10, 2018
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

Abstract

The present disclosure provides a compound of Formula (I′):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R x , X 1 , X 2 , and R 1 are as defined herein, and methods of making and using same.

First claim

What is claimed is:

1 . A method of treating a disease or disorder that is affected by the modulation of IKZF2 protein levels, wherein the disease or disorder is acute lymphoblastic leukemia or lymphoma, comprising administering to the patient in need thereof a compound of Formula (I′)

wherein:
X 1 and X 2 are each independently H, (C 1 -C 4 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 3 -C 7 )cycloalkyl, halogen, —CN, —OH, or —NH 2 ;
R x is H or D;
R 1 is

each R 2 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, halogen, —CN, —OH, or —NH 2 ; or
two R 2 together with the carbon atoms to which they are attached form a (C 3 -C 7 )cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S; or two R 2 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring consisting of 1-3 heteroatoms selected from O, N, and S; or
R 2 and R 6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, —OH, —CN, and —NH 2 ;
each R 3 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, halogen, —OH, or —NH 2 ;
R 4 is —OR 5 or —NR 6 R 6 ;
R 5 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents independently selected from (C 6 -C 10 )aryl and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
R 6 and R 6′ are each independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )hydroxyalkyl, (C 3 -C 7 )cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R 7 and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R 12 ; or
R 6 and R 6′ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four R 8 ; or
R 2 and R 6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, —OH, —CN, and —NH 2 ;
each R 7 is (C 3 -C 7 )cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R 9 ;
each R 8 is independently at each occurrence halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —CN, —OH, —NR 13 R 14 , —NH 2 , —O(C 3 -C 7 )cycloalkyl, —O-4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, —O(C 6 -C 10 )aryl, or —O-5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkoxy is optionally substituted with one to three R 10 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three R 11 ; or
two R 8 together with the atoms to which they are attached form a (C 4 -C 7 )cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with two R 15 ; or two R 8 when on adjacent atoms together with the atoms to which they are attached form a (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S; or two R 8 together with the same atom to which they are attached form a=(O);
each R 9 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 3 -C 6 )cycloalkyl, —OH, —CN, —NH 2 , or —NR 13 R 14 ; or
two R 9 together with the atoms to which they are attached form a (C 4 -C 7 )cycloalkyl or a 5- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with one or more substituents each independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, —OH, —CN, and —NH 2 ; or two Ry when on adjacent atoms together with the atoms to which they are attached form a (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
each R 10 is independently at each occurrence selected from (C 3 -C 7 )cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
each R 11 is independently at each occurrence selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl,

(C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, —OH, —CN, and —NH 2 ;
each R 12 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, —OH, —CN, or —NH 2 ;
two R 12 together with the atoms to which they are attached form a (C 4 -C 7 )cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
R 13 and R 14 are each independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
two R 15 together with the atoms to which they are attached form a (C 4 -C 7 )cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
m and m1 are each independently 0, 1 or 2;
n1 is 0, 1, 2, or 3; and
each s and n is independently 1, 2, or 3, wherein s+n is ≤4;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

2 . The method according to claim 1 where the compound of Formula (I′) is selected from:
3-(5-(((1S,2S)-2-((2,2-difluoroethyl)(ethyl)amino)cyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-(((1S,2R)-2-((2,2-difluoroethyl)(ethyl)amino)cyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-(((1R,2S)-2-((2,2-difluoroethyl)(ethyl)amino)cyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-(((1R,2R)-2-((2,2-difluoroethyl)(ethyl)amino)cyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-((2-((2,2-difluoroethyl)(ethyl)amino)cyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(5-(((1S,2R)-2-(benz

Assignees

• Novartis Ag

Inventors

• Adcock Claire
• Bonazzi Simone
• Cernijenko Artiom
• Lam Philip
• Linkens Kathryn Taylor
• Malik Hasnain Ahmed
• Thomsen Noel Marie-France
• Visser Michael Scott

Classifications

• C07D407/14

  containing three or more hetero rings · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

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