Quinoline compounds and compositions for inhibiting EZH2

Patent metadata

Field	Value
Publication number	US-12473273-B2
Application number	US-202117919490-A
Country	US
Kind code	B2
Filing date	Aug 10, 2021
Priority date	Aug 10, 2020
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

The invention disclosed herein relates to aza-quinoline compounds of Formula (I),

pharmaceutical compositions comprising such compounds; and the use of such compounds for treating a disease or condition mediated by Enhancer of Zeste Homolog 2 (EZH 2 ), Polycomb Repressive Complex 2 (PRC 2 ), or a combination thereof.

First claim

The invention claimed is:

1 . A compound having the structure of Formula (I):

or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein:
Y is N or CR a ;
R a , R 1 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are independently is H, halogen or —C 1 -C 4 alkyl;
R 2 is —CN, —C 1 -C 6 alkyl, -hydroxyC 1 -C 4 alkylene, —C 1 -C 4 alkoxy, —C 2 -C 4 alkoxy substituted with 1-2 hydroxyl;
—(CR 13 R 14 ) n C(═O) NR 11 R 12 , —(CR 13 R 14 ) n C(═O) NR 11 R 15 ;
—(CR 13 R 14 ) n C(═O) R 15 ;
—(CR 2 ) NR 11 C(═O) R 15 , —(CR 2 ) n NR 11 (CR 2 ) 2 C(═O)R 15 ;
—(CR 2 ) n NR—C(═O)OR 11 , —(CR 2 ) n NR—C(═O)O—(CR 2 )—R 15 ;
—NR—C(═O)(CR 2 ) 2 C(═O)R 15 , —NR—C(═O) R 11 ;
—(CR 2 ) n NR 11 R 12 , —(CR 2 ) n NR 11 (CR 2 ) n R 15 ;
—(CR 2 ) n OR 15 , —(CR 2 ) n R 15 ;

or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from O, S and N;
R 4a , R 4b , R 4c and R 4d are independently H or —C 1 -C 4 alkyl;
R 10 is H, halogen, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 haloalkoxy or —NH(C 1 -C 4 alkyl);
R 11 is H, —C 1 -C 4 alkyl, -hydroxyC 1 -C 4 alkylene, -cyanoC 1 -C 4 alkylene or —C 1 -C 4 alkyl substituted with —C 1 -C 4 alkoxy;
R 12 is H or —C 1 -C 4 alkyl;
R 13 is H, halogen, —CN, —OH, —C 1 -C 4 alkyl or -hydroxyC 1 -C 4 alkylene;
R 14 is H, halogen or —C 1 -C 4 alkyl;

R 15 is —C 3 -C 6 cycloalkyl, or a 4- to 6-membered heterocycoalkyl having 1-2 heteroatoms independently selected from O, S, S(═O) 2 , and N; wherein said —C 3 -C 6 cycloalkyl or 4- to 6-membered heterocycloalkyl of R 15 is unsubstituted or substituted with 1-2 substituents selected from —OH, —C 1 -C 4 alkyl, -hydroxyC 1 -C 4 alkylene, —C 1 -C 4 alkoxy, —SO 2 (C 1 -C 4 alkyl) and —N(C 1 -C 4 alkyl) 2 ;
R 16 , if present, is a substituent selected from halogen, —CN, —OH, —C 1 -C 4 alkyl and -hydroxyC 1 -C 4 alkylene;
each R is independently H or —C 1 -C 4 alkyl;
m is 0, 1 or 2; and
each n is independently selected from 0, 1 and 2.

2 . The compound of claim 1 , or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein R 2 is —(CH 2 ) 1-2 C(═O) NR 11 R 15 or —(CR 13 R 14 )—C(═O) NR 11 R 15 .

3 . The compound of claim 1 , or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein R 2 is

4 . The compound of claim 1 , wherein said compound is of Formula (II), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

wherein:
Y is CH or N;
R 1 , R 3 , R 4a , R 4b , R 4c , R 4d and R 11 are independently H or C 1 -C 4 alkyl;
R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently is H, halogen or C 1 -C 4 alkyl;
R 13 is H, halogen, —CN, —OH, —C 1 -C 4 alkyl or -hydroxyC 1 -C 4 alkylene;
R 14 is H, halogen or —C 1 -C 4 alkyl; and
R 15 is a 4- to 6-membered heterocycoalkyl having 1-2 heteroatoms independently selected from O, S and N; and wherein R 15 is unsubstituted or substituted with 1-2 substituents selected from —OH, —C 1 -C 4 alkyl, -hydroxyC 1 -C 4 alkylene, —C 1 -C 4 alkoxy, —SO 2 (C 1 -C 4 alkyl) and —N(C 1 -C 4 alkyl) 2 .

5 . The compound of claim 4 , or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein R 15 is

6 . The compound of claim 5 , or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein m is 1 and R 16 is —C 1 -C 4 alkyl.

7 . A compound selected from:
2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-cyano-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; and 2-(6-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

8 . A compound selected from:
2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-cyano-N-(oxetan-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; and 2-(6-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

9 . The compound of claim 1 , wherein said compound is 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

10 . The compound of claim 1 , wherein said compound is 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)a

Assignees

• Novartis Ag

Inventors

• Dai Xuan
• Dore Michael
• Gu Xiang-Ju Justin
• Li Ling
• Liu Kun Chin
• Mak Sing Yeung Frankie
• Mi Yuan
• Oyang Counde
• Papillon Julien
• Qi Wei (Vicky)
• Yan Xiaoxia
• Yu Zhengtian
• Zhang Ji Yue (Jeff)
• Zhao Kehao

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title