Use of EZH2 inhibitor combined with BTK inhibitor in preparing drug for treating tumor

Patent metadata

Field	Value
Publication number	US-11065239-B2
Application number	US-201816611969-A
Country	US
Kind code	B2
Filing date	May 17, 2018
Priority date	May 18, 2017
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

This application describes a use of an EZH2 inhibitor combined with a BTK inhibitor in preparing a drug for treating a tumor is described.

First claim

What is claimed is:

1. A method for treating a tumor in a subject in need thereof, the method comprising administering to the subject a combination of an EZH2 inhibitor and a BTK inhibitor, wherein the EZH2 inhibitor is a compound of formula (I):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein,
ring A is selected from the group consisting of heterocyclyl and cycloalkyl;
each R 1 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 6 , —C(O)R 6 , —C(O)OR 6 , —S(O) m R 6 , —S(O) m NR 7 R 8 and —(CH 2 ) x R a , wherein the alkyl, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R a is selected from the group consisting of halogen, cycloalkyl, heterocyclyl and —NR 7 R 8 , wherein the cycloalkyl and heterocyclyl are each independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 2 is hydrogen or alkyl, wherein the alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, cycloalkyl and heterocyclyl;
R 3 is selected from the group consisting of hydrogen, alkyl, halogen, cyano, alkoxy and haloalkyl;
each R 4 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxy, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 6 , —C(O)R 6 , —C(O)OR 6 , —S(O) m R 6 , —S(O) m NR 7 R 8 and —NR 7 R 8 ;
each R 5 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, oxo, halogen, haloalkyl, hydroxy, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 6 , —C(O)R 6 , —C(O)OR 6 , —S(O) m R 6 , —S(O) m NR 7 R 8 and —NR 7 R 8 ;
R 6 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 7 and R 8 are identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, alkoxycarbonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently and optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
m is 0, 1 or 2;
n is 0, 1, 2 or 3;
p is 0, 1, 2, 3, 4 or 5;
q is 0, 1 or 2; and
x is 0, 1, 2 or 3.

2. The method according to claim 1 , wherein the EZH2 inhibitor is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein,
G is selected from the group consisting of CR b R c , C═O, NR d , S(O) m and oxygen;
R b and R c are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 6 , —C(O)R 6 , —C(O)OR 6 , —S(O) m R 6 and —NR 7 R 8 ;
R d is selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 6 , —C(O)OR 6 and —S(O) m R 6 ; and
R 1 to R 4 , R 6 to R 8 , n, m and q are as defined in claim 1 .

3. The method according to claim 1 , wherein the EZH2 inhibitor is a compound of formula (TB):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein,
E is CH or nitrogen;
F is selected from the group consisting of CR b R c , C═O, NR d and oxygen;
R b and R c are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 6 , —C(O)R 6 , —C(O)OR 6 , —S(O) m R 6 and —NR 7 R 8 ;
R d is selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 6 , —C(O)OR 6 and —S(O) m R 6 ;
each R e is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
t is 0, 1, 2, 3, 4 or 5;
x is 0, 1, 2 or 3;
y is 0, 1, 2 or 3; and
R 2 to R 4 , R 6 to R 8 , m and n are as defined in claim 1 .

4. The method according to claim 1 , wherein the EZH2 inhibitor is a compound of formula (IC):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein,
each R e is identical or different and is independently selected from the group consisting of hydrogen, alkyl and halogen;
t is 0, 1, 2, 3, 4 or 5; and
R 2 to R 4 and n are as defined in claim 1 .

5. The method according to claim 1 , wherein the EZH2 inhibitor is a compound of formula (ID):

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein,
R e is selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and
R 2 to R 4 and n are as defined in claim 1 .

6. The method according to claim 1 , wherein the BTK inhibitor is a compound of formula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein,
A is selected from the group consisting of CR 1 and N;
R 1 is selected from the group consisting of hydrogen, halogen and optionally substituted alkyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, amino, alkyl, alkoxy and haloalkyl;
R a , R b , R c and R d are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted alkyl and optionally substituted alkoxy, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, amino, alkyl, alkoxy and haloalkyl;
B is selected from the group consisting of hydrogen, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, amino, alkyl, alkoxy and haloalkyl;
L is selected from the group consisting of a bond and optionally substituted alkyl; and
Y is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substitu

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Ma Ke
• Cao Guoqing
• Yang Changyong
• Zhang Lianshan

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D237/00

  Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings · CPC title

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title

• A61K31/4545 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title