Benzofuran derivative, preparation method thereof and use thereof in medicine

Patent metadata

Field	Value
Publication number	US-10759787-B2
Application number	US-201615775958-A
Country	US
Kind code	B2
Filing date	Nov 2, 2016
Priority date	Nov 19, 2015
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present invention relates to a benzofuran derivative, a preparation method thereof and a use thereof in medicine. In particular, the present invention relates to the benzofuran derivative as shown by general formula (I), the preparation method thereof, a pharmaceutical composition containing the derivative, and uses thereof as an EZH2 inhibitor and in the prevention and/or treatment of diseases such as tumours and cancers, etc., and in particular, uses thereof in the prevention and/or treatment of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma and synovial sarcoma, wherein the definitions of the substituents in the general formula (I) are the same as those defined in the description.

First claim

What is claimed is:

1. A compound of formula (I):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt 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)O R 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 groups 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 groups 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 groups 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 groups 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 compound according to claim 1 , wherein n is 2.

3. The compound according to claim 1 , wherein p and q are each 0, 1 or 2.

4. The compound according to claim 1 , wherein each R 1 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, cycloalkyl, heterocyclyl and —(CH 2 ) x R a , wherein the alkyl and heterocyclyl are each independently and optionally substituted by one or more groups selected from the group consisting of alkyl, hydroxyalkyl and halogen; and 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 groups selected from the group consisting of hydroxyalkyl, alkyl and halogen; and R 7 , R 8 and x are as defined in claim 1 .

5. The compound according to claim 1 , wherein each R 1 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cyano and —(CH 2 ) x R a , wherein x is 0, and R a is halogen or cycloalkyl.

6. The compound according to claim 1 , wherein R 2 is alkyl optionally substituted by cycloalkyl.

7. The compound according to claim 1 , wherein R 3 is selected from the group consisting of alkyl, halogen and haloalkyl.

8. The compound according to claim 1 , wherein each R 4 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl and alkoxy.

9. The compound according to claim 1 , wherein each R 5 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, oxo, haloalkyl, —C(O)R 6 , —S(O) m R 6 and —NR 7 R 8 .

10. The compound according to claim 1 , which is a compound of formula (II):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt 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, hydroxy, 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, 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 .

11. The compound according to claim 1 , which is a compound of formula (III):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
E is CH or nitrogen;
F is selected from the group consisting of CR b R c , 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 and heteroaryl;
R d is selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl, aryl and heteroaryl;
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 , and n are as defined in claim 1 .

12. The compound according to claim 11 , which is a compound of formula (IV):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
each R e is identical or different and each 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 11 .

13. The compound according to claim 1 , which is a compound of formula (V):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Assignees

• Jiangsu Hengrui Medicine Co
• Shanghai hengrui pharmaceutical co ltd

Inventors

• Lu Biao
• Shen Xiaodong
• He Mingxun
• Liu Dong
• Zhang Minsheng

Classifications

• C07D409/14

  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

  Antineoplastic agents · CPC title

• A61K31/4433 Primary

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title