Quinazoline derivative and preparation method therefor

Patent metadata

Field	Value
Publication number	US-9725439-B2
Application number	US-201415024472-A
Country	US
Kind code	B2
Filing date	Sep 28, 2014
Priority date	Sep 28, 2013
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

The present invention relates to a quinazoline derivative shown in formula (I) and a preparation method therefor, a pharmaceutical composition comprising the compound shown in formula (I), and an application of the compound in preparing drugs for curing and preventing tumors. The compound of the present invention can irreversibly prevent EGFR phosphorylation, and effectively depress signal transduction of cancer cells, and accordingly has higher anti-tumor activity in vitro and in vivo.

First claim

The invention claimed is:

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

wherein:
ring Ar is an aryl group or a heteroaryl group;
X is selected from the group consisting of —NR 8 —, —S—, —S(═O)—, or —S(═O) 2 —;
n and m are each an integer of 0 to 6, and are not simultaneously 0;
p is an integer of 0 to 5;
q is an integer of 0 to 8;
R 1 is independently selected from the group consisting of a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a heterocycloalkyl group, a halogen atom, an amino group, a mono(C 1-6 alkyl) amino group, a di(C 1-6 alkyl) amino group, a hydroxy group, a C 1-6 alkoxy group, a mercapto group, a C 1-6 alkylthio group, a C 1-6 alkylcarbonyl group, an aryl group, a heteroaryl group, a cyano group, and a nitro group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, and C 2-6 alkynyl group are optionally substituted by a halogen atom, a cyano group, a nitro group, a C 1-6 alkoxy group, an aryl group, a heteroaryl group, or a heterocycloalkyl group; and the aryl group, heteroaryl group and heterocycloalkyl group are optionally further substituted by a halogen atom, a cyano group, a nitro group, a C 1-6 alkyl group, a C 1-6 alkoxy group, or a C 1-6 alkylcarbonyl group;
R 2 is selected from the group consisting of hydrogen, a hydroxy group, a C 1-6 alkoxy group, a heterocycloalkyloxy group, and a C 1-6 alkoxy group substituted by C 1-6 alkoxy or heterocycloalkyl group;
R 3 is independently selected from the group consisting of a halogen atom, a cyano group, a mercapto group, a C 1-6 alkylthio group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a heterocycloalkyl group, an amino group, a mono(C 1-6 alkyl)amino group, a di(C 1-6 alkyl)amino group, a hydroxy group, a C 1-6 alkoxy group, a C 1-6 alkoxycarbonyl group, a C 1-6 alkylamido group, a mono(C 1-6 alkyl)aminoacyl group, and a di(C 1-6 alkyl)aminoacyl group;
R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a heterocycloalkyl group, an amino group, a mono(C 1-6 alkyl)amino group, a di(C 1-6 alkyl)amino group, a C 1-6 alkylamido group, a mono(C 1-6 alkyl)aminoacyl group, a di(C 1-6 alkyl)aminoacyl group, and a C 1-6 alkoxycarbonyl group;
R 7 and R 8 are each independently selected from the group consisting of hydrogen and a C 1-6 alkyl group;
the aryl group has 6-14 ring atoms;
the heteroaryl group has 5-12 ring atoms, in which 1-4 ring atoms are selected from the group consisting of N, O, and S;
the heterocycloalkyl group has 3-12 ring atoms, in which 1-3 ring atoms are replaced by atoms or groups selected from the group consisting of N, O, S, S(O), and S(O) 2 ; and
the heterocycloalkyloxy group has 3-12 ring atoms, in which 1-3 ring atoms are replaced by atoms or groups selected from the group consisting of N, O, S, S(O), and S(O) 2 .

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X is selected from the group consisting of —NR 8 — and —S—.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein n and m are each an integer of 0 to 3, and are not simultaneously 0.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 7 and R 8 are hydrogen.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the ring Ar is a phenyl group.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein p is an integer of 0 to 3.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein q is an integer of 0 to 3.

8. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is independently selected from the group consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halogen atom, an amino group, a hydroxy group, a C 1-6 alkoxy group, a C 1-6 alkylcarbonyl group, a cyano group, and a nitro group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, and C 2-6 alkynyl group are optionally substituted by a halogen atom, a cyano group, a nitro group, a C 1-6 alkoxy group, an aryl group, a heteroaryl group, or a heterocycloalkyl group; and the aryl group, heteroaryl group, and heterocycloalkyl group are optionally further substituted by a halogen atom, a cyano group, a nitro group, a C 1-6 alkyl group, a C 1-6 alkoxy group, or a C 1-6 alkylcarbonyl group.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein R 1 is independently selected from the group consisting of a C 2-6 alkynyl group, a halogen atom, a C 1-6 alkoxy group, and a C 1-6 alkylcarbonyl group, wherein the C 1-6 alkoxy group are optionally substituted by an aryl group, a heteroaryl group, or a heterocycloalkyl group; and the aryl group, heteroaryl group, and heterocycloalkyl group are optionally further substituted by a halogen atom, a cyano group, or a nitro group.

10. The compound or pharmaceutically acceptable salt thereof according to claim 9 , wherein R 1 is independently selected from the group consisting of a C 2-6 alkynyl group, a halogen atom, a heteroaryl-substituted C 1-6 alkoxy group, an aryl-substituted C 1-6 alkoxy group, and a C 1-6 alkylcarbonyl group, wherein the aryl group and heteroaryl group are optionally further substituted by a halogen atom.

11. The compound or pharmaceutically acceptable salt thereof according to claim 10 , wherein R 1 is independently selected from the group consisting of an ethynyl group, a halogen atom, a pyridyl-substituted C 1-6 alkoxy group, and a halophenyl-substituted C 1-6 alkoxy group.

12. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 , R 5 , and R 6 are hydrogen.

13. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, a methoxy group, a tetrahydrofuranyloxy group, a methoxy-substituted ethoxy group, and a morpholinyl-substituted ethoxy group.

14. A compound represented by any one of following formulas or a pharmaceutically acceptable salt thereof:

15. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutical acceptable carrier.

16. A method for inhibiting the growth of a cancer cell, comprising administering to a mammal in need thereof a therapeutic effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 1 ;
wherein the cancer cell is a lung cancer cell or a breast cancer cell.

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Centaurus Biopharma Co Ltd
• Lianyungang Runzhong Pharmaceutical Co Ltd

Inventors

• Xiao Dengming
• Zhu Yan
• Hu Yuandong
• Wang Huting
• Li Jijun
• Peng Yong
• Zhang Hui
• Luo Hong
• Kong Fansheng
• Han Yongxin

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title