Compound having mutant IDH inhibitory activity, preparation method and use thereof

Patent metadata

Field	Value
Publication number	US-10682352-B2
Application number	US-201716087556-A
Country	US
Kind code	B2
Filing date	Mar 21, 2017
Priority date	Mar 22, 2016
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

Provided in the present invention are a compound having the effects of preventing and treating diseases related to IDH mutation, and a preparation method and use thereof. In particular, provided in the present invention are the compound as shown in formula (I), a stereoisomer, a racemic body or a pharmaceutically acceptable salt thereof, and the use thereof in preparing drugs for preventing and treating diseases related to IDH mutation

First claim

The invention claimed is:

1. A compound of formula I, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof:

wherein,
R 3 and R 4 are each independently H, D, or substituted or unsubstituted C 1-4 alkyl;
or R 3 and R 4 together with the carbon atom connecting them form a substituted or unsubstituted C 3-6 cycloalkyl, or a substituted or unsubstituted C 3-6 epoxyalkyl;
R 5 and R 6 are each independently H, a substituted or unsubstituted C 1-4 alkyl, a substituted or unsubstituted C 6-10 aryl, or a substituted or unsubstituted C 3-6 cycloalkyl;
or R 5 and R 6 together with the carbon atom connecting them form a substituted or unsubstituted C 3-6 cycloalkyl;
R 7 and R 8 are each independently H, halogen, or a substituted or unsubstituted C 1-4 alkyl;
R 9 is H or a substituted or unsubstituted C 1-4 alkyl;
R 10 is a substituted or unsubstituted C 1-4 alkyl; or R 9 and R 10 together with the carbon atom connecting them form a substituted or unsubstituted C 3-6 cycloalkyl;
R 11 is a substituted or unsubstituted C 6-10 aryl, or a substituted or unsubstituted C 5-10 heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the term “substituted” means having one or more substituents selected from Group A:
the group consisting of H, D, halogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 3-8 cycloalkyl, a substituted or unsubstituted C 1-4 alkoxy, a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted C 5-10 heteroaryl, a substituted or unsubstituted C 6-10 aryloxy, and —C(O)NHRa′, wherein Ra′ is a substituted or unsubstituted C 1-6 alkyl, or a substituted or unsubstituted C 3-8 cycloalkyl; and
R 12 is H, D, a substituted or unsubstituted C 1-4 alkyl, or a substituted or unsubstituted C 3-6 cycloalkyl,
wherein, for R 3 -R 10 and R 12 , the term “substituted” means having one or more substituents selected from Group B:
the group consisting of H, D, halogen, a substituted or unsubstituted C 1-6 alkyl, —OH, a substituted or unsubstituted C 1-4 alkoxy, C 3-8 cycloalkyl, amino, and nitro; and
in Group A and Group B, the term “substituted” means having one or more substituents selected from the group consisting of D, halogen, C 1-4 alkyl, trifluoromethyl, amino, nitro, and —OH.

2. The compound, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 and R 4 are each independently H, D or methyl.

3. The compound, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 5 is H, R 6 is H, a substituted or unsubstituted C 1-4 alkyl, a substituted or unsubstituted C 6-10 aryl, or a substituted or unsubstituted C 3-6 cycloalkyl.

4. The compound, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 11 has the following structure:

wherein ring A is a substituted or unsubstituted heteroaryl containing 1 to 3 heteroatoms;
ring B is a substituted or unsubstituted heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
Ra is H, halogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 3-8 cycloalkyl, a substituted or unsubstituted C 1-4 alkoxy, a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted C 5-10 heteroaryl, a substituted or unsubstituted C 6-10 aryloxy, or —C(O)NHRa′, wherein Ra′ is a substituted or unsubstituted C 1-6 alkyl, or a substituted or unsubstituted C 3-8 cycloalkyl;
Rb is H, halogen, or a substituted or unsubstituted C 1-4 alkyl; and
n is 0, 1, 2 or 3.

5. The compound, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof according to claim 1 , R 11 is

wherein X is N;
Ra is H, halogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 3-8 cycloalkyl, a substituted or unsubstituted C 1-4 alkoxy, a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted C 5-10 heteroaryl, a substituted or unsubstituted C 6-10 aryloxy, or —C(O)NHRa′, wherein Ra′ is a substituted or unsubstituted C 1-6 alkyl, or a substituted or unsubstituted C 3-8 cycloalkyl;
Rb is selected from H, halogen, or a substituted or unsubstituted C 1-4 alkyl; and
n is 0, 1, 2 or 3.

6. The compound, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof according to claim 1 , R 11 is

wherein Ra is H, halogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 3-8 cycloalkyl, a substituted or unsubstituted C 1-4 alkoxy, a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted C 5-10 heteroaryl, a substituted or unsubstituted C 6-10 aryloxy, or —C(O)NHRa′, wherein Ra′ is a substituted or unsubstituted C 1-6 alkyl, or a substituted or unsubstituted C 3-8 cycloalkyl;
Rb is H, halogen, or a substituted or unsubstituted C 1-4 alkyl; and
n is 0, 1, 2 or 3.

7. The compound, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof according to claim 1 , R 11 is

wherein Ra is H, halogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 3-8 cycloalkyl, a substituted or unsubstituted C 1-4 alkoxy, a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted C 5-10 heteroaryl, a substituted or unsubstituted C 6-10 aryloxy, or —C(O)NHRa′, wherein Ra′ is a substituted or unsubstituted C 1-6 alkyl, or a substituted or unsubstituted C 3-8 cycloalkyl;
Rb is H, halogen, or a substituted or unsubstituted C 1-4 alkyl; and
n is 0, 1, 2 or 3.

8. A compound, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

Assignees

• Shanghai Haihe Pharmaceutical Co Ltd
• Shanghai Inst Materia Medica Cas

Inventors

• Jiang Lei
• Geng Meiyu
• Zheng Qiangang
• Huang Min
• Wan Huixin
• Tang Shuai
• Fu Xianlei
• Lan Xiaojing
• Cao Jianhua
• Liu Feifei
• Ding Jian

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/04 Primary

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

• C07D403/14

  containing three or more hetero rings · CPC title