Sultam compound and application method thereof

Patent metadata

Field	Value
Publication number	US-11111240-B2
Application number	US-201716086721-A
Country	US
Kind code	B2
Filing date	Mar 22, 2017
Priority date	Mar 22, 2016
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

Provided are a sultam compound having isocitrate dehydrogenase 1 (IDH1) inhibitory activity as represented by formula I or pharmaceutically-acceptable salts, solvates or hydrates thereof, a preparation method thereof, and a pharmaceutical composition containing the compound. The compound or the pharmaceutically-acceptable salts, solvates or hydrates thereof, and the pharmaceutical composition containing the compound can be used to treat IDH1 mutation-induced cancers.

First claim

What is claimed is:

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

wherein,
X is CH 2 or NR 5 ;
R 1 is C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 6 ;
R 2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 7 ;
R 3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH 2 —, or 5- to 6-membered heteroaryl CH 2 — containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 8 ;
R 4 is halogen, amino, hydroxyl, C 1-3 haloalkyl or C 1-6 alkyl;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl;
R 7 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl,

 C 1-6 alkyl or C 3-6 cycloalkyl; or R 7 forms a O→N coordination linkage with N atom in R 2 ;
R 8 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 9 is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl, or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 10 ;
R 10 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl;
m is 0 or 1.

2. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein,
X is CH 2 or NR 5 ;
R 1 is C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 6 ;
R 2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 7 ;
R 3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH 2 —, or 5- to 6-membered heteroaryl CH 2 — containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 8 ;
R 4 is halogen, amino, hydroxyl, C 1-3 haloalkyl or C 1-6 alkyl;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl;
R 7 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, aminosulfonyl, N-substituted aminosulfonyl, C 1-6 alkyl or C 3-6 cycloalkyl;
R 8 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
m is 0 or 1.

3. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is represented by formula II,

wherein,
X is CH 2 or NR 5 ;
R 1 is C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 6 ;
R 2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 7 ;
R 3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH 2 —, or 5- to 6-membered heteroaryl CH 2 — containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 8 ;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl;
R 7 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl,

 C 1-6 alkyl or C 3-6 cycloalkyl; or R 7 forms a O→N coordination linkage with N atom in R 2 ,
R 7 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 9 is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl, or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 10 ;
R 10 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl.

4. The compound or the pharmaceutically acceptable salt thereof according to claim 3 , wherein,
X is CH 2 or NR 5 ;
R 1 is C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 6 ;
R 2 is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 7 ;
R 3 is phenyl, 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, phenyl CH 2 —, or 5- to 6-membered heteroaryl CH 2 — containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, which may be optionally substituted with one or more groups R 8 ;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl or C 3-6 cycloalkyl;
R 7 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, aminosulfonyl, N-substituted aminosulfonyl, C 1-6 alkyl or C 3-6 cycloalkyl;
R 8 is halogen, amino, hydroxyl, cyano, C 1-3 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl.

5. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , X is CH 2 , NH or N(CH 3 ).

6. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

7. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl or piperidyl, which may be optionally substituted with one or more groups R 6 .

8. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , R 6 is F, Cl or Br.

9. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , R 2 is phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, which may be optionally substituted with one or more groups R 7 .

10. The compound or the pharmaceutica

Assignees

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

Inventors

• Zhu Li
• Duan Xiaowei
• Dai Liguang
• Yang Zhao
• Yang Yanqing
• Zhang Hui
• Hu Yuandong
• Peng Yong
• Han Yongxin
• Zhao Rui
• Tian Xin
• Wang Shanchun

Classifications

• C07D275/03 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/04

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

• A61K31/433

  Thidiazoles · CPC title

• A61P35/02

  specific for leukemia · CPC title