Antitumor compound targeting IDH2 mutation and method of use thereof

Patent metadata

Field	Value
Publication number	US-10155722-B2
Application number	US-201615748488-A
Country	US
Kind code	B2
Filing date	Jul 29, 2016
Priority date	Jul 30, 2015
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

The present application relates to compounds represented by general formula (I), general formula (II) or general formula (III), and pharmaceutically acceptable salts or hydrates thereof, preparation methods thereof, and pharmaceutical compositions thereof. The compounds represented by general formula (I), general formula (II) or general formula (III) have inhibitory activities against isocitrate dehydrogenase 2 (IDH2), thereby being capable of treating IDH2 mutation-induced cancers.

First claim

What is claimed is:

1. A compound of formula I:

wherein:
Ring A is selected from a benzene ring or a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S;
each R 1 is independently selected from the group consisting of halogen, C 1-3 haloalkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl; or two adjacent R 1 groups, together with the atoms of the Ring A to which they are attached, form a 5- to 7-membered cycloalkyl ring or a 5- to 7-membered heteroalicyclic ring, and a methylene of the 5- to 7-membered cycloalkyl ring or a methylene of the 5- to 7-membered heteroalicyclic ring may optionally further form one or two carbonyl groups;
R 2 is selected from phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and may be optionally substituted with one or more R 8 ;
each R 3 is independently selected from the group consisting of hydrogen, halogen, C 1-3 haloalkyl, hydroxy, amino and C 1-6 alkyl;
each R 4 is independently selected from hydrogen or C 1-6 alkyl;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl; or one of R 5 and R 6 is an oxygen atom of carbonyl, and the other is absent; or R 5 and R 6 , together with the carbon atom to which they are attached, form a 3- to 7-membered cycloalkyl ring or a 3- to 7-membered heteroalicyclic ring, and the 3- to 7-membered cycloalkyl ring or the 3- to 7-membered heteroalicyclic ring may be further optionally substituted with C 1-6 alkyl, halogen, hydroxy or amino;
L 1 and L 2 are each independently selected from the group consisting of —C(O)—, —N(R 4 )—, and —S(O) 2 —, and L 1 is different from L 2 ;
R 7 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl, and may be optionally substituted with one or more R 9 ;
each R 8 and each R 9 are independently selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-3 haloalkyl, C 1-6 alkyl and C 3-6 heteroalicyclyl;
m and n are independently 1, 2 or 3; and
o and p are each independently selected from 0 or 1, but cannot both be 0;
or a pharmaceutically acceptable salt or hydrate thereof.

2. The compound according to claim 1 , wherein the compound is a compound of formula II:

wherein:
Ring A is selected from a benzene ring or a 5- or 6-membered heteroaromatic ring containing 1 or 2 N atoms;
each R 1 is independently selected from the group consisting of halogen, C 1-3 haloalkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl; or two adjacent R 1 groups, together with the atoms of the Ring A to which they are attached, form a 5- to 7-membered cycloalkyl ring or a 5- to 7-membered heteroalicyclic ring, and a methylene of the 5- to 7-membered cycloalkyl ring or a methylene of the 5- to 7-membered heteroalicyclic ring may optionally further form one or two carbonyl groups;
R 2 is selected from phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and may be optionally substituted with one or more R 8 ;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl; or one of R 5 and R 6 is an oxygen atom of carbonyl, and the other is absent; or R 5 and R 6 , together with the carbon atom to which they are attached, form a 3- to 7-membered cycloalkyl ring or a 3- to 7-membered heteroalicyclic ring, and the 3- to 7-membered cycloalkyl ring or the 3- to 7-membered heteroalicyclic ring may be further optionally substituted with C 1-6 alkyl, halogen, hydroxy or amino;
L 1 and L 2 are each independently selected from the group consisting of —C(O)—, —N(R 4 )—, and —S(O) 2 —; L 1 is different from L 2 ; and R 4 is selected from hydrogen or C 1-6 alkyl;
R 7 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl, and may be optionally substituted with one or more R 9 ;
each R 8 and each R 9 are independently selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-3 haloalkyl, C 1-6 alkyl and C 3-6 heteroalicyclyl;
m is 1, 2 or 3; and
o and p are each independently selected from 0 or 1, but cannot both be 0;
or a pharmaceutically acceptable salt or hydrate thereof.

3. The compound according to claim 1 , wherein the compound is a compound of formula III:

wherein:
X is selected from CH or N;
each R 1 is independently selected from the group consisting of halogen, C 1-3 haloalkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl; or two adjacent R 1 groups, together with the atoms of benzene ring or the atoms of pyridine ring to which they are attached, form a 5- to 7-membered cycloalkyl ring or a 5- to 7-membered heteroalicyclic ring, and a methylene of the 5- to 7-membered cycloalkyl ring or a methylene of the 5- to 7-membered heteroalicyclic ring may optionally further form one or two carbonyl groups;
R 2 is selected from phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and may be optionally substituted with one or more R 8 ;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl; or one of R 5 and R 6 is an oxygen atom of carbonyl, and the other is absent; or R 5 and R 6 , together with the carbon atom to which they are attached, form a 3- to 7-membered cycloalkyl ring or a 3- to 7-membered heteroalicyclic ring, and the 3- to 7-membered cycloalkyl ring or the 3- to 7-membered heteroalicyclic ring may be further optionally substituted with C 1-6 alkyl, halogen, hydroxy or amino;
L 1 and L 2 are each independently selected from the group consisting of —C(O)—, —N(R 4 )—, and —S(O) 2 —; L 1 is different from L 2 ; and R 4 is selected from hydrogen or C 1-6 alkyl;
R 7 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl, and may be optionally substituted with one or more R 9 ;
each R 8 and each R 9 are independently selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-3 haloalkyl, C 1-6 alkyl and C 3-6 heteroalicyclyl;
m is 1, 2 or 3; and
o and p are each independently selected from 0 or 1, but cannot both be 0;
or a pharmaceutically acceptable salt or hydrate thereof.

4. The compound according to claim 1 , wherein:
the Ring A is selected from a benzene ring or a 6-membered heteroaromatic ring containing one N atom;
each R 1 is independently selected from the group consisting of halogen, C 1-3 haloalkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 heteroalicyclyl; or two adjacent R 1 groups, together with the atoms of the Ring A to which they are attached, form the 5- to 7-membered cycloalkyl ring or the 5- to 7-membered heteroalicyclic ring, and the methylene of the 5- to 7-membered cycloalkyl ring or the methylene of the 5- to 7-membered heteroalicyclic ring may optionally further form one or two carbonyl groups;
R 2 is selected

Assignees

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

Inventors

• Wang Shulong
• Zhao Na
• Liu Xijie
• Hu Yuandong
• Zhang Hui
• Luo Hong
• Peng Yong
• Xiao Dengming
• Han Yongxin
• Zhang Xiquan
• Tian Xin

Classifications

• C07D409/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07C275/42 Primary

  being further substituted by carboxyl groups · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D333/24

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

• A61P35/02 Primary

  specific for leukemia · CPC title