US 12,459,921 B2
Isoindoline compound, preparation method, pharmaceutical composition and use thereof
Xiaohua Chen, Shanghai (CN); Jia Li, Shanghai (CN); Yu Cheng, Shanghai (CN); Yubo Zhou, Shanghai (CN); Huijun Nie, Shanghai (CN); Yujie Wang, Shanghai (CN); Hongtao Tian, Shanghai (CN); Weijuan Kan, Shanghai (CN); Tian Mi, Shanghai (CN); Xiaobei Hu, Shanghai (CN); Binshan Zhou, Shanghai (CN); Kenian Yan, Shanghai (CN); Gaoya Xu, Shanghai (CN); Yuhua Zhong, Shanghai (CN); and Lei Feng, Shanghai (CN)
Assigned to Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (CN)
Appl. No. 17/281,419
Filed by SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES, Shanghai (CN)
PCT Filed Sep. 30, 2019, PCT No. PCT/CN2019/109368
§ 371(c)(1), (2) Date Mar. 30, 2021,
PCT Pub. No. WO2020/064002, PCT Pub. Date Apr. 2, 2020.
Claims priority of application No. 201811156797.9 (CN), filed on Sep. 30, 2018.
Prior Publication US 2022/0041576 A1, Feb. 10, 2022
Int. Cl. C07D 401/14 (2006.01); A61K 45/06 (2006.01); C07D 401/04 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 413/14 (2006.01); C07D 417/14 (2006.01); C07D 471/10 (2006.01); C07D 491/107 (2006.01); C07D 495/04 (2006.01); C07D 498/20 (2006.01)
CPC C07D 401/14 (2013.01) [A61K 45/06 (2013.01); C07D 401/04 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/14 (2013.01); C07D 417/14 (2013.01); C07D 471/10 (2013.01); C07D 491/107 (2013.01); C07D 495/04 (2013.01); C07D 498/20 (2013.01)] 14 Claims
 
1. A compound represented by formula (I) or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, pharmaceutically acceptable salt, ester, or hydrate thereof:

OG Complex Work Unit Chemistry
wherein, X1 is —CH2— or —O—;
X2 is —CH2— or —CO—;
R1 is hydrogen, deuterium, fluorine or linear or branched C1-C6 hydrocarbon group;
R2 and R4 are each independently hydrogen or deuterium;
R3 is hydrogen, deuterium or halogen;
L is a substituted or unsubstituted linear alkylene group containing 2-8 carbon atoms, and the “substituted” means that one or more hydrogen atoms in the alkylene group are optionally substituted by the following substituents: deuterium, halogen, carbonyl, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, —NHC(O) Ra1, —NHC(O)ORa2, —NRa3Ra4, wherein Ra1, Ra2, Ra3 and Ra4 are each independently selected from hydrogen, C1-6 alkyl unsubstituted or substituted by halogen, hydroxyl, cyano, or nitro, and C3-6 cycloalkyl unsubstituted or substituted by halogen, hydroxyl, cyano, or nitro;
Y is absent, —CO— or —CO—NH—, the corresponding placement of Y, A and L is A-L-, A-CO-L-, and A-CO—NH-L-, A is: i) heterocyclyl selected from the following:

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X3 is N;
n4 is 0, 1, 2 or 3;
n5 is 0, 1, 2 or 3,
Y1 is hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C1-C6 alkyl, C1-C6alkoxyl, C1-C6haloalkyl, or C1-C6haloalkoxyl;
Y2 is substituted or unsubstituted 6-10 membered aryl, or substituted or unsubstituted 6-10 membered heteroaryl, wherein the substituted 6-10 membered aryl or 6-10 membered heteroaryl is substituted by one or more substituents selected from: deuterium, halogen, cyano, nitro, hydroxyl, aminocarbonyl, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3alkylcarbonyl, C1-C3alkoxycarbonyl, C1-C3alkylsulfonyl, C1-C3alkylaminocarbonyl, C3-C6 cycloalkyl or heterocyclyl, C1-C3 acylamino, C1-C3 haloalkyl, C1-C3haloalkoxyl;
Y3 is substituted or unsubstituted 6-10 membered aryl, or substituted or unsubstituted 6-10 membered heteroaryl, wherein the substituted 6-10 membered aryl or 6-10 membered heteroaryl is substituted by one or more substituents selected from: deuterium, halogen, cyano, nitro, hydroxyl, aminocarbonyl, C1-C3 alkyl, C1-C3 alkoxyl, C1-C3alkylcarbonyl, C1-C3alkoxycarbonyl, C1-C3alkylsulfonyl, C1-C3alkylaminocarbonyl, C3-C6 cycloalkyl or heterocyclyl, C1-C3 acylamino, C1-C3 haloalkyl, C1-C3haloalkoxyl;
Y4 and Y5 are absent, or one or more substituents on the heterocyclic ring, Y4 and Y5 are each independently deuterium, halogen, oxo, C1-C3 alkyl, C3 cycloalkyl, C1-C3 haloalkyl or phenyl;
ii) fused heterocyclyl selected from:

OG Complex Work Unit Chemistry
X4 is C, N or O;
n6 is 0, 1, 2 or 3;
n7 is 0, 1, 2 or 3;
n8 is 0, 1, 2, 3 or 4;

OG Complex Work Unit Chemistry
 is 6-10 membered aryl ring or 5-10 membered heteroaryl ring;
R8 is each independently selected from hydrogen, deuterium, C1-C3 alkoxyl, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, carboxyl, C1-Czalkylaminocarbonyl, C1-C3alkoxycarbonyl, nitro, amino, cyano, C1-C3 haloalkyl, hydroxyl, C1-C3alkylsulfonyl, C1-C3 alkylamino, C1-C3 acylamino, aminocarbonyl, C3-C6 heterocyclyl, C1-C3haloalkoxyl, phenyl or 5-6 membered heteroaryl;
with the proviso that when Ra is selected from the following substituents: hydrogen, deuterium, C1-C3 alkoxyl, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, carboxyl, C1-C3 alkyl aminocarbonyl, C1-C3alkoxycarbonyl, nitro, amino, cyano, C1-C3 haloalkyl, hydroxyl, C1-C3alkylsulfonyl, and Y is absent, then X1 is other than —O—;
Y6 and Y7 are absent, or one or more substituents on the heterocyclic ring independently selected from deuterium, halogen, C1-C3 alkyl, C3 cycloalkyl, C1-C3 haloalkyl;
or iii) spiroheterocyclic group selected from:

OG Complex Work Unit Chemistry

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nc1 is 0, 1, 2 or 3;
nc2 is 0, 1, 2 or 3;
nc3 is 1, 2 or 3;
n9 is 0, 1, 2, 3 or 4;

OG Complex Work Unit Chemistry
 is 6-10 membered aryl ring or 5-10 heteroaryl ring;
R9 is independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-C3 alkylamino, C1-C3 acylamino, aminocarbonyl, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxyl, C3-C6cycloalkyloxyl, C3-C6 cycloalkyl or heterocycloalkyl, C1-C3alkylaminocarbonyl, C1-C3alkoxycarbonyl, C1-C3alkylsulfonyl, C1-C3 haloalkyl, C1-C3haloalkoxyl, phenyl, 5-6 membered heteroaryl;
R10 and R11 are independently selected from hydrogen, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, and the species of substituent is the same as the above-mentioned substituent R9 on the

OG Complex Work Unit Chemistry
 ring;
Y8 is a substituent which optionally replaces the hydrogen atom in the non-aromatic moiety of the spiro ring structure, and Y8 is optionally substituted by deuterium, halogen, C1-C3 alkyl, C3 cycloalkyl or C1-C3 haloalkyl.