US 12,351,576 B2
FGFR inhibitor, preparation method therefor and application thereof
Haibing Deng, Shanghai (CN); Hongping Yu, Shanghai (CN); Zhui Chen, Shanghai (CN); and Yaochang Xu, Shanghai (CN)
Assigned to ABBISKO THERAPEUTICS CO., LTD., Shanghai (CN)
Appl. No. 17/253,113
Filed by Abbisko Therapeutics Co., Ltd., Shanghai (CN)
PCT Filed Jul. 23, 2019, PCT No. PCT/CN2019/097361
§ 371(c)(1), (2) Date Dec. 16, 2020,
PCT Pub. No. WO2020/052349, PCT Pub. Date Mar. 19, 2020.
Claims priority of application No. 201811073492.1 (CN), filed on Sep. 14, 2018.
Prior Publication US 2021/0261544 A1, Aug. 26, 2021
Int. Cl. C07D 471/04 (2006.01); A61P 35/00 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [A61P 35/00 (2018.01); C07D 519/00 (2013.01)] 6 Claims
 
1. A compound of formula (II), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
wherein, X is CH or N;
R1 is selected from the group consisting of H, deuterium, C1-4 alkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, methylsulfonyl and aminosulfonyl, above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, F, Cl, cyano, methyl, ethyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, methoxy, ethoxy, hydroxy, amino, isopropylamino, dimethylamino and diethyl amino;
R2 is a 5 membered heteroaryl selected from the group consisting of pyrazolyl, imidazolyl and thiazolyl, above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclyl and —C(O)NR13R14, above groups are optionally more further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 deuterioalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, —S(O)rR10 and —NR13R14;
each R3 is independently selected from the group consisting of H, deuterium, halogen, cyano, C1-4 alkyl, C3-6 cycloalkyl, oxacyclobutyl, azacyclopentyl, azacyclohexyl, hydroxy, methoxy, ethoxy and isopropoxy, above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C1-4 alkyl, trifluoromethyl, difluoromethyl, trideuteriomethyl, dideuteriomethyl, cyclopropyl, oxacyclobutyl, methoxy, ethoxy, hydroxy and carboxy;
each R4 is independently selected from the group consisting of H, deuterium, F, Cl, cyano, C1-4 alkyl, C3-6 cycloalkyl, oxacyclobutyl, azacyclopentyl, azacyclohexyl, hydroxy, methoxy, ethoxy and isopropoxy, above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, F, Cl, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy and hydroxy;
R10 is selected from the group consisting of H, deuterium, hydroxy, C1-10 alkyl, C1-10 alkoxy, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C5-10 aryl, C5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and —NR13R14, above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C5-10 aryl, C5-10 aryloxy, 5-10 heteroaryl, 5-10 membered heteroaryloxy and —NR13R14;
R13 and R14 are each independently selected from the group consisting of H, deuterium, hydroxy, C1-10 alkoxy, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino and C1-10 alkanoyl, above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C1-10 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C5-10 aryl, C5-10 aryloxy, 5-10 heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C1-10 alkanoyl,
or, R13 and R14, together with the nitrogen atom directly attached thereto, form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl, above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C1-10 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C5-10 aryl, C5-10 aryloxy, 5-10 heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C1-10 alkanoyl;
each r is independently 0, 1 or 2.