EZH2 inhibitor and use thereof
The present application provides a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate, or isomer thereof; and a use thereof in preparing drugs used to treat EZH2-mediated disease.
1 . A compound represented by Formula (I) or a pharmaceutically B acceptable salt, ester, solvate, hydrate or isomer thereof:
wherein R 1 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
R 2 is selected from —CR 4 R 5 , —NR 4 R 5 , 4-15-membered heterocyclyl, C 6 -C 10 aryl or 5-14-membered heteroaryl, wherein the heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 6 , and R 6 is selected from halogen, hydroxyl, cyano, amino or C 1 -C 6 alkyl optionally substituted by hydroxyl or cyano;
R 3 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
R 4 and R 5 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 4-15-membered heterocyclyl;
U, V, and L are each independently selected from C or N, and at least one of U, V or L is N;
X and Y are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy;
R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
n=0, 1 or 2; and
represents a single bond or a double bond.
2 . The compound according to claim 1 , wherein Formula (I) is Formula (Ia):
wherein R 1 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
R 2 is selected from —CR 4 R 5 , —NR 4 R 5 , 4-15-membered heterocyclyl, C 6 -C 10 aryl or 5-14-membered heteroaryl, wherein the heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 6 , and R 6 is selected from halogen, hydroxyl, cyano, amino or C 1 -C 6 alkyl optionally substituted by hydroxyl or cyano;
R 3 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
R 4 and R 5 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 4-15-membered heterocyclyl;
U, V, and L are each independently selected from C or N, and at least one of U, V or L is N;
R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
n=0, 1 or 2; and
represents a single bond or a double bond.
3 . The compound according to claim 1 , wherein
R 1 is selected from halogen or C 1 -C 6 alkyl;
R 2 is selected from —CR 4 R 5 , —NR 4 R 5 or 5-6-membered heteroaryl, wherein the heteroaryl is optionally substituted by one or more R 6 , and R 6 is C 1 -C 6 alkyl optionally substituted by hydroxyl or cyano;
R 3 is selected from hydrogen or halogen;
R 4 and R 5 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 4-6-membered heterocyclyl;
U, V, and L are each independently selected from C or N, and at least one of U, V or L is N;
R 7 is selected from hydrogen or C 1 -C 6 alkyl;
n=0 or 1; and
represents a single bond or a double bond.
4 . The compound according to claim 1 , wherein
R 1 is selected from chlorine or methyl;
R 2 is selected from the following substituents:
R 3 is selected from hydrogen or chlorine;
U, V, and L are each independently selected from C or N, and at least one of U, V or L is N;
R 7 is selected from hydrogen or methyl;
n=0 or 1; and
represents a single bond or a double bond.
5 . The compound according to claim 1 , wherein the compound is any one of the following compounds:
10-chloro-9-(3,5-dimethylisoxazol-4-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (1)
10-chloro-9-(ethyl(oxetan-3-yl)amino)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (2)
10-chloro-9-(3,5-dimethylisoxazol-4-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (3)
10-chloro-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-9-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (4)
10-chloro-9-(1,4-dimethyl-1H-pyrazol-5-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (5)
7,10-dichloro-9-(1,4-dimethyl-1H-pyrazol-5-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (6)
10-chloro-9-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (7)
2-(4-(10-chloro-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-HI]indol-9-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetonitrile (8)
10-chloro-9-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (9)
(R)-10-chloro-9-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (10)
(S)-10-chloro-9-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (11)
5-chloro-4-(3,5-dimethylisoxazol-4-yl)-7-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-8,9-dihydro-[1,4]diazepino[6,7,1-HI]indazol-6(7H)-one (12)
5-chloro-4-(3,5-dimethylisoxazol-4-yl)-7-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (13)
9-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-10-methyl-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (14)
9-(3,5-dimethylisoxazol-4-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-10-methyl-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (15)
10-chloro-9-(3,5-dimethylisoxazol-4-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (16)
10-chloro-9-(3,5-dimethylisoxazol-4-yl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (17)
6 . The compound according to claim 1 , wherein the compound is any one of the following compounds:
10-chloro-9-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (9)
(R)-10-chloro-9-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (10)
(S)-10-chloro-9-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-[1,4]diazepino[6,7,1-HI]indol-1(2H)-one (11)
7 . A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable B salt, ester, solvate, hydrate or isomer thereof, and a pharmaceutically acceptable carrier or excipient.
8 . A method for inhibiting wild-type EZH2 and treating B-cell non-Hodgkin's lymphoma, comprising: administering to a patient in need thereof an effective amount of the compound according to claim 1 or a B pharmaceutically acceptable salt, ester, solvate, hydrate or isomer thereof.