Enhancer of zeste homolog 2 inhibitors

摘要

This invention relates to novel compounds according to Formula (I) which are inhibitors of Enhancer of Zeste Homolog 2 (EZH2), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.;

主权项

1. A compound according to Formula (I): wherein: X is S and Y is CR6; or Y is S and X is CR6; Z is CR5; R is hydrogen or (C1-C4)alkyl; R1, R2, and R3 are each independently selected from the group consisting of hydrogen, (C1-C4)alkoxy, (C1-C8)alkyl, (C1-C4)alkoxy(C1-C4)alkyl-, halo(C1-C4)alkyl, (C3-C8)cycloalkyl, hydroxy(C1-C4)alkyl, (C3-C8)cycloalkyl(C1-C4)alkyl-, RaO(O)CNH(C1-C4)alkyl-, (C6-C10)bicycloalkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl-, aryl, aryl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, halogen, cyano, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —C(O)NRaNRaRb, —SRa, —S(O)Ra, —SO2Ra, —SO2NRaRb, nitro, —NRaRb, —NRaC(O)Rb, —NRaC(O)NRaRb, —NRaC(O)ORa, —NRaSO2Rb, —NRaSO2NRaRb, —NRaNRaRb, —NRaNRaC(O)Rb, —NRaNRaC(O)NRaRb, —NRaNRaC(O)ORa, —ORa, —OC(O)Ra, and —OC(O)NRaRb, wherein each (C3-C8)cycloalkyl, (C6-C10)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1, 2, or 3 times, independently, by hydroxyl, halogen, nitro, (C1-C4)alkyl, cyano, (C1-C4)alkoxy, —NRaRb or —CO2Ra; R4 is selected from the group consisting of hydrogen, (C1-C3)alkoxy, (C1-C3)alkyl, hydroxyl, halogen, cyano, (C3-C6)cycloalkyl, heterocycloalkyl, —NRaRb, halo(C1-C3)alkyl, and hydroxy(C1-C3)alkyl; R5 is selected from the group consisting of (C4-C8)alkyl, (C2-C8)alkenyl, (C3-C8)alkoxy, (C4-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C2)alkyl-, (C3-C8)cycloalkyloxy-, heterocycloalkyl, heterocycloalkyl(C1-C2)alkyl-, heterocycloalkyloxy-, heteroaryl, and —NRaRb, wherein said (C4-C8)alkyl, (C2-C8)alkenyl, (C3-C8)alkoxy, (C4-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C2)alkyl-, (C3-C8)cycloalkyloxy-, heterocycloalkyl, heterocycloalkyl(C1-C2)alkyl-, heterocycloalkyloxy-, or heteroaryl is optionally substituted 1, 2, or 3 times, independently, by halogen, —ORa, —NRaRb, —NHCO2Ra, nitro, (C1-C3)alkyl, RaRbN(C1-C3)alkyl-, RaO(C1-C3)alkyl-, (C3-C8)cycloalkyl, cyano, —CO2Ra, —C(O)NRaRb, —SO2NRaRb, heterocycloalkyl, aryl, or heteroaryl, wherein said (C3-C8)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1 or 2 times, independently, by halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, —CO(C1-C4)alkyl, —CO2(C1-C4)alkyl, —NRaRb, —NHCO2Ra, hydroxyl, oxo, (C1-C4)alkoxy, or (C1-C4)alkoxy(C1-C4)alkyl-; or any 2 optional substituents on said (C2-C8)alkenyl taken together with the carbon atom(s) to which they are attached represent a 5-8 membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted 1 or 2 times, independently, by (C1-C4)alkyl, halo(C1-C4)alkyl, —CO(C1-C4)alkyl, —CO2(C1-C4)alkyl, —NRaRb, —NHCO2Ra, hydroxyl, oxo, (C1-C4)alkoxy, or (C1-C4)alkoxy(C1-C4)alkyl-; R6 is selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl, (C1-C4)alkoxy, —B(OH)2, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C4)alkyl-, (C6-C10)bicycloalkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl-, aryl, aryl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, cyano, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —C(O)NRaNRaRb, —SRa, —S(O)Ra, —SO2Ra, —SO2NRaRb, nitro, —NRaRb, RaRbN(C1-C4)alkyl-, —NRaC(O)Rb, —NRaC(O)NRaRb, —NRaC(O)ORa, —NRaSO2Rb, —NRaSO2NRaRb, —NRaNRaRb, —NRaNRaC(O)Rb, —NRaNRaC(O)NRaRb, —NRaNRaC(O)ORa, —ORa, —OC(O)Ra, and —OC(O)NRaRb, wherein each cycloalkyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted 1, 2, or 3 times, independently, by Rc—(C1-C6)alkyl-O—, Rc—(C1-C6)alkyl-S—, Rc—(C1-C6)alkyl-, (C1-C4)alkyl-heterocycloalkyl-, halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, halo(C1-C6)alkyl, cyano, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —SRa, —S(O)Ra, —SO2Ra, —SO2NRaRb, nitro, —NRaRb, —NRaC(O)Rb, —NRaC(O)NRaRb, —NRaC(O)ORa, —NRaSO2Rb, —NRaSO2NRaRb, —ORa, —OC(O)Ra, —OC(O)NRaRb, heterocycloalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; R7 is selected from the group consisting of hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C4)alkyl-, (C6-C10)bicycloalkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl-, aryl, aryl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —C(O)NRaNRaRb, —SO2Ra, —SO2NRaRb, and RaRbN(C1-C4)alkyl-, wherein each cycloalkyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted 1, 2, or 3 times, independently, by Rc—(C1-C6)alkyl-O—, Rc—(C1-C6)alkyl-S—, Rc—(C1-C6)alkyl-, (C1-C4)alkyl-heterocycloalkyl-, halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, halo(C1-C6)alkyl, cyano, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —SRa, —S(O)Ra, —SO2Ra, —SO2NRaRb, nitro, —NRaRb, —NRaC(O)Rb, —NRaC(O)NRaRb, —NRaC(O)ORa, —NRaSO2Rb, —NRaSO2NRaRb, —ORa, —OC(O)Ra, —OC(O)NRaRb, heterocycloalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl; each Rc is independently —S(O)Ra, —SO2Ra, —NRaRb, —NRaC(O)ORa, —NRaSO2Rb, or —CO2Ra; and Ra and Rb are each independently hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl-, (C3-C10)cycloalkyl, heterocycloalkyl, aryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, or heteroaryl, wherein any said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted 1, 2, or 3 times, independently, by halogen, hydroxyl, (C1-C4)alkoxy, amino, —NH(C1-C4)alkyl, —N((C1-C4)alkyl)2, (C1-C4)alkyl, halo(C1-C4)alkyl, —CO2H, —CO2(C1-C4)alkyl, —CONH2, —CONH(C1-C4)alkyl, —CON((C1-C4)alkyl)2, —SO2(C1-C4)alkyl, —SO2NH2, —SO2NH(C1-C4)alkyl, or —SO2N((C1-C4)alkyl)2; or Ra and Rb taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted 1, 2, or 3 times, independently, by (C1-C4)alkyl, halo(C1-C4)alkyl, amino, —NH(C1-C4)alkyl, —N((C1-C4)alkyl)2, hydroxyl, oxo, (C1-C4)alkoxy, or (C1-C4)alkoxy(C1-C4)alkyl-, wherein said ring is optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; or Ra and Rb taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C3-C8)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; or a pharmaceutically acceptable salt thereof.