ENHANCER OF ZESTE HOMOLOG 2 INHIBITORSThis 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. Epigenetic modifications play an important role in the regulation of many cellular processes including cell proliferation, differentiation, and cell survival. Global epigenetic modifications are common in cancer, and include global changes in DNA and/or histone methylation, dysregulation of non-coding RNAs and nucleosome remodeling leading to aberrant activation or inactivation of oncogenes, tumor suppressors and signaling pathways.A compound according to Formula (I):(I)wherein:X is CH or N;Y is O or NH;R1, R2, and R3 are each independently selected from the group consisting of hydrogen, (Ci-C4)alkoxy, (Ci-C8)alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl-, halo(Ci-C4)alkyl, (C3-C8)cycloalkyl, hydroxy(Ci-C4)alkyl, (C3-C8)cycloalkyl(Ci-C4)alkyl-,RaO(0)CNH(Ci-C4)alkyl-, (C6-Ci0)bicycloalkyl, heterocycloalkyl,heterocycloalkyl(Ci-C4)alkyl-, aryl, aryl(Ci-C4)alkyl, heteroaryl, heteroaryl(Ci-C4)alkyl, halogen, cyano, -C(0)Ra, -C02Ra, -C(0)NRaRb, -C(0)NRaNRaRb, -SRa, -S(0)Ra, -S02Ra, -S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -NRaNRaC(0)ORa, -ORa, -OC(0)Ra, and -OC(0)NRaRb, wherein each (C3-C8)cycloalkyl,(C6-Cio)bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1 , 2, or 3 times, independently, by hydroxyl, halogen, nitro, (Ci-C4)alkyl, cyano, (Ci-C4)alkoxy, -NRaRb or -C02Ra;R4 is selected from the group consisting of hydrogen, (Ci-C3)alkoxy, (Ci-C3)alkyl, hydroxyl, halogen, cyano, (C3-C6)cycloalkyl, heterocycloalkyl, -NRaRb, halo(Ci-C3)alkyl, and hydroxy(Ci-C3)alkyl;R5 is selected from the group consisting of (C4-C8)alkyl, (C3-C8)alkoxy,(C4-C8)cycloalkyl, (C3-C8)cycloalkyloxy-, heterocycloalkyl, heterocycloalkyloxy-, aryl, heteroaryl, and -NRaRb, wherein said (C4-C8)alkyl, (C3-C8)alkoxy, (C4-C8)cycloalkyl, (C3-C8)cycloalkyloxy-, heterocycloalkyl, heterocycloalkyloxy-, aryl, or heteroaryl is optionally substituted 1, 2, or 3 times, independently, by halogen, -ORa, -NRaRb,-NHC02Ra, nitro, (Ci-C3)alkyl, RaRbN(Ci-C3)alkyl-, RaO(Ci-C3)alkyl-, (C3-C8)cycloalkyl, cyano, -C02Ra, -C(0)NRaRb, -S02NRaRb, aryl, or heteroaryl;R6 is selected from the group consisting of hydrogen, halogen, (Ci-C8)alkyl, (Ci-C4)alkoxy, -B(OH)2, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(Ci-C4)alkyl-,(C6-Cio)bicycloalkyl, heterocycloalkyl, heterocycloalkyl(Ci-C4)alkyl-, aryl,aryl(Ci-C4)alkyl, heteroaryl, heteroaryl(C C4)alkyl, cyano, -C(0)Ra, -C02Ra,-C(0)NRaRb, -C(0)NRaNRaRb, -SRa, -S(0)Ra, -S02Ra, -S02NRaRb, nitro, -NRaRb, RaRbN(Ci-C4)alkyl-, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb,-NRaS02NRaRb, -NRaNRaRb, -NRaNRaC(0)Rb, -NRaNRaC(0)NRaRb, -NRaNRaC(0)ORa, -ORa, -OC(0)Ra, and -OC(0)NRaRb, wherein each cycloalkyl, bicycloalkyl,heterocycloalkyl, aryl, or heteroaryl group is optionally substituted 1, 2, or 3 times, independently, by Rc-(Ci-C6)alkyl-0-, Rc-(Ci-C6)alkyl-S-, Rc-(Ci-C6)alkyl-,(Ci-C4)alkyl-heterocycloalkyl-, halogen, (Ci-C6)alkyl, (C3-Cg)cycloalkyl,halo(Ci-C6)alkyl, cyano, -C(0)Ra, -C02Ra, -C(0)NRaRb, -SRa, -S(0)Ra, -S02Ra,-S02NRaRb, nitro, -NRaRb, -NRaC(0)Rb, -NRaC(0)NRaRb, -NRaC(0)ORa, -NRaS02Rb, -NRaS02NRaRb, -ORa, -OC(0)Ra, -OC(0)NRaRb, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl, or heteroaryl(Ci-C4)alkyl;each Rc is independently -S(0)Ra, -S02Ra, -NRaRb, -NRaC(0)ORa, -NRaS02Rb, or -C02Ra; andRa and Rb are each independently hydrogen, (Ci-C4)alkyl,(Ci-C4)alkoxy(Ci-C4)alkyl-, (C3-Cio)cycloalkyl, (C5-Cg)cycloalkenyl, heterocycloalkyl, aryl, aryl(Ci-C4)alkyl-, heteroaryl(Ci-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, (Ci-C4)alkoxy, amino, -NH(Ci-C4)alkyl,-N((Ci-C4)alkyl)2, (Ci-C4)alkyl, halo(Ci-C4)alkyl, heterocycloalkyl, -C02H,-C02(Ci-C4)alkyl, -CONH2, -CONH(Ci-C4)alkyl, -CON((Ci-C4)alkyl)2, -S02(Ci-C4)alkyl, -S02NH2, -S02NH(Ci-C4)alkyl, or -S02N((Ci-C4)alkyl)2;or Ra and Rb taken together with the nitrogen to which they are attached represent a5-8 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 (Ci-C4)alkyl, halo(Ci-C4)alkyl, amino, -NH(Ci-C4)alkyl, -N((Ci-C4)alkyl)2, hydroxyl, oxo, (Ci-C4)alkoxy, or(Ci-C4)alkoxy(Ci-C4)alkyl-, wherein said ring is optionally fused to a (C3-Cg)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-Cg)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;or a pharmaceutically acceptable salt thereof.
제스트 인핸서 상동체 2 억제제본 발명은 제스트 인핸서 상동체 2 (EZH2)의 억제제인 화학식 I에 따른 신규 화합물, 그를 함유하는 제약 조성물, 그의 제조 방법, 및 암의 치료를 위한 요법에서의 그의 용도에 관한 것이다. 후성적 변형은 세포 증식, 분화, 및 세포 생존을 비롯한 많은 세포 과정의 조절에서 중요한 역할을 한다. 전반적 후성적 변형은 암에서 흔하고, 종양유전자, 종양 억제자 및 신호전달 경로의 비정상적 활성화 또는 불활성화를 유발하는 DNA 및/또는 히스톤 메틸화에서의 전반적 변화, 비-코딩 RNA의 조절이상 및 뉴클레오솜 재형성을 포함한다. <화학식 I>하기 화학식 I에 따른 화합물 또는 그의 제약상 허용되는 염. <화학식 I> 상기 식에서: X는 CH 또는 N이고; Y는 O 또는 NH이고; R1, R2, 및 R3은 각각 독립적으로 수소, (C1-C4)알콕시, (C1-C8)알킬, (C1-C4)알콕시(C1-C4)알킬-, 할로(C1-C4)알킬, (C3-C8)시클로알킬, 히드록시(C1-C4)알킬, (C3-C8)시클로알킬(C1-C4)알킬-, RaO(O)CNH(C1-C4)알킬-, (C6-C10)비시클로알킬, 헤테로시클로알킬, 헤테로시클로알킬(C1-C4)알킬-, 아릴, 아릴(C1-C4)알킬, 헤테로아릴, 헤테로아릴(C1-C4)알킬, 할로겐, 시아노, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -C(O)NRaNRaRb, -SRa, -S(O)Ra, -SO2Ra, -SO2NRaRb, 니트로, -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, 및 -OC(O)NRaRb로 이루어진 군으로부터 선택되고, 여기서 각각의 (C3-C8)시클로알킬, (C6-C10)비시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴은 히드록실, 할로겐, 니트로, (C1-C4)알킬, 시아노, (C1-C4)알콕시, -NRaRb 또는 -CO2Ra에 의해 독립적으로 1, 2, 또는 3회 임의로 치환되고;R4는 수소, (C1-C3)알콕시, (C1-C3)알킬, 히드록실, 할로겐, 시아노, (C3-C6)시클로알킬, 헤테로시클로알킬, -NRaRb, 할로(C1-C3)알킬, 및 히드록시(C1-C3)알킬로 이루어진 군으로부터 선택되고;R5는 (C4-C8)알킬, (C3-C8)알콕시, (C4-C8)시클로알킬, (C3-C8)시클로알킬옥시-, 헤테로시클로알킬, 헤테로시클로알킬옥시-, 아릴, 헤테로아릴, 및 -NRaRb로 이루어진 군으로부터 선택되고, 여기서 상기 (C4-C8)알킬, (C3-C8)알콕시, (C4-C8)시클로알킬, (C3-C8)시클로알킬옥시-, 헤테로시클로알킬, 헤테로시클로알킬옥시-, 아릴, 또는 헤테로아릴은 할로겐, -ORa, -NRaRb, -NHCO2Ra, 니트로, (C1-C3)알킬, RaRbN(C1-C3)알킬-, RaO(C1-C3)알킬-, (C3-C8)시클로알킬, 시아노, -CO2Ra, -C(O)NRaRb, -SO2NRaRb, 아릴, 또는 헤테로아릴에 의해 독립적으로 1, 2, 또는 3회 임의로 치환되고;R6은 수소, 할로겐, (C1-C8)알킬, (C1-C4)알콕시, -B(OH)2, (C3-C8)시클로알킬, (C3-C8)시클로알킬(C1-C4)알킬-, (C6-C10)비시클로알킬, 헤테로시클로알킬, 헤테로시클로알킬(C1-C4)알킬-, 아릴, 아릴(C1-C4)알킬, 헤테로아릴, 헤테로아릴(C1-C4)알킬, 시아노, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -C(O)NRaNRaRb, -SRa, -S(O)Ra, -SO2Ra, -SO2NRaRb, 니트로, -NRaRb, RaRbN(C1-C4)알킬-, -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, 및 -OC(O)NRaRb로 이루어진 군으로부터 선택되고, 여기서 각각의 시클로알킬, 비시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴 기는 Rc-(C1-C6)알킬-O-, Rc-(C1-C6)알킬-S-, Rc-(C1-C6)알킬-, (C1-C4)알킬-헤테로시클로알킬-, 할로겐, (C1-C6)알킬, (C3-C8)시클로알킬, 할로(C1-C6)알킬, 시아노, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -SRa, -S(O)Ra, -SO2Ra, -SO2NRaRb, 니트로, -NRaRb, -NRaC(O)Rb, -NRaC(O)NRaRb, -NRaC(O)ORa, -NRaSO2Rb, -NRaSO2NRaRb, -ORa, -OC(O)Ra, -OC(O)NRaRb, 헤테로시클로알킬, 아릴, 헤테로아릴, 아릴(C1-C4)알킬, 또는 헤테로아릴(C1-C4)알킬에 의해 독립적으로 1, 2, 또는 3회 임의로 치환되고;각각의 Rc는 독립적으로 -S(O)Ra, -SO2Ra, -NRaRb, -NRaC(O)ORa, -NRaSO2Rb, 또는 -CO2Ra이고;Ra 및 Rb는 각각 독립적으로 수소, (C1-C4)알킬, (C1-C4)알콕시(C1-C4)알킬-, (C3-C10)시클로알킬, (C5-C8)시클로알케닐, 헤테로시클로알킬, 아릴, 아릴(C1-C4)알킬-, 헤테로아릴(C1-C4)알킬-, 또는 헤테로아릴이고, 여기서 임의의 상기 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴 기는 할로겐, 히드록실, (C1-C4)알콕시, 아미노, -NH(C1-C4)알킬, -N((C1-C4)알킬)2, (C1-C4)알킬, 할로(C1-C4)알킬, 헤테로시클로알킬, -CO2H, -CO2(C1-C4)알킬, -CONH2, -CONH(C1-C4)알킬, -CON((C1-C4)알킬)2, -SO2(C1-C4)알킬, -SO2NH2, -SO2NH(C1-C4)알킬, 또는 -SO2N((C1-C4)알킬)2에 의해 독립적으로 1, 2, 또는 3회 임의로 치환되거나;또는 Ra 및 Rb는 이들이 부착되어 있는 질소와 함께, 산소, 질소, 및 황으로부터 선택된 추가의 헤테로원자를 임의로 함유하는 5-8 원 포화 또는 불포화 고리를 나타내고, 여기서 상기 고리는 (C1-C4)알킬, 할로(C1-C4)알킬, 아미노, -NH(C1-C4)알킬, -N((C1-C4)알킬)2, 히드록실, 옥소, (C1-C4)알콕시, 또는 (C1-C4)알콕시(C1-C4)알킬-에 의해 독립적으로 1, 2, 또는 3회 임의로 치환되고, 여기서 상기 고리는 (C3-C8)시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴 고리에 임의로 융합되거나;또는 Ra 및 Rb는 이들이 부착되어 있는 질소와 함께, (C3-C8)시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴 고리에 임의로 융합된 6- 내지 10-원 가교된 비시클릭 고리계를 나타낸다.