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. (I)Formula (i) compound:wherein:l is (c2-c8) alkylidene or (c2-c8) alkenylene；r1for hydrogen, halogen, (c1-c6) alkyl, (c2-c6) thiazolinyl, (c2-c6) alkynyl, halo (c1-c4) alkyl, (c3-c6) cycloalkanes base, (c3-c6) cycloalkyl (c1-c6) alkyl, (c3-c6) cycloalkyl (c2-c6) thiazolinyl, (c5-c6) cycloalkenyl group, (c5-c6) cycloalkenyl group (c1-c6) alkyl, (c5-c6) cycloalkenyl group (c2-c6) thiazolinyl, (c6-c10) bicyclic alkyl, heterocyclylalkyl, heterocyclylalkyl (c1-c6) alkane base-, heterocyclylalkyl (c2-c6) thiazolinyl, phenyl, phenyl (c1-c6) alkyl, phenyl (c2-c6) thiazolinyl, heteroaryl, heteroaryl (c1- c6) alkyl, heteroaryl (c2-c6) thiazolinyl, cyano group ,-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)raor-oc (o) nrarb, the most each cycloalkyl, cycloalkenyl group, bicyclic alkyl, heterocyclylalkyl, phenyl or heteroaryl are appointed choosing is replaced 1,2 or 3 times: r by following group independentlyc-(c1-c6) alkyl-o-, rc-(c1-c6) alkyl-s-, rc-(c1-c6) alkane base-, (c1-c4) alkyl-heterocycloalkyl-, halogen, (c1-c6) alkyl, (c3-c6) cycloalkyl, halo (c1-c6) alkyl, cyano group ,-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, heterocyclylalkyl, benzene base, heteroaryl, phenyl (c1-c2) alkyl or heteroaryl (c1-c2) alkyl；r2for hydrogen, halogen, (c1-c6) alkyl, (c2-c6) thiazolinyl, (c2-c6) alkynyl, halo (c1-c4) alkyl, (c3-c6) cycloalkanes base, (c3-c6) cycloalkyl (c1-c6) alkyl, (c3-c6) cycloalkyl (c2-c6) thiazolinyl, (c5-c6) cycloalkenyl group, (c5-c6) cycloalkenyl group (c1-c6) alkyl, (c5-c6) cycloalkenyl group (c2-c6) thiazolinyl, (c6-c10) bicyclic alkyl, heterocyclylalkyl, heterocyclylalkyl (c1-c6) alkane base-, heterocyclylalkyl (c2-c6) thiazolinyl, phenyl, phenyl (c1-c6) alkyl, phenyl (c2-c6) thiazolinyl, heteroaryl, heteroaryl (c1- c6) alkyl, heteroaryl (c2-c6) thiazolinyl ,-c (o) ra、-co2ra、-c(o)nrarbor-c (o) nranrarb, the most each cycloalkyl, cycloalkenyl group, bicyclic alkyl, heterocyclylalkyl, phenyl or heteroaryl are replaced 1,2 or 3 times: r by following group the most independentlyc-(c1- c6) alkyl-o-, rc-(c1-c6) alkyl-s-, rc-(c1-c6) alkyl-, (c1-c4) alkyl-heterocycloalkyl-, halogen, (c1-c6) alkane base, (c3-c6) cycloalkyl, halo (c1-c6) alkyl, cyano group ,-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, heterocyclylalkyl, phenyl, heteroaryl, phenyl (c1-c2) alkyl or heteroaryl base (c1-c2) alkyl；r3it is selected from: hydrogen, halogen, (c1-c6) alkyl, (c2-c6) thiazolinyl, (c2-c6) alkynyl, (c1-c4) alkoxyl ,-b (oh)2、(c3- c6) cycloalkyl, (c3-c6) cycloalkyl (c1-c4) alkyl-, (c6-c10) bicyclic alkyl, heterocyclylalkyl, heterocyclylalkyl (c1-c4) alkane base-, phenyl, phenyl (c1-c2) alkyl, heteroaryl, heteroaryl (c1-c2) alkyl, cyano group ,-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、rao(c1-c4) alkyl-, rao(c3-c6) alkynyl-,-oc (o) rawith-oc (o)nrarb, the most each cycloalkyl, bicyclic alkyl, heterocyclylalkyl, phenyl or heteroaryl replace 1 by following group optionally the most independently, 2 or 3 times: rc-(c1-c6) alkyl-o-, rc-(c1-c6) alkyl-s-, rc-(c1-c6) alkyl-, (c1-c4) alkyl-heterocycloalkyl-, halogen, (c1-c6) alkyl, (c3-c6) cycloalkyl, halo (c1-c6) alkyl, cyano group ,-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, heterocyclylalkyl, phenyl, heteroaryl, phenyl (c1-c2) alkyl or heteroaryl (c1-c2) alkyl；each rcindependently be-s (o) ra、-so2ra、-nrarb、-nrac(o)ora、-nraso2rbor-co2ra；withraand rbit is each independently hydrogen, (c1-c4) alkyl, (c1-c4) alkoxyl (c1-c4) alkyl-, (c3-c6) cycloalkyl, heterocycle alkyl, phenyl, phenyl (c1-c2) alkyl-, heteroaryl (c1-c4) alkyl-or heteroaryl, the most any described cycloalkyl, heterocycle alkyl, phenyl or heteroaryl are replaced 1,2 or 3 times by following group the most independently: halogen, hydroxyl, (c1-c4) alkoxyl, ammonia base ,-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 raand rbrepresent together with the nitrogen being connected with them that 5-or 6-unit is saturated or unsaturated ring, its optionally with selected from oxygen, nitrogen and the extra hetero atom of sulfur, wherein said ring is replaced 1,2 or 3 times: (c by following group the most independently1-c4) alkyl, halogen gene...
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. <화학식 I>화학식 I에 따른 화합물 또는 그의 제약상 허용되는 염.<화학식 I>[이미지]상기 식에서L은 (C2-C8)알킬레닐 또는 (C2-C8)알케닐레닐이고;R1은 수소, 할로겐, (C1-C6)알킬, (C2-C6)알케닐, (C2-C6)알키닐, 할로(C1-C4)알킬, (C3-C6)시클로알킬, (C3-C6)시클로알킬(C1-C6)알킬, (C3-C6)시클로알킬(C2-C6)알케닐, (C5-C6)시클로알케닐, (C5-C6)시클로알케닐(C1-C6)알킬, (C5-C6)시클로알케닐(C2-C6)알케닐, (C6-C10)비시클로알킬, 헤테로시클로알킬, 헤테로시클로알킬(C1-C6)알킬-, 헤테로시클로알킬(C2-C6)알케닐, 페닐, 페닐(C1-C6)알킬, 페닐(C2-C6)알케닐, 헤테로아릴, 헤테로아릴(C1-C6)알킬, 헤테로아릴(C2-C6)알케닐, 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, 또는 -OC(O)NRaRb이고, 여기서 각각의 시클로알킬, 시클로알케닐, 비시클로알킬, 헤테로시클로알킬, 페닐, 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-C6)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, 페닐, 헤테로아릴, 페닐(C1-C2)알킬, 또는 헤테로아릴(C1-C2)알킬에 의해 독립적으로 1, 2, 또는 3회 임의로 치환되고;R2는 수소, 할로겐, (C1-C6)알킬, (C2-C6)알케닐, (C2-C6)알키닐, 할로(C1-C4)알킬, (C3-C6)시클로알킬, (C3-C6)시클로알킬(C1-C6)알킬, (C3-C6)시클로알킬(C2-C6)알케닐, (C5-C6)시클로알케닐, (C5-C6)시클로알케닐(C1-C6)알킬, (C5-C6)시클로알케닐(C2-C6)알케닐, (C6-C10)비시클로알킬, 헤테로시클로알킬, 헤테로시클로알킬(C1-C6)알킬-, 헤테로시클로알킬(C2-C6)알케닐, 페닐, 페닐(C1-C6)알킬, 페닐(C2-C6)알케닐, 헤테로아릴, 헤테로아릴(C1-C6)알킬, 헤테로아릴(C2-C6)알케닐, -C(O)Ra, -CO2Ra, -C(O)NRaRb, 또는 -C(O)NRaNRaRb이고, 여기서 각각의 시클로알킬, 시클로알케닐, 비시클로알킬, 헤테로시클로알킬, 페닐, 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-C6)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, 페닐, 헤테로아릴, 페닐(C1-C2)알킬, 또는 헤테로아릴(C1-C2)알킬에 의해 독립적으로 1, 2, 또는 3회 임의로 치환되고;R3은 수소, 할로겐, (C1-C6)알킬, (C2-C6)알케닐, (C2-C6)알키닐, (C1-C4)알콕시, -B(OH)2, (C3-C6)시클로알킬, (C3-C6)시클로알킬(C1-C4)알킬-, (C6-C10)비시클로알킬, 헤테로시클로알킬, 헤테로시클로알킬(C1-C4)알킬-, 페닐, 페닐(C1-C2)알킬, 헤테로아릴, 헤테로아릴(C1-C2)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, RaO(C1-C4)알킬-, RaO(C3-C6)알키닐-, -OC(O)Ra, 및 -OC(O)NRaRb로 이루어진 군으로부터 선택되고, 여기서 각각의 시클로알킬, 비시클로알킬, 헤테로시클로알킬, 페닐, 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-C6)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, 페닐, 헤테로아릴, 페닐(C1-C2)알킬, 또는 헤테로아릴(C1-C2)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-C6)시클로알킬, 헤테로시클로알킬, 페닐, 페닐 (C1-C2)알킬-, 헤테로아릴(C1-C4)알킬-, 또는 헤테로아릴이고, 여기서 임의의 상기 시클로알킬, 헤테로시클로알킬, 페닐, 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, -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- 또는 6-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-C6)시클로알킬, 헤테로시클로알킬, 페닐, 또는 헤테로아릴 고리에 임의로 융합되거나;또는 Ra 및 Rb는 이들이 부착되어 있는 질소와 함께 (C3-C6)시클로알킬, 헤테로시클로알킬, 페닐, 또는 헤테로아릴 고리에 임의로 융합된 6- 내지 10-원 가교된 비시클릭 고리계를 나타낸다.