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.Formula (i) compound or its pharmacy acceptable salt:wherein:x is ch or n;l is (c 2-c 8) alkylidene group or (c 2-c 8) alkenylene, its each optionally replace by hydroxyl, wherein said (c 2-c 8) alkylidene group or (c 2-c 8) arbitrary mu (methylene unit) in alkenylene is optionally by-o-,-nh-or-n (c 1-c 4) alkyl-replaced; r 1for hydrogen, halogen, (c 1-c 6) alkyl, (c 2-c 6) thiazolinyl, (c 2-c 6) alkynyl, halo (c 1-c 4) alkyl, (c 3-c 6) cycloalkyl, (c 3-c 6) cycloalkyl (c 1-c 6) alkyl, (c 3-c 6) cycloalkyl (c 2-c 6) thiazolinyl, (c 5-c 6) cycloalkenyl group, (c 5-c 6) cycloalkenyl group (c 1-c 6) alkyl, (c 5-c 6) cycloalkenyl group (c 2-c 6) thiazolinyl, (c 6-c 10) bicyclic alkyl, heterocyclylalkyl, heterocyclylalkyl (c 1-c 6) alkyl-, heterocyclylalkyl (c 2-c 6) thiazolinyl, phenyl, phenyl (c 1-c 6) alkyl, phenyl (c 2-c 6) thiazolinyl, heteroaryl, heteroaryl (c 1-c 6) alkyl, heteroaryl (c 2-c 6) thiazolinyl, cyano group ,-c (o) r a,-co 2r a,-c (o) nr ar b,-c (o) nr anr ar b,-sr a,-s (o) r a,-so 2r a,-so 2nr ar b, nitro ,-nr ar b, r ar bn (c 1-c 4) alkyl-,-nr ac (o) r b,-nr ac (o) nr ar b,-nr ac (o) or a,-nr aso 2r b,-nr aso 2nr ar b,-nr anr ar b,-nr anr ac (o) r b,-nr anr ac (o) nr ar b,-nr anr ac (o) or a,-or a,-oc (o) r aor-oc (o) nr ar b, wherein each cycloalkyl, cycloalkenyl group, bicyclic alkyl, heterocyclylalkyl, phenyl or heteroaryl are optional is replaced 1,2 or 3 time: r by substituents independently c-(c 1-c 6) alkyl-o-, r c-(c 1-c 6) alkyl-s-, r c-(c 1-c 6) alkyl-, (c 1-c 4) alkyl-heterocycloalkyl-, halogen, (c 1-c 6) alkyl, (c 3-c 6) cycloalkyl, halo (c 1-c 6) alkyl, cyano group ,-c (o) r a,-co 2r a,-c (o) nr ar b,-sr a,-s (o) r a,-so 2r a,-so 2nr ar b, nitro ,-nr ar b,-nr ac (o) r b,-nr ac (o) nr ar b,-nr ac (o) or a,-nr aso 2r b,-nr aso 2nr ar b,-or a,-oc (o) r a,-oc (o) nr ar b, heterocyclylalkyl, phenyl, heteroaryl, phenyl (c 1-c 2) alkyl or heteroaryl (c 1-c 2) alkyl; r 2for (c 4-c 8) alkyl, (c 1-c 8) alkoxyl group, (c 4-c 8) cycloalkyl, (c 3-c 8) cycloalkyl oxy-, heterocyclylalkyl, heterocyclylalkyl oxygen base-, aryl, heteroaryl or-nr ar b, wherein said (c 4-c 8) alkyl, (c 3-c 8) alkoxyl group, (c 4-c 8) cycloalkyl, (c 3-c 8) cycloalkyl oxy-, heterocyclylalkyl, heterocyclylalkyl oxygen base-, aryl or heteroaryl are optional is replaced 1,2 or 3 time by substituents independently: halogen ,-or a,-nr ar b,-nhco 2r a, nitro, (c 1-c 3) alkyl, r ar bn (c 1-c 3) alkyl-, r ao (c 1-c 3) alkyl-, (c 3-c 8) cycloalkyl, cyano group ,-co 2r a,-c (o) nr ar b,-so 2nr ar b, aryl or heteroaryl; r 3be selected from: hydrogen, halogen, (c 1-c 6) alkyl, (c 2-c 6) thiazolinyl, (c 2-c 6) alkynyl, (c 1-c 4) alkoxyl group ,-b (oh) 2, (c 3-c 6) cycloalkyl, (c 3-c 6) cycloalkyl (c 1-c 4) alkyl-, (c 6-c 10) bicyclic alkyl, heterocyclylalkyl, heterocyclylalkyl (c 1-c 4) alkyl-, phenyl, phenyl (c 1-c 2) alkyl, heteroaryl, heteroaryl (c 1-c 2) alkyl, cyano group ,-c (o) r a,-co 2r a,-c (o) nr ar b,-c (o) nr anr ar b,-sr a,-s (o) r a,-so 2r a,-so 2nr ar b, nitro ,-nr ar b, r ar bn (c 1-c 4) alkyl-,-nr ac (o) r b,-nr ac (o) nr ar b,-nr ac (o) or a,-nr aso 2r b,-nr aso 2nr ar b,-nr anr ar b,-nr anr ac (o) r b,-nr anr ac (o) nr ar b,-nr anr ac (o) or a,-or a, r ao (c 1-c 4) alkyl-, r ao (c 3-c 6) alkynyl-,-oc (o) r awith-oc (o) nr ar b, wherein each cycloalkyl, bicyclic alkyl, heterocyclylalkyl, phenyl or heteroaryl are optional is replaced 1,2 or 3 time: r by substituents independently c-(c 1-c 6) alkyl-o-, r c-(c 1-c 6) alkyl-s-, r c-(c 1-c 6) alkyl-, (c 1-c 4) alkyl-heterocycloalkyl-, halogen, (c 1-c 6) alkyl, (c 3-c 6) cycloalkyl, halo (c 1-c 6) alkyl, cyano group ,-c (o) r a,-co 2r a,-c (o) nr ar b,-sr a,-s (o) r a,-so 2r a,-so 2nr ar b, nitro ,-nr ar b,-nr ac (o) r b,-nr ac (o) nr ar b,-nr ac (o) or a,-nr aso 2r b,-nr aso 2nr ar b,-or a,-oc (o) r a,-oc (o) nr ar b, heterocyclylalkyl, phenyl, heteroaryl, phenyl (c 1-c 2) alkyl or heteroaryl (c 1-c 2) alkyl; r 4for hydrogen, (c 1-c 4) alkyl or hydroxyl (c 2-c 4) alkyl-; each r cbe-s (o) r independently a,-so 2r a,-nr ar b,-nr ac (o) or a,-nr aso 2r bor-co 2r a; with r aand r bbe hydrogen, (c independently of one another 1-c 4) alkyl, hydroxyl (c 1-c 4) alkyl-, (c 1-c 4) alkoxyl group (c 1-c 4) alkyl-, (c 3-c 6) cycloalkyl, (c 6-c 10) bicyclic alkyl, heterocyclylalkyl, phenyl, phenyl (c 1-c 2) alkyl-, heteroaryl (c 1-c 4) alkyl-or heteroaryl, wherein any described cycloalkyl, bicyclic alkyl, heterocyclylalkyl, phenyl or heteroaryl are optional is replaced 1,2 or 3 time by substituents independently: halogen, hydroxyl, (c 1-c 4) alkoxyl group, amino ,-nh (c 1-c 4) alkyl ,-n ((c 1-c 4) alkyl) 2,-nh (halo (c 1-c 4) alkyl) ,-n (halo (c 1-c 4) alkyl) 2,-n ((c 1-c 4) alkyl) (halo (c 1-c 4) alkyl), (c 1-c 4) alkyl, halo (c 1-c 4) alkyl, hydroxyl (c 1-c 4) alkyl-, (c 1-c 4) alkoxyl group (c 1-c 4) alkyl-, (c 3-c 6) cycloalkyl, (c 3-c 6) cycloalkyl (c 1-c 4) alkyl-, optionally by the heterocyclylalkyl of one or two halogen substiuted, heterocyclylalkyl (c 1-c 4) alkyl-, op...
제스트 인핸서 상동체 2 억제제본 발명은 제스트 인핸서 상동체 2 (EZH2)의 억제제인 하기 화학식 I에 따른 신규 화합물, 그를 함유하는 제약 조성물, 그의 제조 방법, 및 암의 치료를 위한 요법에서의 그의 용도에 관한 것이다. <화학식 I>하기 화학식 I에 따른 화합물 또는 그의 제약상 허용되는 염.<화학식 I>[이미지]상기 식에서,X는 CH 또는 N이고;L은 히드록실에 의해 각각 임의로 치환된 (C2-C8)알킬레닐 또는 (C2-C8)알케닐레닐이고, 여기서 상기 (C2-C8)알킬레닐 또는 (C2-C8)알케닐레닐 중 임의의 하나의 메틸렌 단위는 -O-, -NH-, 또는 -N(C1-C4)알킬-에 의해 임의로 대체되고;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 (C4-C8)알킬, (C1-C8)알콕시, (C4-C8)시클로알킬, (C3-C8)시클로알킬옥시-, 헤테로시클로알킬, 헤테로시클로알킬옥시-, 아릴, 헤테로아릴, 또는 -NRaRb이고, 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;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;R4는 수소, (C1-C4)알킬, 또는 히드록시(C2-C4)알킬-이고;각각의 Rc는 독립적으로 -S(O)Ra, -SO2Ra, -NRaRb, -NRaC(O)ORa, -NRaSO2Rb, 또는 -CO2Ra이고;Ra 및 Rb는 각각 독립적으로 수소, (C1-C4)알킬, 히드록시(C1-C4)알킬-, (C1-C4)알콕시(C1-C4)알킬-, (C3-C6)시클로알킬, (C6-C10)비시클로알킬, 헤테로시클로알킬, 페닐, 페닐(C1-C2)알킬-, 헤테로아릴(C1-C4)알킬-, 또는 헤테로아릴이고, 여기서 임의의 상기 시클로알킬, 비시클로알킬, 헤테로시클로알킬, 페닐, 또는 헤테로아릴 기는 할로겐, 히드록실, (C1-C4)알콕시, 아미노, -NH(C1-C4)알킬, -N((C1-C4)알킬)2, -NH(할로(C1-C4)알킬), -N(할로(C1-C4)알킬)2, -N((C1-C4)알킬)(할로(C1-C4)알킬), (C1-C4)알킬, 할로(C1-C4)알킬, 히드록시(C1-C4)알킬-, (C1-C4)알콕시(C1-C4)알킬-, (C3-C6)시클로알킬, (C3-C6)시클로알킬(C1-C4)알킬-, 1 또는 2개의 할로겐에 의해 임의로 치환된 헤테로시클로알킬, 헤테로시클로알킬(C1-C4)알킬-, (C1-C4)알킬에 의해 임의로 치환된 헤테로아릴, (C1-C4)알킬에 의해 임의로 치환된 헤테로아릴(C1-C4)알킬-, (C1-C4)알콕시카르보닐(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.