[发明专利]用于治疗癌症和免疫和自身免疫疾病的细胞程序死亡诱导药剂有效
| 申请号： | 201080004813.8 | 申请日： | 2010-01-15 |
| 公开（公告）号： | CN102282128A | 公开（公告）日： | 2011-12-14 |
| 发明（设计）人： | A.R.孔泽;S.W.艾尔摩尔;L.赫克萨默;朴哲民;A.J.索尔斯;G.M.萨利文;G.T.王;王锡禄;M.D.温德特 | 申请（专利权）人： | 雅培制药有限公司 |
| 主分类号： | C07C311/51 | 分类号： | C07C311/51;C07D207/36;C07D211/96;C07D231/18;C07D261/10;C07D275/03;C07D277/36;C07D333/34;C07D285/135;C07D295/155;C07D285/125;C07D295/26 |
| 代理公司： | 中国专利代理(香港)有限公司 72001 | 代理人： | 李连涛;刘健 |
| 地址： | 美国伊*** | 国省代码： | 美国;US |
| 权利要求书： | 查看更多 | 说明书： | 查看更多 |
| 摘要： |
公开的是抑制抗凋亡的Bcl-2蛋白的活性的式(I)的化合物、含有该化合物的组合物和治疗疾病的用途，在该疾病期间，抗凋亡Bcl-2蛋白被表达。式中A1、Z1、Z1A、Z2、Z2A、L1和Z3如权利要求书中所定义。 |
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| 搜索关键词： | 用于 治疗 癌症 免疫 自身免疫 疾病 细胞 程序 死亡 诱导 药剂 | ||
【主权项】：
1.具有式I的化合物![]()
或其治疗可接受的盐、前体药物、前体药物的盐或代谢物，其中A1是呋喃基，咪唑基，异噻唑基，异![]()
唑基，![]()
二唑基，![]()
唑基，吡嗪基，吡唑基，哒嗪基，2-吡啶基，4-吡啶基，嘧啶基，吡咯基，四唑基，噻唑基，噻二唑基，噻吩基，三嗪基，三唑基，环烷基，环烯基，杂环烷基或杂环烯基；其每个是未稠合的或与苯、杂芳烃(heteroarene)或A1A稠合；A1A是环烷，环烯，杂环烷或杂环烯；其中A1是未取代的或被一或两个或三个或四个或五个独立地选自下列的取代基取代：R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1, C(O)OR1, OC(O)R1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, C(O)N(R1)2, C(O)NHOH, C(O)NHOR1, C(O)NHSO2R1, NHC(O)R1, NR1C(O)R1, NHC(O)OR1, NR1C(O)OR1, NR1C(O)NHR1, NR1C(O)N(R1)2, NHC(O)NH2, NHC(O)NHR1, NHC(O)N(R1)2, SO2NH2, SO2NHR1, SO2N(R1)2, NHS(O)R1, NHSO2R1, NR1SO2R1, NHSO2NHR1, N(CH3)SO2N(CH3)R1, (O), NH2, NO2, N3, OH, F, Cl, Br, I, CN, CF3, OCF3, CF2CF3, OCF2CF3, C(O)H, C(O)OH, C(N)NH2, C(N)NHR1, C(N)N(R1)2, CNOH, CNOCH3, C(O)NH2或C(O)OR1A；R1是R2、R3、R4或R5；R1A是环烷基，环烯基或环炔基；R2是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R2A稠合；R2A是环烷，环烯，杂环烷或杂环烯；R3是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R3A稠合；R3A是环烷，环烯，杂环烷或杂环烯；R4是环烷基，环烯基，杂环烷基或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R4A稠合；R4A是环烷，环烯，杂环烷或杂环烯；R5是烷基，烯基或炔基，其每个是未取代的或被一或两个或三个独立地选自下列的取代基取代：R6, NC(R6A)(R6B), R7, OR7, SR7, S(O)R7, SO2R7, NHR7, N(R7)2, C(O)R7, C(O)NH2, C(O)NHR7, C(O)N(R7)2, NHC(O)R7, NR7C(O)R7, NHSO2R7, NHC(O)OR7, SO2NH2, SO2NHR7, SO2N(R7)2, NHC(O)NH2, NHC(O)NHR7, NHC(O)CH(CH3)NHC(O)CH(CH3)NH2, NHC(O)CH(CH3)NHC(O)CH(CH3)NHR1, OH, (O), C(O)OH, (O), N3, CN, NH2, CF3, CF2CF3, F, Cl, Br或I；R6是C2-C5-螺烷基，其每个是未取代的或被下列取代：OH, (O), N3, CN, CF3, CF2CF3, F, Cl, Br, I, NH2, NH(CH3)或N(CH3)2；R6A和R6B独立地选自烷基，或与它们相连接的N一起形成R6C；R6C是氮丙啶-1-基，氮杂环丁烷-1-基，吡咯烷-1-基或哌啶-1-基，每个具有一个未被替代的或被下列替代的CH2部分：O, C(O), CNOH, CNOCH3, S, S(O), SO2或NH；R7是R8、R9、R10或R11；R8是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R8A稠合；R8A是环烷，环烯，杂环烷或杂环烯；R9是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R9A稠合；R9A是环烷，环烯，杂环烷或杂环烯；R10是环烷基，环烯基，杂环烷基，或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R10A稠合；R10A是环烷，环烯，杂环烷或杂环烯；R11是烷基，烯基或炔基，其每个是未取代的或被一或两个或三个独立地选自下列的取代基取代：R12, OR12, SR12, S(O)R12, SO2R12, C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, NH2, NHR12, N(R12)2, NHC(O)R12, NR12C(O)R12, NHS(O)2R12, NR12S(O)2R12, NHC(O)OR12, NR12C(O)OR12, NHC(O)NH2, NHC(O)NHR12, NHC(O)N(R12)2, NR12C(O)NHR12, NR12C(O)N(R12)2, C(O)NH2, C(O)NHR12, C(O)N(R12)2, C(O)NHOH, C(O)NHOR12, C(O)NHSO2R12, C(O)NR12SO2R12, SO2NH2, SO2NHR12, SO2N(R12)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R12是R13、R14、R15或R16；R13是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R13A稠合；R13A是环烷，环烯，杂环烷或杂环烯；R14是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R14A稠合；R14A是环烷，环烯，杂环烷或杂环烯；R15是环烷，环烯，杂环烷或杂环烯，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R15A稠合；R15A是环烷，环烯，杂环烷或杂环烯；R16是烷基，烯基或炔基；Z1是R26或R27；Z2是R28、R29或R30；Z1A和Z2A两个都不存在，或结合在一起形成CH2、CH2CH2或Z12A；Z12A是C2-C6-亚烷基，其具有一或两个被下列替代的CH2部分：NH，N(CH3)，S，S(O)或SO2；L1是R37, OR37, SR37, S(O)R37, SO2R37, C(O)R37, C(O)OR37, OC(O)R37, OC(O)OR37, NHR37, C(O)NH, C(O)NR37, C(O)NHOR37, C(O)NHSO2R37, SO2NH, SO2NHR37, C(N)NH, C(N)NHR37；R26是亚苯基，其是未稠合的，或与苯或杂芳烃(heteroarene)或R26A稠合；R26A是环烷，环烯，杂环烷或杂环烯；R27是亚杂芳基，其是未稠合的或与苯或杂芳烃(heteroarene)或R27A稠合；R27A是环烷，环烯，杂环烷或杂环烯；R28是亚苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R28A稠合；R28A是环烷，环烯，杂环烷或杂环烯；R29是亚杂芳基，其是未稠合的或与苯或杂芳烃(heteroarene)或R29A稠合；R29A是环烷，环烯，杂环烷或杂环烯；R30是亚环烷基，亚环烯基，亚杂环烷基或亚杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R30A稠合；R30A是环烷，环烯，杂环烷或杂环烯；R37是键或R37A；R37A是亚烷基，亚烯基或亚炔基，其每个是未取代的或被一或两个或三个独立地选自下列的取代基取代：R37B, OR37B, SR37B, S(O)R37B, SO2R37B, C(O)R37B, C(O)OR37B, OC(O)R37B, OC(O)OR37B, NH2, NHR37B, N(R37B)2, NHC(O)R37B, NR37BC(O)R37B, NHS(O)2R37B, NR37BS(O)2R37B, NHC(O)OR37B, NR37BC(O)OR37B, NHC(O)NH2, NHC(O)NHR37B, NHC(O)N(R37B)2, NR37BC(O)NHR37B, NR37BC(O)N(R37B)2, C(O)NH2, C(O)NHR37B, C(O)N(R37B)2, C(O)NHOH, C(O)NHOR37B, C(O)NHSO2R37B, C(O)NR37BSO2R37B, SO2NH2, SO2NHR37B, SO2N(R37B)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR37B, C(N)N(R37B)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R37B是烷基，烯基，炔基，苯基，杂芳基，环烷基，环烯基，杂环烷基或杂环烯基；Z3是R38、R39或R40；R38是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R38A稠合；R38A是环烷，环烯，杂环烷或杂环烯；R39是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R39A稠合；R39A是环烷，环烯，杂环烷或杂环烯；R40是环烷基，环烯基，杂环烷基，或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R40A稠合；R40A是环烷，环烯，杂环烷或杂环烯；其中R26和R27代表的部分是未取代的或取代的(即，如果Z1A和Z2A不存在)或进一步未取代的或进一步被一个或多个下列取代基取代(即，如果Z1A和Z2A存在)：R41, OR41, SR41, S(O)R41, SO2R41, C(O)R41, C(O)OR41, OC(O)R41, OC(O)OR41, NH2, NHR41, N(R41)2, NHC(O)R41, NR41C(O)R41, NHS(O)2R41, NR41S(O)2R41, NHC(O)OR41, NR41C(O)OR41, NHC(O)NH2, NHC(O)NHR41, NHC(O)N(R41)2, NR41C(O)NHR41, NR41C(O)N(R41)2, C(O)NH2, C(O)NHR41, C(O)N(R41)2, C(O)NHOH, C(O)NHOR41, C(O)NHSO2R41, C(O)NR41SO2R41, SO2NH2, SO2NHR41, SO2N(R41)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR41, C(N)N(R41)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R41是R42，R43，R44或R45；R42是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R42A稠合；R42A是环烷，环烯，杂环烷或杂环烯；R43是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R43A稠合；R43A是环烷，环烯，杂环烷或杂环烯；R44是环烷基，环烯基，杂环烷基，或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R44A稠合；R44A是环烷，环烯，杂环烷或杂环烯；R45是烷基，烯基或炔基，其每个是未取代的或被一或两个独立地选自下列的取代基取代：R46, OR46, SR46, S(O)R46, SO2R46, C(O)R46, C(O)OR46, OC(O)R46, OC(O)OR46, NH2, NHR46, N(R46)2, NHC(O)R46, NR46C(O)R46, NHS(O)2R46, NR46S(O)2R46, NHC(O)OR46, NR46C(O)OR46, NHC(O)NH2, NHC(O)NHR46, NHC(O)N(R46)2, NR46C(O)NHR46, NR46C(O)N(R46)2, C(O)NH2, C(O)NHR46, C(O)N(R46)2, C(O)NHOH, C(O)NHOR46, C(O)NHSO2R46, C(O)NR46SO2R46, SO2NH2, SO2NHR46, SO2N(R46)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR46, C(N)N(R46)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R46是烷基，烯基，炔基，R47，R48或R49；R47是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R47A稠合；R47A是环烷，环烯，杂环烷或杂环烯；R48是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R48A稠合；R48A是环烷，环烯，杂环烷或杂环烯；R49是环烷基，环烯基，杂环烷基，或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R49A稠合；R49A是环烷，环烯，杂环烷或杂环烯；其中R42、R43、R44、R47、R48和R49代表的部分独立地是未取代的或被一个或多个独立地选自下列的取代基取代：R50, OR50, SR50, S(O)R50, SO2R50, C(O)R50, C(O)OR50, OC(O)R50, OC(O)OR50, NH2, NHR50, N(R50)2, NHC(O)R50, NR50C(O)R50, NHS(O)2R50, NR50S(O)2R50, NHC(O)OR50, NR50C(O)OR50, NHC(O)NH2, NHC(O)NHR50, NHC(O)N(R50)2, NR50C(O)NHR50, NR50C(O)N(R50)2, C(O)NH2, C(O)NHR50, C(O)N(R50)2, C(O)NHOH, C(O)NHOR50, C(O)NHSO2R50, C(O)NR50SO2R50, SO2NH2, SO2NHR50, SO2N(R50)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR50, C(N)N(R50)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R50是R51，R52，R53或R54；R51是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R51A稠合；R51A是环烷，环烯，杂环烷或杂环烯；R52是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R52A稠合；R52A是环烷，环烯，杂环烷或杂环烯；R53是环烷基，环烯基，杂环烷基，或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R53A稠合；R53A是环烷，环烯，杂环烷或杂环烯；R54是烷基，烯基或炔基，其每个是未取代的或被一或两个或三个独立地选自下列的取代基取代：R55, OR55, SR55, S(O)R55, SO2R55, C(O)R55, C(O)OR55, OC(O)R55, OC(O)OR55, NH2, NHR55, N(R55)2, NHC(O)R55, NR55C(O)R55, NHS(O)2R55, NR55S(O)2R55, NHC(O)OR55, NR55C(O)OR55, NHC(O)NH2, NHC(O)NHR55, NHC(O)N(R55)2, NR55C(O)NHR55, NR55C(O)N(R55)2, C(O)NH2, C(O)NHR55, C(O)N(R55)2, C(O)NHOH, C(O)NHOR55, C(O)NHSO2R55, C(O)NR55SO2R55, SO2NH2, SO2NHR55, SO2N(R55)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR55, C(N)N(R55)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R55是烷基，烯基，炔基，苯基，杂芳基，环烷基，环烯基，杂环烷基或杂环烯基；其中每个前述环状部分独立地是未取代的、进一步未取代的、或被一个或多个独立地选自下列的取代基取代或进一步取代：R57, OR57, SR57, S(O)R57, SO2R57, C(O)R57, C(O)OR57, OC(O)R57, OC(O)OR57, NH2, NHR57, N(R57)2, NHC(O)R57, NR57C(O)R57, NHS(O)2R57, NR57S(O)2R57, NHC(O)OR57, NR57C(O)OR57, NHC(O)NH2, NHC(O)NHR57, NHC(O)N(R57)2, NR57C(O)NHR57, NR57C(O)N(R57)2, C(O)NH2, C(O)NHR57, C(O)N(R57)2, C(O)NHOH, C(O)NHOR57, C(O)NHSO2R57, C(O)NR57SO2R57, SO2NH2, SO2NHR57, SO2N(R57)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR57, C(N)N(R57)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R57是R58，R59，R60或R61；R58是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R58A稠合；R58A是环烷，环烯，杂环烷或杂环烯；R59是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R59A稠合；R59A是环烷，环烯，杂环烷或杂环烯；R60是环烷基，环烯基，杂环烷基或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R60A稠合；R60A是环烷，环烯，杂环烷或杂环烯；R61是烷基，烯基或炔基，其每个是未取代的或被一或两个或三个独立地选自下列的取代基取代：R62, OR62, SR62, S(O)R62, SO2R62, C(O)R62, C(O)OR62, OC(O)R62, OC(O)OR62, NH2, NHR62, N(R62)2, NHC(O)R62, NR62C(O)R62, NHS(O)2R62, NR62S(O)2R62, NHC(O)OR62, NR62C(O)OR62, NHC(O)NH2, NHC(O)NHR62, NHC(O)N(R62)2, NR62C(O)NHR62, NR62C(O)N(R62)2, C(O)NH2, C(O)NHR62, C(O)N(R62)2, C(O)NHOH, C(O)NHOR62, C(O)NHSO2R62, C(O)NR62SO2R62, SO2NH2, SO2NHR62, SO2N(R62)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR62, C(N)N(R62)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R62是R63，R64，R65或R66；R63是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R63A稠合；R63A是环烷，环烯，杂环烷或杂环烯；R64是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R64A稠合；R64A是环烷，环烯，杂环烷或杂环烯；R65是环烷基，环烯基，杂环烷基或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R65A稠合；R65A是环烷，环烯，杂环烷或杂环烯；R66是烷基，烯基（alkenyl）或烯基（alkenyl），其每个是未取代的或被一或两个或三个独立地选自下列的取代基取代：R67, OR67, SR67, S(O)R67, SO2R67, C(O)R67, C(O)OR67, OC(O)R67, OC(O)OR67, NH2, NHR67, N(R67)2, NHC(O)R67, NR67C(O)R67, NHS(O)2R67, NR67S(O)2R67, NHC(O)OR67, NR67C(O)OR67, NHC(O)NH2, NHC(O)NHR67, NHC(O)N(R67)2, NR67C(O)NHR67, NR67C(O)N(R67)2, C(O)NH2, C(O)NHR67, C(O)N(R67)2, C(O)NHOH, C(O)NHOR67, C(O)NHSO2R67, C(O)NR67SO2R67, SO2NH2, SO2NHR67, SO2N(R67)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR67, C(N)N(R67)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R67是烷基，烯基，炔基，苯基，杂芳基，环烷基，环烯基，杂环烷基或杂环烯基；其中R58、R59、R60、R63、R64、R65和R67代表的部分是未取代的或被一个或多个独立地选自下列的取代基取代：R68, OR68, SR68, S(O)R68, SO2R68, C(O)R68, C(O)OR68, OC(O)R68, OC(O)OR68, NH2, NHR68, N(R68)2, NHC(O)R68, NR68C(O)R68, NHS(O)2R68, NR68S(O)2R68, NHC(O)OR68, NR68C(O)OR68, NHC(O)NH2, NHC(O)NHR68, NHC(O)N(R68)2, NR68C(O)NHR68, NR68C(O)N(R68)2, C(O)NH2, C(O)NHR68, C(O)N(R68)2, C(O)NHOH, C(O)NHOR68, C(O)NHSO2R68, C(O)NR68SO2R68, SO2NH2, SO2NHR68, SO2N(R68)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR68, C(N)N(R68)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R68是R69，R70，R71或R72；R69是苯基，其是未稠合的或与苯、杂芳烃(heteroarene)或R69A稠合；R69A是环烷，环烯，杂环烷或杂环烯；R70是杂芳基，其是未稠合的或与苯、杂芳烃(heteroarene)或R70A稠合；R70A是环烷，环烯，杂环烷或杂环烯；R71是环烷基，环烯基，杂环烷基或杂环烯基，其每个是未稠合的或与苯、杂芳烃(heteroarene)或R71A稠合；R71A是环烷，环烯，杂环烷或杂环烯；R72是烷基，烯基(alkenyl)或烯基(alkenyl)，其每个是未取代的或被一或两个或三个独立地选自下列的取代基取代：R73, OR73, SR73, S(O)R73, SO2R73, C(O)R73, C(O)OR73, OC(O)R73, OC(O)OR73, NH2, NHR73, N(R73)2, NHC(O)R73, NR73C(O)R73, NHS(O)2R73, NR73S(O)2R73, NHC(O)OR73, NR73C(O)OR73, NHC(O)NH2, NHC(O)NHR73, NHC(O)N(R73)2, NR73C(O)NHR73, NR73C(O)N(R73)2, C(O)NH2, C(O)NHR73, C(O)N(R73)2, C(O)NHOH, C(O)NHOR73, C(O)NHSO2R73, C(O)NR73SO2R73, SO2NH2, SO2NHR73, SO2N(R73)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR73, C(N)N(R73)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I；R73是烷基，烯基，烯基，苯基，杂芳基，环烷基，环烯基，杂环烷基或杂环烯基；和R69、R70和R71代表的部分是未取代的或被一个或多个独立地选自下列的取代基取代：NH2, C(O)NH2, C(O)NHOH, SO2NH2, CF3, CF2CF3, C(O)H, C(O)OH, C(N)NH2, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br或I。
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