公开(公告)号：WO2013064538A1

公开(公告)日：2013-05-10

申请号：PCT/EP2012/071560

申请日：2012-10-31

申请人： ASTEX THERAPEUTICS LIMITED

发明人： WOODHEAD, Andrew, James ,  CHESSARI, Gianni ,  BESONG, Gilbert, Ebai ,  CARR, Maria, Grazia ,  HISCOCK, Steven, Douglas ,  O'BRIEN, Michael, Alistair ,  REES, David, Charles ,  SAALAU-BETHELL, Susanne, Maria ,  WILLEMS, Hendrika, Maria, Gerarda ,  THOMPSON, Neil, Thomas

IPC分类号： C07D209/14 ,  C07D213/75 ,  C07D231/12 ,  C07D233/24 ,  C07D233/64 ,  C07D295/02 ,  C07D305/06 ,  C07D305/08 ,  C07D309/14 ,  C07C217/58 ,  A61P31/12 ,  A61K31/137 ,  A61K31/44 ,  A61K31/415 ,  A61K31/4164

CPC分类号： A61K31/505 ,  A61K31/135 ,  A61K31/137 ,  A61K31/165 ,  A61K31/397 ,  A61K31/4409 ,  A61K31/4462 ,  A61K31/4465 ,  A61K45/06 ,  C07B2200/05 ,  C07C217/58 ,  C07C217/60 ,  C07C217/62 ,  C07C217/74 ,  C07C217/90 ,  C07C225/12 ,  C07C233/18 ,  C07C233/25 ,  C07C235/46 ,  C07C237/04 ,  C07C237/06 ,  C07C237/08 ,  C07C237/10 ,  C07C237/12 ,  C07C237/20 ,  C07C243/34 ,  C07C251/48 ,  C07C255/24 ,  C07C255/29 ,  C07C255/37 ,  C07C255/46 ,  C07C255/54 ,  C07C259/06 ,  C07C271/12 ,  C07C275/36 ,  C07C311/04 ,  C07C311/08 ,  C07C311/29 ,  C07C313/06 ,  C07C317/22 ,  C07C323/25 ,  C07C2601/02 ,  C07C2601/04 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2601/16 ,  C07D205/04 ,  C07D207/14 ,  C07D207/335 ,  C07D209/08 ,  C07D209/14 ,  C07D209/44 ,  C07D211/26 ,  C07D211/56 ,  C07D211/70 ,  C07D213/38 ,  C07D213/64 ,  C07D213/65 ,  C07D213/68 ,  C07D213/73 ,  C07D213/74 ,  C07D213/75 ,  C07D213/81 ,  C07D213/84 ,  C07D217/02 ,  C07D231/12 ,  C07D233/24 ,  C07D233/64 ,  C07D237/14 ,  C07D239/34 ,  C07D239/42 ,  C07D241/18 ,  C07D241/20 ,  C07D241/24 ,  C07D243/14 ,  C07D263/32 ,  C07D265/36 ,  C07D271/10 ,  C07D277/68 ,  C07D285/13 ,  C07D295/02 ,  C07D295/027 ,  C07D295/185 ,  C07D295/192 ,  C07D305/06 ,  C07D305/08 ,  C07D307/14 ,  C07D307/22 ,  C07D307/79 ,  C07D309/06 ,  C07D309/12 ,  C07D309/14 ,  C07D319/18 ,  C07D513/04

摘要： The invention provides compounds of the formula (I): or a salt, N-oxide or tautomer thereof, wherein A is CH, CF or nitrogen; E is CH, CF or nitrogen; and R 0 is hydrogen or C 1-2 alkyl; R 1a is selected from CONH 2 ; CO 2 H; an optionally substituted acyclic C 1-8 hydrocarbon group; and an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S; R 2 is selected from hydrogen and a group R 2a ; R 2a is selected from an optionally substituted acyclic d-8 hydrocarbon group; an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1 or 2 ring members are heteroatom ring members selected from O, N and S; and an optionally substituted bicyclic heterocyclic group of 9 or 10 ring members, of which 1 or 2 ring members are nitrogen atoms; wherein at least one of R 1 and R 2 is other than hydrogen; R 3 is an optionally substituted 3- to 10-membered monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0, 1, 2 or 3 heteroatom ring members selected from N, O and S; R 4a is selected from halogen; cyano; C 1-4 alkyl optionally substituted with one or more fluorine atoms; C 1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy-C 1-4 alkyl; and C 1-2 alkoxy-C 1-4 alkyl; R 5 is selected from hydrogen and a substituent R 5a ; and R 5a is selected from C 1-2 alkyl optionally substituted with one or more fluorine atoms; C 1-3 alkoxy optionally substituted with one or more fluorine atoms; halogen; cyclopropyl; cyano; and amino, The compounds have activity against hepatitis C virus and can be used in the prevention or treatment of hepatitis C viral infections.

摘要翻译： 本发明提供式（I）化合物或其盐，N-氧化物或互变异构体，其中A为CH，CF或氮; E是CH，CF或氮; 和R 0是氢或C 1-2烷基; R1a选自CONH2; CO 2 H; 任选取代的非环C 1-8烃基; 和3至7个环成员的任选取代的单环碳环或杂环基，其中0,1,2,3或4是选自O，N和S的杂原子环成员; R2选自氢和基团R 2a; R2a选自任选取代的非环状d-8烃基; 3至7个环成员的任选取代的单环碳环或杂环基，其中0,1或2个环成员是选自O，N和S的杂原子环成员; 和9或10个环成员的任选取代的双环杂环基，其中1或2个环成员是氮原子; 其中R 1和R 2中的至少一个不是氢; R3是含有0,1,2或3个选自N，O和S的杂原子环成员的任选取代的3至10元单环或双环碳环或杂环; R4a选自卤素; 氰基; 任选被一个或多个氟原子取代的C 1-4烷基; 任选被一个或多个氟原子取代的C 1-4烷氧基; 羟基-C 1-4烷基; 和C 1-2烷氧基-C 1-4烷基; R5选自氢和取代基R5a; 并且R 5a选自任选被一个或多个氟原子取代的C 1-2烷基; 任选被一个或多个氟原子取代的C 1-3烷氧基; 卤素; 环丙基; 氰基; 和氨基，该化合物具有抗丙型肝炎病毒的活性，可用于预防或治疗丙型肝炎病毒感染。

公开(公告)号：WO2018178691A1

公开(公告)日：2018-10-04

申请号：PCT/GB2018/050845

申请日：2018-03-28

申请人： ASTEX THERAPEUTICS LIMITED ,  CANCER RESEARCH TECHNOLOGY LIMITED

发明人： HOWARD, Steven ,  CONS, Benjamin, David ,  ST. DENIS, Jeffrey, David ,  GRIFFITHS-JONES, Charlotte, Mary ,  HISCOCK, Steven, Douglas ,  HOLVEY, Rhian, Sara ,  BURNS, Alan, Richard ,  COUSIN, David ,  DEXTER, Hannah, Louise ,  PARRA, Guillaume, François ,  WATTS, John, Paul ,  JEWELL, Robert ,  STOCKWELL, Jennifer, Ann ,  HIRST, Kim, Louise ,  LEMASSON, Isabelle, Anne ,  NASH, David, John ,  OSBORNE, James, Daniel ,  PRIEDE, Jonas, Calleja ,  RICHARDS, Nicholas, Paul ,  DUMAS, Aaron, Michael ,  BISHOP, Brian, Christopher ,  PARRY-JONES, David ,  SCOTT, Jeremy, Peter ,  SHAUNMUGHAM, Meenakshi, Sundaram ,  MULLENS, Peter, Richard ,  LATHBURY, David, Charles ,  DIXON, Darren, James ,  GAUNT, Matthew, James

IPC分类号： C07D405/06

摘要： The invention relates to processes for preparing isoindolin-1-one derivatives, and in particular processes for preparing (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1- (oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid. The invention also relates to crystalline forms of the compound (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4- chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H- isoindol-2-yl]-2-methylpropanoic acid and its salts.