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标题翻译： ALPHA-AMINO BORONIC ACID DERIVATIVES，选择性免疫抑制剂

公开(公告)号：WO2013092979A1

公开(公告)日：2013-06-27

申请号：PCT/EP2012/076595

申请日：2012-12-21

申请人： ARES TRADING S.A.

发明人： SWINNEN, Dominique , MORANDI, Federica

IPC分类号： A61K31/69 , C07F5/02 , A61P37/00

CPC分类号： C07F5/025 , A61K31/69 , A61K45/06 , A61K2201/094 , C07F5/02

摘要： The present invention provides compounds of Formula (I) as inhibitors of LMP7 for the treatment of autoimmune and inflammatory diseases. In formula (I), R b and R c are independently selected from one another from H or C 1 -C 6 -alkyl; whereby R b and R c may be linked to form a 5 or 6 membered-ring containing the oxygen atoms to which they are linked; Q denotes Ar, Het or cycloalkyl; R 1 R 2 independently from each other denotes H, OR a , Hal, C 1 -C 6 -alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; Y denotes CR 3 R 4 , preferably CH 2 or C(CH 3 ) 2 ; R 3 , R 4 independently of one another denote H or C 1 -C 6 -alkyl; L denotes L 1 or L 2 or alkyl; n is an integer selected from 0 to 3; L 1 is Q 1 -CO-M- wherein Q 1 is Ar or Het, preferably, phenyl, naphthyl or pyridine, optionally substituted with 1 to 5 groups independently selected from OR a , Hal, phenyl, and C 1 -C 6 -alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; L 2 is Q 2 -M- wherein Q 2 is a fused bicyclic system containing 1 nitrogen atom and 1 to 3 additional groups independently selected from O, S, N, or CO, and wherein at least one of the rings is aromatic whereby the fused bicyclic system is optionally substituted with 1 to 5 groups independently selected from OR a, Hal, phenyl, and C 1 -C 6 -alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; or Q 2 is unsaturated or aromatic 5 membered-ring system containing 1 to 3 heteroatoms selected from N, O, S and CO, and optionally substituted with a phenyl ring or pyridine ring whereby phenyl ring and pyridine ring are optionally substituted with 1 to 4 groups independently selected from OR a , Hal, phenyl, and C 1 -C 6 -alkyl wherein 1 to 5 H atoms may be independently replaced by OH or Hal; M is a linear or branched alkylene having 1 to 5 carbon atoms wherein 1 or 2 H atoms may be replaced by OR a or a phenyl ring optionally substituted with 1 to 5 groups independently selected from Hal, OR a , and C1-C6-alkyl optionally substituted with 1 to 5 groups independently selected from OH, and Hal; or M denotes a cycloalkylene having 3 to 7 carbon atoms; or M denotes a thiazolidinyl group; R a is H or C 1 -C 6 -alkyl wherein 1 to 5 H atom may be independently replaced by OH or Hal; Ar denotes a 6 membered-aromatic carbocyclic ring optionally fused with another carbocyclic saturated, unsaturated or aromatic ring having 5 to 8 carbon atoms; Het denotes a 5- or 6-membered saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from N, N+O-, O, S, SO, and SO 2 , and optionally fused with another saturated, unsaturated or aromatic ring having 5 to 8 atoms and optionally containing 1 to 3 heteroatoms selected from N, O, and S; Hal denotes CI, Br, I of F; preferably CI or F.

摘要翻译：本发明提供作为LMP7抑制剂的式（I）化合物用于治疗自身免疫性和炎性疾病。在式（I）中，R b和R c彼此独立地选自H或C 1 -C 6 - 烷基; 其中Rb和Rc可以连接形成含有它们所连接的氧原子的5或6元环; Q表示Ar，Het或环烷基; R 1彼此独立地表示H，OR a，Hal，C 1 -C 6 - 烷基，其中1至5个H原子可以独立地被OH或Hal代替; Y表示CR 3R4，优选CH 2或C（CH 3）2; R 3，R 4彼此独立地表示H或C 1 -C 6 - 烷基; L表示L1或L2或烷基; n为0〜3的整数; L 1是Q1-CO-M-，其中Q 1是Ar或Het，优选苯基，萘基或吡啶，任选被1至5个独立地选自OR a，Hal，苯基和C 1 -C 6烷基的基团取代，其中1至 5个H原子可以独立地被OH或Hal取代; L2是Q2-M-，其中Q 2是含有1个氮原子的稠合双环系统和独立选自O，S，N或CO的1至3个另外的基团，并且其中至少一个环是芳族的，由此稠合双环系统任选被1至5个独立地选自OR a，Hal，苯基和C 1 -C 6烷基的基团取代，其中1至5个H原子可以独立地被OH或Hal代替; 或Q 2是含有1至3个选自N，O，S和CO的杂原子的不饱和或芳族5元环系，并且任选被苯环或吡啶环取代，由此苯环和吡啶环任选被1至4个独立地选自OR a，Hal，苯基和C 1 -C 6烷基的基团，其中1至5个H原子可以独立地被OH或Hal代替; M是具有1至5个碳原子的直链或支链亚烷基，其中1或2个H原子可以被OR a或任选被1-5个独立地选自Hal，ORa和任选地被C 1 -C 6烷基的基团取代的苯环被1至5个独立地选自OH和Hal的基团取代; 或M表示具有3至7个碳原子的亚环烷基; 或M表示噻唑烷基; R a是H或C 1 -C 6烷基，其中1至5个H原子可以独立地被OH或Hal代替; Ar表示任选地与具有5至8个碳原子的碳环饱和，不饱和或芳族环稠合的6元芳族碳环; Het表示具有1至3个独立地选自N，N + O-，O，S，SO和SO 2的杂原子的5-或6-元饱和，不饱和或芳族杂环，并且任选地与另一饱和的，不饱和的或不饱和的具有5至8个原子并且任选地含有1至3个选自N，O和S的杂原子的芳环; Hal表示F的CI，Br，I; 优选CI或F.

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