(12S)-5-bromo-20-methoxy-12-(2-methylpropyl)-14-(3-morpholin-4-ylpropyl)-18-oxa-2,11,14,23,25-pentazatetracyclo[17.6.2.03,8.022,26]heptacosa-1(25),3(8),4,6,19,21,23,26-octaene-10,13-dione

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (12S)-5-bromo-20-methoxy-12-(2-methylpropyl)-14-(3-morpholin-4-ylpropyl)-18-oxa-2,11,14,23,25-pentazatetracyclo[17.6.2.03,8.022,26]heptacosa-1(25),3(8),4,6,19,21,23,26-octaene-10,13-dione
• 化学式: C₃₃H₄₃BrN₆O₅
• 分子量: 683.646
• InChiKey: BYKGWKBIEHRFCR-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  45
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (12S)-5-bromo-20-methoxy-12-(2-methylpropyl)-14-(3-morpholin-4-ylpropyl)-18-oxa-2,11,14,23,25-pentazatetracyclo[17.6.2.03,8.022,26]heptacosa-1(25),3(8),4,6,19,21,23,26-octaene-10,13-dione 、 三甲基乙炔基硅 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 作用下， 以 四氢吡咯 为溶剂， 反应 5.0h， 生成 (12S)-20-methoxy-12-(2-methylpropyl)-14-(3-morpholin-4-ylpropyl)-5-(2-trimethylsilylethynyl)-18-oxa-2,11,14,23,25-pentazatetracyclo[17.6.2.03,8.022,26]heptacosa-1(25),3(8),4,6,19,21,23,26-octaene-10,13-dione
  参考文献：
  名称：

  WO2006/61417

  摘要：

  公开号：
• 作为产物：
  描述：

  (2S)-2-[[2-[4-bromo-2-[[7-methoxy-6-[3-(3-morpholin-4-ylpropylamino)propoxy]quinazolin-4-yl]amino]phenyl]acetyl]amino]-4-methylpentanoic acid 在 N-羟基-7-氮杂苯并三氮唑 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 异丁酰胺 为溶剂， 以100%的产率得到(12S)-5-bromo-20-methoxy-12-(2-methylpropyl)-14-(3-morpholin-4-ylpropyl)-18-oxa-2,11,14,23,25-pentazatetracyclo[17.6.2.03,8.022,26]heptacosa-1(25),3(8),4,6,19,21,23,26-octaene-10,13-dione
  参考文献：
  名称：

  WO2006/61417

  摘要：

  公开号：

文献信息

• Macrocyclic quinazole derivatives and their use as MTKI
  申请人：Janssen Pharmaceutica NV

  公开号：US10208062B2

  公开（公告）日：2019-02-19

  The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-5alkyl-NR14—CO—C1-5alkyl-, —C1-2alkyl-NR21—H2—CO—NH—C1-3alkyl- or —C1-2alkyl-NR23—CO—CR16R17—NH—; X1 represents O or —O—C1-2alkyl-; X2 represents a direct bond, C1-2alkyl, —CO—C1-2alkyl or NR12—C1-2alkyl; R1 represents hydrogen or halo; R2 represents halo, acetylene or Het1 R3 represents hydrogen or cyano; R4 represents Ar4—C1-4alkyloxy-, C1-4alkyloxy- or C1-4alkyloxy substituted with one or where possible two or more substituents selected from Het2, NR7R8, hydroxy and C1-4alkyloxy-C1-4alkyloxy-; R7 represents hydrogen or C1-4alkyl; R8 represents C1-4alkyl substituted with NR25R26 or C1-4alkylsulfonyl; R12 represents hydrogen or C1-4alkyl-; R13 represents Ar6-sulfonyl or C1-6alkyloxycarbonyl optionally substituted with phenyl; R16 and R17 represents hydrogen, C1-4alkyl or R16 and R17 taken together with the carbon atom to which they are attached from a C3-6cycloalkyl; R23 represents C1-4alkyl and R23 represents hydrogen when R16 and R17 taken together with the carbon atom to which they are attached from a C3-6cycloalkyl; R25, R26, R27 and R28 each independently represent hydrogen or C1-4alkylcarbonyl; Het1 represents 2-bora-1,3-dioxolanyl; Het2 represents piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl wherein said Het2 is optionally substituted with C1-4alkyloxycarbonyl or NR27R28—C1-4alkyl; Ar4 and Ar5 represents phenyl; Ar6 represents phenyl optionally substituted with nitro.

  本发明涉及式化合物 的 N-氧化物形式、药学上可接受的加成盐及其立体异构形式，其中 Z代表NH；Y代表-C3-9烷基-、-C1-5烷基-NR13-C1-5烷基-、-C1-5烷基-NR14-CO-C1-5烷基-、-C1-2烷基-NR21-H2-CO-NH-C1-3烷基-或-C1-2烷基-NR23-CO-CR16R17-NH-； X1 代表 O 或-O-C1-2烷基-； X2 代表直接键、C1-2烷基、-CO-C1-2烷基或 NR12-C1-2烷基； R1 代表氢或卤素； R2 代表卤素、乙炔或 Het1 R3 代表氢或氰基； R4 代表 Ar4-C1-4烷氧基-、C1-4烷氧基-或被选自 Het2、NR7R8、羟基和 C1-4 烷氧基-C1-4烷氧基-的一个或（如有可能）两个或多个取代基取代的 C1-4 烷氧基； R7 代表氢或 C1-4 烷基；R8 代表被 NR25R26 或 C1-4 烷基磺酰基取代的 C1-4 烷基； R12 代表氢或 C1-4 烷基-； R13 代表 Ar6-磺酰基或任选被苯基取代的 C1-6 烷氧基羰基； R16和R17代表氢、C1-4烷基或R16和R17连同它们所连接的碳原子来自C3-6环烷基； R23 代表 C1-4 烷基，当 R16 和 R17 与来自 C3-6 环烷基的碳原子连接在一起时，R23 代表氢； R25、R26、R27 和 R28 各自独立地代表氢或 C1-4 烷基羰基； Het1 代表 2-硼-1,3-二氧戊环； Het2 代表哌啶基、哌嗪基、吗啉基、硫代吗啉基或 1,1-二氧代硫代吗啉基，其中所述 Het2 任选被 C1-4 烷氧羰基或 NR27R28-C1-4 烷基取代； Ar4 和 Ar5 代表苯基；Ar6 代表任选被硝基取代的苯基。
• US20140256714A1
  申请人：——

  公开号：US20140256714A1

  公开（公告）日：2014-09-11
• MACROCYCLIC QUINAZOLE DERIVATIVES AND THEIR USE AS MTKI
  申请人：Janssen Pharmaceutica NV

  公开号：US20170320894A1

  公开（公告）日：2017-11-09

  The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents NH; Y represents —C 3-9 alkyl-, —C 1-5 alkyl-NR 13 —C 1-5 alkyl-, —C 1-5 alkyl-NR 14 —CO—C 1-5 alkyl-, —C 1-2 alkyl-NR 21 —H 2 —CO—NH—C 1-3 alkyl- or —C 1-2 alkyl-NR 23 —CO—CR 16 R 17 —NH—; X 1 represents O or —O—C 1-2 alkyl-; X 2 represents a direct bond, C 1-2 alkyl, —CO—C 1-2 alkyl or NR 12 —C 1-2 alkyl; R 1 represents hydrogen or halo; R 2 represents halo, acetylene or Het 1 R 3 represents hydrogen or cyano; R 4 represents Ar 4 —C 1-4 alkyloxy-, C 1-4 alkyloxy- or C 1-4 alkyloxy substituted with one or where possible two or more substituents selected from Het 2 , NR 7 R 8 , hydroxy and C 1-4 alkyloxy-C 1-4 alkyloxy-; R 7 represents hydrogen or C 1-4 alkyl; R 8 represents C 1-4 alkyl substituted with NR 25 R 26 or C 1-4 alkylsulfonyl; R 12 represents hydrogen or C 1-4 alkyl-; R 13 represents Ar 6 -sulfonyl or C 1-6 alkyloxycarbonyl optionally substituted with phenyl; R 16 and R 17 represents hydrogen, C 1-4 alkyl or R 16 and R 17 taken together with the carbon atom to which they are attached from a C 3-6 cycloalkyl; R 23 represents C 1-4 alkyl and R 23 represents hydrogen when R 16 and R 17 taken together with the carbon atom to which they are attached from a C 3-6 cycloalkyl; R 25 , R 26 , R 27 and R 28 each independently represent hydrogen or C 1-4 alkylcarbonyl; Het 1 represents 2-bora-1,3-dioxolanyl; Het 2 represents piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl wherein said Het 2 is optionally substituted with C 1-4 alkyloxycarbonyl or NR 27 R 28 —C 1-4 alkyl; Ar 4 and Ar 5 represents phenyl; Ar 6 represents phenyl optionally substituted with nitro.
• US9688691B2
  申请人：——

  公开号：US9688691B2

  公开（公告）日：2017-06-27
• WO2006/61417
  申请人：——

  公开号：——

  公开（公告）日：——