CN117209471A - 一种shp2磷酸酶变构抑制剂 - Google Patents
一种shp2磷酸酶变构抑制剂 Download PDFInfo
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- CN117209471A CN117209471A CN202310907352.4A CN202310907352A CN117209471A CN 117209471 A CN117209471 A CN 117209471A CN 202310907352 A CN202310907352 A CN 202310907352A CN 117209471 A CN117209471 A CN 117209471A
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- China
- Prior art keywords
- dihydrospiro
- carboxylic acid
- indene
- tert
- dichlorophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 title claims description 8
- 102000007607 Non-Receptor Type 11 Protein Tyrosine Phosphatase Human genes 0.000 title claims description 8
- 229940125528 allosteric inhibitor Drugs 0.000 title description 7
- 239000003112 inhibitor Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 35
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims description 13
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
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- 201000010099 disease Diseases 0.000 claims description 2
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- 230000001613 neoplastic effect Effects 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 229940125812 SHP2 phosphatase inhibitor Drugs 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 78
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- IXEXQYZAPGSKJC-UHFFFAOYSA-N ethyl 3-chloro-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxylate Chemical compound ClC=1C(=NC(=C(N=1)C)C1=C(C(=CC=C1)Cl)Cl)C(=O)OCC IXEXQYZAPGSKJC-UHFFFAOYSA-N 0.000 description 9
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- GHRIDABVKDEQNS-UHFFFAOYSA-N ethyl 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate Chemical compound BrC1=C(N=C(C(=N1)C(=O)OCC)Cl)C GHRIDABVKDEQNS-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
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- WRHUDFRWZFBPEF-UHFFFAOYSA-N methanesulfonamide;2,2,2-trifluoroacetic acid Chemical compound CS(N)(=O)=O.OC(=O)C(F)(F)F WRHUDFRWZFBPEF-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
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- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- Epidemiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供了一种SHP2磷酸酶抑制剂,该抑制剂具有如式(I)所示的结构,本发明的抑制剂具有治疗肿瘤疾病的用途。
Description
技术领域
本发明涉及一种SHP2磷酸酶变构抑制剂,以及含有该抑制剂的药物,属于医药领域。
背景技术
SHP2是一个非受体蛋白酪氨酸磷酸酶,由PTPN11基因编码,参与多种信号通路,如Ras-Erk,PI3k-Akt,Jak-Stat,NF-κB,mTOR等(Bing Yu,Wei Liu,Wen-Mei Yu,MignonL.Loh et al.Mol Cancer Ther.2013,12,1738-1748)。
SHP2包含两个串联的SH2结构域和一个起催化作用的PTP结构域。SHP2处于非活性构象,SH2结构域阻挡了底物接近催化位点,直到被细胞因子或生长因子刺激,引起SHP2变构,暴露出其催化位点。
SHP2的过度活化和多种疾病相关,使得SHP2成为一个受关注的靶点。本发明包含一系列化合物,抑制SHP2的活性.
发明内容
本发明的一个目的是提供一种SHP2磷酸酶变构抑制剂化合物或其药学上可接收的盐。
本发明的另一个目的是提供所述化合物的用途。
本发明一方面提供了一种SHP2磷酸酶变构抑制剂化合物或其药学上可接收的盐,该抑制剂化合物具有如下式(Ⅰ)所示的结构:
其中A1选自N或者C;
A2和A3各自独立地选自N、-NCH3、C=O和-CR6中的一种或几种,R6选自H、取代或未取代的C1-6的烷基、卤素、氰基、羟基、氨基、磺酰烷基、磺酰胺基、C1-6取代或未取代的烷基醇或C1-6的烷氧基;
A4选自-CH2-或-O-;
R5选自H、取代或未取代的C1-6的烷基、卤素、氰基、羟基或氨基;
D1为芳香环或者杂芳环;
R1、R2各自独立地选自H、卤素、氰基、羟基、C1-6取代或未取代的烷氧基、-NR1aR1b、C1-6取代或未取代的烷基、-CONR1aR1b、-NR1aCOR1b、-CO2R1a、-COC1-6取代或未取代的烷基、-SO2NR1aR1b、-N=SO(C1-C6烷基)2、-NHSO2(C1-C6烷基)和-C1-6取代或未取代的烷基醇中的一种或几种;
R1a、R1b各自独立地选自H或C1-6取代或未取代的烷基;m,n=0、1或2;
D2为5-12元单环基或稠环基,所述的单环基为芳香基或杂芳香基;所述的稠环基为芳香稠环基、杂芳香稠环基、脂肪环并芳香环基、杂脂肪环并芳香环基、杂脂肪环并杂芳香环基或脂肪环并杂芳香环基;
R3、R4各自独立地选自H、卤素、氰基、羟基、羧基、C1-6取代或未取代的烷氧基、-NR2aR2b、-C1-6取代或未取代的烷基、-CONR2aR2b、-NR2aCOR2b、-COC1-6取代或未取代的烷基、-SO2NR2aR2b、-N=SO(C1-C6烷基)2、-NHSO2(C1-C6烷基)和-C1-6直链和支链烷基醇中的一种或几种;
R2a、R2b各自独立地选自H或C1-6取代或未取代的烷基;
o,p=0、1或2;取代烷基是烷基上的氢被F或-CH3取代,取代烷氧基是烷氧基上的氢被F或-CH3取代,取代烷基醇是烷基醇上的氢被F或-CH3取代。
本发明另一方面提供了本发明所述的SHP2磷酸酶变构抑制剂的光学异构体化合物或其药学上可接受的盐在制备用于治疗肿瘤疾病的药物中的用途。
本发明的有益效果在于,本发明提供了一种SHP2磷酸酶变构抑制剂的光学异构体化合物或其药学上可接受的盐,本发明的化合物具有很好的药学效果。
具体的实施方式
下述非限制性实施例仅仅是说明性的,不以任何方式限制本发明。在本发明保护范围内所做的变形、改变、改造都在本发明的保护范围内。
在某些实施方式中,本发明的一种或多种化合物可以彼此间联合使用,也可以选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备SHP2磷酸酶抑制剂,如果使用的是一组化合物,则可将这些化合物同时、分别或者有序地对受试对象进行给药。
在某些实施方式中,本发明的化合物可以与一种或多种其它抗癌剂联合使用。可联用的抗癌剂包括但不具体实施方式。
以下结合实施例示例性阐述本发明的化合物及其制备方法和用途。合成方法流程1:
流程2
可按照流程1或流程2中所述路线制备本发明所示化合物。流程1及流程2中反应所得的每一个产物可以通过传统分离技术来得到,这种传统技术包括但不限于过滤、蒸馏、结晶、色谱分离等。起始原料可以通过自己合成或从商业机构(例如,但不限于,Adrich或Sigma)购买获得。这些原料可以使用常规手段进行表征,比如物理常数和光谱数据。本发明所描述的化合物可以使用合成方法得到单一的异构体或者是异构体的混合物。
在流程1中,以原料1和2在适当的催化剂、配体及碱的作用下,偶联得到中间体3。中间体3与原料4在碱性条件下通过取代反应得到中间体5,5在酸性条件下脱去保护基得到目标化合物6。在流程2中,原料7与NBS反应得到溴代产物8。8与4在BOP及碱的条件下,反应得到中间体9。9与原料1在适当的催化剂、配体及碱的作用下,偶联得到中间体10。10在酸性条件下脱去保护基得到目标化合物11。
除非另有说明,温度是摄氏温度。试剂购自国药集团化学试剂北京有限公司,阿法埃莎(Alfa Aesar),或北京百灵威科技有限公司等商业供应商,并且这些试剂可直接使用无需进一步纯化,除非另有说明。
除非另有说明,下列反应在室温、无水溶剂中、氮气或氩气的正压下或使用干燥管进行;反应瓶上装有橡胶隔膜,以便通过注射器加入底物和试剂;玻璃器皿烘干和/或加热干燥。
除非另有说明,本文中的柱色谱购自青岛海洋化工厂200-300目硅胶。本文中的薄层色谱板购自烟台市化学工业研究所生产的薄层色谱硅胶预制板,商品号HSGF254;MS的测定用Thermo LCQ Fleet型(ESI)液相色谱-质谱联用仪;旋光测定使用SGW-3自动旋光仪,上海申光仪器仪表有限公司。
核磁数据(1H NMR)使用Varian设备于400MHz运行。核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMSO-d6等,以四甲基硅烷(0.00ppm)为基准或以残留溶剂为基准(CDCl3:7.26ppm;CD3OD:3.31ppm;D2O:4.79ppm;d6-DMSO:2.50ppm)。当标明峰形多样性时,以下简写表示不同峰形:s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数,则以Hertz(Hz)为单位。
缩略语:
实施例1
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-基)甲醇
步骤1:3-羟基-5-甲基吡嗪-2-羧酸乙酯
将1,2-二氨基丙烷(11.0g)溶于无水乙醇(200mL),冷却至0℃,加入酮基丙二酸二乙酯(25.0g),反应升至室温搅拌2小时,然后回流过夜。向反应液中加入冰水(50mL),用二氯甲烷(100mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析(二氯甲烷/甲醇=30/1)纯化得产品(8.0g)。
LC-MS,(ES,m/z):[M+H]+=183。
步骤2:6-溴-3-羟基-5-甲基吡嗪-2-羧酸乙酯
将3-羟基-5-甲基吡嗪-2-羧酸乙酯(8.0g)溶于N,N-二甲基甲酰胺(60mL)中,冷却至0℃。加入NBS(7.86g),室温反应过夜。向反应液中加入冰水(50mL),用二氯甲烷(50mL)萃取3次,有机相用水(100mL)洗涤,用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析(二氯甲烷/甲醇=100/1)纯化得产品(7.2g)。
LC-MS,(ES,m/z):[M+H]+=261。
步骤3:6-溴-3-氯-5-甲基吡嗪-2-羧酸乙酯
将三苯基膦(21.1g)和NCS(10.8g)加入1,4-二氧六环中(100mL)中,室温下反应0.5小时。然后将6-溴-3-羟基-5-甲基吡嗪-2-羧酸乙酯(7.0g)加入,在氮气保护下于100℃反应1小时。将反应液倾入水(300mL)中,用二氯甲烷(100mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析纯化得产品(5.1g)。
LC-MS,(ES,m/z):[M+H]+=279。
步骤4:3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
室温下,将6-溴-3-氯-5-甲基吡嗪-2-羧酸乙酯(2.0g),2,3-二氯苯硼酸(1.4g),Pd(dppf)Cl2(525mg),碳酸钾(2.0g)加入乙腈(100mL)中。在氮气保护下,升至90℃反应过夜。然后将反应液倾入水(200mL)中,用二氯甲烷(100mL)萃取3次,用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析纯化得到产品(0.98g)。
LC-MS,(ES,m/z):[M+H]+=345。
步骤5:1-酮-1,3-二氢螺[茚-2,4'-哌啶]-4'-羧酸叔丁酯
将2,3-二氢-1H-茚-1-酮(13.0g)溶于N,N-二甲基甲酰胺(200mL),冷却至0o℃,加入60%的氢化钠(11.8g)。升至室温搅拌0.5小时,加入二(2-氯乙基)氨基甲酸叔丁酯(23.8g),升温至60℃反应过夜。然后将反应液倾入水(500mL)中,用二氯甲烷(150mL)萃取3次,有机相用水(300mL)洗涤,用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析(石油醚/乙酸乙酯=5/1)纯化得产品(7.3g)。
LC-MS,(ES,m/z):[M+H]+=302。
步骤6:(R)-1-((叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将1-酮-1,3-二氢螺[茚-2,4'-哌啶]-4'-羧酸叔丁酯(7.0g),(R)-2-甲基丙烷-2-亚磺酰胺(2.8g)加入四乙氧基钛(90mL)中,在90℃下反应过夜。然后将反应液用水(500mL)和二氯甲烷(400mL)稀释,经硅藻土过滤,有机相用无水硫酸钠干燥,除去溶剂得粗产品(2.0g),直接用于下一步。
LC-MS,(ES,m/z):[M+H]+=404。
步骤7:(S)-1-(((R)-叔丁基亚磺酰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将(R)-1-((叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯粗产品(2.0g)溶于四氢呋喃(40mL),冷却至-50℃。分批加入硼氢化钠(752mg),保持在该温度下2小时,升至室温反应过夜。然后将反应液倾入水(50mL)中,用二氯甲烷(50mL)萃取两次,用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析(石油醚/乙酸乙酯=4/1)得产品(1.1g)
LC-MS,(ES,m/z):[M+H]+=406。
步骤8:(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐
将(S)-1-(((R)-叔丁基亚磺酰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(1.0g)溶于二氯甲烷(20mL)中,加入三氟乙酸(4mL),在室温下反应1小时。真空除去溶剂得到粗产品,直接用于下一步。
LC-MS,(ES,m/z):[M+H]+=307。
步骤9:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
室温下,将3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(100mg),(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺的三氟乙酸盐(200mg),碳酸钾(200mg)加入N-甲基吡咯烷酮(5mL)中。将反应液升温至100℃反应过夜。然后将反应液冷却至室温后,倾入水(20mL)中,用二氯甲烷(10mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,柱层析(二氯甲烷/甲醇=20/1)纯化得到产品(150mg)
LC-MS,(ES,m/z):[M+H]+=615。
步骤10:(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
将3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(150mg)加入1,4-二氧六环(3mL)和浓盐酸(1mL)的混合液中,在室温下反应4小时。然后将反应液倾入水(10mL),用碳酸氢钠溶液中和至pH值7,用二氯甲烷(10mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,柱层析(二氯甲烷/甲醇=20/1)纯化,得到产品(96mg)。
LC-MS,(ES,m/z):[M+H]+=511。
步骤11:(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-基)甲醇
将(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(96mg)溶于四氢呋喃(10mL)中,在氮气保护下冷却至-78℃。加入DIBAL-H(0.5mL),保持在该温度下1小时,升至0℃反应2小时,然后室温反应过夜。向反应液中加入饱和氯化铵溶液(5mL),用二氯甲烷(10mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,柱层析(二氯甲烷/甲醇=20/1)纯化,得到产品(10mg)。
LC-MS,(ES,m/z):[M+H]+=469。
1H NMR(400MHz,D6-DMSO)δ=7.74(dd,J=7.9Hz,1.7,1H),7.49(t,J=7.8Hz,1H),7.44(dd,J=7.6Hz,1.7Hz,1H),7.39-7.33(m,1H),7.26-7.15(m,3H),5.29(t,J=5.8Hz,1H),4.53(d,J=5.7Hz,2H),3.98(s,1H),3.80-3.70(m,2H),3.15-3.05(m,3H),2.69(d,J=15.8Hz,1H),2.20(s,3H),1.92-1.82(m,2H),1.57(d,J=12.5Hz,1H),1.27-1.24(m,1H)。
实施例2
(S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-腈
步骤1:1-(叔丁基)4-乙基4-(4-溴苄基)哌啶-1,4-二羧酸酯
将1-叔丁基4-乙基哌啶-1,4-二羧酸酯(8.0g)溶于无水四氢呋喃(200mL),氮气保护,冷却至-78℃。缓慢滴加LDA(2mol/L,16mL),保持在该温度下反应1小时。然后加入1-溴-4-(溴甲基)苯(7.8g),保持在该温度下反应3小时后,升至室温反应过夜。加入饱和氯化铵溶液(50mL)后,倾入水(400mL)中,用二氯甲烷(100mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析(二氯甲烷/甲醇=80/1)纯化,得产品(14.0g)。
LC-MS,(ES,m/z):[M+H]+=426。
步骤2:4-(4-溴苄基)-1-(叔丁氧羰基)哌啶-4-羧酸
将1-(叔丁基)4-乙基4-(4-溴苄基)哌啶-1,4-二羧酸酯(13.0g),氢氧化钠(3.6g)加入乙醇(80mL)和水(80mL)的混合液中,回流过夜。反应液冷至室温后,倾入水(200mL)中,用2N的盐酸中和至pH值6,用二氯甲烷(100mL)萃取3次,用无水硫酸钠干燥,除去溶剂得粗产品(16.5g),直接用于下一步。
LC-MS,(ES,m/z):[M-H]+=396。
步骤3:6-溴-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将4-(4-溴苄基)-1-(叔丁氧羰基)哌啶-4-羧酸粗产品(16.0g)加入多聚磷酸(100mL)中,升温至120℃下,反应0.5小时。将反应液倾入冰水混合物(300mL)中,用氢氧化钠调节pH值至10。加入二碳酸二叔丁酯(35.0g),室温反应过夜。反应液用二氯甲烷(100mL)萃取3次,用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析纯化得到产品(10.2g)。
LC-MS,(ES,m/z):[M+H]+=380。
步骤4:6-氰基-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将6-溴-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(8.0g),DBU(832mg),四三苯基膦钯(1.9g),亚铁氰化钾(3.6g)加入叔丁醇(50mL)和水(50mL)的混合液中,在氮气保护下于90℃下反应过夜。反应液冷却至室温后,用乙酸乙酯(120mL)稀释,过滤,滤饼用乙酸乙酯(60mL)淋洗。有机相合并,用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析(二氯甲烷/甲醇=100/1)纯化,得到产品(3.2g)。
LC-MS,(ES,m/z):[M+H]+=327。
步骤5:(R)-1-((叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤6类似方法,由6-氰基-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(1.0g),得到粗产品(1.2g),直接用于下一步
LC-MS,(ES,m/z):[M+H]+=430。
步骤6:(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤7类似方法,由(R)-1-((叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(1.0g),得到产品(1.1g)。
LC-MS,(ES,m/z):[M+H]+=432。
步骤7:(R)-N-((S)-5-氰基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐
按实施例1步骤8类似方法,由(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(100mg),得到粗产品(98mg),直接用于下一步。
LC-MS,(ES,m/z):[M+H]+=332。
步骤8:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(100mg),(R)-N-((S)-5-氰基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐(207mg),得到产品(150mg)。
LC-MS,(ES,m/z):[M+H]+=640。
步骤9:(S)-3-(1-氨基-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(90mg),得到产品(70mg)。
LC-MS,(ES,m/z):[M+H]+=536。
步骤10:(S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-腈
将(S)-3-(1-氨基-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(26mg)加入四氢呋喃(2mL)中,冷却至0℃。加入硼氢化锂(26mg),保持在该温度下反应2小时,然后室温反应过夜。向反应液中加入水(5mL),用二氯甲烷(10mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,经柱层析纯化得产品(3mg)。
LC-MS,(ES,m/z):[M+H]+=494。
1H NMR(400MHz,D6-DMSO)δ=8.02(s,1H),7.78-7.70(m,2H),7.53-7.41(m,3H),5.31(br,1H),4.53(s,2H),3.84-3.68(m,3H),3.23-2.91(m,3H),2.20(s,3H),2.10-1.98(m,1H),1.50-1.45(m,4H)。
实施例3
(S)-N-(1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)甲磺酰胺
步骤1:6-(甲基磺酰胺基)-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将6-溴-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(534mg),甲磺酰胺(740mg),N1,N2-二甲基乙烷-1,2-二胺(170mg),碘化亚铜(147mg)加入1,4-二氧六环(20mL)中,在氮气保护下升温至110℃反应过夜。然后将反应液倾入水(50mL)中,用二氯甲烷(30mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,经柱层析纯化,得到产品(410mg)。
LC-MS,(ES,m/z):[M+H]+=395。
步骤2:(R)-1-((叔丁基亚磺酰基)亚氨基)-6-(甲基磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤6类似方法,6-(甲基磺酰胺基)-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(300mg),得到粗产品(250mg),直接用于下一步
LC-MS,(ES,m/z):[M+H]+=498。
步骤3:(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-(甲基磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤7类似方法,由(R)-1-((叔丁基亚磺酰基)亚氨基)-6-(甲基磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(250mg),得到产品(200mg)。
LC-MS,(ES,m/z):[M+H]+=500。
步骤4:N-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)甲基磺酰胺三氟乙酸盐
按实施例1步骤8类似方法,由(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-(甲基磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(200mg),得到粗产品(180mg),直接用于下一步。
LC-MS,(ES,m/z):[M+H]+=400。
步骤5:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-(甲基磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(156mg),N-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)甲基磺酰胺三氟乙酸盐(180mg),得到产品(90mg)。
LC-MS,(ES,m/z):[M+H]+=708。
步骤6:(S)-3-(1-氨基-6-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-(甲基磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(90mg),得到产品(30mg)。
LC-MS,(ES,m/z):[M+H]+=605。
步骤7:(S)-N-(1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)甲磺酰胺
按实施例2步骤10类似方法,由(S)-3-(1-氨基-6-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(28mg),得到产品(9mg)。
LC-MS,(ES,m/z):[M+H]+=562。
1H NMR(400MHz,D6-DMSO)δ=9.59(br,1H),7.74(dd,J=7.9Hz,1.7Hz,1H),7.60(t,J=3.5Hz,1H),7.49(t,J=7.8Hz,1H),7.43(m,1.7,1H),7.19(d,J=8.1Hz,1H),7.08(m,2.0,1H),5.28(br,1H),4.53(s,2H),3.75-3.65(m,3H),3.14-3.01(m,3H),2.98(s,3H),2.78(d,J=15.7Hz,1H),2.20(s,3H),2.09-1.89(m,2H),1.57-1.29(m,2H)。
实施例4
(S)-1-(1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)丙烷-2-醇
步骤1:(S)-6-(乙酰基)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(2.1g)加入无水四氢呋喃(20mL)中。氮气保护,冷却至-50℃。缓慢滴加甲基溴化镁(2mol/L,10mL),保持在该温度下反应2小时,升至室温反应过夜。将反应液倾入水(50mL)中,用二氯甲烷(50mL)萃取3次。有机相用无水硫酸钠干燥,除去溶剂,经柱层析(石油醚/乙酸乙酯=5/1)纯化,得到产品(700mg)。
LC-MS,(ES,m/z):[M+H]+=449。
步骤2:(R)-N-((S)-5-(2-羟基丙烷-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺
将(S)-6-(乙酰基)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(700mg)溶于无水四氢呋喃(10mL),氮气保护,冷却至-78℃。滴加甲基锂(2.4mol/L,1.6mL),保持在该温度下反应2小时,升至室温反应过夜。然后向反应液中加入饱和氯化铵溶液(20mL),用二氯甲烷(20mL)萃取3次。有机相用无水硫酸钠干燥,除去溶剂,经柱层析(二氯甲烷/甲醇=20/1)纯化,得到产品(420mg)。
LC-MS,(ES,m/z):[M+H]+=365。
步骤3:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-(2-羟基丙烷-2基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(320mg),(R)-N-((S)-5-(2-羟基丙烷-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(400mg),得到产品(120mg)。
LC-MS,(ES,m/z):[M+H]+=673。
步骤4:(S)-3-(1-氨基-6-(2-羟基丙烷-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由3-((S)-6-乙酰基-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(100mg),得到产品(40mg)。
LC-MS,(ES,m/z):[M+H]+=569。
步骤5:(S)-2-(1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-基)丙烷-2-醇
按实施例2步骤10类似方法,由(S)-3-(1-氨基-6-(2-羟基丙烷-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(38mg),得到产品(6mg)。
LC-MS,(ES,m/z):[M+H]+=527。
1H NMR(400MHz,D6-DMSO)δ=7.81(s,1H),7.75(dd,J=8.0Hz,2.0Hz,1H),7.51-7.36(m,3H),7.14(d,J=7.9Hz,1H),5.28(br,1H),4.93(br,1H),4.53(s,2H),3.74-3.65(m,3H),3.10-3.04(m,3H),2.78(d,J=16Hz,1H),2.20(s,3H),2.11-1.93(m,1H),1.57-1.44(m,3H),1.43(d,J=7.5Hz,6H)。
实施例5
(S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺
步骤1:(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氨基甲酰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(400mg)加入双氧水(2mL)和1N氢氧化钠水溶液(5mL)的混合液中。氮气保护下,在60℃下反应2小时。然后将反应液倾入水(10mL)中,用二氯甲烷(20mL)萃取3次。有机相用无水硫酸钠干燥,除去溶剂,经柱层析(石油醚/乙酸乙酯=5/1)纯化,得到产品(310mg)。
LC-MS,(ES,m/z):[M+H]+=450。
步骤2:(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺三氟乙酸盐
按实施例1步骤8类似方法,由(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氨基甲酰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(300mg),得到粗产品(210mg),直接用于下一步。
LC-MS,(ES,m/z):[M+H]+=350。
步骤3:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氨基甲酰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(197mg),(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺三氟乙酸盐(200mg),得到产品(100mg)。
LC-MS,(ES,m/z):[M+H]+=658。
步骤4:(S)-3-(1-氨基-6-氨基甲酰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-6-氨基甲酰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(100mg),得到产品(35mg)。
LC-MS,(ES,m/z):[M+H]+=554。
步骤5:(S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-6-甲酰胺
按实施例2步骤10类似方法,由(S)-3-(1-氨基-6-氨基甲酰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(13mg),得到产品(2mg)。
LC-MS,(ES,m/z):[M+H]+=512。
1H NMR(400MHz,D6-DMSO)δ=8.37(S,1H),8.20(s,1H),7.87(d,J=10.4Hz,1H),7.76(dd,J=7.8Hz,1.6Hz,1H),7.75(S,1H),7.51-7.47(m,1H),7.46(dd,J=15.2Hz,4.8Hz,1H),7.29(d,J=7.9Hz,1H),5.59-5.31(m,3H),4.54(s,2H),3.78-3.65(m,3H),3.18-3.04(m,3H),2.85(d,J=16.1Hz,1H),2.20(s,3H),2.12-1.88(m,1H),1.61-1.41(m,3H)。
实施例6
(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲酰胺
步骤1:3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲酰胺
将3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(80mg)加入甲醇(2mL)。在氨气气氛下,室温反应过夜。析出白色固体,过滤洗涤得到产品(60mg)。
LC-MS,(ES,m/z):[M+H]+=315。
步骤2:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲酰胺
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯)-5-甲基吡嗪-2-甲酰胺(60mg),(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐(200mg),得到产品(30mg)。
LC-MS,(ES,m/z):[M+H]+=586。
步骤3:(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲酰胺
按实施例1步骤10类似方法,由3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲酰胺(30mg),得到产品(4mg)。
LC-MS,(ES,m/z):[M+H]+=482。
1H NMR(400MHz,D6-DMSO)δ=8.39(s,2H),7.84(s,1H),7.73(dd,J=6.8Hz,2.7Hz,1H),7.49-7.45(m,2H),7.34-7.32(m,1H),7.21-7.16(m,2H),4.00-3.89(m,1H),3.43-3.06(m,5H),2.66(d,J=15.8Hz,1H),2.20(s,3H),1.90-1.67(m,2H),1.52-1.15(m,2H)。
实施例7
(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲腈
步骤1:3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲腈
在0℃,氮气保护下,将3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲酰胺(100mg),吡啶(0.11mL)加入三氯氧磷(1mL)中。升至130℃反应10分钟,除去溶剂得粗产品(100mg),直接用于下一步。
LC-MS,(ES,m/z):[M+H]+=297。
步骤2:(R)-N-((S)-1'-(3-氰基-5-(2,3-二氯苯基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲腈(100mg),(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐(103mg),得到产品(31mg)。
LC-MS,(ES,m/z):[M+H]+=568。
步骤3:(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-甲腈
按实施例1步骤10类似方法,由(R)-N-((S)-1'-(3-氰基-5-(2,3-二氯苯基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(31mg),得到产品(5mg)。
LC-MS,(ES,m/z):[M+H]+=463。
1H NMR(400MHz,D6-DMSO)δ=7.81-7.72(m,3H),7.64(d,J=7.7Hz,1H),7.56-7.44(m,3H),4.67-4.62(m,2H),4.13-4.10(m,1H),3.29-3.17(m,3H),2.69-2.67(m,1H),2.28(s,3H),2.19-2.12(m,2H),1.77-1.47(m,2H)。
实施例8
(S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-7-甲腈
步骤1:1-(叔丁基)4-乙基4-(3-溴苄基)哌啶-1,4-二羧酸酯
按实施例2步骤2类似方法,由1-(叔丁基)4-乙基哌啶-1,4-二羧酸酯(25.7g),1-溴-3-(溴甲基)苯(25.0g)得到粗产品(50.1g),直接用于下一步。
LC-MS,(ES,m/z):[M+H]+=426。
步骤2:4-(3-溴苄基)-1-(叔丁氧羰基)哌啶-4-羧酸
按实施例2步骤3类似方法,由1-(叔丁基)4-乙基4-(3-溴苄基)哌啶-1,4-二羧酸酯(50.1g),得到粗产品(30.5g)。
LC-MS,(ES,m/z):[M-H]-=396。
步骤3:7-溴-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例2步骤4类似方法,由4-(3-溴苄基)-1-(叔丁氧羰基)哌啶-4-羧酸(30g),得到产品(1.1g)。
LC-MS,(ES,m/z):[M+H]+=380。
步骤4:7-氰基-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例2步骤5类似方法,由7-溴-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(1.0g),得到产品(501mg)。
LC-MS,(ES,m/z):[M+H]+=327。
步骤5:(R)-1-((叔丁基亚磺酰基)亚氨基)-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤6类似方法,由7-氰基-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(500mg),得到粗产品(701mg)。
LC-MS,(ES,m/z):[M+H]+=430。
步骤6:(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤7类似方法,由(R)-1-((叔丁基亚磺酰基)亚氨基)-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(700mg),得到产品(520mg)。
LC-MS,(ES,m/z):[M+H]+=432。
步骤7:(R)-N-((S)-4-氰基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-亚磺酰胺三氟乙酸盐
按实施例1步骤8类似方法,由(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(140mg),得到粗产品(107mg)。
LC-MS,(ES,m/z):[M+H]+=332。
步骤8:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(100mg),(R)-N-((S)-4-氰基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-亚磺酰胺三氟乙酸盐(107mg),得到产品(101mg)。
LC-MS,(ES,m/z):[M+H]+=640。
步骤9:(S)-3-(1-氨基-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(100mg),得到产品(61mg)。
LC-MS,(ES,m/z):[M+H]+=536。
步骤10:(S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-7-甲腈
按实施例2步骤10类似方法,由(S)-3-(1-氨基-7-氰基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(25mg),得到产品(6mg)。
LC-MS,(ES,m/z):[M+H]+=494。
1H NMR(400MHz,D6-DMSO)δ=7.74(dd,J=7.9Hz,1.7Hz,1H),7.64-7.54(m,2H),7.51-7.36(m,3H),5.34-5.28(m,1H),4.54-4.50(m,2H),4.1-3.53(m,2H),3.27-2.78(m,4H),2.20(s,3H),2.03-1.92(m,2H),1.74-1.30(m,2H)。
实施例9
N-((S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-5-基)甲磺酰胺
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步骤1:5-溴-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例2步骤4类似方法,由4-(3-溴苄基)-1-(叔丁氧羰基)哌啶-4-羧酸(30g),得到产品(6.1g)。
LC-MS,(ES,m/z):[M+H]+=380。
步骤2:5-(甲磺酰胺基)-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例3步骤1类似方法,由7-溴-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(2.0g),得到粗产品(2.5g)。
LC-MS,(ES,m/z):[M+H]+=395。
步骤3:(R)-1-((叔丁基亚磺酰基)亚氨基)-5-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤6类似方法,由5-(甲磺酰胺基)-1-酮-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(2.5g),得到粗产品(3.0g)。
LC-MS,(ES,m/z):[M+H]+=498。
步骤4:(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-5-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
按实施例1步骤7类似方法,由(R)-1-((叔丁基亚磺酰基)亚氨基)-5-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(3.0g),得到产品(1.1g)。
LC-MS,(ES,m/z):[M+H]+=500。
步骤5:N-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-5-基)甲磺酰胺三氟乙酸盐
按实施例1步骤8类似方法,由(S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-5-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯(175mg),得到粗产品(140mg)。
LC-MS,(ES,m/z):[M+H]+=400。
步骤6:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-7-(甲磺酰基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(100mg),N-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-5-基)甲磺酰胺三氟乙酸盐(140mg),得到产品(31mg)。
LC-MS,(ES,m/z):[M+H]+=708。
步骤7:(S)-3-(1-氨基-5-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-7-(甲磺酰基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(80mg),得到产品(61mg)。
LC-MS,(ES,m/z):[M+H]+=603。
步骤8:N-((S)-1-氨基-1'-(5-(2,3-二氯苯基)-3-(羟甲基)-6-甲基吡嗪-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-5-基)甲磺酰胺
按实施例2步骤10类似方法,由(S)-3-(1-氨基-5-(甲磺酰胺基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)-5-甲基吡嗪-2-羧酸乙酯(57mg),得到产品(11mg)。
LC-MS,(ES,m/z):[M+H]+=562。
1H NMR(400MHz,D6-DMSO)δ=9.62(s,1H),7.74(dd,J=7.8Hz,1.7Hz,1H),7.51-7.42(m,2H),7.27(d,J=7.8Hz,1H),7.06-7.04(m,2H),4.64-4.51(m,3H),3.69-3.65(m,2H),3.36-3.12(m,3H),3.02-2.63(m,5H),2.20(s,3H),1.98–1.75(m,2H),1.58-1.33(m,2H)。
实施例10
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2-氨基-3-氯吡啶-4-基)-5-甲基吡嗪-2-基)甲醇
步骤1:2-(N,N-(二叔丁氧羰基)氨基)-3-氯-5-碘吡啶
将3-氯-4-碘吡啶-2-胺(15.0g),二碳酸二叔丁酯(51.5g),三乙胺(23.8g)加入无水四氢呋喃(500mL)中。反应液回流过夜,然后倾入水(500mL)中。用二氯甲烷(400mL)萃取3次,无水硫酸钠干燥,除去溶剂,经柱层析(石油醚/乙酸乙酯=5/1)纯化得到产品(21.2g)。
LC-MS,(ES,m/z):[M+H]+=455。
步骤2:2-(N,N-(二叔丁氧羰基)氨基)-3-氯吡啶-4-硼酸频那醇酯
将2-(N,N-(二叔丁氧羰基)氨基)-3-氯-5-碘吡啶(9.0g),连硼酸频那醇酯(6.0g),Pd(dppf)Cl2(103mg),无水乙酸钾(3.9g)加入N,N-二甲基乙酰胺(60mL)中。氮气保护下,在100℃下反应3小时。然后将反应液倾入水(200mL)中,用乙酸乙酯(50mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,经柱层析(二氯甲烷/甲醇=50/1)纯化得产品(2.2g)。
LC-MS,(ES,m/z):[M+H]+=372。
步骤3:6-(2-(N,N-二叔丁氧羰基)氨基-3-氯吡啶-4-基)-3-氯-5-甲基吡嗪-2-羧酸乙酯
将2-(N,N-(二叔丁氧羰基)氨基)-3-氯吡啶-4-硼酸频那醇酯(2.0g),6-溴-3-氯-5-甲基吡嗪-2-羧酸乙酯(1.4g),Pd(dppf)Cl2(525mg),碳酸钾(1.9g)加入乙腈(100mL)中。在氮气保护下,升至90℃反应过夜。然后将反应液倾入水(200mL)中,用二氯甲烷(100mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,经柱层析(二氯甲烷/甲醇=50/1)纯化,得到产品(970mg)。
LC-MS,(ES,m/z):[M+H]+=527。
步骤4:6-(2-(N,N-二叔丁氧羰基)氨基-3-氯吡啶-4-基)-3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由6-(2-(N,N-二叔丁氧羰基)氨基-3-氯吡啶-4-基)-3-氯-5-甲基吡嗪-2-羧酸乙酯(200mg),(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐(177mg),得到产品(150mg)。
LC-MS,(ES,m/z):[M+H]+=797。
步骤5:(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2-氨基-3-氯吡啶-4-基)-5-甲基吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由6-(2-(N,N-二叔丁氧羰基)氨基-3-氯吡啶-4-基)-3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基吡嗪-2-羧酸乙酯(150mg),得到产品(50mg)。
LC-MS,(ES,m/z):[M+H]+=493。
步骤6:(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2-氨基-3-氯吡啶-4-基)-5-甲基吡嗪-2-基)甲醇
按实施例2步骤10类似方法,由(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2-氨基-3-氯吡啶-4-基)-5-甲基吡嗪-2-羧酸乙酯(50mg),得到产品(6mg)。
LC-MS,(ES,m/z):[M+H]+=451。
实施例11
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)吡嗪-2-基)甲醇
步骤1:3-氯-6-(2,3-二氯苯基)吡嗪-2-羧酸
室温下,将6-溴-3-氯吡嗪-2-羧酸乙酯(1.0g),2,3-二氯苯硼酸(760g),Pd(dppf)Cl2(290mg),碳酸钠(1.3g)加入1,4-二氧六环(20mL)与水(5mL)的混合液中。在氮气保护下,升至100℃反应4小时。然后将反应液倾入水(200mL)中,用乙酸乙酯(100mL)萃取3次,有机相用饱和食盐水洗涤,用无水硫酸钠干燥,除去溶剂得粗产品。经柱层析纯化得到产品(0.7g)。
LC-MS,(ES,m/z):[M+H]+=303。
步骤2:3-氯-6-(2,3-二氯苯基)吡嗪-2-羧酸甲酯
室温下,将3-氯-6-(2,3-二氯苯基)吡嗪-2-羧酸(0.7g),碳酸钾(0.5g)加入N,N-二甲基甲酰胺(7mL)中,滴加碘甲烷(0.8mL)。保持在室温下反应2小时,然后将反应液倾入水(20mL)中,用乙酸乙酯(20mL)萃取3次,有机相用饱和食盐水洗涤,用无水硫酸钠干燥,除去溶剂得产品(550mg)。
LC-MS,(ES,m/z):[M+Na]+=339。
步骤3:3-((S)-1(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)吡嗪-2-羧酸甲酯
按实施例1步骤9类似方法,由3-氯-6-(2,3-二氯苯基)吡嗪-2-羧酸甲酯(141mg),(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐(206mg),得到产品(252mg)。
LC-MS,(ES,m/z):[M+H]+=587。
步骤4:(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)吡嗪-2-羧酸甲酯
按实施例1步骤10类似方法,由3-((S)-1(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)吡嗪-2-羧酸甲酯(202mg),得到产品(139mg)。
LC-MS,(ES,m/z):[M+H]+=483。
步骤5:(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)吡嗪-2-基)甲醇
按实施例2步骤10类似方法,由(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(2,3-二氯苯基)吡嗪-2-羧酸甲酯(23mg),得到产品(8mg)。
LC-MS,(ES,m/z):[M+H]+=455。
1H NMR(400MHz,CDCl3)δ=8.49(s,1H),7.57-7.49(m,2H),7.40-7.32(m,3H),7.28-7.23(m,2H),4.79(d,J=5.7Hz,2H),4.06(s,1H),3.66-3.56(m,3H),3.26-3.11(m,3H),2.77(d,J=15.8Hz,1H),2.05-1.88(m,1H),1.70-1.45(m,2H)。
实施例12
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-基)甲醇
步骤1:3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2-(三氟甲基)吡啶
将3-溴-2-(三氟甲基)吡啶(500mg),联硼酸频那醇酯(562mg),Pd(dppf)Cl2(113mg),醋酸钾(433mg)加入1,4-二氧六环(5mL)中。在氮气保护下,升至105℃反应2小时。然后冷却至室温,倾入水(10mL)中。用二氯甲烷(20mL)萃取3次,无水硫酸钠干燥,除去溶剂,经柱层析(石油醚/乙酸乙酯=3/1)纯化得到产品(401mg)。
LC-MS,(ES,m/z):[M+H]+=274。
步骤2:3-氯-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-羧酸乙酯
将3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2-(三氟甲基)吡啶(400mg),6-溴-3-氯-5-甲基吡嗪-2-羧酸乙酯(400mg),Pd(dppf)Cl2(240mg),碳酸钾(800mg)加入乙腈(4mL)中。在氮气保护下,回流反应过夜。然后将反应液冷却至室温,倾入水(20mL)中,用二氯甲烷(100mL)萃取3次,有机相用无水硫酸钠干燥,除去溶剂,经柱层析(石油醚/乙酸乙酯=5/1)纯化,得到产品(149mg)。
LC-MS,(ES,m/z):[M+H]+=346。
步骤3:3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-羧酸乙酯
按实施例1步骤9类似方法,由3-氯-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-羧酸乙酯(149mg),(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺三氟乙酸盐(180mg),得到产品(60mg)。
LC-MS,(ES,m/z):[M+H]+=616。
步骤4:(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-羧酸乙酯
按实施例1步骤10类似方法,由3-((S)-1-(((R)-叔丁基亚磺酰基)亚氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-羧酸乙酯(60mg),得到产品(32mg)。
LC-MS,(ES,m/z):[M+H]+=512。
步骤5:(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-基)甲醇
按实施例2步骤10类似方法,由(S)-3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-甲基-6-(2-(三氟甲基)吡啶-3-基)吡嗪-2-羧酸乙酯(30mg),得到产品(4mg)。
LC-MS,(ES,m/z):[M+H]+=470。
1H NMR(400MHz,D6-DMSO)δ=8.86-8.83(m,1H),8.06-8.04(m,1H),7.86-7.83(m,1H),7.71-7.68(m,1H),7.25-7.17(m,3H),5.60-5.45(m,2H),5.24(t,J=5.8Hz,1H),4.51(d,J=5.7Hz,2H),3.77-3.70(m,3H),3.15-3.04(m,3H),2.79(d,J=15.8Hz,1H),2.17(s,3H),2.05-1.96(m,2H),1.57-1.28(m,2H)。
生物活性实验
1.化合物的体外蛋白活性测定:
采用荧光检测方法建立了SHP2的蛋白活性筛选方法。其基本原理是:SHP2作为磷酸酶能催化底物DiFMUP脱磷,生成DiFMU和游离磷酸基团,产物DiFMU在340nm激发光作用下发射荧光,收集450nm发射光。小分子化合物与SHP2结合后若能抑制SHP2酶活性,则检测到的450nm发射光减弱,最终通过荧光值的强弱反映SHP2的酶活性。
具体操作如下:首先将10mM的化合物储存液用DMSO稀释至1mM,之后用DMSO进行3倍梯度稀释。取黑色底透96孔板(costar,3603),每孔加入95μL反应缓冲液(60mM HEPES;75mM NaCl;75mM KCl;1mM EDTA;5mM二硫代苏糖醇(DTT)),1μL梯度稀释的化合物,2μLSHP2(浓度为2μg/μL),1μL多肽(浓度为50mM),将上述测试混合物置于室温避光孵育60分钟,之后每孔加入2μL10mM DiFMUP,继续室温孵育30分钟。置于酶标仪中在Ex340/Em450下进行荧光值测定。通过数据分析软件Prism处理数据并得到该化合物的IC50值。
2.化合物的细胞增殖活性测定:
采用Promega公司的CellTiter-检测试剂建立了细胞增殖抑制筛选方法。
人非小细胞肺癌细胞NCI-H358用含有有10%胎牛血清()的RPMI-1640()培养基进行培养,培养条件是37℃,95%空气和5%的CO2,培养于25cm2或75cm2塑料组织培养瓶(/>)中,一周传代培养2~3次。
将细胞以2×103/孔的密度接种在96-孔细胞培养板()中,90μL/孔,并在37℃,95%空气和5%的CO2中进行培养。24小时后加入待测化合物:将化合物从2mM(溶于DMSO中)开始用DMSO进行3倍梯度稀释,每个浓度取5μL加入到45μL的含有1% DMSO的完全培养基中,最后取10μL培养基稀释后的化合物加入到接种有细胞的培养版中。细胞培养液中DMSO的终浓度为0.1%,所试化合物的终浓度是0.3nM~2μM。将上述细胞37℃温育3天。吸掉培养基,更换为90μL/孔新鲜的完全培养基,按照上述的化合物稀释方法,重新加入待测化合物。
5天后,通过CellTiter-Glu(Promega)试剂盒进行细胞活力测定,最后通过Prism程序计算化合物对细胞增殖的半抑制浓度,即IC50值。
所选的部分化合物的生物学数据
根据本文所述的生物学方法对上述制备的所选化合物进行分析。其结果显示于下表:
蛋白活性数据
化合物编号 | SHP2 IC50(nM) | H358 IC50(nM) |
1 | 9 | 1.5 |
2 | 35 | 11 |
5 | - | 3.2 |
Claims (3)
1.一种SHP2磷酸酶变构抑制剂的光学异构体化合物或其药学上可接受的盐,该抑制剂化合物具有如下式(Ⅱ)所示的结构:
其中,R1为-CH3;R2为-CH2OH;R3选自H、卤素、-CF3、-OCH3、-OCF3、-CN、-C(O)NH2、-NHSO2CH3、C1-6的烷基或CH3SO2-;R4、R5或R6各自独立地选自H、-Cl、-CH3、-CF3、CH3O-、CH3NH-或CH3SO2-。
2.根据权利要求1所述的抑制剂或其药学上可接受的盐,所述的抑制剂包括:
3.权利要求1-2中任一项所述的SHP2抑制剂的光学异构体化合物或其药学上可接受的盐在制备用于治疗肿瘤疾病的药物中的用途。
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