WO2023279938A1 - 2,6,8-多取代咪唑并[1,2-a]吡嗪及其合成方法和应用 - Google Patents

2,6,8-多取代咪唑并[1,2-a]吡嗪及其合成方法和应用 Download PDF

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WO2023279938A1
WO2023279938A1 PCT/CN2022/099407 CN2022099407W WO2023279938A1 WO 2023279938 A1 WO2023279938 A1 WO 2023279938A1 CN 2022099407 W CN2022099407 W CN 2022099407W WO 2023279938 A1 WO2023279938 A1 WO 2023279938A1
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substituted
compound
pharmaceutically acceptable
preparation
cycloalkyl
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王鑫
邓凯元
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无锡市第二人民医院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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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  • the invention belongs to the field of pharmaceutical synthesis and chemical industry, and relates to 2,6,8-multi-substituted imidazo[1,2-a]pyrazine and its synthesis method and application, in particular to a 2,6,8- Multi-substituted imidazo[1,2-a]pyrazine compound and its preparation method and application.
  • Tyrosine kinase 2 (TYK2) is a member of the JAK family of non-receptor protein tyrosine kinases. Death plays an important role.
  • the downstream protein STAT can be recruited by the activated JAK, and then phosphorylated by JAK to form a homologous or heterodimer, enter the nucleus, bind to the promoter of the downstream gene, and regulate the transcription of the downstream gene.
  • the JAK-STAT signaling pathway is closely related to the occurrence and development of tumors, and it is overactivated in many malignant tumors.
  • TYK2 is closely related to many tumors.
  • ACL anaplastic large cell lymphoma
  • TYK2 is highly expressed, and promotes the growth of ALCL cells through the abnormal activation of TYK2-STAT1/3-Bcl2 pathway, and the use of TYK2 inhibitors can promote the apoptosis of ALCL cells.
  • TYK2 was generally overexpressed in malignant peripheral nerve sheath tumors (MPNSTs) patient samples, and cell death was significantly increased by lowering TYK2 in mouse and human MPNST cells, and TYK2-STAT1/3-Bcl2 was also detected in MPNSTs Abnormal activation of pathways.
  • MPNSTs malignant peripheral nerve sheath tumors
  • TYK2(-/-) mice In animal studies, it was found that 4T1 breast cancer cells were injected into TYK2(-/-) mice and TYK2(+/+) mice respectively, and the tumor growth was observed. The tumors in TYK2(-/-) mice grew rapidly and metastasized The ability is obviously stronger than that of TYK2(+/+) mice. Therefore, based on the biological function of TYK2 and the extensive research results in tumors, it can be concluded that TYK2 plays an important regulatory role in the occurrence and development of tumors, and TYK2 is a very potential target for tumor therapy.
  • TYK2 is abnormal in samples of patients with various types of tumors, which is closely related to the occurrence of tumors. Although some reported TYK2 inhibitors have entered the clinical trial stage, there is no TYK2 inhibitor applied to tumor treatment. TYK2 is a potential drug target for anti-tumor therapy, and its targeted inhibitors are very promising for the development of anti-tumor drugs. There is an urgent need to develop TYK2 inhibitors for tumor therapy.
  • the 2,6,8-multi-substituted imidazo[1,2-a]pyrazine compound provided by the present invention is a TYK2 inhibitor, which can be used to treat various tumors, including lymphoma, ovarian cancer, gastric cancer, breast cancer, lung cancer, etc. A variety of malignant tumors.
  • R 1 is selected from Wherein E, Y, A, Q are each independently selected from C, N, O, S, and in ( 1 ) R is selected from hydrogen, amino, methylamino, dimethylamino, hydroxyl, halogen atom, cyano , hydrocarbyl, cycloalkyl, heteroatom cycloalkyl, aryl or heteroaryl ring, substituted aryl or substituted heteroaryl ring, In (2) L is selected from R is selected from hydrogen, aryl or heteroaryl, substituted aryl or substituted heteroaryl;
  • R is selected from cycloalkyl or substituted cycloalkyl, heteroatom cycloalkyl or substituted heteroatom cycloalkyl or When R2 is selected from the structure in ( 3 ), M, X, Z, T are each independently selected from C, N, and R6 is selected from hydrogen, amino, substituted amino, hydroxyl, halogen, cycloalkyl or substituted Cycloalkyl group, heteroatom cycloalkyl group or heteroatom cycloalkyl group containing substituent, cyano group, hydrocarbyl group, aryl group or heteroaryl ring, substituted aryl group or substituted heteroaryl ring;
  • R 3 is selected from hydrogen atom
  • R 1 is selected from Wherein E, Y, A, Q are each independently selected from C, N, in (1) R 4 is selected from amino, cyano, in (2) L is selected from R 5 selected from R 2 is selected from cyclopropane or Wherein M, X, Z, T are each independently selected from C, N, and R is selected from halogen atoms, R 3 is selected from hydrogen atom,
  • R 1 is selected from Wherein E, Y, A, Q are each independently selected from C, N, in (1) R 4 is selected from amino, cyano, in (2) L is selected from R 5 selected from R 2 is selected from cyclopropane or Wherein M, X, Z, T are each independently selected from C, N, and R is selected from fluorine atom, R 3 is selected from hydrogen atom,
  • the present invention also provides a pharmaceutical composition, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or diluents, prepared as Pharmaceutical preparations suitable for clinical use.
  • the pharmaceutical composition is formulated into tablets, capsules or liquid preparations and the like.
  • the compounds of the present invention can be mixed with pharmaceutical carriers or excipients (such as pharmaceutically acceptable carriers and excipients) according to conventional pharmaceutical preparation techniques to form pharmaceutical preparations.
  • the 2,6,8-multi-substituted imidazo[1,2-a]pyrazine compound can be mixed as an active ingredient in any commonly used oral dosage form, and the oral dosage form includes tablets, capsules and liquid preparations (such as elixirs and suspensions), which contain coloring, flavoring, stabilizing and taste-masking substances.
  • the 2,6,8-multi-substituted imidazo[1,2-a]pyrazine compound can be mixed with various common tablet materials (such as starch, calcium carbonate, lactose, sucrose, etc.) and dicalcium phosphate) to facilitate tableting and filling into capsules
  • the 2,6,8-multi-substituted imidazo[1,2-a]pyrazine compound can be used in a pharmaceutically acceptable aseptic liquid carrier
  • a pharmaceutically acceptable aseptic liquid carrier For example, dissolved or suspended in sterile water, sterile organic solvent or a mixture of the two.
  • the liquid carrier can be a carrier suitable for injection, such as physiological saline, propylene glycol or polyethylene glycol aqueous solution.
  • composition may also be prepared by dispersing the micronized active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose or in a suitable oil such as peanut oil.
  • Liquid pharmaceutical preparations meaning sterile solutions or suspensions
  • the pharmaceutical composition may also comprise one or more inorganic or organic, solid or liquid pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable refers to an additive or composition that is physiologically tolerable and generally does not produce allergic or similar adverse reactions (such as dizziness, etc.) when administered to animals such as mammals (such as humans).
  • Pharmaceutical carriers and excipients may include, but are not limited to, diluents such as lactose, dextrose, mannose and/or glycerin; lubricants; polyethylene glycols; binders such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and, if desired, disintegrants such as starch, agar, alginic acid or a salt thereof such as sodium alginate; and/or adsorbents, colorants preservatives, stabilizers, flavoring and sweetening agents.
  • diluents such as lactose, dextrose, mannose and/or glycerin
  • lubricants such as lactose, dextrose, mannose and/or glycerin
  • polyethylene glycols such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvin
  • the present invention also provides the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the application of the pharmaceutical composition in the preparation of a TYK2 inhibitor.
  • the present invention also provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of drugs for preventing and treating tumors or inflammatory diseases.
  • said tumor includes various malignant tumors such as lymphoma, ovarian cancer, gastric cancer, breast cancer, and lung cancer.
  • the compound or its pharmaceutically acceptable salt, or the pharmaceutical composition is used for inhibiting tumor cell proliferation, growth, infiltration and migration, or promoting tumor cell apoptosis.
  • the present invention also provides a preparation method of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof: 2-substituted-6,8-di Bromoimidazo[1,2-a]pyrazine, followed by substitution reaction to obtain 2,6-multi-substituted-8-dibromoimidazo[1,2-a]pyrazine, and finally the target compound 2 through coupling reaction ,6,8-Multisubstituted imidazo[1,2-a]pyrazines:
  • the beneficial effects of the present invention are that the compounds of the present invention are subjected to cell activity assay experiments and TYK2 enzyme activity assays
  • the starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.
  • the invention also relates to novel intermediates and/or starting materials. Particular preference is given to reaction conditions and novel intermediates which are the same or similar to those mentioned in the examples.
  • Both intermediates and final products can be worked up and/or purified according to conventional methods, including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.
  • the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.
  • Step 1.4 Preparation of 6-(3-aminophenyl)-N-(4-morpholinephenyl)imidazo[1,2-a]pyrazin-8-amine (1e)
  • 6-bromo-N-(4-morpholine phenyl)imidazo[1,2-a]pyrazin-8-amine (1mmol), aminoboronate (1.2mmol ), PdCl 2 (dppf) (0.1 mmol), 1M aqueous sodium carbonate solution (1.5 mmol), and heated to 100° C. to react overnight. After the reaction, cool to room temperature, filter through celite, and distill off the organic solvent. Ethyl acetate was added to dissolve, washed with water and saturated brine successively, and the organic phase was dried over anhydrous sodium sulfate. It was separated by column chromatography on silica gel to obtain a pure product with a yield of 54%.
  • Step 1.5 3-cyano-N-(3-(8-((4-morpholinephenyl)amino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide (1 ) preparation
  • 6-bromo-N-(4-morpholine phenyl)imidazo[1,2-a]pyrazin-8-amine (1.5mmol), 5-aminopyridine-3 - boric acid pinacol ester (1.8 mmol), PdCl 2 (dppf) (0.15 mmol), 1M aqueous sodium carbonate solution (3 mmol), heated to 100° C. for overnight reaction. After the reaction, cool to room temperature, filter with diatomaceous earth, remove the organic solvent by rotary evaporation, add ethyl acetate to dissolve, wash with water and saturated brine successively, and dry the organic phase with anhydrous sodium sulfate.
  • Step 4.1 Preparation of 6-bromo-N-cyclopropylimidazol[1,2-a]pyrazin-8-amine (4b)
  • Step 4.2 Preparation of 6-(5-aminopyridin-3-yl)-N-cyclopropylimidazol[1,2-a]pyrazin-8-amine (4c)
  • Step 4.3 N-(5-(8-(cyclopropylamino)imidazol[1,2-a]pyrazin-6-yl)-pyridin-3-yl)-3-fluorobenzamide (4) preparation
  • N-(3-(8-cyclopropylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)-3-(methylthio)benzamide 0.4 mmol was dissolved in dichloromethane, and excess m-chloroperoxybenzoic acid (1.6 mmol) was added with stirring. After the reaction, a saturated solution of sodium sulfite was added to separate the layers, and the organic phase was dried with anhydrous sodium sulfate and separated by column analysis to obtain a white solid with a yield of 65%.
  • 6-bromo-N-(4-((1R,4R)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptane- 2-yl)phenyl)imidazol[1,2-a]pyrazin-8-amine (1.0mmol), 5-aminopyridine-3-boronic acid pinacol ester (1.2mmol), PdCl 2 (dppf) (0.1 mmol), 1M aqueous sodium carbonate solution (2.0 mmol), heated to 100°C for overnight reaction. After the reaction, cool to room temperature, filter through celite, and distill off the organic solvent.
  • Step 11.2 Preparation of ethyl 6-bromo-8-((4-morpholinephenyl)amino)imidazo[1,2-a]pyrazine-2-carboxylate (11c)
  • Step 11.3 Preparation of 6-bromo-N-methyl-8-((4-morpholinephenyl)amino)imidazo[1,2-a]pyrazine-2-carboxamide (11d)
  • Step 11.4 6-(3-Cyanophenyl)-N-methyl-8-((4-morpholinephenyl)amino)imidazo[1,2-a]pyrazine-2-benzamide (11 ) preparation
  • 6-bromo-N-methyl-8-((4-morpholine phenyl)amino)imidazol[1,2-a]pyrazine-2-carboxamide (0.23 mmol)
  • 3-cyanophenylboronic acid pinacol ester (0.27mmol)
  • PdCl 2 (dppf) 0.2mmol
  • 1M aqueous sodium carbonate solution (0.46mmol)
  • heated to 100°C for overnight reaction After the reaction, cool to room temperature, filter through celite, and distill off the organic solvent. Ethyl acetate was added to dissolve, washed with water and saturated brine successively, and the organic phase was dried over anhydrous sodium sulfate.
  • kinase reactions are carried out in a 25 ⁇ L volume of reaction solution containing the following components: 5 ⁇ L compound (in 10% DMSO), 20 ⁇ L in assay buffer (25 mM HEPES, pH 7.5, 0.001% Brij-35, 0.01% Mixture of TYK2, peptide and ATP in Triton, 0.5 mM EGTA).
  • Cells in the logarithmic growth phase were inoculated in a 96-well plate at a density of 3000 cells/100 ⁇ L per well. After the cells adhered to the wall, 100 ⁇ L of different concentrations of the compound to be tested were added, and 6-8 concentration gradients were taken. Five parallel wells were set up for each group, and a control group was set up. After the compound and tumor cells were co-incubated for 72 hours, 10 ⁇ L of CCK-8 solution was added to each well.
  • TOD mean OD value of the administration group
  • COD mean OD value of the solvent control group.

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Abstract

本发明公开了一类如式(I)所述的2,6,8-多取代咪唑并[1,2-a]吡嗪或其药学上可接受的盐。本发明还公开了所述2,6,8-多取代咪唑并[1,2-a]吡嗪或其药学上可接受的盐作为TYK2抑制剂，在制备防治肿瘤或炎症类疾病的药物中的应用。本发明还提供了所述2,6,8-多取代咪唑并[1,2-a]吡嗪或其药学上可接受的盐的合成方法。

Description

2,6,8-多取代咪唑并[1,2-a]吡嗪及其合成方法和应用 技术领域
本发明属于医药合成化工领域，涉及2,6,8-多取代咪唑并[1,2-a]吡嗪及其合成方法和应用，具体涉及一种作为TYK2抑制剂的2,6,8-多取代咪唑并[1,2-a]吡嗪化合物及其制备方法和应用。
背景技术
酪氨酸激酶2(Tyrosine kinase 2,TYK2)是一类非受体蛋白酪氨酸激酶JAK家族中的一员，是多种信号转导通路的交汇点，对正常肿瘤细胞增殖、分化和凋亡都发挥着重要的作用。下游蛋白STAT可被激活了的JAK招募，既而被JAK磷酸化，形成同源或异源二聚体，进入细胞核，与下游基因的启动子结合，调控下游基因的转录。JAK-STAT信号通路与肿瘤的发生发展密切相关，在许多恶性肿瘤中呈现过度激活。
近年来，越来越多的研究表明TYK2与诸多肿瘤关系密切。在间变性大细胞淋巴瘤(ALCL)中，TYK2高表达，并通过TYK2-STAT1/3-Bcl2通路的异常活化促进ALCL细胞的生长，通过使用TYK2抑制剂可促使ALCL细胞凋亡。在恶性外周神经鞘瘤(MPNSTs)病人样本中发现TYK2普遍高表达，通过在鼠和人的MPNST细胞中较低TYK2可显著增加细胞死亡，同时在MPNST中也检测到TYK2-STAT1/3-Bcl2通路的异常活化。在动物体内的研究中发现，分别在TYK2(-/-)鼠和TYK2(+/+)鼠体注射4T1乳腺癌细胞，观察其肿瘤生长情况，TYK2(-/-)鼠肿瘤生长迅速，转移能力明显强于TYK2(+/+)鼠。因此，基于TYK2的生物学功能和在肿瘤中的广泛研究结果，可以断定TYK2在肿瘤的发生发展过程中具有重要的调控作用，TYK2是一个非常有潜力的肿瘤治疗的靶点。
总之，在多种类型肿瘤病人样本中，TYK2的表达水平异常，这与肿瘤的发生密切相关。虽然有报道过的TYK2抑制剂已进入临床试验阶段，但并未有应用于肿瘤治疗的TYK2抑制剂。TYK2作为潜在的抗肿瘤治疗的药物靶标，其靶向抑制剂用于抗肿瘤药物的开发是非常有潜力的，迫切需要开发用于肿瘤治疗的TYK2抑制剂。
发明内容
本发明提供的2,6,8-多取代咪唑并[1,2-a]吡嗪化合物是TYK2抑制剂，可用于治疗多种肿瘤，包括淋巴瘤、卵巢癌、胃癌、乳腺癌、肺癌等多种恶性肿瘤。
本发明所提供的2,6,8-多取代咪唑并[1,2-a]吡嗪及其在药学上可接受的盐，其结构通式如(I)表示：
Figure PCTCN2022099407-appb-000001
其中：
R 1选自
Figure PCTCN2022099407-appb-000002
其中E、Y、A、Q各自独立选自C、N、O、S，在(1)中R 4选自氢基、氨基、甲基氨基、二甲基氨基、羟基、卤原子、氰基、烃基、环烷基、杂原子环烷基、芳基或杂芳环、取代芳基或取代杂芳环、
Figure PCTCN2022099407-appb-000003
Figure PCTCN2022099407-appb-000004
在(2)中L选自
Figure PCTCN2022099407-appb-000005
Figure PCTCN2022099407-appb-000006
Figure PCTCN2022099407-appb-000007
R 5选自氢基、芳基或杂芳环、取代芳基或取代杂芳环；
R 2选自环烷基或含取代基的环烷基、杂原子环烷基或含有取代基的杂原子环烷基或
Figure PCTCN2022099407-appb-000008
当R 2选自(3)中结构时，M、X、Z、T各自独立选自C、N，R 6选自氢基、氨基、取代氨基、羟基、卤原子、环烷基或含取代基的环烷基、杂原子环烷基或含有取代基的杂原子环烷基、氰基、烃基、芳基或杂芳环、取代芳基或取代杂芳环；
R 3选自氢原子、
Figure PCTCN2022099407-appb-000009
Figure PCTCN2022099407-appb-000010
优选地，R 1选自
Figure PCTCN2022099407-appb-000011
其中E、Y、A、Q各自独立选 自C、N，在(1)中R 4选自氨基、氰基，在(2)中L选自
Figure PCTCN2022099407-appb-000012
R 5选自
Figure PCTCN2022099407-appb-000013
Figure PCTCN2022099407-appb-000014
R 2选自环丙烷或
Figure PCTCN2022099407-appb-000015
其中M、X、Z、T各自独立选自C、N，R 6选自卤原子、
Figure PCTCN2022099407-appb-000016
R 3选自氢原子、
Figure PCTCN2022099407-appb-000017
进一步优选地，R 1选自
Figure PCTCN2022099407-appb-000018
其中E、Y、A、Q各自独立选自C、N，在(1)中R 4选自氨基、氰基，在(2)中L选自
Figure PCTCN2022099407-appb-000019
R 5选自
Figure PCTCN2022099407-appb-000020
Figure PCTCN2022099407-appb-000021
R 2选自环丙烷或
Figure PCTCN2022099407-appb-000022
其中M、X、Z、T各自独立选自C、N，R 6选自氟原子、
Figure PCTCN2022099407-appb-000023
R 3选自氢原子、
Figure PCTCN2022099407-appb-000024
本发明还提供了一种药物组合物，所述药物组合物包括式(I)所示的化合物或其药学上可接受的盐与一种或多种药用载体和/或稀释剂，制成适用于临床的药物制剂。其中，所述药物组合物被配制成片剂、胶囊剂或液体制剂等。本发明所述的化合物可以根据常规药物配制技术与药物载体或赋形剂(例如药学上可接受的载体和赋形剂)混合形成药物制剂。可以将所述2,6,8-多取代咪唑并[1,2-a]吡嗪化合物作为活性成分混合在任何常用的口服剂型中，所述口服剂型包括片剂、胶囊剂和液体制剂(例如酏剂和混悬剂)，其中包含 着色剂、矫味剂、稳定剂和掩盖味道的物质。对于混合口服剂型来说，所述2,6,8-多取代咪唑并[1,2-a]吡嗪化合物作为活性成分可以与各种普通片剂材料(例如淀粉、碳酸钙、乳糖、蔗糖和磷酸二钙)混合以助于压片和装入胶囊，可以将所述2,6,8-多取代咪唑并[1,2-a]吡嗪化合物在药学上可接受的无菌液体载体例如无菌水、无菌有机溶剂或者两者的混合物中溶解或混悬。液体载体可以是适合注射剂的载体，比如生理盐水、丙二醇或者聚乙二醇水溶液。在其他情况下，还可以将微粉化的活性成分分散在淀粉或羧甲基纤维素钠的水溶液中或分散在适当的油(例如花生油)中来制得。液体药物制剂(指无菌溶液或混悬剂)可以用于静脉注射、肌肉注射、腹膜内注射或者皮下注射。所述药物组合物还可以包含一种或多种无机或有机、固体或液体的药学上可接受的载体或者赋形剂。术语“药学上可接受的”是指当给药至动物例如哺乳动物(例如人类)时生理学上可耐受且通常不会产生过敏或类似的不良反应(例如头晕等)的添加剂或组合物。药物载体和赋形剂可以包括但不限于稀释剂，例如乳糖、葡萄糖、甘露糖和/或甘油；润滑剂；聚乙二醇；粘合剂，例如硅酸铝镁、淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮；并且，如果需要的话，还包括崩解剂，例如淀粉、琼脂、海藻酸或其盐如海藻酸钠；和/或吸附剂、着色剂、防腐剂、稳定剂、矫味剂和甜味剂。
本发明还提供了式(I)所示的化合物或其药学上可接受的盐、或所述的药物组合物在制备TYK2抑制剂中的应用。
本发明还提供了式(I)所示的化合物或其药学上可接受的盐、或所述的药物组合物在制备防治肿瘤或炎症类疾病的药物中的应用。其中所述肿瘤包括淋巴瘤、卵巢癌、胃癌、乳腺癌、肺癌等多种恶性肿瘤。
所述的化合物或其药学上可接受的盐、或所述的药物组合物用于抑制肿瘤细胞的增殖、生长、浸润和迁移，或促进肿瘤细胞的凋亡。
本发明还提供了式(I)所示的化合物或其药学上可接受的盐的制备方法：通过2-氨基-3,5-二溴吡嗪关环得到2-取代-6,8-二溴咪唑并[1,2-a]吡嗪，然后发生取代反应得到2，6-多取代-8-二溴咪唑并[1,2-a]吡嗪，最后经过偶练反应得到目标化合物2,6,8-多取代咪唑并[1,2-a]吡嗪：
Figure PCTCN2022099407-appb-000025
本发明的有益效果是，将本发明所述化合物进行细胞活性测定实验和TYK2酶活性测定
实验，实验结果表明本发明化合物对于防治癌症或炎症类相关疾病有良好的应用。
具体实施方式
下面对本发明的较佳实施例进行详细阐述，以使本发明的优点和特征能更易于被本领域技术人员理解，从而对本发明的保护范围做出更为清楚明确的界定。
下面对本发明的各个方面和特点作进一步的描述。
本文所用的缩略语通常为本领域技术人员所熟知的，或者可以是根据基础知识易于理解的。
在本发明化合物的制备中所采用的起始原料是已知的、能够根据已知方法制备的或者可商购获得的。
本发明还涉及新的中间体和/或起始原料。特别优选与实施例中提到的那些相同或者相似的反应条件和新中间体。
中间体和终产物都可以根据常规方法进行后处理和/或纯化，所述常规方法包括调节pH、萃取、过滤、干燥、浓缩、色谱法、研磨、结晶等。
另外，本发明化合物还可以通过本领域已知的各种方法或者本文所述方法的变通方法进行制备。
下列实施例仅用于举例说明本发明，不以任何方式对本发明进行限制。
实施例1
3-氰基-N-(3-(8-((4-吗啡啉苯基)氨基)咪唑并[1,2-a]吡嗪-6-基)苯基)苯甲酰胺的制备
Figure PCTCN2022099407-appb-000026
步骤1.1：4-(4-硝基苯基)吗啡啉(1b)的制备
Figure PCTCN2022099407-appb-000027
在100mL单口瓶中对氟硝基苯(35.44mmol)和过量的吗啡啉(205mmol)在80℃下搅拌5小时。反应完毕，将反应混合物缓慢倒入至1000mL冰水中，有黄色固体析出，过滤，烘干，得到黄色粉末状固体，收率99％。 1H NMR(400MHz,CDCl 3)δ8.14(d,J＝9.4Hz,2H),6.84(d,J＝9.4Hz,2H),3.90–3.83(m,4H),3.37(dd,J＝5.9,4.0Hz,4H). 13C NMR(101MHz,CDCl 3)δ155.0,138.9,125.9,112.6,66.4,47.1.
步骤1.2：4-吗啡啉苯胺(1c)的制备
Figure PCTCN2022099407-appb-000028
在氩气保护下，在两口瓶中将4-(4-硝基苯基)吗啡啉(19mmol)溶解于60mL乙醇，依次加入10％钯碳和水合肼，加热到75℃反应8小时。反应结束后，用硅藻土过滤，减压蒸除有机溶剂，柱层析分离得到目标化合物，收率95％。 1H NMR(400MHz,DMSO-d 6)δ6.68(d,J＝8.8Hz,2H),6.51(d,J＝8.8Hz,2H),4.58(s,2H),3.73–3.65(m,4H),2.88–2.85(m,4H)； 13C NMR(101MHz,DMSO-d 6)δ142.8,142.8,118.0,115.2,66.8,51.1.
步骤1.3：6-溴-N-(4-吗啡啉苯基)咪唑[1,2-a]吡嗪-8-胺(1d)的制备
Figure PCTCN2022099407-appb-000029
将4-吗啡啉苯胺(5.6mmol)溶解于60mL异丙醇溶液，依次加入DIPEA(8.4mmol)和6,8-二溴-咪唑[1,2-a]吡嗪(6.72mmol)，加热到85℃反应8小时。反应结束后，冷却至室温，减压除去有机溶剂，残余物加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤一次，有机相用无水硫酸钠干燥，过滤，用柱层析硅胶分离得到白色固体，收率85％。 1H NMR(400MHz,DMSO-d 6)δ9.81(s,1H),8.18(d,J＝5.7Hz,1H),7.91(d,J＝3.1Hz,1H),7.80(d,J＝9.3Hz,2H),7.60(d,J＝2.4Hz,1H),6.92(d,J＝8.3Hz,2H),3.73(d,J＝3.1Hz,4H),3.06(dt,J ＝8.3,4.6Hz,4H)； 13C NMR(101MHz,DMSO-d 6)δ147.58,144.9,132.9,132.1,131.8,122.0,121.3,116.7,115.7,111.2,66.6,49.4.
步骤1.4：6-(3-氨基苯基)-N-(4-吗啡啉苯基)咪唑[1,2-a]吡嗪-8-胺(1e)的制备
Figure PCTCN2022099407-appb-000030
在氩气流下，向两口瓶中依次加入6-溴-N-(4-吗啡啉苯基)咪唑[1,2-a]吡嗪-8-胺(1mmol)、氨基硼酸酯(1.2mmol)、PdCl 2(dppf)(0.1mmol)、1M碳酸钠水溶液(1.5mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，蒸除有机溶剂。加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率54％。 1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),8.39(s,1H),8.05(d,J＝8.6Hz,2H),7.98(s,1H),7.61(s,1H),7.22(d,J＝2.2Hz,1H),7.12(d,J＝4.7Hz,2H),6.99(d,J＝8.6Hz,2H),6.59(dt,J＝6.1,2.7Hz,1H),5.42–5.13(m,2H),3.76–3.72(m,4H),3.07(t,J＝4.7Hz,4H)； 13C NMR(101MHz,DMSO-d 6)δ149.4,146.8,145.1,138.4,137.6,133.2,132.6,132.6,129.6,121.2,116.7,116.0,114.3,113.8,111.9,108.3,66.6,49.6.
步骤1.5：3-氰基-N-(3-(8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-6-基)苯基)苯甲酰胺(1)的制备
Figure PCTCN2022099407-appb-000031
常温下，向单口瓶中依次加入化合物6-(3-氨基苯基)-N-(4-吗啡啉苯基)咪唑[1,2-a]吡嗪-8-胺(0.5mmol)、3-氰基苯甲酸(0.7mmol)、以及EDCI(0.9mmol)、HOBt(0.9mmol)、DIEA(1.2mmol)，搅拌过夜。TLC监测反应结束后，用乙酸乙酯稀释反应液，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品收率53％。 1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),9.58(s,1H),8.70(s,1H),8.56(s,1H),8.49(s,1H),8.34(d,J＝8.0Hz,1H),8.10(dd,J＝8.3,5.8Hz,3H),8.03(s,1H),7.81–7.72(m,2H), 7.67(d,J＝9.9Hz,2H),7.48(t,J＝7.9Hz,1H),7.03(d,J＝8.6Hz,2H),3.74(t,J＝4.6Hz,4H),3.07(t,J＝4.8Hz,4H). 13C NMR(101MHz,DMSO-d 6)δ164.04,146.79,145.13,139.69,138.12,136.70,136.31,135.51,133.08,132.96,132.43,131.88,130.31,129.45,121.52,121.48,120.55,118.83,118.73,117.02,116.07,112.04,66.60,49.62.
实施例2
6-(5-氨基吡啶-3-基)-N-(4-吗啡啉苯基)咪唑[1,2-a]吡嗪-8-胺(2)的制备
Figure PCTCN2022099407-appb-000032
在氩气流下，向两口瓶中依次加入6-溴-N-(4-吗啡啉苯基)咪唑[1,2-a]吡嗪-8-胺(1.5mmol)、5-氨基吡啶-3-硼酸频哪醇酯(1.8mmol)、PdCl 2(dppf)(0.15mmol)、1M碳酸钠水溶液(3mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，旋蒸除去有机溶剂，加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率73％。 1H NMR(400MHz,DMSO-d 6)δ9.51(s,1H),8.51(s,1H),8.35(s,1H),8.07–7.91(m,4H),7.63(s,1H),7.48(t,J＝2.3Hz,1H),6.99(d,J＝8.5Hz,2H),5.51(s,2H),3.75(t,J＝4.8Hz,4H),3.08(t,J＝4.8Hz,4H).； 13C NMR(101MHz,DMSO-d 6)δ146.51,145.00,135.80,134.65,134.45,133.85,132.97,132.46,132.25,132.14,120.97,116.79,116.44,115.48,108.41,66.17,49.11.
实施例3
N-(5-(8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-6-基)-吡啶-3-基)-3-(三氟甲基)苯甲酰胺(3)的制备
Figure PCTCN2022099407-appb-000033
常温下，向单口瓶中依次加入化合物6-(3-氨基苯基)-N-(4-吗啡啉苯基)咪唑[1,2-a]吡嗪-8-胺(0.26mmol)、3-三氟甲基苯甲酸(0.28mmol)、EDCI(0.39mmol)、HOBt(0.39mmol)和DIEA(0.52mmol)，常温搅拌过夜。TLC监测反应结束后，用乙酸乙酯稀释反应液，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率66％。 1H NMR(400MHz,DMSO-d 6)δ10.83(s,1H),9.64(s,1H),9.04(s,1H),8.95(s,1H),8.85(d,J＝2.4Hz,1H),8.71(s,1H),8.44–8.32(m,2H),8.11–7.99(m,4H),7.83(t,J＝7.8Hz,1H),7.66(s,1H),7.02(d,J＝8.6Hz,2H),3.77–3.69(m,4H),3.11–3.02(m,4H). 13C NMR(101MHz,DMSO-d 6)δ164.48,146.58,145.12,141.87,141.08,135.71,135.23,133.55,132.88,132.47,132.41,132.21,131.93,129.89,125.37,124.59,124.46,124.42,121.29,116.71,115.52,108.97,66.17,49.56,49.08.
实施例4
N-(5-(8-(环丙基氨基)咪唑[1,2-a]吡嗪-6-基)-吡啶-3-基)-3-氟苯甲酰胺(4)的制备
Figure PCTCN2022099407-appb-000034
Figure PCTCN2022099407-appb-000035
步骤4.1：6-溴-N-环丙基咪唑[1,2-a]吡嗪-8-胺(4b)的制备
Figure PCTCN2022099407-appb-000036
在100mL两口瓶中加入6,8-二溴-咪唑[1,2-a]吡嗪(9.1mmol)溶解于20mL异丙醇中，依次加入环丙氨(13.6mmol)和DIPEA(13.6mmol)，加热至80℃，反应3小时。反应结束后，冷却至室温，减压除去有机溶剂，残余物加入乙酸乙酯溶解后有黄色固体析出，过滤，得纯品，收率92％。 1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝4.3Hz,1H),8.04(s,1H),7.83(s,1H),7.49(s,1H),2.91(tt,J＝8.1,3.8Hz,1H),0.75–0.63(m,4H). 13C NMR(101MHz,DMSO-d 6)δ148.47,132.03,131.47,122.16,115.81,109.40,23.85,6.16.
步骤4.2：6-(5-氨基吡啶-3-基)-N-环丙基咪唑[1,2-a]吡嗪-8-胺(4c)的制备
Figure PCTCN2022099407-appb-000037
在氩气流下，向两口瓶中依次加入6-溴-N-环丙基咪唑[1,2-a]吡嗪-8-胺(2.1mmol)、5-氨基吡啶-3-硼酸频哪醇酯(2.5mmol)、PdCl 2(dppf)(0.2mmol)、1M碳酸钠水溶液(4.2mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，蒸除有机溶剂。加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率81％。 1H NMR(400MHz,DMSO-d 6)δ8.37(s,2H),8.03–7.84(m,2H),7.75(d,J＝4.2Hz,1H),7.56–7.49(m,2H),5.41(s,2H),3.07(tq,J＝7.7,4.0Hz,1H),0.77(dh,J＝8.1,3.9Hz,2H),0.69(hept,J＝4.1Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ148.72,135.72,135.03,134.62,131.87,116.99,115.87,113.79,111.51,109.58,107.07,23.68,6.23.
步骤4.3：N-(5-(8-(环丙基氨基)咪唑[1,2-a]吡嗪-6-基)-吡啶-3-基)-3-氟苯甲酰胺(4) 的制备
Figure PCTCN2022099407-appb-000038
常温下，向单口瓶中依次加入化合物6-(5-氨基吡啶-3-基)-N-环丙基咪唑[1,2-a]吡嗪-8-胺(0.4mmol)、3-氟苯甲酸(0.4mmol)、以及EDCI(0.6mmol)、HOBt(0.6mmol)、DIPEA(0.6mmol)，常温下搅拌过夜。TLC监测反应结束后，用乙酸乙酯稀释反应液，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率28％。 1H NMR(400MHz,DMSO-d 6)δ10.63(s,1H),8.96(d,J＝2.0Hz,1H),8.91(d,J＝2.4Hz,1H),8.83(t,J＝2.3Hz,1H),8.53(s,1H),7.94(s,1H),7.85(dd,J＝16.8,7.9Hz,3H),7.63(td,J＝8.0,5.8Hz,1H),7.54(s,1H),7.49(td,J＝8.6,2.7Hz,1H),3.11(tq,J＝7.6,4.0Hz,1H),0.80(dt,J＝6.7,3.2Hz,2H),0.72(q,J＝4.1Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ164.68,163.16,160.73,148.88,142.14,141.21,135.55,134.05,133.09,132.10,132.08,130.76,130.68,124.47,124.05,124.02,118.71,116.14,114.75,114.53,107.69,23.73,6.26.
实施例5
N-(3-(8-环丙基氨基)咪唑[1,2-a]吡嗪-6-基)苯基)-1H-1,2,4-三氮唑-3-甲酰胺(5)的制备
Figure PCTCN2022099407-appb-000039
步骤5.1 6-(3-氨基苯基)-N-环丙基咪唑[1,2-a]吡嗪-8-胺(5a)的制备
Figure PCTCN2022099407-appb-000040
在氩气保护下，向两口瓶中依次加入6-溴-N-环丙基咪唑[1,2-a]吡嗪-8-胺(4.0mmol)、3-氨基苯硼酸频哪醇酯(4.8mmol)、PdCl 2(dppf)(0.4mmol)、1M碳酸钠水溶液(8.0mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，蒸除有机溶剂。加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率69％。 1H NMR(400MHz,DMSO-d 6)δ8.24(s,1H),7.88(s,1H),7.64(d,J＝4.2Hz,1H),7.49(s,1H),7.26(t,J＝1.9Hz,1H),7.09(dt,J＝15.3,7.7Hz,2H),6.56(dt,J＝7.8,1.6Hz,1H),5.12(s,2H),3.08(tq,J＝7.7,4.0Hz,1H),0.77(td,J＝7.1,4.6Hz,2H),0.68(q,J＝4.0Hz,2H). 13C NMR(101MHz,DMSO)δ148.71,148.39,138.04,137.42,132.03,131.71,128.88,115.69,113.66,113.43,111.54,106.46,23.68,6.24.
步骤5.2 N-(3-(8-环丙基氨基)咪唑[1,2-a]吡嗪-6-基)苯基)-1H-1,2,4-三氮唑-3-甲酰胺(5)的制备
Figure PCTCN2022099407-appb-000041
常温下，向单口瓶中依次加入化合物6-(3-氨基苯基)-N-环丙基咪唑[1,2-a]吡嗪-8-胺(0.4mmol)、1H-1,2,4-三氮唑-3-羧酸(0.5mmol)、EDCI(0.7mmol)、HOBt(0.7mmol)、DIPEA(1.02mmol)，常温下搅拌过夜。TLC监测反应结束后，用乙酸乙酯稀释反应液，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率35％。 1H NMR(400MHz,DMSO-d 6)δ14.81(s,1H),10.56(s,1H),8.59(d,J＝34.5Hz,2H),8.38(s,1H),7.93(s,1H),7.82–7.72(m,3H),7.52(s,1H),7.43(t,J＝7.9Hz,1H),3.13(tq,J＝7.9,4.1Hz,1H),0.80(dq,J＝6.9,4.3Hz,2H),0.70(p,J＝4.4Hz,2H). 13C NMR(101MHz,DMSO)δ148.57,146.87,138.48,138.01,136.56,132.05,131.91,131.43,128.75,121.44,120.21,118.18,115.94,112.74,106.98,23.71,6.26.
实施例6
N-(3-(8-环丙基氨基)咪唑[1,2-a]吡嗪-6-基)苯基)-3-(甲硫基)苯甲酰胺(6)的制备
Figure PCTCN2022099407-appb-000042
Figure PCTCN2022099407-appb-000043
常温下，向单口瓶中依次加入化合物6-(3-氨基苯基)-N-环丙基咪唑[1,2-a]吡嗪-8-胺(0.6mmol)、3-(甲硫基)苯甲酸(0.9mmol)、EDCI(1.2mmol)、HOBt(1.2mmol)和DIPEA(1.6mmol)，常温下搅拌过夜。TLC监测反应结束后，用乙酸乙酯稀释反应液，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率72％。 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),8.49–8.42(m,1H),8.38(s,1H),7.97–7.91(m,1H),7.84(s,1H),7.76(q,J＝5.7,3.9Hz,4H),7.54–7.42(m,4H),3.13(tt,J＝7.5,3.7Hz,1H),2.56(s,3H),0.80(dh,J＝7.8,3.5Hz,2H),0.71(q,J＝3.9Hz,2H). 13C NMR(101MHz,DMSO)δ165.18,148.59,139.28,138.74,137.97,136.63,135.67,132.06,131.89,128.99,128.72,124.71,124.19,121.24,120.23,120.19,118.08,115.95,106.93,23.73,14.62,6.28.
实施例7
N-(3-(8-环丙基氨基)咪唑[1,2-a]吡嗪-6-基)苯基)-3-(甲硫基)苯甲酰胺(7)的制备
Figure PCTCN2022099407-appb-000044
在0℃下，将N-(3-(8-环丙基氨基)咪唑[1,2-a]吡嗪-6-基)苯基)-3-(甲硫基)苯甲酰胺(0.4mmol)溶于二氯甲烷，搅拌下加入过量间氯过氧苯甲酸(1.6mmol)。反应结束后，加入亚硫酸钠饱和溶液，分液，有机相用无水硫酸钠干燥，柱分析分离，得白色固体，收率65％。 1H NMR(400MHz,DMSO-d 6)δ10.64(s,1H),8.51(t,J＝1.8Hz,1H),8.45(t,J＝2.0Hz, 1H),8.39(s,1H),8.33(dt,J＝7.8,1.4Hz,1H),8.15(dt,J＝7.7,1.4Hz,1H),7.94(d,J＝1.1Hz,1H),7.85(t,J＝7.8Hz,1H),7.80–7.74(m,3H),7.52(d,J＝1.1Hz,1H),7.46(t,J＝7.9Hz,1H),3.13(tt,J＝7.2,3.9Hz,1H),0.80(td,J＝7.1,4.7Hz,2H),0.73–0.67(m,2H). 13C NMR(101MHz,DMSO)δ164.09,148.61,141.13,139.01,138.07,136.53,135.99,132.75,132.06,131.93,129.86,129.83,128.85,126.20,121.48,120.35,118.23,115.99,107.00,43.50,23.74,6.29.
实施例8
6-(5-氨基吡啶-3-基)-N-(4-((1R,4R)-5-异丙基-2,5-二氮杂二环[2.2.1]庚烷-2-基)苯基)咪唑[1,2-a]吡嗪-8-胺(8)的制备
Figure PCTCN2022099407-appb-000045
在氩气流下，向两口瓶中依次加入6-溴-N-(4-((1R,4R)-5-异丙基-2,5-二氮杂二环[2.2.1]庚烷-2-基)苯基)咪唑[1,2-a]吡嗪-8-胺(1.0mmol)、5-氨基吡啶-3-硼酸频哪醇酯(1.2mmol)、PdCl 2(dppf)(0.1mmol)、1M碳酸钠水溶液(2.0mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，蒸除有机溶剂。加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率30％。 1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.47(s,1H),8.34(s,1H),7.98–7.92(m,4H),7.62(s,1H),7.45(d,J＝2.7Hz,1H),6.68(d,J＝8.5Hz,2H),5.48(s,2H),4.40(s,1H),3.21(s,5H),2.89–2.59(m,2H),1.97(s,1H),1.12–1.01(m,6H). 13C NMR(101MHz,DMSO)δ145.05,144.73,142.50,142.32,135.96,134.81,134.68,133.01,132.21,132.17,121.61,116.71,116.45,112.85,108.16,59.81,58.55,57.98,56.40,55.02,20.82,14.13.
实施例9
6-(3-氨基苯基)-N-(5-氟嘧啶-2-基)咪唑[1,2-a]吡嗪-8-胺(9)的制备
Figure PCTCN2022099407-appb-000046
步骤9.1 6-溴-N-(5-氟嘧啶-2-基)咪唑[1,2-a]吡嗪-8-胺(9b)的制备
Figure PCTCN2022099407-appb-000047
在氩气流下，向两口瓶中依次加入6,8-二溴-咪唑[1,2-a]吡嗪(3.6mmol)、2-氨基-5-氟-吡啶(5.4mmol)、Pd 2(dba) 3(0.36mmol)、Xantphos(0.72mmol)和碳酸铯(7.2mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，蒸除有机溶剂。加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率45％。 1H NMR(400MHz,DMSO-d 6)δ9.33(s,1H),8.41(s,1H),8.38(d,J＝3.1Hz,1H),8.33(dd,J＝9.2,4.1Hz,1H),8.01(d,J＝1.1Hz,1H),7.87(td,J＝8.7,3.1Hz,1H),7.68(d,J＝1.1Hz,1H). 13C NMR(101MHz,DMSO)δ147.95,143.08,135.76,135.51,133.42,131.35,125.58,125.38,119.71,116.84,114.32,113.32.
步骤9.2 6-(3-氨基苯基)-N-(5-氟嘧啶-2-基)咪唑[1,2-a]吡嗪-8-胺(9)的制备
Figure PCTCN2022099407-appb-000048
在氩气流下，向两口瓶中依次加入6-溴-N-(5-氟嘧啶-2-基)咪唑[1,2-a]吡嗪-8-胺(2.0mmol)、3-氨基苯硼酸频哪醇酯(2.4mmol)、PdCl 2(dppf)(0.2mmol)、1M碳酸钠水溶液(4.0mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，蒸除有机溶剂。加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率45％。 1H NMR(400MHz,DMSO-d 6)δ8.96(s,1H),8.74(dd,J＝9.2,4.0Hz,1H),8.58(s,1H),8.37(d,J＝3.1Hz,1H),8.06(d,J＝1.1Hz,1H),7.89(td,J＝8.7,3.1Hz,1H),7.68(d,J＝1.1Hz,1H),7.24(t,J＝1.9Hz,1H),7.16–7.09(m,2H),6.61(dt,J＝7.5,1.9Hz,1H),5.27(s,2H). 13C NMR(101MHz,DMSO)δ156.42,153.97,149.05,148.66,143.08,137.27,136.70,135.63,135.38,133.07,131.69,129.31,125.61,125.42,116.85,113.97,113.74,113.70,113.21,111.42,109.89.
实施例10
3-氰基-N-(3-(8-((5-氟嘧啶-2-基)氨基)咪唑[1,2-a]吡嗪-6-基)苯基)苯甲酰胺的制备
Figure PCTCN2022099407-appb-000049
常温下，向单口瓶中依次加入化合物6-(3-氨基苯基)-N-(5-氟嘧啶-2-基)咪唑[1,2-a]吡嗪-8-胺(0.5mmol)、3-氰基苯甲酸(0.7mmol)、以及EDCI(0.9mmol)、HOBt(0.9mmol)、DIPEA(1.2mmol)，常温下搅拌过夜。TLC监测反应结束后，用乙酸乙酯稀释反应液，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率77％。 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),8.96(s,1H),8.86(dd,J＝9.2,4.1Hz,1H),8.73(s,1H),8.68(s,1H),8.47(s,1H),8.33(dd,J＝9.5,5.4Hz,2H),8.08(d,J＝ 8.9Hz,2H),7.83(ddd,J＝21.8,10.9,5.5Hz,2H),7.67(td,J＝11.3,9.2,4.8Hz,3H),7.46(t,J＝7.9Hz,1H). 13C NMR(101MHz,DMSO)δ163.78,156.46,154.01,148.55,143.15,139.40,137.13,135.96,135.70,135.56,135.31,135.02,133.14,132.58,131.70,131.35,129.87,129.05,125.54,125.35,120.91,119.96,118.39,117.84,117.04,114.08,111.55,110.31.
实施例11
6-(3-氰基苯基)-N-甲基-8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-2-苯甲酰胺(11)的制备
Figure PCTCN2022099407-appb-000050
步骤11.1 6,8-二溴咪唑[1,2-a]吡嗪-2-羧酸乙酯(11b)的制备
Figure PCTCN2022099407-appb-000051
在100mL单口瓶中，将2-氨基-3,5-二溴吡嗪(20mmol)和3-溴丙酮酸乙酯(24mmol)溶于40mL乙二醇二甲醚，在100℃下搅拌过夜。反应完毕，将反应混合物中加入乙醚，过滤，烘干，得棕色固体，收率47％。 1H NMR(400MHz,CDCl 3)δ8.31(dd,J＝7.2,1.7Hz,2H),4.48(qd,J＝7.1,1.6Hz,2H),1.43(td,J＝7.1,1.7Hz,3H). 13C NMR(101MHz,CDCl 3)δ161.81,139.73,138.31,135.93,121.68,119.55,119.32,62.14,14.46.
步骤11.2：6-溴-8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-2-羧酸乙酯(11c)的制备
Figure PCTCN2022099407-appb-000052
将4-吗啡啉苯胺(7.2mmol)溶解于30mL乙腈溶液，依次加入DIPEA(16.2mmol)和6,8-二溴咪唑[1,2-a]吡嗪-2-羧酸乙酯(6.0mmol)，加热到85℃反应过夜。反应结束后，冷却至室温，减压除去有机溶剂，残余物加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤一次，有机相用无水硫酸钠干燥，过滤，用柱层析硅胶分离得到黄色固体，收率39％。 1H NMR(400MHz,CDCl 3)δ8.13(s,1H),8.00(s,1H),7.70(d,J＝8.6Hz,2H),7.60(s,1H),6.92(d,J＝8.5Hz,2H),4.44(q,J＝7.1Hz,2H),3.85(t,J＝4.5Hz,5H),3.12(t,J＝4.6Hz,4H),1.41(d,J＝14.1Hz,3H). 13C NMR(101MHz,CDCl 3)δ162.31,148.02,144.66,136.04,132.43,130.76,123.83,121.06,118.96,116.32,110.01,66.94,61.57,49.68,14.47.
步骤11.3：6-溴-N-甲基-8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-2-甲酰胺(11d)的制备
Figure PCTCN2022099407-appb-000053
将6-溴-8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-2-羧酸乙酯(2.35mmol)溶解于10mL四氢呋喃溶液中，加入12mL 30％的甲胺水溶液，于室温下搅拌过夜。反应结束后，过滤，得到淡黄色固体，收率85％。 1H NMR(400MHz,CDCl 3)δ8.01(s,1H),7.79(s,1H),7.74(d,J＝8.5Hz,2H),7.67(s,1H),7.23(d,J＝5.6Hz,1H),7.00(s,2H),3.90(s,4H),3.17(t,J＝4.8Hz,4H),3.05(d,J＝5.0Hz,3H). 13C NMR(101MHz,CDCl3)δ162.84,149.54,144.59,137.06,133.61,130.59,123.82,121.06,119.08,116.31,110.76,77.48,77.16,76.84,66.92,61.67,26.07.
步骤11.4：6-(3-氰基苯基)-N-甲基-8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-2-苯甲酰胺(11)的制备
Figure PCTCN2022099407-appb-000054
在氩气流下，向两口瓶中依次加入6-溴-N-甲基-8-((4-吗啡啉苯基)氨基)咪唑[1,2-a]吡嗪-2-甲酰胺(0.23mmol)、3-氰基苯硼酸频哪醇酯(0.27mmol)、PdCl 2(dppf)(0.02mmol)、1M碳酸钠水溶液(0.46mmol)，加热至100℃反应过夜。反应结束后，冷却至室温，硅藻土过滤，蒸除有机溶剂。加入乙酸乙酯溶解，依次用水洗、饱和食盐水洗涤，有机相用无水硫酸钠干燥。用柱层析硅胶分离，得到纯品，收率42％。 1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.72(s,1H),8.35(d,J＝1.8Hz,1H),8.32–8.28(m,2H),8.14(q,J＝4.8Hz,1H),7.92–7.88(m,2H),7.85(dt,J＝7.7,1.4Hz,1H),7.71(t,J＝7.8Hz,1H),7.02–6.97(m,2H),3.77–3.73(m,4H),3.12–3.07(m,4H),2.86(d,J＝4.8Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ161.85,147.01,145.19,139.32,138.14,135.12,131.70,131.62,131.55,130.22,130.13,128.96,121.36,118.83,117.14,115.38,111.88,109.47,66.17,48.95,25.60.
实施例12
生物学测定
TYK2酶活性测定
384-孔微孔板TR-FRET(时间分辨-荧光能量转移)终点测定用于TYK2激酶活性测定。相同的测定用于小分子抑制剂的IC 50测定。一般地，激酶反应是在25μL体积包含如下成分的反应溶液中进行的：5μL化合物(在10％的DMSO中)、20μL在测定缓冲液(25mM HEPES，pH 7.5，0.001％Brij-35,0.01％Triton,0.5mM EGTA)中的TYK2、多肽和ATP的混合物。所有反应在室温下在384孔白色平底光密度板(Perkin Elmer)中进行60min，然后加入25μL终止反应液(100mM HEPES，pH 7.5，0.015％Brij-35,0.2％Coating Reagent#3,50mM EDTA)。在Evision Multilabel读数器(Perkin Elmer，Envision 2102-0010)上读数。
表1
实施例编号 Inhibition against TYK2 at 1μM(％)
1 76％(IC 50＝0.2μM)
2 55％
3 3％
4 10％
5 8％
6 6％
7 3％
细胞活性测定
取对数生长期细胞按每孔3000个细胞/100μL密度接种于96孔板，待细胞贴壁后，加入100μL不同浓度的待测化合物，取6-8个浓度梯度。每组设五个平行孔，设置对照组。化合物和肿瘤细胞共孵育72小时后，每孔加10μL CCK-8溶液。在细胞培养箱中孵育1-2小时后，用酶联免疫检测仪测定每孔吸光度(OD值)，计算抑制率：抑制率(IR％)＝(1-TOD/COD)x 100％，TOD：给药组OD均值；COD：溶剂对照组OD均值。
表2
Figure PCTCN2022099407-appb-000055
以上实施方式只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人了解本发明的内容并加以实施，并不能以此限制本发明的保护范围，凡根据本发明精神实质所做的等效变化或修饰，都应涵盖在本发明的保护范围内。

Claims (9)

  1. 一种由通式(I)表示的化合物或其药学上可接受的盐：
    Figure PCTCN2022099407-appb-100001
    其中：
    R 1选自
    Figure PCTCN2022099407-appb-100002
    其中E、Y、A、Q各自独立选自C、N、O、S，在(1)中R 4选自氢基、氨基、甲基氨基、二甲基氨基、羟基、卤原子、氰基、烃基、环烷基、杂原子环烷基、芳基或杂芳环、取代芳基或取代杂芳环、
    Figure PCTCN2022099407-appb-100003
    Figure PCTCN2022099407-appb-100004
    在(2)中L选自
    Figure PCTCN2022099407-appb-100005
    Figure PCTCN2022099407-appb-100006
    Figure PCTCN2022099407-appb-100007
    R 5选自氢基、芳基或杂芳环、取代芳基或取代杂芳环；
    R 2选自环烷基或含取代基的环烷基、杂原子环烷基或含有取代基的杂原子环烷基或
    Figure PCTCN2022099407-appb-100008
    当R 2选自(3)中结构时，M、X、Z、T各自独立选自C、N，R 6选自氢基、氨基、取代氨基、羟基、卤原子、环烷基或含取代基的环烷基、杂原子环烷基或含有取代基的杂原子环烷基、氰基、烃基、芳基或杂芳环、取代芳基或取代杂芳环；
    R 3选自氢原子、
    Figure PCTCN2022099407-appb-100009
    Figure PCTCN2022099407-appb-100010
  2. 根据权利要求1的式(I)化合物，R 1选自
    Figure PCTCN2022099407-appb-100011
    其中E、Y、A、Q各自独立选自C、N，在(1)中R 4选自氨基、氰基，在(2)中L选自
    Figure PCTCN2022099407-appb-100012
    R 5选自
    Figure PCTCN2022099407-appb-100013
    R 2选自环丙烷或
    Figure PCTCN2022099407-appb-100014
    其中M、X、Z、T各自独立选自C、N，R 6选自卤原子、
    Figure PCTCN2022099407-appb-100015
    Figure PCTCN2022099407-appb-100016
    R 3选自氢原子、
    Figure PCTCN2022099407-appb-100017
  3. 根据权利要求1的式(I)化合物，R 1选自
    Figure PCTCN2022099407-appb-100018
    其中E、Y、A、Q各自独立选自C、N，在(1)中R 4选自氨基、氰基，在(2)中L选自
    Figure PCTCN2022099407-appb-100019
    R 5选自
    Figure PCTCN2022099407-appb-100020
    R 2选自环丙烷或
    Figure PCTCN2022099407-appb-100021
    其中M、X、Z、T各自独立选自C、N，R 6选自氟原子、
    Figure PCTCN2022099407-appb-100022
    Figure PCTCN2022099407-appb-100023
    R 3选自氢原子、
    Figure PCTCN2022099407-appb-100024
  4. 一种药物组合物，其特征在于，包含权利要求1-3任一项所述的化合物或其药学上可接受的盐与一种或多种药用载体和/或稀释剂，制成适用于临床的药物制剂。
  5. 根据权利要求4所述的药物组合物，其中所述药物制剂选自片剂、胶囊剂或液体制剂。
  6. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、或根据权利要求4所述的药物组合物在制备TYK2抑制剂中的应用。
  7. 根据权利要求1-3任一项所述化合物或其药学上可接受的盐、或根据权利要求4所述的药物组合物在制备防治肿瘤或炎症类疾病的药物中的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述的化合物或其药学上可接受的盐、或所述的药物组合物用于抑制肿瘤细胞的增殖、生长、浸润和迁移，或促进肿瘤细胞的凋亡。
  9. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐的制备方法，其特征在于，2-氨基-3,5-二溴吡嗪通过关环得到2-取代-6,8-二溴咪唑并[1,2-a]吡嗪，然后发生取代反应得到2，6-多取代-8-二溴咪唑并[1,2-a]吡嗪，最后经过偶联反应得到目标化合物2,6,8-多取代咪唑并[1,2-a]吡嗪：
    Figure PCTCN2022099407-appb-100025
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