WO2020098466A1 - 嘧啶并噻唑类杂环化合物，组合物及其治疗淋巴细胞白血病的用途 - Google Patents

嘧啶并噻唑类杂环化合物，组合物及其治疗淋巴细胞白血病的用途 Download PDF

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WO2020098466A1
WO2020098466A1 PCT/CN2019/112958 CN2019112958W WO2020098466A1 WO 2020098466 A1 WO2020098466 A1 WO 2020098466A1 CN 2019112958 W CN2019112958 W CN 2019112958W WO 2020098466 A1 WO2020098466 A1 WO 2020098466A1
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general formula
pharmaceutically acceptable
compound represented
phenyl
acid
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PCT/CN2019/112958
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French (fr)
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马晓东
王长远
孙秀丽
陈立学
郑旭
刘克辛
许家文
李艳霞
爱民
迟冨云
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大连医科大学
大连医科大学附属第一医院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—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
    • 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

Definitions

  • the invention relates to a pyrimidothiazole heterocyclic compound, a composition and its use for treating lymphocytic leukemia, which belongs to the technical field of medicine.
  • PTKs Protein tyrosine kinases
  • Receptor-type tyrosine kinases are a class of kinases that cross cell membranes, have ligand-bound extracellular domains, transmembrane domains, and act as kinases—phosphorylate specific tyrosine residues and thereby affect cell proliferation Intracellular domain.
  • Abnormal expression of the kinase has been found in numerous cancers (such as lung cancer, breast cancer, gastric cancer, ovarian cancer, and lymphoma).
  • JAK3 gene mutations are basically present in lymphocytic leukemia, and JAK-STAT inhibitors are an effective way to treat patients with lymphoma.
  • a JAK inhibitor for the treatment of rheumatoid diseases that is being evaluated in a phase III clinical study can also induce apoptosis and promote the death of lymphoma cell lines (Cancer Discov. 2012, 2, 591-597), which is used for JAK3 inhibitors. Treatment of lymphocytic leukemia provides an important basis and new ideas.
  • One of the objects of the present invention is to provide a pyrimidothiazole heterocyclic compound or a pharmaceutically acceptable salt thereof, which has good anti-lymphocytic leukemia activity.
  • Another object of the present invention is to provide a pharmaceutical composition containing the pyrimidothiazole heterocyclic compound or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide the pyrimidothiazole heterocyclic compound or a pharmaceutically acceptable salt thereof, or the use of the composition.
  • the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound represented by general formula (I) has the following structure:
  • X is selected from NH or O
  • R 1 is selected from hydrogen, chlorine, methyl, fluorine or methoxy
  • R is selected from
  • the compound represented by the general formula (I) has a structure represented by I-1 to I-9:
  • the compound represented by the general formula (I) is I-3.
  • the structural compounds shown above are pyrimidothiazole heterocyclic compounds.
  • Anti-tumor activity screening showed that the compounds of the present invention have a strong ability to inhibit the proliferation of lymphoma cells (Ramos cells and Raji cells), and some of the compounds showed more
  • the drugs Spebrutinib and HM71224 had unexpectedly better anti-JAK3 kinase activity.
  • the compounds of the present invention have the potential to be developed as new and highly effective JAK3 inhibitors, and have great application in the treatment of related tumor diseases, especially lymphoma, follicular lymphoma or chronic lymphocytic leukemia value.
  • the present invention provides a pharmaceutical composition containing an effective dose of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the salts of the compounds of the invention are preferably pharmaceutically acceptable salts.
  • the compound of the present invention is a base, wherein the desired salt form can be prepared by a suitable method known in the art, including treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc .; or Treatment of free base with organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyran Pyranosidy acid, such as glucuronic acid or galacturonic acid, ⁇ -hydroxy acid, such as citric acid or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid or cinnamic acid, Sulfonic acids, such as p-
  • Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, Caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolates, oxalate, malonate, benzoate, chlorine Benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate Acid salt, phenylbutrates, citrate, lactate, ⁇ -hydroxybutyrate, glycolate, tartrate, amygdalate and sulfonate, such as xylene sulfonate , Methanesulfonate, propanesulfonate, naphthalene-1-sulfonate and na
  • the pharmaceutical composition of the present invention usually contains a compound of the present invention. However, in some embodiments, the pharmaceutical composition of the present invention contains more than one compound of the present invention. In addition, the pharmaceutical composition of the present invention may optionally include one or more other pharmaceutically active compounds.
  • the invention also provides the use of the pyrimidothiazole heterocyclic compound or a pharmaceutically acceptable carrier thereof.
  • the pharmaceutical composition inhibits JAK3 tyrosine kinase, thereby inhibiting tumor proliferation.
  • the use is mainly for the preparation of a medicament for treating Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia.
  • the present invention provides the use of the compound shown or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the present invention in the preparation of a JAK3 tyrosine kinase inhibitor.
  • the present invention provides the use of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the present invention in the preparation of a medicament for treating tumors.
  • the tumor is selected from one or more of diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia, further preferably chronic lymphocytic leukemia. More preferably, the use is mainly achieved by inhibiting JAK3 tyrosine kinase.
  • Figure 1 is a graph of the experimental results of compound I-3 against Ramos lymphocyte proliferation activity.
  • Figure 2 is a graph of the morphological observation results of compound I-3 against Ramos lymphocyte proliferation.
  • Figure 3 is a graph showing the results of compound I-3 cytotoxicity test on PBMC.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications used for thin layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4 mm-0.5mm.
  • the raw materials used in the present invention are mainly purchased from Sinopharm Group Chemical Reagent Co., Ltd., Beijing Coupling Technology Co., Ltd., Aladdin Chemical Reagent Co., Ltd., Darui Chemicals and other companies.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20 ° C-30 ° C.
  • the target molecule was synthesized according to the above method.
  • the physical and chemical data of the synthesized target molecule are as follows:
  • Preparation method of inorganic acid salt dissolve target molecule (1mmol) in 10mL anhydrous methanol, and slowly add 5mL anhydrous methanol solution of inorganic acid (1mmol) dropwise under ice bath. After the dropwise addition, stir at this temperature After 30 minutes, the methanol was distilled off at room temperature to obtain the inorganic acid salt of the target molecule.
  • Preparation method of organic acid salt Take the target molecule (1mmol) dissolved in 10mL of anhydrous methanol, slowly add 5mL of organic acid (1mmol) dry ether under ice bath, after the addition is complete, stir at this temperature for 30 minutes Then, the solvent is distilled off at room temperature to obtain the organic acid salt of the target molecule.
  • Ramos cells human Burkitt's lymphoma cells, high expression of JAK3 kinase
  • Raji cells human Burkitt's lymphoma cells, high expression of JAK3 kinase
  • Raji cells human NAMAWAL lymphoma cells, high JAK3 kinase
  • Cell seeding collect cells in the logarithmic growth phase, adjust the concentration of the cell suspension, inoculate 4 ⁇ 10 3 cells per well, inoculate 100 ⁇ L per well into a 96-well plate, and set up 3 double wells per group (for edge wells) Sterile PBS filling);
  • cell growth inhibition rate (control group absorbance value-experimental group absorbance value) / control group absorbance value ⁇ 100%
  • cell proliferation rate (experiment group absorbance value / control group absorbance value) ⁇ 100;
  • Plot the cell growth curve plot the cell growth curve with time as the abscissa and the inhibition rate / proliferation rate as the ordinate.
  • Table 2 shows the active effects of the obtained compounds in inhibiting JAK3 kinase and anti-tumor cell proliferation (A: 1-10 nM; B: 10-50 nM; C: 1-10 ⁇ M; D: 10 -20 ⁇ M).
  • PBMC Peripheral blood mononuclear cells
  • lymphocytes lymphocytes, monocytes, dendritic cells and a small number of other cells (hematopoietic stem cells, etc.). Carrying out a toxicity test on it can prove whether the drug of the present invention has lethality to normal immune cells.
  • the common method for separating PBMC at home and abroad is dextran-Pan Ying meglumine density gradient centrifugation. The experimental steps are as follows:
  • Blood collection and dilution 2ml of blood is taken intravenously, added to the test tube containing the ACD anticoagulant solution, and mixed to make the blood anticoagulant. Dilute the anticoagulated blood with PBS solution twice;
  • Centrifugation centrifuge at 2000r / min for 20min at 18 °C ⁇ 20 °C with a horizontal centrifuge. After centrifugation, it is divided into four layers from the bottom of the tube to the liquid surface, followed by the red blood cell and granulocyte layer, the layered liquid layer, the mononuclear cell layer, and the plasma layer;
  • Washing Wash the cells 3 times with PBS solution. The first time 2000r / min, 10min; the second to third times 1500r / min, 10min, can remove most of the mixed platelets;
  • Counting and plating adjust the concentration of the cell suspension, inoculate 2.5 ⁇ 10 5 cells per well, and inoculate a volume of 500 ⁇ L per well into a 24-well plate, and set 2 duplicate wells per group;
  • IC 50 1-10 nM
  • the results of anti-cell proliferation activity revealed that most of the compounds had very effective inhibitory effects on B lymphoma tumor cells Ramos and Raji, with IC 50 values between 1-10 ⁇ M, better than the reference drugs Ibrutinib and Spebrutinib (10-20 ⁇ M).
  • Figure 3 shows that the cytotoxicity of Compound I-3 is also significantly reduced compared with Spebrutinib, which reduces the toxicity of the drug while maintaining the drug activity, and has potential medicinal value.
  • the compounds of the present invention have profound potential significance for the treatment of diseases caused by JAK3 tyrosine kinase, especially for the treatment of diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. This indicates that such molecules have the potential to be developed into new and highly effective JAK3 tyrosine kinase inhibitors.

Abstract

本发明提供了嘧啶并噻唑类杂环化合物，组合物及其制备用于治疗淋巴细胞白血病的药物的用途，所述嘧啶并噻唑类杂环化合物具体为通式(I)所示的化合物，通式(I)的各取代基如说明书中的定义。本发明还提供了所述通式(I)所示的化合物或其药学上可接受的盐，或含其的药物组合物通过抑制JAK3酪氨酸激酶，进而治疗肿瘤疾病，特别是用于制备用于治疗伯基特氏淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病的药物中的用途。

Description

嘧啶并噻唑类杂环化合物，组合物及其治疗淋巴细胞白血病的用途 技术领域
本发明涉及嘧啶并噻唑类杂环化合物，组合物及其治疗淋巴细胞白血病的用途，属于医药技术领域。
背景技术
蛋白酪氨酸激酶(protein tyrosine kinase,PTKs)通过控制细胞的信号传导通路调节细胞的生长、分化、凋亡等一系列生理生化过程，是抗肿瘤药物研发的重要靶点之一。受体型酪氨酸激酶是一类横跨细胞膜的激酶，具有配体结合的胞外结构域、跨膜结构域和起激酶作用—在磷酸化特定酪氨酸残基并且由此影响细胞增殖的胞内结构域。在众多的癌症中(如肺癌、乳腺癌、胃癌、卵巢癌、淋巴瘤)均已发现所述激酶的异常表达。
新近研究显示：淋巴细胞白血病中基本都存在JAK3基因突变，JAK-STAT抑制剂是治疗淋巴瘤患者的有效途径。正在进行三期临床研究评估的一种治疗类风湿疾病的JAK抑制剂，也能诱导细胞凋亡，促使淋巴瘤细胞株死亡(Cancer Discov.2012,2,591-597)，这为JAK3抑制剂用于治疗淋巴细胞白血病提供了一个重要依据和新的思路。
鉴于治疗白血病的迫切需要，本领域有必要开发作用机制独特，结构新颖的抗淋巴细胞白血病药物。
发明内容
本发明的目的之一在于提供一种嘧啶并噻唑类杂环化合物或其药学上可接受的盐，该类化合物具有良好的抗淋巴细胞白血病活性。
本发明的另一目的在于提供含所述嘧啶并噻唑类杂环化合物或其药学上可接受的盐的药物组合物。
本发明的再一目的在于提供所述嘧啶并噻唑类杂环化合物或其药学上可接受的 盐，或所述组合物的用途。
一方面，本发明提供一种通式(I)所示的化合物或其药学上可接受的盐，所述通式(I)所示的化合物具有如下结构：
Figure PCTCN2019112958-appb-000001
其中，
X选自NH或O；
R 1选自氢、氯、甲基、氟或甲氧基；
R选自
Figure PCTCN2019112958-appb-000002
在一些实施方式中，所述通式(I)所示的化合物具有I-1～I-9所示的结构：
Figure PCTCN2019112958-appb-000003
Figure PCTCN2019112958-appb-000004
优选地，所述通式(I)所示的化合物为I-3。
如上所示结构化合物为嘧啶并噻唑类杂环化合物，抗肿瘤活性性筛选显示本发明中的化合物具有较强的抑制淋巴细胞瘤细胞(Ramos细胞和Raji细胞)增殖能力，部分化合物显示出比参照药物Spebrutinib和HM71224预料不到的更加优良的抗JAK3激酶活性。作为一类结构新颖的分子，本发明中的化合物具有开发成新型高效JAK3抑制剂的潜力，对治疗相关的肿瘤疾病尤其是淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病有较大的应用价值。
前述I-1～I-9所示的结构分别具有如下名称：
(I-1)N-[3-[[2-[[3-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氧基]苯基]-2-丙烯酰胺；
(I-2)N-[3-[[2-[[3-甲基-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺；
(I-3)N-[3-[[2-[[3-甲基-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺；
(I-4)N-[3-[[2-[[3-氯-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺；
(I-5)N-[3-[[2-[[4-(2-[[4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氧基]苯基]-2-丙烯酰胺；
(I-6)N-[3-[[2-[[4-(2-[[4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺；
(I-7)N-[3-[[2-[[4-(2-[[3-甲基-4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺；
(I-8)N-[3-[[2-[[4-(2-[[3-氯-4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺；
(I-9)N-[3-[[2-[[4-(2-[[2-甲基-4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺；
另一方面，本发明提供一种药物组合物，其含有有效剂量的本发明所述通式(I)所示的化合物或其药学上可接受的盐，及药用载体。
本发明所述化合物由于它们在药物中的可能用途，式(I)化合物的盐优选药物可接受的盐。本发明的化合物为碱，其中所需盐形式可以通过本领域已知的合适方法制备，包括用无机酸处理游离碱，所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等；或用有机酸处理游离碱、所述有机酸例如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、羟基乙酸、水杨酸、吡喃糖苷酸(pyranosidy1acid)，例如葡糖醛酸或半乳糖醛酸，α-羟基酸，例如柠檬酸或酒石酸，氨基酸，例如天冬氨酸或谷氨酸，芳香酸，例如苯甲酸或肉桂酸，磺酸，例如p-甲苯磺酸、甲磺酸、乙磺酸等。药学上可接受的盐的实施例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙酸盐(propiolates)、草酸盐、丙二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐(phenylbutrates)、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、羟基乙酸盐、酒石酸盐、苦杏仁酸盐和磺酸盐、例如二甲苯磺酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐和萘-2-磺酸盐。
本发明的药物组合物通常含有一种本发明化合物。然而，在一些实施方案中，本发明的药物组合物含有超过一种本发明的化合物。另外，本发明的药物组合物还可任选包括一种或多种其它药学活性化合物。
本发明还提供所述嘧啶并噻唑类杂环化合物或其药学上可接受的载体，所述药物组合物通过抑制JAK3酪氨酸激酶，进而抑制肿瘤增殖的用途。具体地，该用途主要为制备用于治疗伯基特氏淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病的药物中的用途。
本发明提供所示的化合物或其药学上可接受的盐，或本发明所述的药物组合物在制备JAK3酪氨酸激酶抑制剂中的应用。
本发明提供所述通式(I)所示的化合物或其药学上可接受的盐，或本发明所述 的药物组合物在制备治疗肿瘤的药物中的用途。优选地，所述肿瘤选自弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和慢性淋巴细胞白血病中的一种或多种，进一步优选慢性淋巴细胞白血病。更优选地，所述用途主要通过抑制JAK3酪氨酸激酶实现的。
附图说明
图1为化合物I-3抗Ramos淋巴细胞增殖活性实验结果图。
图2为化合物I-3抗Ramos淋巴细胞增殖的形态学观察结果图。
图3为化合物I-3对PBMC细胞毒性实验结果图。
具体实施方式
以下结合具体实施例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1目标分子的制备
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胺板采用的规格是0.15mm-0.2mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
本发明使用的原料主要购自可购买自国药集团化学试剂有限公司，北京偶合科技有限公司、阿拉丁化学试剂有限公司、达瑞化学品等公司。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。
本发明采用的技术方案如下：
Figure PCTCN2019112958-appb-000005
化合物I-(1-9)的合成路线、试剂及条件:(条件1)二异丙基乙基胺,二氧六环,60℃,2h；(条件2)三氟乙酸,异丙醇,12h,100℃。
M-2的合成
Figure PCTCN2019112958-appb-000006
取2,4-二氯噻吩并[3,2-D]嘧啶(7.24mmol)和中间体M-1(7.24mmol)、DIPEA(10.86mmol)于烧瓶中，加入1,4-二氧六环，60℃反应2小时，反应液减压蒸干，加水析出固体，抽滤，烘干，得固体M-2。
目标物I的合成
Figure PCTCN2019112958-appb-000007
取氨基化合物M-3或M-4(1.0mmol)与嘧啶中间体M-2(1.0mmol)分别反应，溶于10mL 2-BuOH中，慢慢滴加三氟乙酸(1.5mmol)，升温100℃反应12小时，反应完毕后抽干溶剂，加MeOH 10mL，再加饱和碳酸氢钠析出固体，薄层层析分离纯化得目标化合物I-(1-9)。
根据以上方法合成了目标分子，所合成目标分子的理化数据如下：
(I-1)N-[3-[[2-[[3-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氧基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.36(s,1H),8.29(d,J＝5.4Hz,1H),7.73(t,J＝2.0Hz,1H),7.62(d,J＝8.3Hz,1H),7.55(d,J＝7.6Hz,2H),7.46(s,1H),7.38–7.29(m,1H),7.08(dd,J＝7.9,1.9Hz,1H),6.76(dd,J＝30.0,8.7Hz,2H),6.46(dd,J＝16.9,10.1Hz,1H),6.29(d,J＝1.8Hz,1H),5.79(dt,J＝10.2,5.0Hz,1H),4.24(s,2H),3.80(s,4H),3.15(d,J＝50.8Hz,6H)； 13C NMR(101MHz,DMSO-d6)δ166.11(s),165.01(s),164.77(s),159.19(s),153.59(s),141.73(s),138.24(s),135.90(s),133.01(s),131.29(s),128.71(s),126.53(s),124.54(s),121.55(s),118.43(s),118.04(s),115.86(s),114.30(s),64.92(s),56.70(s),53.26(s)；HRMS(ESI)for C 28H 29N 5O 4S,[M+H] +理论计算:532.2013,实测:532.21043；
(I-2)N-[3-[[2-[[3-甲基-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.32(s,1H),8.18(d,J＝5.2Hz,1H),7.68(t,J＝2.0Hz,1H),7.58(d,J＝8.3Hz,1H),7.48(d,J＝7.6Hz,2H),7.41(s,1H),7.38–7.20(m,2H),7.00(dd,J＝8.0,2.0Hz,1H),6.70(dd,J＝30.0,8.8Hz,2H),6.40(dd,J＝16.0,10.0Hz,1H),6.20(d,J＝1.8Hz,1H),5.70(dt,J＝10.0,5.0Hz,1H),4.20(s,2H),3.80(s,4H),3.10(d,J＝50.8Hz,6H)； 13C NMR(101MHz,DMSO-d6)δ166.11(s),165.00(s),164.70(s),159.10(s),153.50(s),141.68(s),138.20(s),135.90(s),133.00(s),131.20(s),128.70(s),126.50(s),124.48(s),120.11(s),118.33(s),118.00(s),115.02(s),114.20(s),64.90(s),56.52(s),53.20(s)；HRMS(ESI)for C 28H 30N 6O 3S,[M+H] +理论计算:531.2173,实测:531.2199；
(I-3)N-[3-[[2-[[3-甲基-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.49(s,1H),8.19(d,J＝5.4Hz,1H),7.70(t,J＝2.0Hz,1H),7.53(d,J＝0.9Hz,1H),7.40(t,J＝8.1Hz,1H),7.19(dd,J＝11.7,7.0Hz,2H),7.05(dd,J＝8.1,1.7Hz,1H),6.72(d,J＝2.7Hz,1H),6.59(dd,J＝8.7,2.6Hz,1H),6.45(dd,J＝17.0,10.1Hz,1H),6.28(dd,J＝16.9,1.9Hz,1H),5.78(dd,J＝10.1,2.0Hz,1H),3.94(t,J＝6.3Hz,2H),3.64–3.50(m,4H),2.40 (dd,J＝15.6,8.0Hz,6H),2.12(s,3H),1.90–1.79(m,2H)； 13C NMR(101MHz,DMSO-d6)δ166.47(s),164.94(s),164.69(s),161.04(s),156.92(s),153.48(s),141.59(s),137.82(s),133.02(s),132.24(s),131.18(s),128.69(s),128.33(s),124.45(s),118.28(s),117.79(s),117.17(s),114.09(s),112.88(s),108.21(s),67.55(s),67.10(s),56.24(s),54.74(s),27.28(s),19.65(s)；HRMS(ESI)for C 29H 31N 5O 4S,[M+H] +理论计算:546.2170,实测:546.2155；
(I-4)N-[3-[[2-[[3-氯-4-(2-(4-吗啉基)丙氧基)苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),10.12(s,1H),9.51(s,1H),8.31(d,J＝5.2Hz,1H),7.76(d,J＝18.1Hz,2H),7.68–7.22(m,4H),7.02(dd,J＝46.5,8.3Hz,2H),6.64–6.02(m,2H),5.77(d,J＝10.1Hz,1H),4.01(d,J＝24.6Hz,4H),3.67(s,2H),3.19(d,J＝63.8Hz,4H),2.50(s,2H),2.13(s,2H)； 13C NMR(101MHz,DMSO-d6)δ165.94(s),165.06(s),164.75(s),158.88(s),153.49(s),149.32(s),141.83(s),138.53(s),136.42(s),133.04(s),131.41(s),128.68(s),124.55(s),122.65(s),121.29(s),119.72(s),118.22(d,J＝6.7Hz),115.87(s),114.08(s),109.23(s),67.83(s),64.87(s),55.12(s),52.67(s),24.65(s)；HRMS(ESI)for C 28H 28ClN 5O 4S,[M+H] +理论计算:566.1623,实测:566.1620；
(I-5)N-[3-[[2-[[4-(2-[[4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氧基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.30(s,1H),8.27(d,J＝5.4Hz,1H),7.72(t,J＝2.0Hz,1H),7.62–7.58(m,1H),7.47(dd,J＝16.8,8.6Hz,3H),7.34(d,J＝5.4Hz,1H),7.10–7.06(m,1H),6.72(d,J＝8.8Hz,2H),6.44(dd,J＝17.0,10.1Hz,1H),6.27(dd,J＝17.0,1.9Hz,1H),5.78(dd,J＝10.1,1.9Hz,1H),3.64–3.54(m,4H),3.46(s,4H),3.33(s,2H)； 13C NMR(101MHz,DMSO-d6)δ167.57(s),166.15(s),165.00(s),164.73(s),159.24(s),154.01(s),153.59(s),141.69(s),138.15(s),135.48(s),132.99(s),131.32(s),128.73(s),124.58(s),121.58(s),118.45(s),118.02(s),115.65(s),114.30(s),108.60(s),67.53(d,J＝17.6Hz),46.21(s),42.97(s)；HRMS(ESI)for C 27H 25N 5O 5S,[M+H] +理论计算:532.1649,实测:532.1635；
(I-6)N-[3-[[2-[[4-(2-[[4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.13(s,1H),8.20(d,J＝5.4Hz,1H),7.62(t,J＝2.0Hz,1H),7.62–7.60(m,1H),7.40(dd,J＝16.8,8.6Hz,3H),7.30(d,J＝5.4Hz,1H),7.10–7.00(m,2H),6.70(d,J＝8.8Hz,2H),6.40(dd,J＝16.0,10.0Hz,1H),6.20(dd,J＝17.0,1.9Hz,1H),5.70(dd,J＝10.1,1.9Hz,1H),3.64–3.50(m,4H),3.40(s,4H),3.30(s,2H)； 13C NMR(101MHz,DMSO-d6)δ167.50 (s),166.10(s),165.00(s),164.70(s),159.20(s),154.00(s),153.50(s),141.60(s),138.10(s),135.40(s),132.90(s),131.30(s),128.70(s),124.50(s),121.50(s),118.40(s),118.00(s),115.60(s),114.28(s),108.45(s),67.50(d,J＝16.0Hz),46.20(s),42.97(s)；HRMS(ESI)for C27H26N6O4S,[M+H] +理论计算:531.1809,实测:531.1756；
(I-7)N-[3-[[2-[[4-(2-[[3-甲基-4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺； 1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.51(s,1H),8.19(d,J＝5.4Hz,1H),7.70(t,J＝2.1Hz,1H),7.56–7.50(m,1H),7.41(t,J＝8.1Hz,1H),7.23(d,J＝5.4Hz,1H),7.19(d,J＝8.7Hz,1H),7.09–7.03(m,1H),6.75(d,J＝2.8Hz,1H),6.62(dd,J＝8.7,2.7Hz,1H),6.44(dd,J＝17.0,10.1Hz,1H),6.27(dd,J＝17.0,2.0Hz,1H),5.78(dd,J＝10.1,2.0Hz,1H),3.66–3.54(m,4H),3.46(d,J＝3.3Hz,4H),3.34(s,2H),2.12(s,3H)； 13C NMR(101MHz,DMSO-d6)δ167.53(s),166.45(s),164.96(s),164.70(s),161.01(s),156.27(s),153.48(s),141.59(s),137.80(s),135.69(s),133.01(s),132.70(s),131.20(s),128.71(s),128.32(s),124.51(s),118.34(s),117.84(s),117.31(s),114.08(s),113.07(s),108.28(s),67.45(s),46.20(s),42.98(s),19.70(s)；HRMS(ESI)for C 28H 27N 5O 5S,[M+H] +理论计算:546.1806,实测:546.1790；
(I-8)N-[3-[[2-[[4-(2-[[3-氯-4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.47(s,1H),8.30(d,J＝5.4Hz,1H),7.73(dd,J＝8.7,6.7Hz,2H),7.64–7.57(m,1H),7.56–7.25(m,3H),7.13–7.03(m,1H),6.85(d,J＝9.1Hz,1H),6.43(dd,J＝17.0,10.1Hz,1H),6.26(dd,J＝17.0,2.0Hz,1H),5.79–5.75(m,1H),4.83(s,2H),3.71–3.50(m,4H),3.46(s,4H)； 13C NMR(101MHz,DMSO)δ16-d67.05(s),165.94(s),165.04(s),164.71(s),158.90(s),153.47(s),149.17(s),141.79(s),138.45(s),136.17(s),133.01(s),131.41(s),128.69(s),124.58(s),122.12(s),121.39(s),119.61(s),118.23(d,J＝10.7Hz),115.32(s),114.04(s),109.19(s),68.24(s),67.44(s),46.24(s),43.02(s)；HRMS(ESI)for C 27H 24ClN 5O 5S,[M+H] +理论计算:566.1259,实测:566.1265；
(I-9)N-[3-[[2-[[4-(2-[[2-甲基-4-[((1-吗啡啉)乙酰基)氧基]苯基]氨基]噻吩并[3,2-D]嘧啶-4-基]氨基]苯基]-2-丙烯酰胺, 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.50(s,1H),8.10(d,J＝5.6Hz,1H),7.78(t,J＝2.0Hz,1H),7.52–7.50(m,2H),7.40(t,J＝8.0Hz,1H),7.20(d,J＝5.4Hz,1H),7.10(d,J＝8.6Hz,1H),7.08–7.00(m,1H),6.58(d,J＝2.8Hz,1H),6.60(dd,J＝8.7,2.7Hz,1H),6.40(dd,J＝17.0,10.0Hz,1H),6.26(dd,J＝17.0,2.0Hz,1H),5.70(dd,J＝10.6,2.0Hz,1H),3.66–3.48(m,4H),3.40(d,J＝3.3Hz,4H),3.30(s,2H),2.10(s,3H)； 13C NMR(101MHz,DMSO-d6)δ167.18(s),166.42 (s),164.90(s),164.60(s),161.00(s),156.20(s),153.40(s),141.50(s),137.70(s),135.60(s),133.00(s),132.25(s),131.29(s),128.66(s),128.24(s),124.50(s),118.30(s),117.80(s),117.30(s),114.00(s),113.12(s),108.20(s),67.40(s),46.10(s),42.50(s),19.59(s)；HRMS(ESI)for C 28H 28N 6O 4S,[M+H] +理论计算:545.1966,实测:545.1906。
目标分子成盐的方法
无机酸盐的制备方法：取目标分子(1mmol)溶于10mL无水甲醇中，冰浴下，慢慢滴加无机酸(1mmol)的5mL无水甲醇溶液，滴加完毕，于此温度下搅拌30分钟，然后常温蒸除甲醇，即得目标分子的无机酸盐。
有机酸盐的制备方法：取目标分子(1mmol)溶于10mL无水甲醇中，冰浴下，慢慢滴加有机酸(1mmol)的5mL干燥乙醚，滴加完毕，于此温度下搅拌30分钟，然后常温蒸除溶剂，即得目标分子的有机酸盐。
两个目标分子混合物的制备
取等摩尔量(1mmol)的上述两个目标分子于无水甲醇中(5mL)，室温搅拌10分钟，常温蒸除溶剂，即得目标分子的混合物。
实施例2目标分子生物活性评价
1、体外对受体酪氨酸激酶抑制活性测试方法
(1)制备激酶检测缓冲液
①在室温融解激酶检测缓冲液(Kinase Detection Buffer)，观察是否有沉淀。
②如果出现沉淀，就在37℃孵育(Kinase Detection Buffer)15分钟并经常摇动，溶解沉淀。或者，小心吸走上清，去除沉淀。
(2)制备激酶检测试剂
①使用前在室温平衡激酶检测缓冲液(Kinase Detection Buffe)和激酶检测底物(Kinase Detection Substrate)。
②将激酶检测缓冲液(Kinase Detection Buffer)全部倒进装有激酶检测底物(Kinase Detection Substrate)的棕色瓶中，使冻干粉底物溶解，这样就制成了激酶检测试剂。
③轻轻震荡、涡旋或颠倒混匀，成为均质溶液，底物应在1分钟内溶解。
④激酶检测试剂配好后应立即使用，或分装存于-20℃，我们认为配好的试剂经过几次冻融后循环信号活性都没有损失。
(3)制作ATP转化成ADP的标准曲线
①用1×激酶反应缓冲液(kinase reaction buffer)稀释试剂盒提供的Ultra Pure ATP和ADP，制成900μL 50μM ATP和500μL 50μM ADP。
②将上一步配好的50μM ATP和50μM ADP溶液按表1所示在384孔板A1-A12中混合，模拟每个转化百分比的ATP和ADP的浓度，混合好。
表1.制备50μM系列ATP+ADP标准品
Figure PCTCN2019112958-appb-000008
③每孔加入5μL的ADP-Glo TM试剂来终止激酶反应。在室温孵育40分钟。
④每孔加入10μL激酶检测试剂(Kinase Detection Reagent)将ADP转化成ATP，并引进萤光素酶和萤光素来检测ATP。
⑤在室温孵育30-60分钟，用多功能酶标仪测量萤光并记录萤光值。
⑥绘制ATP转化成ADP的标准曲线。
(4)确定激酶抑制物的IC 50值
①按照promega试剂盒说明书配制1×激酶反应缓冲液(kinase reaction buffer)，2.5×50ng/μL激酶和2.5×0.5μg/μL底物和125μM ATP。
②在无酶对照孔中加入3μL 1×激酶反应缓冲液(kinase reaction buffer)，2μL 2.5×0.5μg/μL底物和125μM ATP。在阴性对照孔中加入1μL 1×激酶反应缓冲液(kinase reaction buffer)，2μL 2.5×50ng/μL激酶，2μL 2.5×0.5μg/μL底物和125μM ATP。在测试孔中加入1μL 5×待测药物，2μL 2.5×50ng/μL激酶，2μL 2.5×0.5μg/μL底物和125μM ATP。
③混合好平板，孵育60分钟。
④每孔加入5μL的ADP-Glo TM试剂来终止激酶反应。在室温孵育40分钟。
⑤每孔加入10μL激酶检测试剂(Kinase Detection Reagent)将ADP转化成ATP，并引进萤光素酶和萤光素来检测ATP。在室温孵育30-60分钟，用多功能酶标仪测量萤光并记录萤光值。
⑥结果分析，结果如表2所示。
2、抑制JAK3高表达细胞生长实验(CCK-8检测法)
(1)细胞类型及选择：Ramos细胞(人Burkitt's淋巴瘤细胞，JAK3激酶高表达)、Raji细胞(人Burkitt's淋巴瘤细胞，JAK3激酶高表达)、Raji细胞(人NAMAWAL淋巴瘤细胞，JAK3激酶高表达)。
(2)细胞接种：收集对数生长期细胞，调整细胞悬液浓度，以每孔4×10 3个细胞，每孔体积100μL接种到96孔板，每组设3个复孔(边缘孔用无菌PBS填充)；
(3)细胞培养：细胞接种后，对照组用10％FBS RPMI-1640培养，实验组分别用10μL不同浓度梯度的Spebrutinib或Ibrutinib(1.25-40μmol/L)、各不同药物(1.25-40μmol/L)干预，37℃，5％CO 2培养箱中继续培养(按实验要求分别培养不同时间)；
(4)呈色：两组细胞分别于培养48h后加入10μL CCK-8溶液(5mg/ml)，4h后终止培养，于摇床上低速振荡10min，使结晶充分溶解；
(5)比色：在酶联免疫检测仪上测定各孔光度值(OD值)，选择450nm波长，以无细胞的即RPMl-1640培养液空白孔调零，测各孔的吸光度值。实验重复三次；
(6)记录结果：细胞生长抑制率＝(对照组吸光度值—实验组吸光度值)/对照组吸光度值×100％，细胞增殖率＝(实验组吸光度值/对照组吸光度值)×100；
(7)绘制细胞生长曲线：以时间为横坐标，抑制率/增殖率为纵坐标绘制细胞生长曲线。在GraphPad软件中的GraphPad Prism作图软件中针对抑制剂浓度做图，以便由log[抑制剂]相对于反应，可变斜率模型估算出IC 50。
测试结果如表2所示，表2显示所获得的化合物在抑制JAK3激酶和抗肿瘤细胞增殖中的活性效果(A:1-10nM；B:10-50nM；C:1-10μM；D:10-20μM)。
表2
Figure PCTCN2019112958-appb-000009
Figure PCTCN2019112958-appb-000010
同时，本实验发现化合物I-3对Ramos细胞的增殖活性与时间和浓度有着很大的关系，如图1所示，随着浓度的增大，细胞存活率减小，尤其72h后的Ramos细胞在药物浓度达10μmol/L时，几乎不能存活，明显高于48h，由此可证明本药物属于浓度和时间依赖性药物。此外，与参照药Spebrutinib相比，化合物I-3在72h后对Ramos的杀伤效果有了出其不意的提高。另外，图2中显示的给药后的细胞形态和数量也进一步证明了，化合物I-3较Spebrutinib的抗Ramos细胞活性有了明显增强。
3、活性药物毒性试验
外周血单个核细胞(Peripheral blood mononuclear cell,PBMC)包含淋巴细胞、单核细胞(monocyte)、树突状细胞和其它少量细胞(造血干细胞等)。对其进行毒性试验可以证明本发明的药物是否对正常免疫细胞具有杀伤力。目前国内外分离PBMC的常用方法是葡聚糖-泛影葡胺密度梯度离心法，实验步骤如下：
(1)采血并稀释：静脉取血2ml，加入含ACD抗凝溶液的试管中，混匀，使血液抗凝。用PBS溶液将抗凝血稀释1倍；
(2)加样：吸取2ml淋巴细胞分层液(天津TBD)置于刻度离心管中，然后将离心管倾斜45°角，用毛细滴管将稀释的全血沿管壁缓慢加至分离液上面，应注意保持两者界面清晰；
(3)离心：在18℃～20℃下，用水平离心机以2000r/min离心20min。离心后从管底至液面分四层，依次为红细胞和粒细胞层、分层液层、单个核细胞层、血浆层；
(4)回收：用毛细吸管轻轻插到混浊带，沿管壁轻轻吸出此层细胞，移入另一支离心管中。即要吸取所有单个核细胞，又要避免吸取过多的分层液或血浆，以免混入其他细胞成分；
(5)洗涤：用PBS液洗涤细胞3次。第一次2000r/min，10min；第2～3次1500r/min，10min，可去掉大部分混杂的血小板；
(6)将沉淀细胞悬于培养基中备用；
(7)计数铺板：调整细胞悬液浓度，以每孔2.5×10 5个细胞，每孔体积500μL接种到24孔板，每组设2个复孔；
(8)细胞培养：细胞接种后，对照组用10％FBS RPMI-1640培养，实验组分别用50μL不同浓度梯度的Spebrutinib(5-20μmol/L)、I-3(5-20μmol/L)干预，37℃，5％CO 2培养箱中继续培养(按实验要求分别培养不同时间)；
(9)染色：培养24h后加入20μL 1μg/μl AO(吖啶橙)，20μL 1μg/μl PI(碘化丙啶)染色5min，倒置荧光显微镜下观察并拍照。
(10)测试结果如图3所示，图3是化合物I-3对PBMC细胞毒性数据。
由表2的生物活性结果表明，本发明中的分子对JAK3激酶有较强的抑制效果(IC 50＝1-10nM)，达到纳摩尔水平的活性级别，比参照药Ibrutinib和Spebrutinib的活性有了明显提高。抗细胞增殖活性结果揭示，大部分化合物对B淋巴肿瘤细胞Ramos和Raji有非常有效的抑制作用，IC 50值在1-10μM之间，优于参照药Ibrutinib和Spebrutinib(10-20μM)。同时图3显示,化合物I-3的细胞毒性也比Spebrutinib显著减小，在保持药物活性的同时减轻药物的毒性，具有潜在的药用价值。综上所述，本发明的化合物对治疗JAK3酪氨酸激酶引起的疾病具有很深刻的潜在意义，特别是用于治疗弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病。预示此类分子具有开发成新型高效JAK3酪氨酸激酶抑制剂的潜力。
以上所述仅是本发明的优先实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (9)

  1. 一种通式(I)所示的化合物或其药学上可接受的盐，所述通式(I)所示的化合物具有如下结构：
    Figure PCTCN2019112958-appb-100001
    其中，
    X选自NH或O；
    R 1选自氢、氯、甲基、氟或甲氧基；
    R选自
    Figure PCTCN2019112958-appb-100002
  2. 根据权利要求1所述的通式(I)所示的化合物或其药学上可接受的盐，其中，所述通式(I)所示的化合物具有I-1～I-9所示的结构：
    Figure PCTCN2019112958-appb-100003
    Figure PCTCN2019112958-appb-100004
  3. 根据权利要求1所述的通式(I)所示的化合物或其药学上可接受的盐，其中，所述通式(I)所示的化合物为I-3。
  4. 一种药物组合物，其含有有效剂量的权利要求1～3中任一项所述通式(I)所示的化合物或其药学上可接受的盐，及药用载体。
  5. 权利要求1～3中任一项所述通式(I)所示的化合物或其药学上可接受的盐，或权利要求4所述的药物组合物在制备JAK3酪氨酸激酶抑制剂中的应用。
  6. 权利要求1～3中任一项所述通式(I)所示的化合物或其药学上可接受的盐，或权利要求4所述的药物组合物在制备治疗肿瘤的药物中的用途。
  7. 根据权利要求6所述的用途，其中，所述肿瘤选自弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和慢性淋巴细胞白血病中的一种或多种。
  8. 根据权利要求7所述的用途，其中，所述肿瘤为慢性淋巴细胞白血病。
  9. 根据权利要求5～8中任一项所述的用途，其中，所述用途主要通过抑制JAK3酪氨酸激酶实现的。
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