WO2022148243A1 - 一种嘧啶类小分子化合物及其应用 - Google Patents

一种嘧啶类小分子化合物及其应用 Download PDF

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WO2022148243A1
WO2022148243A1 PCT/CN2021/140401 CN2021140401W WO2022148243A1 WO 2022148243 A1 WO2022148243 A1 WO 2022148243A1 CN 2021140401 W CN2021140401 W CN 2021140401W WO 2022148243 A1 WO2022148243 A1 WO 2022148243A1
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compound
pyrimidine
small molecule
substituted
based small
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French (fr)
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李校堃
刘志国
林丽
郑小辉
钱建畅
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温州医科大学
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Priority to US18/331,758 priority Critical patent/US11858914B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • 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

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to a pyrimidine type small molecule compound and a preparation method and application thereof.
  • PDGFRs Platelet-derived growth factor receptors
  • PDGFR ⁇ and PDGFR ⁇ are two subtypes, PDGFR ⁇ and PDGFR ⁇ , which play an important role in the growth, development, angiogenesis and tissue wound repair of organisms.
  • PDGFRs signaling pathway is generally in a quiescent state in adults.
  • PDGFRs overexpression, gene mutation and gene rearrangement can lead to abnormal activation of PDGFRs-mediated signaling pathways and lead to a series of diseases such as fibrotic diseases, tumors and various ophthalmic diseases such as wet macular degeneration (AMD) and uveitis Therefore, PDGFRs have become important drug targets for the treatment of these diseases.
  • AMD wet macular degeneration
  • the inventors of the present invention have found a selective PDGFRs inhibitor, which can effectively alleviate tumors and various ophthalmic diseases caused by high expression or mutation of PDGFRs, ABL or FLT3 genes.
  • a pyrimidine-type small molecule compound which is one of the compound represented by formula (I), (II) or (III), its salt, its solvate, its hydrate or its prodrug;
  • R 1 is selected from H, -CF 3 or C 1 -C 5 alkyl
  • R 2 is selected from H, -CF 3 , C 1 -C 5 alkyl, C 1 -C 5 alkoxy, halogen, C 1 -C 5 alkoxycarbonyl
  • R 1 and R 2 form a five-membered ring with the two Cs connecting R 1 and R 2 ;
  • R 3 is a substituted or unsubstituted aryl group, and the substituents on the aryl group are selected from C 1 -C 5 alkyl groups;
  • R 4 is a substituted or unsubstituted aryl group, and the substituents on the aryl group are C 1 -C 5 alkyl, C 1 -C 5 alkoxy, piperazinyl, substituted piperazinyl, 1,1 -One or more of thiomorpholinyl dioxide, piperidinyl group and substituted piperidinyl group, the substituents on the piperazinyl group and piperidinyl group are selected from C 1 -C 5 alkyl or halogen.
  • the aryl group is a phenyl group.
  • the R 1 is selected from H, -CF 3 or methyl
  • R 2 is selected from H, -CF 3 , methyl, methoxy, F, Cl, ethoxycarbonyl
  • R 1 , R 2 Forms an S-containing five - membered ring with the two Cs connecting R1 and R2.
  • the R 3 is substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted quinolinyl, indanyl;
  • the substituents on the indolyl, indazolyl, quinoxalinyl and quinolinyl are methyl or ethyl.
  • the R 4 is a substituted or unsubstituted phenyl group, and the substituents on the phenyl group are methyl, methoxy, piperazinyl, substituted piperazinyl, 1,1-thiomorpholine dioxide
  • the substituted piperidinyl group, the piperidinyl group and the substituted piperidinyl group, the piperazinyl group and the substituents on the piperidinyl group are selected from methyl, ethyl, F or Cl.
  • One of compound 6n, its salt, its solvate, its hydrate or its prodrug, the structural formula is as follows:
  • the present invention also provides an application of the pyrimidine-based small molecule compound for preparing PDGFRs, ABL or FLT3 inhibitors.
  • the inhibitor can efficiently inhibit PDGFR ⁇ , PDGFR ⁇ , ABL or FLT3, and has moderate or weak inhibitory activity against other kinases.
  • the pyrimidine-based small molecule compound is used for preparing antitumor drugs.
  • the antitumor drug is used for inhibiting human juvenile osteosarcoma and hematological tumors.
  • the pyrimidine small molecule compound is used to prepare a medicine for treating ophthalmic diseases
  • the medicament is used for inhibiting the proliferation of fundus blood vessels, thereby relieving the ophthalmic diseases wet macular degeneration or uveitis.
  • the present invention also provides an application of the pyrimidine-based small molecule compound for preparing an antitumor drug
  • the antitumor drug is used for the treatment of leukemia, colon cancer, rectal cancer, gastric cancer, breast cancer, ovarian cancer, chorioepithelial cancer, malignant mole, head and neck squamous cell carcinoma, skin cancer, liver cancer, bladder cancer, lung cancer, One or more of prostate cancer, uterine cancer, kidney cancer, and lymphoma.
  • the pyrimidine-based small-molecule compound of the present invention has high inhibitory activity on PDGFR ⁇ , PDGFR ⁇ , ABL or FLT3 ⁇ kinases, but moderate or weak inhibitory activity on other kinases, so it has high selectivity;
  • the pyrimidine-based small molecule compound of the present invention has better anti-osteosarcoma and hematological tumor effects, and is a potential anti-tumor drug;
  • the pyrimidine-based small molecule compounds of the present invention can effectively inhibit the proliferation of fundus blood vessels, thereby relieving the ophthalmic diseases wet macular degeneration or uveitis.
  • Fig. 1 is the experimental result that active compound 6i inhibits the adhesion and metastasis of osteosarcoma cells in Example 7;
  • Figure 2 shows the results of the inhibitory activity of the active compound 6i in Example 8 on two types of PDGFR signaling pathway-related proteins in osteosarcoma cells.
  • the synthetic route is as follows:
  • the nucleophilic substitution reaction with 6-aminoindazole takes 1a-1i as raw material to generate intermediate 2a-2i. Then 4-(4-methylpiperazine)aniline undergoes a nucleophilic substitution reaction with the obtained intermediate 2a-i to generate the final product 3a-3i.
  • the synthetic route is as follows:
  • DIPEA N,N-Diisopropylethylamine
  • 2,4-Dichloro-5-methylpyrimidine (1d) reacts with 6-aminoindazole to produce intermediate 2d, which undergoes nucleophilic substitution with various substituted amines to generate final products 6a-6m.
  • Compound 2d was prepared according to Example 1.
  • Compound 2d (259.7 mg, 1 mmol) and 4-(4-methylpiperazine)aniline (191.27 mg, 1 mmol) were dissolved in 4 ml of methanol, and TFA (148.56 ⁇ L, 2 mmol) was added. , warmed to 80 °C, and monitored the reaction by TLC. After the completion of the reaction, it was cooled to room temperature, the resulting mixture was adjusted to neutral pH with saturated sodium bicarbonate, extracted with ethyl acetate (3 ⁇ 25 mL), washed with saturated brine, dried over anhydrous Na 2 SO 4 and concentrated, passed through silica gel Column chromatography gave product 6a.
  • the method used in the experiment is Caliper Mobility Shift Assay, which is a detection platform based on the mobility detection technology of microfluidic chip technology.
  • Experimental procedure configure 1.25x kinase reaction buffer (62.5mmol/L HEPES, pH 7.5; 0.001875% Brij-35; 12.5mmol/LMgCl 2 ; 2.5mM DTT) and kinase reaction stop solution (100mmol/L HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3); add 10 ⁇ L of 2.5x kinase solution (in 1.25x kinase reaction buffer) to 5 ⁇ L of 5x concentration compound solution (dissolved in DMSO, diluted 10 times with water) Add kinase), incubate at room temperature for 10 min, then add 10 ⁇ L of 2.5x substrate peptide solution (add FAM-labeled peptide and ATP in 1.25x kinase reaction buffer), and add 25 ⁇ L of kina
  • the inhibitory activity of the active compound against various other kinases is determined to characterize the kinase selectivity of the active inhibitor.
  • the log-phase osteosarcoma cells were seeded in a 96-well plate at a cell concentration of 1500 cells/well, with 200 ⁇ L of cell suspension per well, and cultured for 6 h.
  • the samples were prepared into 0.5, 2.5, 5, 10, 25 ⁇ mol/L solutions with 5 concentration gradients, each sample was set up with 5 duplicate wells, placed in an incubator for 48 hours (37 ° C, 5% CO 2 ), and MTT was added.
  • Example 7 Active compound 6i inhibits the adhesion and metastasis of osteosarcoma cells
  • 96-well plates were pre-incubated with human plasma fibronectin (Human Plasma Fibronectin), inoculated with osteosarcoma cells treated with 0, 0.1, 0.2, 0.4 ⁇ M 6i and 0.4 ⁇ M Pazopanib, 0.4 ⁇ M Imatinib for 48 hours, 5 ⁇ 10 per well.
  • human plasma fibronectin Human Plasma Fibronectin
  • Osteosarcoma cells treated with 0, 0.1, 0.2, 0.4 ⁇ M 6i and 0.4 ⁇ M Pazopanib, 0.4 ⁇ M Imatinib at a density of 5 ⁇ 10 for 48 h were seeded into 6 -well plates, and RMPL 1640 medium containing 10% serum was added. Put it into the incubator to make it adhere to the wall to form a monolayer of cells, use a 200uL pipette tip to make "+" cross scratches, wash three times with sterile PBS, add 2.5 ⁇ LTCS-containing basal medium, respectively, at 0h, 24, 48h Photographs were taken under an inverted microscope, and the migration distance was measured with Imag J software.
  • Example 8 Inhibitory activity of active compound 6i on PDGFR signaling pathway-related proteins in two osteosarcoma cells
  • the medium was aspirated, washed with PBS three times, and the total protein was extracted after lysis, and the phosphorylation levels of PDGFR signaling pathway-related proteins were detected by Western Blot.
  • the active compound 6i had a strong inhibitory activity on human immortalized human cerebral microvascular endothelial cells (HCMEC/D3) and human cerebral perivascular cells (HBVP) compared with several positive drugs, while at low concentrations it inhibited normal human cerebrovascular cells.
  • HCMEC/D3 human immortalized human cerebral microvascular endothelial cells
  • HBVP human cerebral perivascular cells
  • the retinal cell ARPE-19 has almost no inhibitory activity, indicating that the active compound 6i can effectively inhibit the proliferation of retinal blood vessels, thereby relieving ophthalmic diseases such as wet macular degeneration or uveitis, with low toxicity.

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Abstract

本发明公开了一种嘧啶类小分子化合物及其应用，该嘧啶类小分子化合物对PDGFRα和PDGFRβ激酶具有高效的抑制活性，而对其他激酶抑制活性较弱，因而具有很高的选择性，可以作为一种潜在的抗肿瘤或缓解眼科疾病湿性黄斑变性或葡萄膜炎的药物。

Description

一种嘧啶类小分子化合物及其应用 技术领域
本发明属于生物医药领域，具体涉及一种嘧啶类小分子化合物及其制备方法和应用。
背景技术
血小板衍生生长因子受体(PDGFRs)共有PDGFRα和PDGFRβ两个亚型，它们在生物体的生长、发育、血管形成和组织创伤修复的过程中发挥着重要作用。正常生理条件下，除了在发育过程和组织创伤修复过程中，PDGFRs信号通路在成体中一般处于静息状态。PDGFRs过表达、基因突变和基因重排会导致PDGFRs介导的信号通路的异常激活，并导致一系列疾病如纤维化疾病、肿瘤和各种眼科疾病，如湿性黄斑变性(AMD)以及葡萄膜炎等，因此PDGFRs已经成为治疗这些疾病的重要药物靶点。
目前报道的针对PDGFRs选择性的抑制剂包括伊马替尼、CP-673451等，这些抑制剂通常存在激酶抑制活性差、多靶点抑制导致的毒副作用大以及易导致耐药等多种缺陷。因此，有必要提供一类选择性抑制PDGFRα或PDGFRβ、以及双靶向于PDGFRα和PDGFRβ的抑制剂，以便为精准靶向医疗提供研究基础。
发明内容
本发明的发明人经过实验，发现了一种选择性PDGFRs的抑制剂，该抑制剂可以有效缓解PDGFRs、ABL或FLT3基因高表达或突变引起的肿瘤及各类眼科疾病。
本发明的技术方案如下：
一种嘧啶类小分子化合物，为式(I)、(II)或(III)所示的化合物、其盐、其溶剂化物、其水合物或其前药中的一种；
Figure PCTCN2021140401-appb-000001
Figure PCTCN2021140401-appb-000002
式(I)～(III)中，R 1选自H、-CF 3或C 1～C 5烷基；R 2选自H、-CF 3、C 1～C 5烷基、C 1～C 5烷氧基、卤素、C 1～C 5烷氧羰基；或者R 1、R 2与连接R 1和R 2的两个C形成五元环；
R 3为取代或者未取代的芳基，该芳基上的取代基选自C 1～C 5烷基；
R 4为取代或者未取代的芳基，所述芳基上的取代基为C 1～C 5烷基、C 1～C 5烷氧基、哌嗪基、取代的哌嗪基、1,1-二氧化硫代吗啉基、哌啶基、取代的哌啶基中的一个或者多个，所述哌嗪基和哌啶基上的取代基选自C 1～C 5烷基或者卤素。作为优选，所述的芳基为苯基。
作为优选，所述的R 1选自H、-CF 3或甲基；R 2选自H、-CF 3、甲基、甲氧基、F、Cl、乙氧羰基；或者R 1、R 2与连接R 1和R 2的两个C形成含S五元环。
作为优选，所述的R 3为取代或者未取代的吲哚基、取代或者未取代的吲唑基、取代或者未取代的喹喔啉基、取代或者未取代的喹啉基、茚满基；所述吲哚基、吲唑基、喹喔啉基、喹啉基上的取代基为甲基或者乙基。
作为优选，所述R 4为取代或者未取代的苯基，所述苯基上的取代基为甲基、甲氧基、哌嗪基、取代的哌嗪基、1,1-二氧化硫代吗啉基、哌啶基、取代的哌啶基中的一个或者多个，所述哌嗪基和哌啶基上的取代基选自甲基、乙基、F或者Cl。
作为优选，为化合物3a、化合物3b、化合物3c、化合物3d、化合物3e、化合物3f、化合物3g、化合物3h、化合物3i、化合物5a、化合物5b、化合物5c、化合物5d、化合物5e、化合物5f、化合物5g、化合物5h、化合物5i、化合物5j、化合物5k、化合物6a、化合物6b、化合物6c、化合物6d、化合物6e、化合物6f、化合物6g、化合物6h、化合物6i、化合物6j、化合物6k、化合物6m、化合物6n、其盐、其溶剂化合物、其水合物或者其前药中的一种，结构式如下：
Figure PCTCN2021140401-appb-000003
Figure PCTCN2021140401-appb-000004
本发明还提供了一种所述的嘧啶类小分子化合物的应用，所述的嘧啶类小分子化合物用于制备PDGFRs、ABL或FLT3抑制剂。
作为优选，所述的抑制剂能高效抑制PDGFRα、PDGFRβ、ABL或FLT3，而对其 他激酶抑制活性中等或较弱。
作为优选，所述的嘧啶类小分子化合物用于制备抗肿瘤药物。
作为优选，所述的抗肿瘤药物用于抑制人青少年骨肉瘤、血液肿瘤。
作为优选，所述的嘧啶类小分子化合物用于制备治疗眼科疾病的药物；
所述的药物用于抑制眼底血管增生，进而缓解眼科疾病湿性黄斑变性或葡萄膜炎。
本发明还提供了一种所述的嘧啶类小分子化合物的应用，所述的嘧啶类小分子化合物用于制备抗肿瘤药物；
所述的抗肿瘤药物用于治疗白血病、结肠癌、直肠癌、胃癌、乳腺癌、卵巢癌、绒毛膜上皮癌、恶性葡萄胎、头颈部鳞癌、皮肤癌、肝癌、膀胱癌、肺癌、前列腺癌、子宫癌、肾癌、淋巴瘤中的一种或者多种。
同现有技术相比，本发明的有益效果体现在：
(1)本发明的嘧啶类小分子化合物对PDGFRα、PDGFRβ、ABL或FLT3β激酶具有高效的抑制活性，而对其他激酶抑制活性中等或较弱，因而具有很高的选择性；
(2)本发明的嘧啶类小分子化合物具有更好的抗骨肉瘤、血液肿瘤效果，是一种潜在的抗肿瘤药物；
(3)本发明的嘧啶类小分子化合物能有效抑制眼底血管增生，进而缓解眼科疾病湿性黄斑变性或葡萄膜炎。
附图说明
图1为实施例7中活性化合物6i抑制骨肉瘤细胞的黏附和转移实验结果；
图2为实施例8中活性化合物6i对两种骨肉瘤细胞PDGFR信号通路相关蛋白的抑制活性结果。
具体实施方式
实施例1：化合物3a-3i的化学合成
合成路线如下：
Figure PCTCN2021140401-appb-000005
一般过程如下：
以1a-1i为原料与6-氨基吲唑发生亲核取代反应，生成中间体2a-2i。然后4-(4-甲基哌嗪)苯胺与得到的中间体2a-i发生亲核取代反应生成终产物3a-3i。
以化合物3a合成为例，具体过程如下：
将2,4-二氯-5-氟嘧啶(333.94mg，2mmol)和N,N-二异丙基乙胺(DIPEA)(516.96mg，4mmol)溶解在DMF(4mL)中并冷却至0℃。再向混合液中逐滴加入溶于DMF(2mL)中的6-氨基吲唑(266.3mg，2mmol)。将反应混合物在0℃下搅拌约1小时。接下来，移去冰浴，将反应混合物在室温下搅拌，并在通过TLC监测反应，将所得混合物用乙酸乙酯(3×25mL)萃取，用饱和食盐水洗涤，经无水Na 2SO 4干燥并浓缩,通过硅胶柱层析得到产物2a.
将化合物2a(263.66mg，1mmol)和4-(4-甲基哌嗪)苯胺(191.27mg，1mmol)溶解在甲醇(4ml)中，再加入三氟乙酸(TFA)(148.56μL，2mmol)，升温至80℃，并在通过TLC监测反应。反应完成后冷却至室温，将所得混合物用饱和碳酸氢钠调PH至中性，用乙酸乙酯(3×25mL)萃取，饱和食盐水洗涤，经无水Na 2SO 4干燥并浓缩，通过硅胶柱层析得到终产物3a。
化合物3a-3i的表征数据如下：
5-氟-N 4-(1氢-吲唑-6-基)-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(3a)黄色固体,产率：26.9％. 1H NMR(500MHz,DMSO-d 6)δ12.93(s,1H),9.41(s,1H),8.99(s,1H),8.08(d,J＝3.5Hz,1H),8.01(s,1H),7.91(s,1H),7.69(d,J＝8.5Hz,1H),7.52(d,J＝8.5Hz,3H),6.81(d,J＝8.5Hz,2H),3.06(s,4H),2.57(s,4H),2.30(s,3H). 13C NMR(126MHz,DMSO-d 6)δ170.28,155.87,149.81,149.73,145.77,140.26,139.40,137.05,133.30,133.15,120.02,119.33,116.55,115.88,101.58,54.61,48.85,14.05；ESI-MS m/z:419.2(M﹢H) +.
5-氯-N 4-(1氢-吲唑-6-基)-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(3b) 1H NMR(400MHz,DMSO-d 6)δ9.06(s,1H),8.89(s,1H),8.10(s,1H),8.04(s,1H),7.76(s,1H),7.71(d,J＝8.6Hz,1H),7.42(d,J＝8.8Hz,2H),7.36(d,J＝8.6Hz,1H),6.69(d,J＝8.8Hz,2H),5.76(s,1H),2.99(s,4H),2.44(s,4H),2.21(s,3H). 13C NMR(100MHz,DMSO-d 6)δ158.40,156.64,155.15,146.47,137.26,133.78,133.03,120.79,120.44,120.34,118.62,116.20,104.46,104.00,103.67,55.17,49.34,46.27.
N 4-(1氢-吲唑-6-基)-N 2-(4-(4-甲基哌嗪-1-基)苯基)-5-(三氟甲基)嘧啶-2,4-二胺(3c)White solid,16.5％yield. 1H NMR(400MHz,DMSO-d 6)δ9.70(s,1H),8.63(s,1H),8.33(s,1H),7.92(s,1H),7.72(dd,J＝5.6,3.2Hz,1H),7.68–7.65(m,1H),7.48(d,J＝8.8Hz, 1H),7.29(d,J＝8.8Hz,3H),7.01(d,J＝8.8Hz,2H),3.18–3.14(m,4H),2.51(d,J＝1.6Hz,4H),2.24(s,3H). 13C NMR(126MHz,DMSO-d 6)δ166.94,160.70,155.18,148.42,140.43,138.08,133.18,131.68,131.47,129.73,128.62,127.55,126.84,119.81,118.54,115.35,99.13,54.50,48.25,45.65；ESI-MS m/z:469.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(3d)White solid.31.5％yield. 1H NMR(500MHz,DMSO-d 6)δ12.89(s,1H),8.74(s,1H),8.36(s,1H),8.00(s,1H),7.86(s,1H),7.82(s,1H),7.68(d,J＝9.0Hz,1H),7.51(d,J＝9.0Hz,2H),7.42(d,J＝9.0Hz,1H),6.72(d,J＝9.0Hz,2H),2.99(d,J＝4.0Hz,4H),2.46(d,J＝4.5Hz,4H),2.23(s,3H),2.12(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.36,158.45,155.73,145.35,140.38,138.06,133.62,133.23,119.71,119.18,117.52,115.93,105.03,102.29,54.64,48.98,45.61,13.49；ESI-MS m/z:415.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-5-甲氧基-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(3e) 1H NMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.65(s,1H),7.96(s,2H),7.83(s,1H),7.65(d,J＝8.7Hz,1H),7.55-7.53(m,3H),6.79(d,J＝9.0Hz,2H),3.86(s,3H),3.01(s,4H),2.45(s,4H),2.22(s,3H). 13C NMR(100MHz,DMSO-d 6)δ154.60,152.26,145.77,138.16,137.40,134.87,134.48,133.77,120.40,119.79,119.69,119.52,117.10,116.54,101.56,57.42,55.25,49.61,46.27.
乙基-4-((1氢-吲唑-6-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-5-羧酸酯(3f)Yellow solid,95.1％yield. 1H NMR(400MHz,DMSO-d 6)δ13.05(s,1H),10.34(s,1H),9.86(s,1H),8.73(s,1H),8.08(s,1H),7.76(d,J＝8.4Hz,1H),7.53(d,J＝5.6Hz,2H),7.29(d,J＝7.3Hz,1H),6.81(s,2H),4.34(q,J＝6.8Hz,2H),3.17(s,4H),2.75(s,4H),2.43(s,3H),1.37(t,J＝7.0Hz,3H). 13C NMR(100MHz,DMSO-d 6)δ166.39,160.64,160.44,153.10,146.23,140.24,136.11,136.03,133.47,133.43,131.57,121.48,120.57,115.83,60.36,53.65,47.55,44.23,14.16；ESI-MS m/z:473.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-N 2-(4-(4-甲基哌嗪-1-基)苯基)-6-(三氟甲基)嘧啶-2,4-二胺(3g)Yellow solid,50.7％yield. 1H NMR(500MHz,DMSO-d 6)δ13.07(s,1H),9.47(s,1H),8.81(s,1H),8.31(s,1H),8.08(s,1H),7.74(d,J＝8.5Hz,1H),7.57(s,1H),7.26(s,2H),7.17(s,1H),6.43(s,2H),2.93(s,4H),2.41(s,4H),2.20(s,3H). 13C NMR(126MHz,DMSO-d 6)δ160.52,157.77,155.55,155.51,146.34,140.18,136.35,133.20,131.54,126.00,123.86,120.76,120.73,120.52,119.94,115.31,54.58,48.62,45.70；ESI-MS m/z: 469.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-6-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(3h)，Yellow liquid,29.3％yield. 1H NMR(500MHz,DMSO-d 6)δ12.76(s,1H),9.24(s,1H),8.85(s,1H),7.96(s,1H),7.82(s,1H),7.64(d,J＝8.5Hz,1H),7.60(d,J＝8.5Hz,2H),7.32(d,J＝8.5Hz,1H),6.84(d,J＝8.0Hz,2H),6.07(s,1H),3.05(s,4H),2.50(s,4H),2.24(s,3H),2.20(s,3H). 13C NMR(126MHz,DMSO-d 6)δ164.46,161.29,159.59,146.55,140.88,139.50,133.04,132.11,121.71,120.21,119.76,117.86,116.03,115.10,97.80,54.45,48.48,45.62,23.61；ESI-MS m/z:415.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-6-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)噻吩[2,3-d]嘧啶-2,4-二胺(3i)， 1H NMR(400MHz,DMSO-d 6)δ9.51(s,1H),8.86(s,1H),8.05(d,J＝5.4Hz,1H),8.03(s,1H),7.93(s,1H),7.71(d,J＝8.7Hz,1H),7.62(d,J＝9.0Hz,2H),7.54-7.49(m,1H),7.18(d,J＝5.4Hz,1H),6.80(d,J＝9.0Hz,2H),3.03(s,4H),2.44(s,4H),2.20(S,3H). 13C NMR(100MHz,DMSO-d 6)δ162.66,158.62,155.98,146.08,140.80,137.97,134.18,134.11,133.81,123.85,120.58,120.51,120.40,119.98,117.83,116.43,107.67,103.16,55.24,49.54,46.29.
实施例2：化合物5a-5j的化学合成
合成路线如下：
Figure PCTCN2021140401-appb-000006
一般过程如下：
2,4-二氯-5-甲基嘧啶(1d)与各种取代胺发生亲核取代反应，生成中间体4a-4j。然后4-(4-甲基哌嗪)苯胺与得到的中间体4a-4j发生亲核取代反应生成终产物5a-5j。
以化合物5a合成为例，具体过程如下：
N,N-二异丙基乙胺(DIPEA)(516.96mg，4mmol)溶解在DMF(4mL)中并冷却至0℃。再向混合液中逐滴加入溶于DMF(2mL)中的5-氨基吲哚(264.3mg，2mmol)。将反应混合物在0℃下搅拌约1小时。接下来，移去冰浴，将反应混合物在室温下搅 拌，并在通过TLC监测反应。反应完成后将所得混合物用乙酸乙酯(3×25mL)萃取，用饱和食盐水洗涤，经无水Na 2SO 4干燥并浓缩，通过硅胶柱层析得到中间体4a。将4a(258.7mg，1mmol)和4-(4-甲基哌嗪)苯胺(191.27mg，1mmol)溶解在甲醇(4ml)中，再加入TFA(148.56μL，2mmol)，升温至80℃，并在通过TLC监测反应。反应完成后冷却至室温,将所得混合物用饱和碳酸氢钠调PH至中性，用乙酸乙酯(3×25mL)萃取，饱和食盐水洗涤，经无水Na 2SO 4干燥并浓缩，通过硅胶柱层析得到终产物5a。
得到的化合物5a-5k的结构和表征数据如下：
N 4-(1氢-吲哚-5-基)-5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(5a)，Pink solid,41.91％yield. 1H NMR(500MHz,DMSO-d 6)δ11.00(s,1H),8.54(s,1H),8.09(s,1H),7.83(s,1H),7.76(s,1H),7.47(d,J＝9.0Hz,2H),7.39–7.30(m,2H),7.25(d,J＝8.5Hz,1H),6.65(d,J＝9.0Hz,2H),6.39(s,1H),2.96(d,J＝4.5Hz,4H),2.47–2.38(m,4H),2.21(s,3H),2.09(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.95,158.57,154.90,145.17,133.84,133.01,131.42,127.55,125.44,119.65,118.64,115.98,114.77,110.70,104.30,101.05,54.74,49.16,45.75,13.52；ESI-MS m/z:414.2(M﹢H) ﹢.
N 4-(1氢-吲哚-4-基)-5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(5b)Gray solid,74.49％yield. 1H NMR(400MHz,DMSO-d 6)δ11.15(s,1H),8.60(s,1H),8.08(s,1H),7.85(s,1H),7.43–7.35(m,3H),7.31(t,J＝2.8Hz,1H),7.26(d,J＝8.1Hz,1H),7.12(t,J＝8.0Hz,1H),6.65(d,J＝8.8Hz,2H),6.49–6.33(m,1H),3.02–2.96(m,4H),2.50–2.44(m,4H),2.25(s,3H),2.19(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.94,158.51,155.20,145.12,136.81,133.78,131.53,124.20,123.06,120.90,119.42,115.74,114.12,107.71,104.64,99.56,54.67,49.10,45.67,13.38；ESI-MS m/z:414.2(M﹢H) ﹢.
5甲基-N 4-(1-甲基-1氢-吲哚-5-基)-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(5c)，Gray solid,52.1％yield. 1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.18(s,1H),7.90(d,J＝2.0Hz,1H),7.80(s,1H),7.50(d,J＝9.2Hz,2H),7.43(d,J＝8.8Hz,1H),7.33(dd,J＝7.2,2.8Hz,2H),6.69(d,J＝9.2Hz,2H),6.40(d,J＝2.8Hz,1H),3.83(s,3H),3.04–2.97(m,4H),2.49–2.43(m,4H),2.24(s,3H),2.12(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.88,158.55,154.96,145.17,133.76,133.55,131.65,129.71,127.89,119.73,118.59,115.82,114.93,109.00,104.29,100.22,54.73,49.02,45.75,32.51,13.52；ESI-MS m/z:428.6(M﹢H) ﹢.
N 4-(1氢-吲唑-5-基)-5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(5d) Yellow oil,63.5％yield. 1H NMR(500MHz,DMSO-d 6)δ8.80(s,1H),8.76(d,J＝3.5Hz,1H),8.56(s,1H),8.50(s,1H),8.12(d,J＝8.0Hz,1H),8.04(dd,J＝9.0,2.0Hz,1H),7.96–7.89(m,3H),7.48(d,J＝8.5Hz,2H),6.78(d,J＝9.0Hz,1H),3.06–3.00(m,4H),2.48–2.43(m,4H),2.23(s,2H),2.16(s,3H). 13C NMR(126MHz,DMSO-d 6)δ158.89,158.64,156.12,148.42,145.85,144.42,138.08,135.19,133.13,128.64,128.28,125.73,121.23,120.85,116.54,115.85,105.27,54.73,48.98,45.76,13.48；ESI-MS m/z:414.3(M﹢H) ﹢.
5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)-N 4-(苯并吡嗪-6-基)-嘧啶-2,4-二胺(5e)Yellow solid,68.8％yield. 1H NMR(500MHz,DMSO-d 6δ8.90(s,1H),8.86(s,1H),8.79(d,J＝1.5Hz,1H),8.76(s,1H),8.57(s,1H),8.32(dd,J＝9.0,2.0Hz,1H),8.00(d,J＝9.0Hz,1H),7.96(s,1H),7.53(d,J＝8.5Hz,2H),6.80(d,J＝8.5Hz,2H),3.02(s,4H),2.45(s,4H),2.22(s,3H),2.20(s,3H). 13C NMR(126MHz,DMSO-d 6)δ158.69,158.50,156.56,145.72,145.46,143.27,143.18,141.62,138.81,133.13,128.52,126.27,120.34,116.74,115.96,105.74,54.72,49.02,45.76,13.56；ESI-MS m/z:427.2(M﹢H) ﹢.
5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)-N 4-(喹喔啉-7-基)-嘧啶-2,4-二胺(5f)Gray solid,44.6％yield. 1H NMR(500MHz,DMSO)δ8.75(dd,J＝6.0,2.5Hz,2H),8.53(s,1H),8.50(s,1H),8.11(d,J＝7.5Hz,1H),8.02(d,J＝9.0Hz,1H),7.95–7.89(m,2H),7.45(t,J＝7.0Hz,3H),6.78(d,J＝8.5Hz,2H),3.02(d,J＝4.0Hz,4H),2.45(d,J＝4.5Hz,4H),2.22(s,3H),2.15(s,3H). 13C NMR(126MHz,DMSO-d 6)δ158.90,158.62,156.10,148.45,145.88,144.29,138.04,135.31,133.03,128.55,128.27,125.76,121.29,120.98,116.56,115.86,105.31,54.64,48.89,45.67,13.42；ESI-MS m/z:426.2(M﹢H) ﹢.
5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)-N 4-(5,6,7,8-四氢萘-2-基)-嘧啶-2,4-二胺(5g)，Gray solid,71.2％yield. 1H NMR(400MHz,DMSO-d 6)δ8.62(s,1H),7.96(s,1H),7.79(s,1H),7.37(d,J＝9.2Hz,2H),7.23–7.14(m,2H),7.08–7.01(m,1H),6.64(d,J＝8.8Hz,2H),3.03–2.95(m,4H),2.83(s,2H),2.61(s,2H),2.51–2.47(m,4H),2.26(s,3H),2.10(s,3H),1.69(s,4H). 13C NMR(126MHz,DMSO-d 6)δ160.32,158.46,154.96,144.92,137.86,137.35,134.04,133.50,126.21,125.11,124.56,118.99,115.78,104.01,54.60,49.08,45.58,29.32,24.52,22.43,22.36,13.28；ESI-MS m/z:429.3(M﹢H) ﹢.
N 4-(2,3-二氢-1H-茚-5-基)-5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)-嘧啶-2,4-二胺(5h)，Yellow solid,43.4％yield. 1H NMR(400MHz,DMSO)δ8.70(s,1H),8.12(s,1H),7.83(s,1H),7.65(d,J＝1.2Hz,1H),7.51(d,J＝9.2Hz,2H),7.38(dd,J＝8.0,1.6Hz,1H),7.18(d, J＝8.0Hz,1H),6.79(d,J＝9.2Hz,2H),3.07–3.01(m,4H),2.87(t,J＝7.6Hz,4H),2.50–2.45(m,4H),2.24(s,3H),2.10(s,3H),2.05(dd,J＝14.8,7.6Hz,2H). 13C NMR(126MHz,DMSO)δ159.24,158.51,155.42,145.43,143.59,138.01,137.82,133.56,123.63,120.23,120.00,118.48,115.84,104.63,54.71,49.08,45.73,32.58,31.81,25.29,13.48；ESI-MS m/z:415.3(M﹢H) ﹢.
5-甲基-N 4-(3-甲基-1氢-吲唑-6-基)-N 2-(4-(4-甲基哌嗪-1-基)苯基)-嘧啶-2,4-二胺(5i)，White solid,35.4％yield. 1H NMR(500MHz,DMSO-d 6)δ12.48(s,1H),8.73(s,1H),8.37(s,1H),7.85(s,1H),7.80(s,1H),7.59(d,J＝8.0Hz,1H),7.51(d,J＝7.5Hz,2H),7.36(d,J＝8.0Hz,1H),6.72(d,J＝8.0Hz,2H),3.01(s,4H),2.47(s,4H),2.25(s,4H),2.12(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.41,158.41,155.63,145.20,141.34,138.09,133.68,119.71,119.10,118.55,116.73,115.95,105.08,102.37,54.45,48.77,45.36,13.52,11.69；ESI-MS m/z:429.3(M﹢H) ﹢.
叔丁基(2-(6-((5-甲基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-嘧啶-4基)氨基)-2氢-吲唑-2-基)乙基)氨基甲酸酯(5j)，Gray solid,12.7％yield. 1H NMR(500MHz,DMSO-d 6)δ8.75(s,1H),8.21(s,1H),8.14(s,2H),7.84(s,1H),7.61(d,J＝8.5Hz,1H),7.55(d,J＝8.5Hz,1H),7.28(d,J＝8.0Hz,1H),7.05(s,1H),6.79(d,J＝8.5Hz,2H),4.41(d,J＝6.0Hz,2H),3.49–3.45(m,2H),3.02(s,4H),2.45(s,4H),2.21(s,3H),2.12(s,3H),1.37(s,9H). 13C NMR(126MHz,DMSO-d 6)δ159.25,158.53,155.58,155.51,148.76,145.43,137.09,133.50,123.78,119.93,119.78,119.28,118.05,116.03,107.06,105.02,77.95,54.71,52.05,49.09,45.73,40.51,28.17,13.52；ESI-MS m/z:558.3(M﹢H) ﹢.
5-甲基-N 4-(1-甲基-1氢-吲唑-6-基)-N 2-(4-(4-甲基哌嗪-1-基)苯基)-嘧啶-2,4-二胺(5k)Gray solid,54.1％yield. 1H NMR(400MHz,DMSO-d 6)δ8.83(s,1H),8.44(s,1H),8.14(s,1H),7.97(s,1H),7.91(s,1H),7.68(s,1H),7.52(s,2H),7.44(s,1H),6.75(s,2H),3.91(s,3H),3.02(s,4H),2.46(s,4H),2.24(s,3H),2.17(s,3H). 13C NMR(100MHz,DMSO-d 6)δ159.17,158.41,155.84,145.55,140.11,138.42,133.40,132.08,120.14,119.46,117.03,115.78,105.23,100.67,54.71,48.97,45.73,35.20,13.54；ESI-MS m/z:429.2(M﹢H) ﹢.
实施例3：化合物6a-6m的化学合成
化合物6a-6m的合成路线如下：
Figure PCTCN2021140401-appb-000007
一般合成路线如下：
2,4-二氯-5-甲基嘧啶(1d)与6氨基吲唑反应生产中间体2d，中间体2d再与各种取代胺发生亲核取代反应，生成终产物6a-6m。
以化合物6a合成为例，具体合成如下：
化合物2d按照实施例1制备，将化合物2d(259.7mg，1mmol)和4-(4-甲基哌嗪)苯胺(191.27mg，1mmol)溶解在4ml甲醇中,再加入TFA(148.56μL，2mmol)，升温至80℃，并在通过TLC监测反应。反应完成后冷却至室温,将所得混合物用饱和碳酸氢钠调PH至中性，用乙酸乙酯(3×25mL)萃取，饱和食盐水洗涤，经无水Na 2SO 4干燥并浓缩,通过硅胶柱层析得到产物6a。
化合物6a-6m的结构和表征数据如下：
N 4-(1氢-吲唑-6-基)-5-甲基-N 2-(4-吗啡啉苯基)-嘧啶-2,4-二胺(6a)，Yellow solid,33.9％yield. 1H NMR(500MHz,DMSO-d 6)δ12.89(s,1H),8.72(s,1H),8.35(s,1H),8.00(s,1H),7.86(s,1H),7.82(s,1H),7.67(d,J＝8.5Hz,1H),7.50(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,1H),6.70(d,J＝9.0Hz,2H),2.89(d,J＝4.5Hz,4H),2.82(d,J＝4.5Hz,4H),2.12(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.35,158.46,155.74,146.12,140.43,138.06,133.52,133.18,119.72,119.17,117.53,115.92,104.99,102.32,50.38,45.62,13.48；ESI-MS m/z:402.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-5-甲基-N 2-(4-(哌嗪-1-基)苯基)-嘧啶-2,4-二胺(6b)，Yellow solid,29.4％yield. 1H NMR(500MHz,DMSO-d 6)δ12.93(s,1H),8.93(s,1H),8.55(s,1H),8.01(s,1H),7.84(d,J＝18.5Hz,2H),7.69(d,J＝8.5Hz,1H),7.50(d,J＝9.0Hz,2H),7.41(d,J＝8.0Hz,1H),6.73(d,J＝8.5Hz,2H),3.74–3.67(m,4H),3.01–2.92(m,4H),2.13(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.84,156.85,152.41,146.01,140.31,137.43,133.25,132.61,120.52,119.89,119.51,117.78,115.57,105.57,103.16,66.11,49.26,13.41；ESI-MS m/z:401.2(M﹢H) ﹢.
N 2-(4-(4,4-二氟哌嗪-1-基)苯基)-N 4-(1氢-吲唑-6-基)-5-甲基嘧啶-2,4-二胺(6c)， Gray solid,61.1％yield. 1H NMR(500MHz,DMSO-d 6)δ12.98(s,1H),8.79(s,1H),8.44(s,1H),7.99(s,1H),7.92(s,1H),7.86(s,1H),7.66(d,J＝8.5Hz,1H),7.55(d,J＝9.0Hz,2H),7.44(d,J＝8.5Hz,1H),6.79(d,J＝9.0Hz,2H),3.19–3.10(m,4H),2.14(s,3H),2.07–1.99(m,4H). 13C NMR(126MHz,DMSO-d 6)δ159.38,158.36,155.70,144.03,140.58,140.41,138.04,134.15,133.18,119.67,119.14,117.52,116.94,105.19,102.39,54.87,46.85,33.07,13.54；ESI-MS m/z:436.2(M﹢H) ﹢.
4-(4-((4-((1氢-吲唑-6-基)氨基)-5-甲基嘧啶-2-基)氨基)苯基)硫代吗啉1,1-二氧化物(6d)，Gray solid,81.4％yield. 1H NMR(500MHz,DMSO-d 6)δ13.00(s,1H),8.83(s,1H),8.45(s,1H),8.01–7.84(m,3H),7.67(d,J＝8.5Hz,1H),7.57(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,2H),3.62(s,4H),3.11(s,4H),2.14(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.39,158.85,158.29,155.68,142.01,138.02,134.28,133.10,119.84,119.67,119.11,117.52,116.69,105.32,102.49,49.91,47.86,13.56；ESI-MS m/z:450.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-N 2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5-甲基嘧啶-2,4-二胺(6e)，Gray solid,26.6％yield. 1H NMR(500MHz,DMSO-d 6)δ12.92(s,1H),8.45(s,1H),7.98(s,1H),7.91-7.81(m,3H),7.64(d,J＝9.0Hz,1H),7.41(d,J＝8.5Hz,1H),7.26(s,1H),6.61(s,1H),6.31(d,J＝7.5Hz,1H),3.81(s,3H),3.07(s,4H),2.48(s,4H),2.24(s,3H),2.13(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.34,158.44,155.70,149.45,146.79,140.43,138.05,133.17,121.81,120.86,119.72,119.07,117.28,106.97,105.48,101.85,100.14,55.60,54.71,48.97,45.74,13.47；ESI-MS m/z:445.3(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-N 2-(3-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5-甲基嘧啶-2,4-二胺(6f)，Yellow solid,55.9％yield. 1H NMR(500MHz,DMSO-d 6)δ12.85(s,1H),8.79(s,1H),8.37(s,1H),7.99(s,1H),7.89(s,1H),7.81(s,1H),7.66(d,J＝8.5Hz,1H),7.40(d,J＝8.5Hz,1H),7.29(s,1H),7.24(d,J＝9.5Hz,1H),6.63(s,1H),3.43(s,3H),2.86(s,4H),2.47(s,4H),2.24(s,3H),2.13(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.28,158.30,155.70,151.91,140.40,138.05,136.65,134.85,133.21,119.78,119.18,117.76,117.43,110.62,105.47,103.75,102.14,55.01,54.84,50.31,45.84,13.50；ESI-MS m/z:445.2(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-5-甲基-N 2-(4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(6g)，Yellow solid,29.4％yield. 1H NMR(500MHz,DMSO-d 6)δ12.93(s,1H),8.93(s,1H), 8.55(s,1H),8.01(s,1H),7.84(d,J＝18.5Hz,2H),7.69(d,J＝8.5Hz,1H),7.50(d,J＝9.0Hz,2H),7.41(d,J＝8.0Hz,1H),6.73(d,J＝8.5Hz,2H),3.74–3.67(m,4H),3.01–2.92(m,4H),2.13(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.84,156.85,152.41,146.01,140.31,137.43,133.25,132.61,120.52,119.89,119.51,117.78,115.57,105.57,103.16,66.11,49.26,13.41；ESI-MS m/z:401.2(M﹢H) ﹢.
N 2-(4-(4-乙基哌嗪-1-基)-2-甲氧基苯基)-N 4-(1氢-吲唑-6-基)-5-甲基嘧啶-2,4-二胺(6h)White solid,19.2％yield. 1H NMR(500MHz,DMSO-d 6)δ12.82(s,1H),8.38(s,1H),7.99(s,1H),7.91–7.82(m,3H),7.65(d,J＝8.5Hz,1H),7.39(d,J＝9.5Hz,1H),7.28(s,1H),6.61(d,J＝2.0Hz,1H),6.31(d,J＝10.0Hz,1H),3.81(s,3H),3.06(s,4H),2.51(s Hz,4H),2.38(q,J＝7.0Hz,2H),2.12(s,3H). 13C NMR(126MHz,DMSO-d 6)δ159.34,158.42,155.69,149.45,146.81,140.40,138.03,133.19,121.81,120.86,119.71,119.06,117.28,106.95,105.47,101.86,100.16,55.61,52.37,51.58,49.06,13.47,11.92；ESI-MS m/z:459.3(M﹢H) ﹢.
N 2-(4-(4-乙基哌嗪-1-基)-3-甲氧基苯基)-N 4-(1氢-吲唑-6-基)-5-甲基嘧啶-2,4-二胺(6i)Colorless oil,65.1％yield. 1H NMR(400MHz,DMSO-d 6)δ12.90(s,1H),8.82(s,1H),8.42(s,1H),7.99(s,1H),7.89(s,1H),7.85(s,1H),7.64(d,J＝8.4Hz,1H),7.41(d,J＝8.8Hz,1H),7.30(s,1H),7.25(d,J＝8.8Hz,1H),6.63(d,J＝8.8Hz,1H),5.33(s,1H),3.43(s,3H),2.86(s,4H),2.39-2.37(m,2H),2.13(s,4H),1.77(s,3H),1.22(t,J＝6.8Hz,1H). 13C NMR(126MHz,DMSO-d 6)δ159.29,158.27,155.68,151.90,140.42,138.07,136.66,134.84,133.18,119.74,119.12,117.71,117.39,110.60,105.52,103.74,102.17,52.63,52.07,51.67,50.36,13.53,11.87；ESI-MS m/z:459.3(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-5-甲基-N 2-(4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2,4-二胺(6j)，White solid,73.6％yield. 1H NMR(500MHz,DMSO-d 6)δ12.89(s,1H),8.71(s,1H),8.35(s,1H),7.99(s,1H),7.84(d,J＝12.5Hz,2H),7.67(d,J＝8.7Hz,1H),7.49(d,J＝8.9Hz,2H),7.42(d,J＝8.6Hz,1H),6.71(d,J＝8.9Hz,2H),3.52(d,J＝12.0Hz,2H),2.54(s,1H),2.30(s,4H),2.26–2.18(m,2H),1.80(d,J＝11.6Hz,3H),1.54–1.42(m,3H). 13C NMR(126MHz,DMSO-d 6)δ159.35,158.46,155.74,145.54,138.07,133.40,133.21,119.72,119.15,117.51,116.40,105.01,102.28,83.88,79.19,60.85,55.15,49.26,48.54,45.74,27.88,13.51；ESI-MS m/z:498.3(M﹢H) ﹢.
N 4-(1氢-吲唑-6-基)-N 2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5-甲基 嘧啶-2,4-二胺(6k)
Yellow solid,68.9％yield. 1H NMR(500MHz,DMSO-d 6)δ12.83(s,1H),8.38(s,1H),7.98(s,1H),7.85(d,J＝7.0Hz,3H),7.64(d,J＝8.5Hz,1H),7.38(d,J＝8.0Hz,1H),7.27(s,1H),6.60(s,1H),6.31(d,J＝7.0Hz,1H),3.80(s,3H),3.61(d,J＝12.0Hz,2H),2.58(t,J＝11.5Hz,3H),2.36–2.20(m,4H),2.13(d,J＝9.0Hz,6H),1.83(d,J＝11.3Hz,2H),1.56–1.42(m,2H). 13C NMR(126MHz,DMSO-d 6)δ159.36,158.47,155.66,150.46,149.64,146.99,138.02,133.30,121.54,121.21,119.78,119.04,117.34,107.47,105.40,101.95,100.62,60.84,55.57,54.98,49.11,48.46,45.63,27.76,13.39；ESI-MS m/z:528.3(M﹢H) ﹢.
(4-((4-((1氢-吲唑-6-基))氨基)-5-甲基嘧啶-2-基)氨基)苯基)(4-甲基哌嗪-1-基)甲酮(6m)，Colorless liquid,13.8％yield. 1H NMR(400MHz,DMSO-d 6)δ9.30(s,1H),8.53(s,1H),7.96(s,1H),7.88(s,1H),7.79(s,1H),7.71(d,J＝8.8Hz,2H),7.64(d,J＝8.4Hz,1H),7.33(d,J＝8.8Hz,1H),7.11(d,J＝8.8Hz,2H),2.84(s,4H),2.44(s,4H),2.10(s,3H),1.70(s,3H). 13C NMR(126MHz,DMSO-d 6)δ169.22,159.54,157.86,155.63,142.65,140.46,137.79,133.12,127.81,126.85,119.73,119.34,117.88,117.29,106.37,103.04,54.55,53.86,45.59,13.57；ESI-MS m/z:473.2(M﹢H) ﹢.
(4-((4-((1氢-吲唑-6-基))氨基)-5-甲基嘧啶-2-基)氨基)-N-(2-吗啡啉乙基)苯甲酰胺(6n)，White solid,60.2％yield. 1H NMR(500MHz,DMSO-d 6)δ13.02(s,1H),9.33(s,1H),8.59(s,1H),8.24(s,1H),8.15–7.88(m,3H),7.79(d,J＝8.0Hz,2H),7.71(d,J＝8.5Hz,1H),7.63(d,J＝8.0Hz,2H),7.46(d,J＝8.0Hz,1H),3.57(s,4H),2.43(d,J＝13.5Hz,6H),2.17(s,3H). 13C NMR(126MHz,DMSO-d 6)δ165.92,159.44,157.76,155.56,143.90,140.41,137.84,133.18,127.69,125.85,119.69,119.25,117.63,116.82,106.65,102.50,66.14,57.44,53.26,36.35,13.64；ESI-MS m/z:473.2(M﹢H) ﹢.
实施例4：化合物的激酶(PDGFRα、PDGFRβ、ABL1和FLT3)抑制试验
实验采用方法为Caliper Mobility Shift Assay，该方法是以微流体芯片技术的迁移率检测技术为核心的检测平台。实验步骤：配置1.25x激酶反应缓冲液(62.5mmol/L HEPES，pH 7.5；0.001875％Brij-35；12.5mmol/LMgCl 2；2.5mM DTT)和激酶反应终止液(100mmol/L HEPES，pH 7.5；0.015％Brij-35；0.2％Coating Reagent#3)；在5μL的5x浓度的化合物溶液中(用DMSO溶解，用水稀释10倍)加入10μL的2.5x的激酶溶液(在1.25x激酶反应缓冲液中加激酶)，室温孵育10min后再加入10μL的2.5x 底物肽溶液(在1.25x激酶反应缓冲液中加FAM标记肽和ATP)，在28℃下反应特定的时间后加入25μL激酶反应终止液。在Caliper上测试收集数据，对激酶活性的抑制率＝(max-conversion)/(max-min)*100。“max”为未加化合物的DMSO对照，“min”为低对照。测定IC 50时每种样品设10个稀释度各2个复孔，3次重复，结果见表1。
表1所合成化合物的化学结构及在100nM浓度下对PDGFRα、PDGFRβ、ABL1和FLT3激酶的抑制率(％)
序号 化合物 PDGFR-α PDGFR-β ABL1 FLT3
1 3a 87.1 94.4 90.4 87.5
2 3b 93.7 95.8 95.1 90.2
3 3c 62.3 81.0 84.2 78.6
4 3d 94.2 99.6 95.2 90.5
5 3e 32.9 55.0 54.3 51.2
6 3f 1.3 3.5 4.3 34.8
7 3g 6.0 7.2 6.9 14.6
8 3h 3.2 21.2 5.9 13.8
9 3i 6.6 30.7 23.6 42.6
10 5a 57.3 78.6 58.9 60.3
11 5b 66.1 90.3 78.8 60.9
12 5c 67.7 79.2 58.9 65.4
13 5d 59.1 84.1 80.9 80.4
14 5e 57.8 74.1 65.5 69.8
15 5f 82.5 91.0 90.2 90.5
16 5h 71.8 88.9 80.2 87.1
17 5g 78.3 90.4 89.2 85.7
18 5j 60.6 71.1 71.6 74.3
19 5k 91.1 96.4 90.4 88.7
20 5i 94.5 98.0 85.2 93.4
21 6a 84.4 93.8 98.2 87.2
22 6b 55.0 68.7 91.2 87.3
23 6c 48.9 48.5 50.6 74.6
24 6d 66.6 70.3 59.6 78.4
25 6e 64.8 63.4 78.8 79.5
26 6f 94.4 97.0 98.0 97.8
27 6g 87.7 93.8 89.6 87.6
28 6h 69.3 80.2 87.5 82.6
29 6i 97.5 99.8 95.3 98.9
30 6j 82.5 85.4 87.6 91.0
31 6k 65.0 76.4 47.5 58.4
32 6m 66.8 78.4 81.0 85.6
33 6n 80.5 82.4 81.2 82.3
34 Pazopanib 96.9 76.7 75.3 80.6
表2.部分活性化合物对PDGFRα和PDGFRβ激酶抑制的IC 50值
Figure PCTCN2021140401-appb-000008
表3.部分化合物对相关激酶抑制的IC 50值
Figure PCTCN2021140401-appb-000009
结果表明，10个活性化合物可以高效抑制激酶PDGFRα和PDGFRβ，而对其他激酶抑制活性相对较弱，表明具有良好的激酶选择性。特别是化合物6g、6i和6f对PDGFRα和PDGFRβ抑制活性显著，其中6i抑制活性最强。
实施例5活性化合物的激酶选择性实验
依照上述激酶抑制活性测定方法，测定活性化合物对其他多种激酶的抑制活性，以表征活性抑制剂的激酶选择性。
表4.活性化合物在100nM浓度下6i对16种激酶的选择性抑制活性
Compounds％inhibition@100nM
Figure PCTCN2021140401-appb-000010
结果表明，活性化合物6i在100nM浓度下可以高效抑制激酶PDGFRα和PDGFRβ，抑制率达到100％以上，而对其他激酶抑制活性相对较弱，表明具有良好的激酶选择性。
实施例6活性化合物对骨肉瘤细胞的抑制试验
采用MTT法，将对数期的骨肉瘤细胞以1500cell/孔的细胞浓度接种于96孔板，每孔200μL细胞悬液，培养6h。将样品配成0.5,2.5,5,10,25μmol/L，5个浓度梯度的溶液，每个样品设5个复孔，置于培养箱培养48h(37℃，5％CO 2)，加MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐)每孔20μL，继续培养4h后，吸弃培养液，每孔加入200μL DMSO，震荡溶解10min后，用多功能酶标仪在490nM处测定各孔的OD值并计算抑制率。IC 50值计算方法：利用GraphPad Prism软件通过曲线拟合得 到函数计算样品的IC 50值。
表5.MTT法测定活性化合物对四种骨肉瘤细胞的抑制活性(IC50)
Figure PCTCN2021140401-appb-000011
结果表明，三个活性化合物相对于三个阳性药物均具有强烈的抑制四种骨肉瘤瘤细胞株增殖的活性，表明这些化合物具有优异的抗骨肉瘤效果。
实施例7活性化合物6i抑制骨肉瘤细胞的黏附和转移实验
96孔板预孵人血浆纤连蛋白(Human Plasma Fibronectin),接种分别经、0,0.1,0.2,0.4μM 6i和0.4μM Pazopanib,0.4μM Imatinib作用48小时的骨肉瘤细胞，每孔5×10 4个，每组设6个复孔，37℃，5％的CO 2培养40min，PBS洗去未黏附的细胞，4％多聚甲醛100μL每孔,室温固定15min,100uL,每孔200μLPBS洗涤三次，弃掉PBS，每孔50μL结晶紫室温染色5min,染色结束后每孔200μL超纯水洗涤三次，弃超纯水并拍干，每孔加入100μL 33％冰醋酸，震荡10min溶解结晶紫，酶标仪570nM测吸光度，黏附率(％)＝(加药处理组肿瘤细胞OD值-Hu FN OD值)/(未处理肿瘤细胞OD值-Hu FN OD值)×100％。
将密度为5×10 4个0,0.1,0.2,0.4μM 6i和0.4μM Pazopanib,0.4μM Imatinib处理48h后的骨肉瘤细胞接种到6孔板中，加入含10％血清的RMPL 1640培养液，放入培养箱使其贴壁形成单层细胞，用200uL枪头作“+”十字划痕，用无菌PBS洗涤3次，分别加入含2.5μLTCS的基础培养基，分别于0h,24,48h在倒置显微镜下拍照，用Imag J软件测量其迁移距离。
结果见图1，结果表明，0.1、0.2和0.4uM的活性化合物6i相对于阳性药物均具有强烈的剂量依赖性抑制骨肉瘤细胞MG63和MNNG黏附(4A)和转移(4B)的活性。
实施例8活性化合物6i对两种骨肉瘤细胞PDGFR信号通路相关蛋白的抑制活性
将化合物预处理骨肉瘤细胞株48h后，吸掉培养基，PBS洗涤3次，裂解后提取总蛋白，利用Western Blot检测PDGFR信号通路相关蛋白的磷酸化水平。
结果见图2，结果表明，0.1、0.2和0.4uM的活性化合物6i相对于阳性药物均具 有强烈的剂量依赖性抑制骨肉瘤细胞MG63和MNNG相关信号通路蛋白磷酸化活性。实施例9活性化合物对两种人新生血管细胞的抑制活性试验
采用与实施例6相同的MTT法，测定活性化合物6i对两种视网膜细胞的抑制活性。
表6.MTT法测定活性化合物对三种人视网膜细胞的抑制活性(IC50，uM)
Figure PCTCN2021140401-appb-000012
结果表明，活性化合物6i相对于多个阳性药物均具有强烈的抑制人永生化人脑微血管内皮细胞(HCMEC/D3)和人脑血管周细胞(HBVP)的活性，而低浓度下对人的正常视网膜细胞ARPE-19几乎无抑制活性，表明活性化合物6i可以有效抑制眼底血管增生，进而缓解眼科疾病湿性黄斑变性或葡萄膜炎，且毒性较低。

Claims (13)

  1. 一种嘧啶类小分子化合物，其特征在于，为式(I)、(II)或(III)所示的化合物、其盐、其溶剂化物、其水合物或其前药中的一种；
    Figure PCTCN2021140401-appb-100001
    式(I)～(III)中，R 1选自H、-CF 3或C 1～C 5烷基；R 2选自H、-CF 3、C 1～C 5烷基、C 1～C 5烷氧基、卤素或者C 1～C 5烷氧羰基；或者R 1、R 2与连接R 1和R 2的两个C形成五元环；
    R 3为取代或者未取代的芳基，该芳基上的取代基选自C 1～C 5烷基；
    R 4为取代或者未取代的芳基，所述芳基上的取代基为C 1～C 5烷基、C 1～C 5烷氧基、哌嗪基、取代的哌嗪基、1,1-二氧化硫代吗啉基、哌啶基、取代的哌啶基，所述哌嗪基和哌啶基上的取代基选自C 1～C 5烷基或者卤素。
  2. 根据权利要求1所述的嘧啶类小分子化合物，其特征在于，所述的R 1选自H、-CF 3或甲基；R 2选自H、-CF 3、甲基、甲氧基、F、Cl、乙氧羰基；或者R 1、R 2与连接R 1和R 2的两个C形成含S五元环。
  3. 根据权利要求1所述的嘧啶类小分子化合物，其特征在于，所述的R 3为取代或者未取代的吲哚基、取代或者未取代的吲唑基、取代或者未取代的喹喔啉基、取代或者未取代的喹啉基、茚满基；所述吲哚基、吲唑基、喹喔啉基、喹啉基上的取代基为甲基或者乙基。
  4. 根据权利要求1所述的嘧啶类小分子化合物，其特征在于，所述R 4为取代或者未取代的苯基，所述苯基上的取代基为甲基、甲氧基、哌嗪基、取代的哌嗪基、1,1-二氧化硫代吗啉基、哌啶基、取代的哌啶基，所述哌嗪基和哌啶基上的取代基选自甲基、F或者Cl。
  5. 根据权利要求1所述的嘧啶类小分子化合物，其特征在于，为式(III)所示的化合物、其盐、其溶剂化物、其水合物或其前药中的一种；
    Figure PCTCN2021140401-appb-100002
    所述R 4为取代或者未取代的苯基，所述苯基上的取代基为甲基、甲氧基、哌嗪基、取代的哌嗪基、1,1-二氧化硫代吗啉基、哌啶基、取代的哌啶基中的一个或者多个，所述哌嗪基和哌啶基上的取代基选自甲基或乙基。
  6. 根据权利要求1所述的所述的嘧啶类小分子化合物，其特征在于，为化合物3a、化合物3b、化合物3c、化合物3d、化合物3e、化合物3f、化合物3g、化合物3h、化合物3i、化合物5a、化合物5b、化合物5c、化合物5d、化合物5e、化合物5f、化合物5g、化合物5h、化合物5i、化合物5j、化合物5k、化合物6a、化合物6b、化合物6c、化合物6d、化合物6e、化合物6f、化合物6g、化合物6h、化合物6i、化合物6j、化合物6k、化合物6m、化合物6n、其盐、其溶剂化合物、其水合物或者其前药中的一种，结构式如下：
    Figure PCTCN2021140401-appb-100003
    Figure PCTCN2021140401-appb-100004
  7. 一种如权利要求1～6任一项所述的嘧啶类小分子化合物的应用，其特征在于，所述的嘧啶类小分子化合物用于制备PDGFRs抑制剂。
  8. 根据权利要求7所述的嘧啶类小分子化合物的应用，其特征在于，所述的PDGFRs抑制剂能高效抑制PDGFRα和PDGFRβ，而对其他激酶抑制活性中等或者较弱。
  9. 根据权利要求7所述的嘧啶类小分子化合物的应用，其特征在于，所述的嘧啶类小分子化合物用于制备抗肿瘤药物。
  10. 根据权利要求9所述的嘧啶类小分子化合物的应用，其特征在于，所述的抗肿瘤药物用于抑制骨肉瘤细胞。
  11. 根据权利要求10所述的嘧啶类小分子化合物的应用，其特征在于，所述的嘧啶类小分子化合物用于制备治疗眼科疾病的药物；
    所述的药物用于抑制眼底血管增生，进而缓解眼科疾病湿性黄斑变性或葡萄膜炎。
  12. 一种如权利要求1～6任一项所述的嘧啶类小分子化合物的应用，其特征在于，所述的嘧啶类小分子化合物用于制备抗肿瘤药物；
    所述的抗肿瘤药物用于治疗白血病、结肠癌、直肠癌、胃癌、乳腺癌、卵巢癌、 绒毛膜上皮癌、恶性葡萄胎、头颈部鳞癌、皮肤癌、肝癌、膀胱癌、肺癌、前列腺癌、子宫癌、肾癌、淋巴瘤中的一种或者多种。
  13. 根据权利要求12所述的嘧啶类小分子化合物的应用，其特征在于，所述的抗肿瘤药物为ABL或FLT3抑制剂。
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