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CN113968852B - Thiazole hydrazide derivative and preparation method and application thereof - Google Patents

Thiazole hydrazide derivative and preparation method and application thereof Download PDF

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CN113968852B
CN113968852B CN202010716661.XA CN202010716661A CN113968852B CN 113968852 B CN113968852 B CN 113968852B CN 202010716661 A CN202010716661 A CN 202010716661A CN 113968852 B CN113968852 B CN 113968852B
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CN113968852A (en
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倪廷峻弘
姜远英
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明提供了一种噻唑酰肼类衍生物及其制备方法和应用，属于有机合成领域。本发明提供了如下式所示的化合物或其在药理学上允许的盐，式中R1为H或甲基；R2为H、烷基、酯基、四氢吡喃基、芳环基、取代芳环基、苯甲基或取代苯甲基中的任意一种；R3为H或烷基；R4为H、烷基、氰甲基或苯基中的任意一种。本发明提供的噻唑酰肼类衍生物不仅具有毒性低、抗真菌谱广等优点，还具有合成简单，产品提纯容易等优点，可用于制备新型的抗真菌药物。The invention provides a thiazole hydrazide derivative and its preparation method and application, which belong to the field of organic synthesis. The present invention provides a compound represented by the following formula or a pharmacologically acceptable salt thereof, In the formula, R1 is H or methyl; R2 is any one of H, alkyl, ester group, tetrahydropyranyl, aromatic ring group, substituted aromatic ring group, benzyl group or substituted benzyl group; R 3 is H or alkyl; R 4 is any one of H, alkyl, cyanomethyl or phenyl. The thiazole hydrazide derivatives provided by the invention not only have the advantages of low toxicity, broad antifungal spectrum, etc., but also have the advantages of simple synthesis, easy product purification, etc., and can be used to prepare novel antifungal drugs.

Description

一种噻唑酰肼类衍生物及其制备方法和应用Thiazole hydrazide derivative and preparation method and application thereof

技术领域Technical Field

本发明涉及一种医药化合物技术领域，具体涉及一种噻唑酰肼类衍生物及其制备方法和应用。The present invention relates to the technical field of pharmaceutical compounds, and in particular to a thiazole hydrazide derivative and a preparation method and application thereof.

背景技术Background Art

近年来，随着广谱抗菌素、抗肿瘤药、免疫抑制剂的大量应用，放射治疗和器官移植的广泛进行，导管和插管的普遍开展，以及免疫缺陷患者尤其是艾滋病患者的急速增加，致使真菌感染特别是深部真菌感染大幅度上升，深部真菌感染现已成为艾滋病和肿瘤等重大疾病死亡的主要原因。In recent years, with the extensive use of broad-spectrum antibiotics, anti-tumor drugs, and immunosuppressants, the widespread implementation of radiotherapy and organ transplantation, the widespread use of catheters and intubation, and the rapid increase in immunodeficiency patients, especially AIDS patients, fungal infections, especially deep fungal infections, have increased significantly. Deep fungal infections have now become the main cause of death from major diseases such as AIDS and tumors.

现有的抗真菌药物主要为作用于角鲨烯环氧化酶的烯丙胺类、作用于羊毛甾醇14a去甲基化酶的氮唑类和作用于细胞壁b-(1,3)-葡聚糖合成酶的脂肽类等。但就目前临床应用的抗真菌药物而言，存在副作用大、抗菌谱窄、易产生耐药性等问题，有效的抗真菌药物特别是抗深部真菌药物十分缺乏，远不能满足治疗需要。The existing antifungal drugs mainly include allylamines acting on squalene epoxidase, azoles acting on lanosterol 14a demethylase, and lipopeptides acting on cell wall b-(1,3)-glucan synthase. However, the antifungal drugs currently used in clinical practice have problems such as large side effects, narrow antibacterial spectrum, and easy drug resistance. Effective antifungal drugs, especially those against deep fungi, are in short supply and far from meeting the treatment needs.

发明内容Summary of the invention

本发明是为了解决上述问题而进行的，目的在于提供一种噻唑酰肼类衍生物及其制备方法和应用。The present invention is made to solve the above problems, and aims to provide a thiazole hydrazide derivative and a preparation method and application thereof.

本发明提供了一种噻唑酰肼类衍生物，具有这样的特征，如式I所示的化合物或其在药理学上允许的盐，The present invention provides a thiazole hydrazide derivative having the following characteristics: a compound as shown in formula I or a pharmacologically acceptable salt thereof,

式中，R1为H或甲基；R2为H、烷基、酯基、四氢吡喃基、芳环基、取代芳环基、苯基烷基或取代苯烷基中的任意一种；或R1与R2键结成芳环；R3为H或烷基；R4为H、烷基、炔基、烯基、氰甲基或苯基中的任意一种。In the formula, R1 is H or methyl; R2 is any one of H, alkyl, ester, tetrahydropyranyl, aromatic ring, substituted aromatic ring, phenylalkyl or substituted phenylalkyl; or R1 and R2 are bonded to form an aromatic ring; R3 is H or alkyl; R4 is any one of H, alkyl, alkynyl, alkenyl, cyanomethyl or phenyl.

本发明提供了一种噻唑酰肼类衍生物，还具有这样的特征，其中，取代芳环基或取代苯甲基中的取代基为下述取代基中的任意一种：a)卤素；b)吸电子基团；c)低级烷基，低级烷基为含有1-6个碳原子的烷基或有卤素取代的含有1-6个碳原子的烷基；d)低级烷氧基，低级烷氧基含有1-6个碳原子的烷氧基或卤素取代的含有1-6个碳原子的烷氧基；e)供电子基团；f)苄氧基或苄氧羰基胺基。The present invention provides a thiazole hydrazide derivative, which also has the following characteristics: the substituent in the substituted aromatic ring group or the substituted benzyl group is any one of the following substituents: a) halogen; b) electron withdrawing group; c) lower alkyl group, which is an alkyl group containing 1 to 6 carbon atoms or an alkyl group containing 1 to 6 carbon atoms substituted by halogen; d) lower alkoxy group, which is an alkoxy group containing 1 to 6 carbon atoms or an alkoxy group containing 1 to 6 carbon atoms substituted by halogen; e) electron donating group; f) benzyloxy group or benzyloxycarbonylamino group.

本发明提供了一种噻唑酰肼类衍生物，还具有这样的特征，其中，低级烷基为甲基或三氟甲基。The present invention provides a thiazole hydrazide derivative, which also has the following characteristics: the lower alkyl group is methyl or trifluoromethyl.

本发明提供了一种噻唑酰肼类衍生物，还具有这样的特征，其中，低级烷氧基为甲氧基、三氟甲氧基或二氟甲氧基中的任意一种。The present invention provides a thiazole hydrazide derivative, which also has the following characteristics: the lower alkoxy group is any one of a methoxy group, a trifluoromethoxy group or a difluoromethoxy group.

本发明提供了一种噻唑酰肼类衍生物，还具有这样的特征，为下述化合物中的任意一种：The present invention provides a thiazole hydrazide derivative, which also has the following characteristics and is any one of the following compounds:

本发明提供了一种噻唑酰肼类衍生物的制备方法，用于制备上述任意一项的噻唑酰肼类衍生物，还具有这样的特征，其反应式为：The present invention provides a method for preparing a thiazole hydrazide derivative, which is used to prepare any one of the above thiazole hydrazide derivatives, and further has the following characteristics: the reaction formula is:

其中，R1为H或甲基；R2为H、烷基、酯基、四氢吡喃基、芳环基、取代芳环基、苯甲基或取代苯甲基中的任意一种；R3为H或烷基；R4为H、烷基、氰甲基或苯基中的任意一种。Wherein, R1 is H or methyl; R2 is any one of H, alkyl, ester, tetrahydropyranyl, aromatic ring, substituted aromatic ring, benzyl or substituted benzyl; R3 is H or alkyl; R4 is any one of H, alkyl, cyanomethyl or phenyl.

本发明提供了一种噻唑酰肼类衍生物的制备方法，还具有这样的特征：其中，的制备方法如下：The present invention provides a method for preparing thiazole hydrazide derivatives, which also has the following characteristics: The preparation method is as follows:

本发明提供了一种药物组合物，具有这样的特征，含有上述任意一项的噻唑酰肼类衍生物。The present invention provides a pharmaceutical composition having the following characteristics, comprising any one of the above-mentioned thiazole hydrazide derivatives.

本发明提供了一种药物组合物，具有这样的特征，还包括药学上可接受的载体或辅料。The present invention provides a pharmaceutical composition having such characteristics and further comprising a pharmaceutically acceptable carrier or excipient.

本发明提供了一种药物组合物，具有这样的特征，还包括一种或多种药学上可接受的助剂、润湿剂、乳化剂、悬浮剂、防腐剂、影响渗透压的盐、缓冲剂、甜味剂、调味剂、着色剂或前述的任何组合。The present invention provides a pharmaceutical composition having such characteristics and further comprising one or more pharmaceutically acceptable excipients, wetting agents, emulsifiers, suspending agents, preservatives, salts affecting osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents or any combination of the foregoing.

本发明提供药物组合物可以通过使用本领域所熟知的步骤配制，以对受治疗者提供施用后活性成分的快速释放、持续释放或延缓释放。The pharmaceutical compositions provided by the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures well known in the art.

本发明提供了一种噻唑酰肼类衍生物在制备抗真菌药物中的应用，具有这样的特征，抗真菌药物为用于预防或治疗真菌感染的疾病。The present invention provides an application of a thiazole hydrazide derivative in the preparation of an antifungal drug, which has the following characteristics: the antifungal drug is used for preventing or treating diseases caused by fungal infection.

本发明提供了一种噻唑酰肼类衍生物在制备抗真菌药物中的应用，还具有这样的特征，真菌为白念珠菌、新型隐球菌或烟曲霉菌中的任意一种。The present invention provides an application of thiazole hydrazide derivatives in the preparation of antifungal drugs, and also has the characteristic that the fungus is any one of Candida albicans, Cryptococcus neoformans or Aspergillus fumigatus.

发明的作用与效果Functions and Effects of the Invention

根据上述实施例所涉及的噻唑酰肼类衍生物，创造性地将酰肼类结构与噻唑环相结合，从而设计并合成了一系列噻唑酰肼类衍生物，因为得到噻唑酰肼类衍生物不仅具有毒性低、抗真菌谱广等优点，还具有合成简单，产品提纯容易等优点，所以上述实施例提供的噻唑酰肼类衍生物可用于制备新型的抗真菌药物。According to the thiazole hydrazide derivatives involved in the above embodiments, the hydrazide structure is creatively combined with the thiazole ring to design and synthesize a series of thiazole hydrazide derivatives. Since the obtained thiazole hydrazide derivatives not only have the advantages of low toxicity and a broad antifungal spectrum, but also have the advantages of simple synthesis and easy product purification, the thiazole hydrazide derivatives provided in the above embodiments can be used to prepare new antifungal drugs.

具体实施方式DETAILED DESCRIPTION

为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，以下结合实施例对本发明作具体阐述。In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below in conjunction with embodiments.

<实施例1><Example 1>

一种噻唑酰肼类衍生物N-1的制备Preparation of a thiazole hydrazide derivative N-1

噻唑酰肼类衍生物N-1的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-1 is as follows:

步骤一：将化合物1(50mmol)和化合物2(50mmol)溶于DMF(50mL)中，室温下反应2小时，反应完全后，向反应体系中加入DMF(50mL)，得含有化合物3的混合溶液，含有化合物3的混合溶液不经进一步处理直接用于步骤二；Step 1: Compound 1 (50 mmol) and Compound 2 (50 mmol) were dissolved in DMF (50 mL), and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, DMF (50 mL) was added to the reaction system to obtain a mixed solution containing Compound 3. The mixed solution containing Compound 3 was directly used in Step 2 without further treatment;

步骤二：将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物4(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-1。Step 2: Dissolve compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 4 (1 mmol) in DMF (2 mL), react at 60°C for 2 hours. After the reaction is complete, add water to precipitate a solid. Filter the solid and recrystallize it once with ethanol and water to obtain compound N-1.

化合物N-1的表征数据如下：The characterization data of compound N-1 are as follows:

MS(ESI)m/z:366.1[M+H]+.Purity:96％(LC-MS).MS(ESI)m/z:366.1[M+H]+.Purity:96%(LC-MS).

<实施例2><Example 2>

一种噻唑酰肼类衍生物N-2的制备Preparation of a thiazole hydrazide derivative N-2

噻唑酰肼类衍生物N-2的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-2 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物5(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-2。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 5 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-2.

化合物N-2的核磁数据：NMR data of compound N-2:

1H NMR(300MHz,DMSO)δ10.55(s,1H),9.56(s,1H),7.65(d,J＝8.8Hz,2H),6.95(s,1H),6.72(d,J＝8.9Hz,2H),3.80(s,2H),2.92(s,6H). 1 H NMR (300MHz, DMSO) δ10.55(s,1H),9.56(s,1H),7.65(d,J＝8.8Hz,2H),6.95(s,1H),6.72(d,J＝8.9 Hz,2H),3.80(s,2H),2.92(s,6H).

<实施例3><Example 3>

一种噻唑酰肼类衍生物N-3的制备Preparation of a thiazole hydrazide derivative N-3

噻唑酰肼类衍生物N-3的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-3 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物6(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-3。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 6 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-3.

化合物N-3的核磁数据：NMR data of compound N-3:

1H NMR(300MHz,DMSO)δ10.48(s,1H),9.45(s,1H),6.42(s,1H),3.88(m,2H),3.77(s,2H),3.45-3.36(m,2H),2.68(m,1H),1.87-1.72(m,2H),1.57(m,2H). 1 H NMR (300MHz, DMSO) δ10.48(s,1H),9.45(s,1H),6.42(s,1H),3.88(m,2H),3.77(s,2H),3.45-3.36(m ,2H),2.68(m,1H),1.87-1.72(m,2H),1.57(m,2H).

<实施例4><Example 4>

一种噻唑酰肼类衍生物N-4的制备Preparation of a thiazole hydrazide derivative N-4

噻唑酰肼类衍生物N-4的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-4 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物7(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-4。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 7 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-4.

化合物N-4的核磁数据：NMR data of compound N-4:

1H NMR(300MHz,DMSO)δ10.46(s,1H),9.41(s,1H),6.40(s,1H),3.76(s,2H),1.83(m,1H),0.89–0.60(m,4H). 1 H NMR (300MHz, DMSO) δ10.46(s,1H),9.41(s,1H),6.40(s,1H),3.76(s,2H),1.83(m,1H),0.89–0.60(m ,4H).

<实施例5><Example 5>

一种噻唑酰肼类衍生物N-5的制备Preparation of a thiazole hydrazide derivative N-5

噻唑酰肼类衍生物N-5的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-5 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物8(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-5。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 8 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-5.

化合物N-5的核磁数据：NMR data of compound N-5:

1H NMR(300MHz,DMSO)δ10.46(s,1H),9.43(s,1H),6.36(s,1H),3.76(s,2H),1.20(s,9H). 1 H NMR (300MHz, DMSO) δ10.46(s,1H),9.43(s,1H),6.36(s,1H),3.76(s,2H),1.20(s,9H).

<实施例6><Example 6>

一种噻唑酰肼类衍生物N-6的制备Preparation of a thiazole hydrazide derivative N-6

噻唑酰肼类衍生物N-6的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-6 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物9(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-6。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 9 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-6.

化合物N-6的核磁数据：NMR data of compound N-6:

1H NMR(300MHz,DMSO)δ10.64(s,1H),9.81(s,1H),7.73(s,1H),4.23(q,J＝7.1Hz,2H),3.82(s,2H),1.27(t,J＝7.1Hz,3H). 1 H NMR (300MHz, DMSO) δ10.64 (s, 1H), 9.81 (s, 1H), 7.73 (s, 1H), 4.23 (q, J = 7.1Hz, 2H), 3.82 (s, 2H), 1.27(t,J＝7.1Hz,3H).

<实施例7><Example 7>

一种噻唑酰肼类衍生物N-7的制备Preparation of a thiazole hydrazide derivative N-7

噻唑酰肼类衍生物N-7的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-7 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物10(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-7。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 10 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-7.

化合物N-7的核磁数据：NMR data of compound N-7:

1H NMR(300MHz,DMSO)δ10.49(s,1H),9.45(s,1H),7.32–7.06(m,5H),6.41(s,1H),3.78(s,2H),2.94–2.69(m,4H). 1 H NMR (300MHz, DMSO) δ10.49(s,1H),9.45(s,1H),7.32–7.06(m,5H),6.41(s,1H),3.78(s,2H),2.94–2.69 (m,4H).

<实施例8><Example 8>

一种噻唑酰肼类衍生物N-8的制备Preparation of a thiazole hydrazide derivative N-8

噻唑酰肼类衍生物N-8的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-8 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物11(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-8。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 11 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-8.

N-8的核磁数据：N-8 NMR data:

1H NMR(300MHz,DMSO)δ10.62(s,1H),9.72(s,1H),8.56(d,J＝4.6Hz,1H),7.92–7.77(m,2H),7.50(s,1H),7.36–7.22(m,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.62 (s, 1H), 9.72 (s, 1H), 8.56 (d, J = 4.6Hz, 1H), 7.92–7.77 (m, 2H), 7.50 (s, 1H) ),7.36–7.22(m,1H),3.83(s,2H).

<实施例9><Example 9>

一种噻唑酰肼类衍生物N-9的制备Preparation of a thiazole hydrazide derivative N-9

噻唑酰肼类衍生物N-9的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-9 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物12(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-9。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 12 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-9.

化合物N-9的核磁数据：NMR data of compound N-9:

1H NMR(300MHz,DMSO)δ10.47(s,1H),9.43(s,1H),6.36(s,1H),3.76(s,2H),2.77(m,1H),1.16(d,J＝6.8Hz,6H). 1 H NMR (300MHz, DMSO) δ10.47(s,1H),9.43(s,1H),6.36(s,1H),3.76(s,2H),2.77(m,1H),1.16(d,J =6.8Hz,6H).

<实施例10><Example 10>

一种噻唑酰肼类衍生物N-10的制备Preparation of a thiazole hydrazide derivative N-10

噻唑酰肼类衍生物N-10的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-10 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物13(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-10。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 13 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-10.

化合物N-10的核磁数据：NMR data of compound N-10:

1H NMR(300MHz,DMSO)δ10.64(s,1H),9.80(s,1H),8.58(dd,J＝4.6,1.4Hz,2H),7.76(dd,J＝4.5,1.6Hz,2H),7.67(s,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.64(s,1H),9.80(s,1H),8.58(dd,J＝4.6,1.4Hz,2H),7.76(dd,J＝4.5,1.6Hz,2H ),7.67(s,1H),3.83(s,2H).

<实施例11><Example 11>

一种噻唑酰肼类衍生物N-11的制备Preparation of a thiazole hydrazide derivative N-11

噻唑酰肼类衍生物N-11的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-11 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物14(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-11。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 14 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-11.

化合物N-11的核磁数据：NMR data of compound N-11:

1H NMR(300MHz,DMSO)δ10.63(s,1H),9.77(s,1H),9.04(d,J＝1.7Hz,1H),8.49(dd,J＝4.7,1.5Hz,1H),8.16(dt,J＝7.9,1.9Hz,1H),7.52–7.35(m,2H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.63 (s, 1H), 9.77 (s, 1H), 9.04 (d, J = 1.7Hz, 1H), 8.49 (dd, J = 4.7, 1.5Hz, 1H), 8.16(dt,J＝7.9,1.9Hz,1H),7.52–7.35(m,2H),3.83(s,2H).

<实施例12><Example 12>

一种噻唑酰肼类衍生物N-12的制备Preparation of a thiazole hydrazide derivative N-12

噻唑酰肼类衍生物N-12的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-12 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物15(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-12。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 15 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-12.

化合物N-12的核磁数据：NMR data of compound N-12:

1H NMR(300MHz,DMSO)δ10.58(s,1H),9.86(s,1H),9.63(s,1H),7.74(d,J＝8.7Hz,2H),7.58–7.29(m,7H),7.14(s,1H),5.16(s,2H),3.81(s,2H). 1 H NMR (300MHz, DMSO) δ10.58(s,1H),9.86(s,1H),9.63(s,1H),7.74(d,J＝8.7Hz,2H),7.58–7.29(m,7H ),7.14(s,1H),5.16(s,2H),3.81(s,2H).

<实施例13><Example 13>

一种噻唑酰肼类衍生物N-13的制备Preparation of a thiazole hydrazide derivative N-13

噻唑酰肼类衍生物N-13的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-13 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物16(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-13。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 16 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-13.

化合物N-13的核磁数据：NMR data of compound N-13:

1H NMR(300MHz,DMSO)δ10.63(s,1H),9.75(s,1H),8.05(d,J＝2.0Hz,1H),7.81(dd,J＝8.4,2.0Hz,1H),7.68-7.63(m,1H),7.51(s,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.63 (s, 1H), 9.75 (s, 1H), 8.05 (d, J = 2.0Hz, 1H), 7.81 (dd, J = 8.4, 2.0Hz, 1H), 7.68-7.63(m,1H),7.51(s,1H),3.83(s,2H).

<实施例14><Example 14>

一种噻唑酰肼类衍生物N-14的制备Preparation of a thiazole hydrazide derivative N-14

噻唑酰肼类衍生物N-14的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-14 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物17(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-14。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 17 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-14.

化合物N-14的核磁数据：NMR data of compound N-14:

1H NMR(300MHz,DMSO)δ10.60(s,1H),9.70(s,1H),7.75(d,J＝8.4Hz,2H),7.63(d,J＝8.4Hz,2H),7.36(s,1H),3.82(s,2H). 1 H NMR (300MHz, DMSO) δ10.60 (s, 1H), 9.70 (s, 1H), 7.75 (d, J = 8.4Hz, 2H), 7.63 (d, J = 8.4Hz, 2H), 7.36 ( s,1H),3.82(s,2H).

<实施例15><Example 15>

一种噻唑酰肼类衍生物N-15的制备Preparation of a thiazole hydrazide derivative N-15

噻唑酰肼类衍生物N-15的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-15 is as follows:

将化合物18(1mmol)和化合物19(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-15。Compound 18 (1 mmol) and compound 19 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-15.

化合物N-15的核磁数据：NMR data of compound N-15:

1H NMR(300MHz,DMSO)δ8.06-7.97(m,2H),7.81(dd,J＝6.2,1.9Hz,3H),7.57-7.40(m,5H),7.34(t,J＝7.3Hz,1H),5.81(s,2H). 1 H NMR (300MHz, DMSO) δ8.06-7.97(m,2H),7.81(dd,J＝6.2,1.9Hz,3H),7.57-7.40(m,5H),7.34(t,J＝7.3Hz ,1H),5.81(s,2H).

<实施例16><Example 16>

一种噻唑酰肼类衍生物N-16的制备Preparation of a thiazole hydrazide derivative N-16

噻唑酰肼类衍生物N-16的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-16 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物20(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-16。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 20 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-16.

化合物N-16的核磁数据：NMR data of compound N-16:

1H NMR(300MHz,DMSO)δ10.57(s,1H),9.63(s,1H),7.42-7.38(m,2H),7.19(s,1H),6.96(d,J＝8.1Hz,1H),4.16-4.10(m,4H),3.81(s,2H),2.19-1.99(m,2H). 1 H NMR (300MHz, DMSO) δ10.57(s,1H),9.63(s,1H),7.42-7.38(m,2H),7.19(s,1H),6.96(d,J＝8.1Hz,1H ),4.16-4.10(m,4H),3.81(s,2H),2.19-1.99(m,2H).

<实施例17><Example 17>

一种噻唑酰肼类衍生物N-17的制备Preparation of a thiazole hydrazide derivative N-17

噻唑酰肼类衍生物N-17的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-17 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物21(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-17。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 21 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-17.

化合物N-17的核磁数据：NMR data of compound N-17:

1H NMR(300MHz,DMSO)δ10.62(s,1H),9.70(s,1H),7.92(d,J＝8.4Hz,2H),7.71(d,J＝8.0Hz,4H),7.50-7.45(m,3H),7.34(s,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.62(s,1H),9.70(s,1H),7.92(d,J＝8.4Hz,2H),7.71(d,J＝8.0Hz,4H),7.50- 7.45(m,3H),7.34(s,1H),3.83(s,2H).

<实施例18><Example 18>

一种噻唑酰肼类衍生物N-18的制备Preparation of a thiazole hydrazide derivative N-18

噻唑酰肼类衍生物N-18的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-18 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物22(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-18。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 22 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-18.

化合物N-18的核磁数据：NMR data of compound N-18:

1H NMR(300MHz,DMSO)δ10.59(s,1H),9.68(s,1H),7.94-7.75(m,2H),7.27-7.19(m,3H),3.82(s,2H). 1 H NMR (300MHz, DMSO) δ10.59(s,1H),9.68(s,1H),7.94-7.75(m,2H),7.27-7.19(m,3H),3.82(s,2H).

<实施例19><Example 19>

一种噻唑酰肼类衍生物N-19的制备Preparation of a thiazole hydrazide derivative N-19

噻唑酰肼类衍生物N-19的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-19 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物23(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-19。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 23 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-19.

化合物N-19的核磁数据：NMR data of compound N-19:

1H NMR(300MHz,DMSO)δ10.61(s,1H),9.73(s,1H),8.01(td,J＝8.9,6.9Hz,1H),7.42-7.24(m,1H),7.24-7.10(m,2H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.61 (s, 1H), 9.73 (s, 1H), 8.01 (td, J = 8.9, 6.9Hz, 1H), 7.42-7.24 (m, 1H), 7.24-7.10 (m,2H),3.83(s,2H).

<实施例20><Example 20>

一种噻唑酰肼类衍生物N-20的制备Preparation of a thiazole hydrazide derivative N-20

噻唑酰肼类衍生物N-20的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-20 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物24(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-20。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 24 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-20.

化合物N-20的核磁数据：NMR data of compound N-20:

1H NMR(300MHz,DMSO)δ10.61(s,1H),9.72(s,1H),7.87(s,1H),7.80(d,J＝7.7Hz,1H),7.51-7.24(m,3H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.61 (s, 1H), 9.72 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 7.7Hz, 1H), 7.51-7.24 (m, 3H ),3.83(s,2H).

<实施例21><Example 21>

一种噻唑酰肼类衍生物N-21的制备Preparation of a thiazole hydrazide derivative N-21

噻唑酰肼类衍生物N-21的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-21 is as follows:

将化合物25(1mmol)和化合物26(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-21。Compound 25 (1 mmol) and compound 26 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-21.

化合物N-21的核磁数据：NMR data of compound N-21:

1H NMR(300MHz,DMSO)δ10.20(s,1H),9.52(s,1H),8.04(d,J＝2.0Hz,1H),7.81(dd,J＝8.4,2.0Hz,1H),7.65(d,J＝8.5Hz,1H),7.45(s,1H),1.91(s,3H). 1 H NMR (300MHz, DMSO) δ10.20 (s, 1H), 9.52 (s, 1H), 8.04 (d, J = 2.0Hz, 1H), 7.81 (dd, J = 8.4, 2.0Hz, 1H), 7.65(d,J=8.5Hz,1H),7.45(s,1H),1.91(s,3H).

<实施例22><Example 22>

一种噻唑酰肼类衍生物N-22的制备Preparation of a thiazole hydrazide derivative N-22

噻唑酰肼类衍生物N-22的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-22 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物277(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-22。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 277 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-22.

化合物N-22的核磁数据：NMR data of compound N-22:

1H NMR(300MHz,DMSO)δ10.57(s,1H),9.62(s,1H),7.75(d,J＝8.8Hz,2H),7.11(s,1H),6.95(dd,J＝9.1,2.3Hz,2H),3.81(s,2H),3.78(s,3H). 1 H NMR (300MHz, DMSO) δ10.57 (s, 1H), 9.62 (s, 1H), 7.75 (d, J = 8.8Hz, 2H), 7.11 (s, 1H), 6.95 (dd, J = 9.1 ,2.3Hz,2H),3.81(s,2H),3.78(s,3H).

<实施例23><Example 23>

一种噻唑酰肼类衍生物N-23的制备Preparation of a thiazole hydrazide derivative N-23

噻唑酰肼类衍生物N-23的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-23 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物28(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-23。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 28 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-23.

化合物N-23的核磁数据：NMR data of compound N-23:

1H NMR(300MHz,DMSO)δ10.50(s,1H),9.37(s,1H),7.59-7.23(m,7H),7.05(d,J＝8.8Hz,2H),5.13(s,3H),3.78(s,2H),2.34(s,3H). 1 H NMR (300MHz, DMSO) δ10.50 (s, 1H), 9.37 (s, 1H), 7.59-7.23 (m, 7H), 7.05 (d, J = 8.8Hz, 2H), 5.13 (s, 3H) ),3.78(s,2H),2.34(s,3H).

<实施例24><Example 24>

一种噻唑酰肼类衍生物N-24的制备Preparation of a thiazole hydrazide derivative N-24

噻唑酰肼类衍生物N-24的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-24 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物29(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-24。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 29 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-24.

化合物N-24的核磁数据：NMR data of compound N-24:

1H NMR(300MHz,DMSO)δ10.65(s,1H),9.79(s,1H),8.08(d,J＝8.5Hz,2H),7.94(d,J＝8.5Hz,2H),7.59(s,1H),3.83(s,2H),3.23(s,3H). 1 H NMR (300MHz, DMSO) δ10.65(s,1H),9.79(s,1H),8.08(d,J＝8.5Hz,2H),7.94(d,J＝8.5Hz,2H),7.59( s,1H),3.83(s,2H),3.23(s,3H).

<实施例25><Example 25>

一种噻唑酰肼类衍生物N-25的制备Preparation of a thiazole hydrazide derivative N-25

噻唑酰肼类衍生物N-25的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-25 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物30(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-25。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 30 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-25.

化合物N-25的核磁数据：NMR data of compound N-25:

1H NMR(300MHz,DMSO)δ10.66(s,1H),9.83(s,1H),8.26(d,J＝8.9Hz,2H),8.09(d,J＝8.9Hz,2H),7.68(s,1H),3.84(s,2H). 1 H NMR (300MHz, DMSO) δ10.66(s,1H),9.83(s,1H),8.26(d,J＝8.9Hz,2H),8.09(d,J＝8.9Hz,2H),7.68( s,1H),3.84(s,2H).

<实施例26><Example 26>

一种噻唑酰肼类衍生物N-26的制备Preparation of a thiazole hydrazide derivative N-26

噻唑酰肼类衍生物N-26的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-26 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物31(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-26。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 31 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-26.

化合物N-26的核磁数据：NMR data of compound N-26:

1H NMR(300MHz,DMSO)δ10.64(s,1H),9.72(s,1H),8.37(s,1H),8.05-7.85(m,4H),7.60-7.39(m,3H),3.85(s,2H). 1 H NMR (300MHz, DMSO) δ10.64(s,1H),9.72(s,1H),8.37(s,1H),8.05-7.85(m,4H),7.60-7.39(m,3H),3.85 (s,2H).

<实施例27><Example 27>

一种噻唑酰肼类衍生物N-27的制备Preparation of a thiazole hydrazide derivative N-27

噻唑酰肼类衍生物N-27的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-27 is as follows:

将化合物32(1mmol)和化合物1(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-27。Compound 32 (1 mmol) and compound 1 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-27.

化合物N-27的核磁数据：NMR data of compound N-27:

1H NMR(300MHz,DMSO)δ8.03(d,J＝7.7Hz,1H),7.85(d,J＝8.0Hz,1H),7.56-7.44(m,1H),7.37(dd,J＝11.1,4.1Hz,1H),5.78(s,2H),4.45(s,2H). 1 H NMR (300MHz, DMSO) δ8.03 (d, J = 7.7Hz, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.56-7.44 (m, 1H), 7.37 (dd, J = 11.1 ,4.1Hz,1H),5.78(s,2H),4.45(s,2H).

<实施例28><Example 28>

一种噻唑酰肼类衍生物N-28的制备Preparation of a thiazole hydrazide derivative N-28

噻唑酰肼类衍生物N-28的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-28 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物33(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-28。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 33 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-28.

化合物N-28的核磁数据：NMR data of compound N-28:

1H NMR(300MHz,DMSO)δ10.57(s,1H),9.61(s,1H),7.60(d,J＝3.2Hz,1H),7.39(s,1H),7.02(d,J＝9.0Hz,1H),6.85(dd,J＝8.9,3.3Hz,1H),3.84(s,3H),3.81(s,2H),3.73(s,3H). 1 H NMR (300MHz, DMSO) δ10.57 (s, 1H), 9.61 (s, 1H), 7.60 (d, J = 3.2Hz, 1H), 7.39 (s, 1H), 7.02 (d, J = 9.0 Hz,1H),6.85(dd,J＝8.9,3.3Hz,1H),3.84(s,3H),3.81(s,2H),3.73(s,3H).

<实施例29><Example 29>

一种噻唑酰肼类衍生物N-29的制备Preparation of a thiazole hydrazide derivative N-29

噻唑酰肼类衍生物N-29的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-29 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物34(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-29。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 34 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-29.

化合物N-29的核磁数据：NMR data of compound N-29:

1H NMR(300MHz,DMSO)δ10.60(s,1H),9.70(s,1H),7.84(d,J＝8.6Hz,2H),7.45(d,J＝8.6Hz,3H),7.36(s,1H),3.82(s,2H). 1 H NMR (300MHz, DMSO) δ10.60(s,1H),9.70(s,1H),7.84(d,J＝8.6Hz,2H),7.45(d,J＝8.6Hz,3H),7.36( s,1H),3.82(s,2H).

<实施例30><Example 30>

一种噻唑酰肼类衍生物N-30的制备Preparation of a thiazole hydrazide derivative N-30

噻唑酰肼类衍生物N-30的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-30 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物35(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-30。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 35 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-30.

化合物N-30的核磁数据：NMR data of compound N-30:

1H NMR(300MHz,DMSO)δ10.58(s,1H),9.63(s,1H),7.72(d,J＝8.1Hz,2H),7.21-7.18(m,3H),3.82(s,2H),2.31(s,3H). 1 H NMR (300MHz, DMSO) δ10.58 (s, 1H), 9.63 (s, 1H), 7.72 (d, J = 8.1Hz, 2H), 7.21-7.18 (m, 3H), 3.82 (s, 2H) ),2.31(s,3H).

<实施例31><Example 31>

一种噻唑酰肼类衍生物N-31的制备Preparation of a thiazole hydrazide derivative N-31

噻唑酰肼类衍生物N-31的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-31 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物36(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-31。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 36 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-31.

化合物N-31的核磁数据：NMR data of compound N-31:

1H NMR(300MHz,DMSO)δ10.58(s,1H),9.63(s,1H),7.43-7.32(m,2H),7.17(s,1H),6.96(d,J＝9.0Hz,1H),3.84-3.75(m,8H). 1 H NMR (300MHz, DMSO) δ10.58(s,1H),9.63(s,1H),7.43-7.32(m,2H),7.17(s,1H),6.96(d,J＝9.0Hz,1H ),3.84-3.75(m,8H).

<实施例32><Example 32>

一种噻唑酰肼类衍生物N-32的制备Preparation of a thiazole hydrazide derivative N-32

噻唑酰肼类衍生物N-32的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-32 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物37(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-32。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 37 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-32.

化合物N-32的核磁数据：NMR data of compound N-32:

1H NMR(300MHz,DMSO)δ10.61(s,1H),9.72(s,1H),7.88(d,J＝8.5Hz,1H),7.68(d,J＝2.2Hz,1H),7.49(dd,J＝8.5,2.2Hz,1H),7.39(s,1H),3.82(s,2H). 1 H NMR (300MHz, DMSO) δ10.61(s,1H),9.72(s,1H),7.88(d,J＝8.5Hz,1H),7.68(d,J＝2.2Hz,1H),7.49( dd,J＝8.5,2.2Hz,1H),7.39(s,1H),3.82(s,2H).

<实施例33><Example 33>

一种噻唑酰肼类衍生物N-33的制备Preparation of a thiazole hydrazide derivative N-33

噻唑酰肼类衍生物N-33的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-33 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物38(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-33。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 38 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-33.

化合物N-33的核磁数据：NMR data of compound N-33:

1H NMR(300MHz,DMSO)δ10.61(s,1H),9.70(s,1H),7.78(d,J＝8.6Hz,2H),7.58(d,J＝8.6Hz,2H),7.37(s,1H),3.82(s,2H). 1 H NMR (300MHz, DMSO) δ10.61(s,1H),9.70(s,1H),7.78(d,J＝8.6Hz,2H),7.58(d,J＝8.6Hz,2H),7.37( s,1H),3.82(s,2H).

<实施例34><Example 34>

一种噻唑酰肼类衍生物N-34的制备Preparation of a thiazole hydrazide derivative N-34

噻唑酰肼类衍生物N-34的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-34 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物39(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-34。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 39 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-34.

化合物N-34的核磁数据：NMR data of compound N-34:

1H NMR(300MHz,DMSO)δ10.59(s,1H),9.67(s,1H),7.91-7.76(m,2H),7.51-7.20(m,4H),3.82(s,2H). 1 H NMR (300MHz, DMSO) δ10.59(s,1H),9.67(s,1H),7.91-7.76(m,2H),7.51-7.20(m,4H),3.82(s,2H).

<实施例35><Example 35>

一种噻唑酰肼类衍生物N-35的制备Preparation of a thiazole hydrazide derivative N-35

噻唑酰肼类衍生物N-35的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-35 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物40(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-35。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 40 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-35.

化合物N-35的核磁数据：NMR data of compound N-35:

1H NMR(300MHz,DMSO)δ10.64(s,1H),9.77(s,1H),8.04(d,J＝8.1Hz,2H),7.75(d,J＝8.3Hz,3H),7.54(s,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.64(s,1H),9.77(s,1H),8.04(d,J＝8.1Hz,2H),7.75(d,J＝8.3Hz,3H),7.54( s,1H),3.83(s,2H).

<实施例36><Example 36>

一种噻唑酰肼类衍生物N-36的制备Preparation of a thiazole hydrazide derivative N-36

噻唑酰肼类衍生物N-36的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-36 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物41(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-36。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 41 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-36.

化合物N-36的核磁数据：NMR data of compound N-36:

1H NMR(300MHz,DMSO)δ10.63(s,1H),9.77(s,1H),7.74-7.67(m,1H),7.44-7.27(m,2H),7.27-7.11(m,1H),3.84(s,2H). 1 H NMR (300MHz, DMSO) δ10.63(s,1H),9.77(s,1H),7.74-7.67(m,1H),7.44-7.27(m,2H),7.27-7.11(m,1H) ,3.84(s,2H).

<实施例37><Example 37>

一种噻唑酰肼类衍生物N-37的制备Preparation of a thiazole hydrazide derivative N-37

噻唑酰肼类衍生物N-37的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-37 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物42(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-37。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 42 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-37.

化合物N-37的核磁数据：NMR data of compound N-37:

1H NMR(300MHz,DMSO)δ10.61(s,1H),9.75(s,1H),7.44(t,J＝4.5Hz,2H),7.12(s,1H),7.07(dd,J＝5.0,3.7Hz,1H),3.81(s,2H). 1 H NMR (300MHz, DMSO) δ10.61 (s, 1H), 9.75 (s, 1H), 7.44 (t, J = 4.5Hz, 2H), 7.12 (s, 1H), 7.07 (dd, J = 5.0 ,3.7Hz,1H),3.81(s,2H).

<实施例38><Example 38>

一种噻唑酰肼类衍生物N-38的制备Preparation of a thiazole hydrazide derivative N-38

噻唑酰肼类衍生物N-38的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-38 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物43(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-38。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 43 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-38.

化合物N-38的核磁数据：NMR data of compound N-38:

1H NMR(300MHz,DMSO)δ10.64(s,1H),9.79(s,1H),8.01(d,J＝8.5Hz,2H),7.85(d,J＝8.5Hz,2H),7.60(s,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.64(s,1H),9.79(s,1H),8.01(d,J＝8.5Hz,2H),7.85(d,J＝8.5Hz,2H),7.60( s,1H),3.83(s,2H).

<实施例39><Example 39>

一种噻唑酰肼类衍生物N-39的制备Preparation of a thiazole hydrazide derivative N-39

噻唑酰肼类衍生物N-39的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-39 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物44(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-39。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 44 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-39.

化合物N-39的核磁数据：NMR data of compound N-39:

1H NMR(300MHz,DMSO)δ10.61(s,1H),9.72(s,1H),7.94(d,J＝8.8Hz,2H),7.40-7.38(m,3H),3.82(s,2H). 1 H NMR (300MHz, DMSO) δ10.61 (s, 1H), 9.72 (s, 1H), 7.94 (d, J = 8.8Hz, 2H), 7.40-7.38 (m, 3H), 3.82 (s, 2H) ).

<实施例40><Example 40>

一种噻唑酰肼类衍生物N-40的制备Preparation of a thiazole hydrazide derivative N-40

噻唑酰肼类衍生物N-40的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-40 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物45(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-40。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 45 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-40.

化合物N-40的核磁数据：NMR data of compound N-40:

1H NMR(300MHz,DMSO)δ10.55(s,1H),9.57(s,1H),9.52(s,1H),7.63(d,J＝8.6Hz,2H),7.00(s,1H),6.76(d,J＝8.6Hz,2H),3.80(s,2H). 1 H NMR (300MHz, DMSO) δ10.55 (s, 1H), 9.57 (s, 1H), 9.52 (s, 1H), 7.63 (d, J = 8.6Hz, 2H), 7.00 (s, 1H), 6.76(d,J＝8.6Hz,2H),3.80(s,2H).

<实施例41><Example 41>

一种噻唑酰肼类衍生物N-41的制备Preparation of a thiazole hydrazide derivative N-41

噻唑酰肼类衍生物N-41的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-41 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物46(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-41。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 46 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-41.

化合物N-41的核磁数据：NMR data of compound N-41:

1H NMR(300MHz,DMSO)δ10.45(s,1H),9.40(s,1H),6.31(s,1H),3.76(s,2H),2.00-1.69(m,15H). 1 H NMR (300MHz, DMSO) δ10.45(s,1H),9.40(s,1H),6.31(s,1H),3.76(s,2H),2.00-1.69(m,15H).

<实施例42><Example 42>

一种噻唑酰肼类衍生物N-42的制备Preparation of a thiazole hydrazide derivative N-42

噻唑酰肼类衍生物N-42的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-42 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物47(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-42。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 47 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-42.

化合物N-42的核磁数据：NMR data of compound N-42:

1H NMR(300MHz,DMSO)δ10.68(s,1H),9.90(s,1H),7.85(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.45(s,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ10.68(s,1H),9.90(s,1H),7.85(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.45( s,1H),3.83(s,2H).

<实施例43><Example 43>

一种噻唑酰肼类衍生物N-43的制备Preparation of a thiazole hydrazide derivative N-43

噻唑酰肼类衍生物N-43的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-43 is as follows:

将化合物3(0.5mmol/mL的DMF溶液,2mL)和化合物48(1mmol)溶于DMF(2mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-43。Compound 3 (0.5 mmol/mL DMF solution, 2 mL) and compound 48 (1 mmol) were dissolved in DMF (2 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-43.

化合物N-43的核磁数据：NMR data of compound N-43:

1H NMR(300MHz,DMSO)δ12.91(s,1H),10.63(s,1H),9.75(s,1H),7.95(s,4H),7.49(s,1H),3.83(s,2H). 1 H NMR (300MHz, DMSO) δ12.91(s,1H),10.63(s,1H),9.75(s,1H),7.95(s,4H),7.49(s,1H),3.83(s,2H ).

<实施例44><Example 44>

一种噻唑酰肼类衍生物N-44的制备Preparation of a thiazole hydrazide derivative N-44

噻唑酰肼类衍生物N-44的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-44 is as follows:

将化合物25(1mmol)和化合物34(1mmol)溶于乙醇(5mL)中，回流反应1小时，反应完全后，加入水中，析出固体，过滤后再真空干燥，得产物N-44。Compound 25 (1 mmol) and compound 34 (1 mmol) were dissolved in ethanol (5 mL) and refluxed for 1 hour. After the reaction was complete, the mixture was added into water to precipitate a solid, which was filtered and then dried in vacuo to obtain product N-44.

化合物N-44的核磁数据：NMR data of compound N-44:

1H NMR(300MHz,DMSO)δ10.18(s,1H),9.46(s,1H),7.83(d,J＝8.6Hz,3H),7.44(d,J＝8.6Hz,2H),7.30(s,1H),1.91(s,3H). 1 H NMR (300MHz, DMSO) δ10.18(s,1H),9.46(s,1H),7.83(d,J＝8.6Hz,3H),7.44(d,J＝8.6Hz,2H),7.30( s,1H),1.91(s,3H).

<实施例45><Example 45>

一种噻唑酰肼类衍生物N-45的制备Preparation of a thiazole hydrazide derivative N-45

噻唑酰肼类衍生物N-45的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-45 is as follows:

将化合物49(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-45。Compound 49 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-45.

化合物N-45的核磁数据：NMR data of compound N-45:

1H NMR(300MHz,DMSO)δ10.98(s,1H),7.88(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.39(s,1H),3.85(s,2H),3.32(s,3H). 1 H NMR (300MHz, DMSO) δ10.98 (s, 1H), 7.88 (d, J = 8.6Hz, 2H), 7.46 (d, J = 8.6Hz, 2H), 7.39 (s, 1H), 3.85 ( s,2H),3.32(s,3H).

<实施例46><Example 46>

一种噻唑酰肼类衍生物N-46的制备Preparation of a thiazole hydrazide derivative N-46

噻唑酰肼类衍生物N-46的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-46 is as follows:

将化合物50(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-46。Compound 50 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-46.

化合物N-46的表征数据如下：The characterization data of compound N-46 are as follows:

MS(ESI)m/z:280.0[M+H]+.Purity:98％(LC-MS).MS(ESI)m/z:280.0[M+H]+.Purity:98%(LC-MS).

<实施例47><Example 47>

一种噻唑酰肼类衍生物N-47的制备Preparation of a thiazole hydrazide derivative N-47

噻唑酰肼类衍生物N-47的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-47 is as follows:

将化合物51(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-47。Compound 51 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-47.

化合物N-47的表征数据如下：The characterization data of compound N-47 are as follows:

MS(ESI)m/z:282.0[M+H]+.Purity:97％(LC-MS).MS(ESI)m/z:282.0[M+H]+.Purity:97%(LC-MS).

<实施例48><Example 48>

一种噻唑酰肼类衍生物N-48的制备Preparation of a thiazole hydrazide derivative N-48

噻唑酰肼类衍生物N-48的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-48 is as follows:

将化合物52(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-48。Compound 52 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-48.

化合物N-48的表征数据如下：The characterization data of compound N-48 are as follows:

MS(ESI)m/z:278.0[M+H]+.Purity:96％(LC-MS).MS(ESI)m/z:278.0[M+H]+.Purity:96%(LC-MS).

<实施例49><Example 49>

一种噻唑酰肼类衍生物N-49的制备Preparation of a thiazole hydrazide derivative N-49

噻唑酰肼类衍生物N-49的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-49 is as follows:

将化合物53(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-49。Compound 53 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-49.

化合物N-49的表征数据如下：The characterization data of compound N-49 are as follows:

MS(ESI)m/z:296.1[M+H]+.Purity:97％(LC-MS).MS(ESI)m/z:296.1[M+H]+.Purity:97%(LC-MS).

<实施例50><Example 50>

一种噻唑酰肼类衍生物N-50的制备Preparation of a thiazole hydrazide derivative N-50

噻唑酰肼类衍生物N-50的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-50 is as follows:

将化合物54(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-50。Compound 54 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-50.

化合物N-50的表征数据如下：The characterization data of compound N-50 are as follows:

MS(ESI)m/z:310.1[M+H]+.Purity:97％(LC-MS).MS(ESI)m/z:310.1[M+H]+.Purity:97%(LC-MS).

<实施例51><Example 51>

一种噻唑酰肼类衍生物N-51的制备Preparation of a thiazole hydrazide derivative N-51

噻唑酰肼类衍生物N-51的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-51 is as follows:

将化合物55(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-51。Compound 55 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-51.

化合物N-51的表征数据如下：The characterization data of compound N-51 are as follows:

MS(ESI)m/z:296.0[M+H]+.Purity:96％(LC-MS).MS(ESI)m/z:296.0[M+H]+.Purity:96%(LC-MS).

<实施例52><Example 52>

一种噻唑酰肼类衍生物N-52的制备Preparation of a thiazole hydrazide derivative N-52

噻唑酰肼类衍生物N-52的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-52 is as follows:

将化合物56(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-52。Compound 56 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-52.

化合物N-52的表征数据如下：The characterization data of compound N-52 are as follows:

MS(ESI)m/z:310.1[M+H]+.Purity:96％(LC-MS).MS(ESI)m/z:310.1[M+H]+.Purity:96%(LC-MS).

<实施例53><Example 53>

一种噻唑酰肼类衍生物N-53的制备Preparation of a thiazole hydrazide derivative N-53

噻唑酰肼类衍生物N-53的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-53 is as follows:

将化合物57(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-53。Compound 57 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-53.

化合物N-53的表征数据如下：The characterization data of compound N-53 are as follows:

MS(ESI)m/z:324.1[M+H]+.Purity:95％(LC-MS).MS(ESI)m/z:324.1[M+H]+.Purity:95%(LC-MS).

<实施例54><Example 54>

一种噻唑酰肼类衍生物N-54的制备Preparation of a thiazole hydrazide derivative N-54

噻唑酰肼类衍生物N-54的制备方法如下述所示：The preparation method of thiazole hydrazide derivative N-54 is as follows:

将化合物58(1mmol)和化合物34(1mmol)溶于DMF(5mL)中，60℃条件下反应2小时，反应完全后，加水有固体析出，固体经过滤后再用乙醇和水重结晶一次，得化合物N-54。Compound 58 (1 mmol) and compound 34 (1 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 2 hours. After the reaction was complete, water was added to precipitate a solid. The solid was filtered and then recrystallized once with ethanol and water to obtain compound N-54.

化合物N-54的表征数据如下：The characterization data of compound N-54 are as follows:

MS(ESI)m/z:338.1[M+H]+.Purity:97％(LC-MS).MS(ESI)m/z:338.1[M+H]+.Purity:97%(LC-MS).

<测试例><Test example>

抗真菌活性测试Antifungal activity test

由于实验条件的限制，在本测试例中对部分实施例得到噻唑酰肼类衍生物进行抗真菌活性测试。在本测试例中对三种真菌菌株进行抗真菌活性测试，分别为：白念珠菌(Candida albicans，SC5314)，新型隐球菌(Cryptococcus neoformans，H99)，烟曲霉菌(Aspergillus fumigatus，7544)。本实施例中使用的真菌菌株由上海长征医院真菌室提供或购自中科院药物所，Due to the limitation of experimental conditions, the antifungal activity of thiazole hydrazide derivatives obtained in some embodiments was tested in this test example. In this test example, the antifungal activity of three fungal strains was tested, namely: Candida albicans (SC5314), Cryptococcus neoformans (H99), and Aspergillus fumigatus (7544). The fungal strains used in this example were provided by the Fungi Laboratory of Shanghai Changzheng Hospital or purchased from the Institute of Materia Medica, Chinese Academy of Sciences.

抗真菌活性测试实验步骤如下：The experimental steps for antifungal activity testing are as follows:

1.1溶液配制：1.1 Solution preparation:

1.1.1菌悬液配制：上述真菌经YEPD液体培养基在35℃下培养16小时，两次活化，用血细胞计数板计数，以RPM1640液体培养基调整菌浓度至1*104～1*105个/mL。1.1.1 Preparation of bacterial suspension: The above fungi were cultured in YEPD liquid medium at 35°C for 16 hours, activated twice, counted with a hemocytometer, and the bacterial concentration was adjusted to 1*104~1*105/mL with RPM1640 liquid medium.

1.1.2药液配制：取本发明待测化合物溶于二甲亚砜，配成6.4mg/mL的药物储存液。1.1.2 Preparation of drug solution: Dissolve the test compound of the present invention in dimethyl sulfoxide to prepare a 6.4 mg/mL drug storage solution.

1.2接种：96孔板1号孔加RPM1640 100μL作空白对照；3-12号孔各加菌悬液100μL，2号孔加菌悬液200μL和药液2μL，2-11号孔的药物浓度作10级倍比稀释，各孔药物浓度依次为64、32、16、8、4、2、1、0.5、0.25、0.125μg/mL，12号孔不加药液，作阳性对照，药物对照选用氟康唑(Fluconazole)和伏立康唑(Voriconazole)。1.2 Inoculation: Add 100 μL of RPM1640 to well 1 of the 96-well plate as a blank control; add 100 μL of bacterial suspension to each of wells 3-12, add 200 μL of bacterial suspension and 2 μL of drug solution to well 2, and dilute the drug concentrations in wells 2-11 in 10 steps. The drug concentrations in each well are 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, and 0.125 μg/mL, respectively. No drug solution is added to well 12 as a positive control. Fluconazole and voriconazole are used as drug controls.

1.3实验结果1.3 Experimental Results

抗真菌活性结果如表1。The antifungal activity results are shown in Table 1.

表1目标化合物体外抗真菌最小抑菌浓度值(MIC80，μg/mL)Table 1 Minimum inhibitory concentration values of target compounds for antifungal treatment in vitro (MIC80, μg/mL)

注：表中“-”表示没有进行测试。Note: “-” in the table means no test was performed.

如表1所示，表中的噻唑酰肼类衍生物均体现出来一定的抗真菌活性，其中一部分化合物的抗真菌活性甚至优于目前常用的抗真菌药物氟康唑(Fluconazole)，尤其针对白念珠菌(Candida albicans，SC5314)以及新型隐球菌(Cryptococcus neoformans，H99)有更好的抗真菌活性。As shown in Table 1, the thiazole hydrazide derivatives in the table all exhibit certain antifungal activity, and the antifungal activity of some of the compounds is even better than that of the currently commonly used antifungal drug fluconazole, especially against Candida albicans (SC5314) and Cryptococcus neoformans (H99).

此外，还对实施例1-54提供的噻唑酰肼类衍生物进行了毒性测试，毒性测试的结果表明实施例1-54提供的噻唑酰肼类衍生物均毒性较低，具有在抗真菌药物中应用的前景。In addition, toxicity tests were performed on the thiazole hydrazide derivatives provided in Examples 1-54. The results of the toxicity tests showed that the thiazole hydrazide derivatives provided in Examples 1-54 were all of low toxicity and had prospects for use in antifungal drugs.

实施例的作用和效果Functions and Effects of the Embodiments

根据上述实施例所涉及的噻唑酰肼类衍生物，创造性地将酰肼类结构与噻唑环相结合，从而设计并合成了一系列噻唑酰肼类衍生物，因为得到噻唑酰肼类衍生物不仅具有毒性低、抗真菌谱广等优点，还具有合成简单，产品提纯容易等优点，所以上述实施例提供的噻唑酰肼类衍生物可用于制备新型的抗真菌药物。According to the thiazole hydrazide derivatives involved in the above embodiments, the hydrazide structure is creatively combined with the thiazole ring to design and synthesize a series of thiazole hydrazide derivatives. Since the obtained thiazole hydrazide derivatives not only have the advantages of low toxicity and a broad antifungal spectrum, but also have the advantages of simple synthesis and easy product purification, the thiazole hydrazide derivatives provided in the above embodiments can be used to prepare new antifungal drugs.

上述实施方式为本发明的优选案例，并不用来限制本发明的保护范围。The above-mentioned embodiments are preferred examples of the present invention and are not intended to limit the protection scope of the present invention.

Claims (6)

1. A thiazole hydrazide derivative, which is characterized by being any one of the following compounds:
2. a method for preparing thiazole hydrazide derivatives, which is used for preparing the thiazole hydrazide derivatives according to claim 1, and is characterized in that the reaction formula is as follows:
wherein ,R1 、R 2 、R 3 、R 4 Is shown as a corresponding group in the thiazole hydrazide derivative according to claim 1.
3. The method for preparing thiazole hydrazide derivatives according to claim 2, which is characterized in that:
wherein ,the preparation method of (2) is as follows:
4. a pharmaceutical composition comprising the thiazole hydrazide derivative according to claim 1.
5. The use of thiazole hydrazide derivatives as defined in claim 1 for the preparation of an antifungal drug, wherein the antifungal drug is a disease for preventing or treating fungal infection.
6. The use of thiazole hydrazide derivatives according to claim 5 for the preparation of antifungal drugs, wherein the fungus is any of candida albicans, cryptococcus neoformans or aspergillus fumigatus.
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