WO2023093700A1 - 咪唑并噻唑衍生物及其制备方法与应用 - Google Patents
咪唑并噻唑衍生物及其制备方法与应用 Download PDFInfo
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- WO2023093700A1 WO2023093700A1 PCT/CN2022/133420 CN2022133420W WO2023093700A1 WO 2023093700 A1 WO2023093700 A1 WO 2023093700A1 CN 2022133420 W CN2022133420 W CN 2022133420W WO 2023093700 A1 WO2023093700 A1 WO 2023093700A1
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- imidazothiazole
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- Nonalcoholic fatty liver disease is a genetic-environment-metabolism-stress-related liver disease characterized by fatty degeneration and fat accumulation in hepatic parenchymal cells. Clinically, it includes three types: simple fatty liver, steatohepatitis (NASH) and fatty liver cirrhosis.
- the C1-C6 alkoxycarbonyl group in the present invention refers to -C(O)R 4 , wherein R 4 is selected from C1-C6 alkoxy groups.
- imidazothiazole derivatives of the above formula (I) are preferably compounds 1-55 or their stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts thereof,
- R 1 has the same definition as above, X is halogen, preferably chlorine, bromine, iodine.
- Diabetes and its complications are specifically described as impaired glucose tolerance, diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetes mellitus cataract, diabetic retinopathy, diabetic maculopathy, diabetic foot syndrome, diabetic coma, diabetic hyperosmolar coma, hypoglycemic coma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis, intracapillary Glomerular nephropathy, diabetic muscular atrophy, diabetic autonomic neuropathy, diabetic mononeuropathy, diabetic polyneuropathy, diabetic vascular disease, diabetic peripheral vascular disease, diabetic ulcer, diabetic arthropathy, diabetes sexual obesity.
- Fig. 4 is the example figure of the insulin resistance experiment of each group in db/db mouse
- MNK1 and MNK2 kinase inhibitory activity assays were performed using the LANCE Ultra kinase activity assay developed by PerkinElmer. Staurosporine (STSP) was used as a positive control in this experiment.
- the test procedure is: at 25°C, 1.00ng MNK1 or 0.05ng MNK2 and different concentrations (10000, 1000, 100, 10, 1nM) of the compound to be tested are prepared into a reaction mixture with a total volume of 10 ⁇ L (MNK1: 12.5nM CREB, 450 ⁇ M ATP , 2mM DTT, 1 ⁇ buffer; MNK2: 12.5nM CREB, 100 ⁇ M ATP, 2mM DTT, 1 ⁇ buffer), incubate for 60min; then add 5 ⁇ L EDTA/Detection buffer and 5 ⁇ L Eu-CREB/Detection buffer to terminate the reaction; detect after incubation for 60min Ratio of HTRF signals at 615nm and 665nm. First measure the compound
- Embodiment 74 High-fat feeding obesity model weight loss test
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Abstract
公开了涉及咪唑并噻唑的衍生物及其制备方法与应用，所述咪唑并噻唑衍生物具有式（I）所示结构： R 1、R 3各自独立地选自任选被取代的含有1-2个氮原子的5元至6元杂环基，R 2、R 4各自独立地选自任选被取代的芳基或杂芳基。该咪唑并噻唑衍生物具有较好的MNK抑制活性，优异的选择性和优秀的体内降血糖的作用，具有广泛的药用背景。
Description
本发明属于药物化学领域，具体涉及咪唑并噻唑衍生物及其制备方法与应用。
代谢综合征是一组由基因和环境因素共同决定的、以多种代谢疾病如肥胖、2型糖尿病(T2D)等合并出现为特点的临床症候群，可进一步引发血脂异常、高血压、非酒精性脂肪肝、痛风等。随着社会经济的发展，人们生活方式的改变(能量摄入增加和运动减少等)，代谢综合征的发病率在全球范围内呈现逐年增加的趋势，已成为全球面临的公共健康挑战。
非酒精性脂肪性肝病(NAFLD)是遗传-环境-代谢-应激相关性肝脏疾病，以肝实质细胞脂肪变性和脂肪贮积为病理特征。临床上包括单纯性脂肪肝、脂肪性肝炎(NASH)和脂肪性肝硬化三种类型。
MNK(人丝裂源蛋白激酶相互作用酶)，包括两个亚型MNK1和MNK2。现已证明MNK在体内能够使eIF4E磷酸化，从而调节生物体中蛋白合成。已有研究发现，调控MNK活性可以调控体重、葡萄糖耐受性，增强胰岛素敏感度，能量的消耗能力，肝脏脂肪的堆积以及在动物脂肪中的炎症，提示MNK可以作为糖尿病、肥胖、NAFLD等代谢性疾病的潜在药物开发靶点。
本领域迫切需要更多种类及能够更好抑制MNK活性的小分子化合物。
发明内容
为了解决上述技术问题，我们发明了一系列咪唑并噻唑或咪唑并噻二唑的衍生化合物，可以通过调控MNK蛋白酶的活性来调节体内血糖、减少体重增加、减轻脂肪积累等变化，进而改善糖尿病病人及其他代谢类疾病病人的状况。
本发明提供一种咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐，其特征在于所述咪唑并噻唑衍生物具有式(I)所示结构：
式(I)包括通式一和通式二，R
1、R
3各自独立地选自任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷基胺基、C1-C6烷氧基、5元至6元杂环、卤素、羟基、氰基、硝基、氨基、羰基等基团取代的
含有1-2个氮原子的5元至6元杂环基，或者R
1选自任选被一个或多个羟基、卤素、氨基、二甲氨基、5
元至6元杂环取代的C1-C6烷氧基，R
1选自任选被一个或多个羟基、卤素、氨基、二甲氨基、5元至6
元杂环取代的C1-C6烷硫基，R
1选自任选被一个或多个羟基、卤素、氨基、二甲氨基、5元至6元杂环
取代的C1-C6烷胺基，R
2、R
4各自独立地选自任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6
烷基胺基、C1-C6烷氧基、C1-C6烷氧基羰基、羟基取代的C1-C6烷基、卤素、羟基、氰基、硝基、氨
基、羰基等基团取代的芳基或杂芳基。
本发明所述C1-C6烷基指含有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基，代表性实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。C1-C6烷基可进一步优选C1-C3烷基。
本发明所述C1-C6卤代烷基是指上述定义的“C1-C6烷基”中的一个或多个氢原子被相同或不同的卤素原子取代。C1-C6卤代烷基可进一步优选C1-C3卤代烷基。代表性实例包括但不限于三氟甲基、二氟甲基、一氟甲基、三氯甲基、1,1,1-三氟乙基、五氟乙基等。
本发明所述C1-C6烷基胺基是指氨基(-NH
2)中的一个或两个氢原子被相同或不同的上述定义的“C1-C6烷基”取代；即可表示为-NR
1R
2，R
1、R
2各自独立地选自H、C1-C6烷基，且R
1、R
2不能同时为H。
本发明所述C1-C6烷氧基是指-OR
3，其中R
3选自C1-C6烷基；C1-C6烷氧基可进一步优选C1-C3烷氧基，更进一步优选甲氧基、乙氧基等。
本发明所述C1-C6烷氧基羰基是指-C(O)R
4，其中R
4选自C1-C6烷氧基。
本发明所述5元至6元杂环是指环系统中具有环碳原子和1-4个环杂原子(优选1、2、3个环杂原子)，其中每个环杂原子独立地选自氮、氧、硫；在含有一个或多个氮原子的杂环基中，连接点可以是碳或氮原子，只要化合价允许。进一步优选哌嗪环、吗啉环、哌啶环、六氢吡喃环、四氢呋喃环、四氢噻吩环、吡咯环、四氢吡咯环等。
本发明所述芳基优选含有6-12个碳原子的单环或多环芳基，优选苯基、萘基等；杂芳基优选5元至6元杂芳基，5元至6元杂芳基是指杂芳基系统中具有环碳原子和1-4个环杂原子(优选1、2、3个环杂原子)，其中每个环杂原子独立地选自氮、氧、硫。进一步优选呋喃基、噻吩基、吡啶基、噻唑基、咪唑基等。
本发明所述卤素原子或卤素优选氟、氯、溴、碘。
上述式(I)结构的咪唑并噻唑衍生物优选化合物1-55或其立体异构体、互变异构体、几何异构体或其药学上可接受的盐，
本发明的另一实施方案提供上述式(I)结构的咪唑并噻唑衍生物的制备方法，其特征在于包括如下步骤：通式一的合成方法：
式(II)化合物与相应的硼酸衍生物(B(OH)
2R
2)发生Suzuki缩合反应得到通式一化合物，其中R
1和R
2定义同上，X为卤素，优选氯、溴、碘；
通式二的合成方法：
式(III)化合物与相应的乙炔衍生物
在碱性条件下反应得到通式二化合物，其中R
3和R
4定义同上。
本发明的另一实施方案提供上述式(I)结构的咪唑并噻唑衍生物的制备方法，其特征在于包括如下步骤：
通式一的合成方法包括由式(IV)化合物制备式(II)化合物的步骤：
通式二的合成方法包括由式(V)化合物制备式(III)化合物的步骤：
本发明的另一实施方案提供上述式(I)结构的咪唑并噻唑衍生物的制备方法，其特征在于式(I)结构的咪唑并噻唑衍生物选自R2为4-氰基苯基时的通式一，以化合物N表示，包括如下步骤：
化合物M与R
1H发生缩合反应得到化合物N，R
1的定义同上。
本发明的另一实施方案提供用于制备式(I)结构的咪唑并噻唑衍生物的中间体，其特征在于所述中间体具有式(II)所示结构：
本发明的另一实施方案提供用于制备式(I)结构的咪唑并噻唑衍生物的中间体，其特征在于所述中间体具有式(III)所示结构：
本发明的另一实施方案提供用于制备式(II)的中间体，其特征在于所述中间体具有式(IV)所示结构：
本发明的另一实施方案提供用于制备式(III)的中间体，其特征在于所述中间体具有式(V)所示结构：
本发明的另一实施方案提供一种制备所述式(I)结构的咪唑并噻唑衍生物的中间体，其特征在于所述中
间体具有如下结构：
本发明的另一实施方案提供式(II)、式(III)、式(IV)、式(V)化合物在制备式(I)结构的咪唑并噻唑衍生物中的应用。
本发明的另一实施方案提供上述式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐在抑制MNK1或者MNK2或其变体的激酶活性中的应用；或者制备用于预防和/或治疗由MNK1和/或MNK2水平失常引起的的癌症的药物中的应用。
本发明的另一实施方案提供上述式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐制备用于预防和/或治疗与MNK活性相关的代谢类疾病的药物中的应用。所述与MNK活性相关的代谢类疾病选自1型糖尿病、2型糖尿病、高血脂、肥胖症、脂肪肝病，及其并发症和与其有关的病症。
本发明的另一实施方案提供上述式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐在制备MNK1和/或MNK2抑制剂中的应用。
本发明的另一实施方案提供一种药物组合物，其特征在于该药物组合物以上述式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐作为有效成分。该药物组合物还可包括药学上可接受的辅料。该药物组合物还可包括其他MNK1和/或MNK2抑制剂(已上市的治疗药物)。其剂型可以为固体制剂、液体制剂或半固体制剂，优选片剂、胶囊、注射剂等。
本发明的方法与技术通常根据本领域已知的传统方法实施，除另有说明。本发明中所描述的术语根据化学、生物学、药理学命名，实验方法与技术为本领域已知且常用的。化学合成学、化学分析学、医药制法及 调配，患者的治疗法均采用标准技术。除另有说明，否则本发明中所使用的科学与技术术语应具有那些本领域普通技术人员通常理解的含义。但下列术语具有如下定义：
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或两种构型的混合物。
糖尿病及其并发症具体描述为葡萄糖耐量降低，糖尿病性坏疽，糖尿病性关节病变，糖尿病性骨质减少，糖尿病性肾小球硬化，糖尿病性肾病变，糖尿病性皮肤病变，糖尿病性神经病变，糖尿病性白内障，糖尿病性视网膜病变，糖尿病性黄斑病变，糖尿病性足综合症，糖尿病性昏迷，糖尿病高渗性昏迷，低血糖昏迷，高血糖昏迷，糖尿病酸中毒，糖尿病酮症酸中毒，毛细血管内肾小球性肾病，糖尿病性肌萎缩，糖尿病性自律神经病变，糖尿病性单神经病变，糖尿病性多神经病变，糖尿病性血管病，糖尿病性外周血管病，糖尿病性溃疡，糖尿病性关节病变，糖尿病性肥胖。
高血脂及其并发症具体为：高胆固醇血症，家族性高胆固醇血症，佛氏高脂蛋白血症，高β脂蛋白血症，高血脂，低密度脂蛋白型高脂蛋白血症，纯高甘油酯血症，内源性高甘油酯血症，单纯高胆固醇血症，单纯高甘油三脂血症，心血管疾病。其中心血管疾病包括：高血压，缺血，静脉曲张，视网膜静脉闭塞，动脉粥样硬化，心绞痛，心肌梗塞，狭心症，肺性高血压，充血性心力衰竭，肾小球病，肾小管间质性病症，肾衰竭，血管狭窄或脑血管疾病(脑卒中)。
脂肪肝病包括但不限于非酒精脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)以及由此引发的慢性炎症从而导致渐进性纤维化，肝硬化等。
图1是实验中各组小鼠的血糖变化图；
图2是各给药组的葡萄糖耐量和胰岛素耐量变化图；
图3是各给药组对血清中各相关指标变化的示例图；
图4是db/db小鼠中各组的胰岛素耐受实验的示例图；
图5是db/db实验小鼠肝功能各个相关指标变化的示例图；
图6是db/db实验小鼠血清中各个相关指标变化的示例图。
化合物的通用合成方法
通式一的合成方法：
以市售的5-溴-2-氨基-1,3,4-噻二唑为原料，与氯乙醛或者2-溴-1,1-二乙氧基乙烷在醇溶液(例如乙醇，正丁醇等)中回流1-2天得到环合产物A，然后与4-甲酯苯硼酸发生Suzuki缩合反应得到化合物B，与NBS(亦可以用NIS)在二氯甲烷溶液中发生亲核取代反应得到C，并在碱性条件下(例如在氢氧化锂，氢氧化钠，或氢氧化钾水溶液，溶液可为水，四氢呋喃，醇的混合溶液中)水解，调酸后(酸可以为盐酸，硫酸，乙酸，甲酸等水溶液)得到羧酸结构的化合物D，随后在酰胺缩合试剂条件下(例如EDCI和NHS，EDCI和Hobt或者EDCI和Hoat等组合)与氨基化合物R
1H发生酰胺化反应得到化合物E，最后与硼酸类化合物B(OH)
2R
2发生Suzuki缩合反应得到最终的化合物F(通式一)，其中R
1和R
2定义同前。
由上述反应得到的中间体C，与4-氰基苯硼酸发生Suzuki缩合反应得到化合物L，并在碱性条件下(例如在氢氧化锂，氢氧化钠，或氢氧化钾水溶液，溶液可为水，四氢呋喃，醇的混合溶液中)水解，调酸后(酸可以为盐酸，硫酸，乙酸，甲酸等水溶液)得到羧酸结构的化合物M，随后在缩合试剂条件下(例如EDCI和NHS，EDCI和Hobt或者EDCI和Hoat等组合)与R
1H(胺基化合物、醇类化合物、巯基化合物)发生缩合反应得到最终的化合物N(R
2为4-氰基苯基时的通式一)，R
1定义同前。
通式二的合成方法：
以市售的4-乙酰基苯甲酸甲酯为原料，与NBS在对甲苯磺酸、乙腈溶液中回流反应得到化合物G，随后与2-氨基-1,3,4-噻二唑在醇溶液中回流反应6h得到化合物H，并在碱性条件下(例如在氢氧化锂，氢氧化钠，或氢氧化钾水溶液，溶液可为水，四氢呋喃，醇的混合溶液中)水解，调酸后(酸可以为盐酸，硫酸，乙酸，甲酸等水溶液)得到羧酸结构的化合物I，随后在酰胺缩合试剂条件下(例如EDCI和NHS，EDCI和Hobt或者EDCI和Hoat等组合)与氨基化合物R
3H发生酰胺化反应得到化合物J，最后在DMF溶液中，叔丁醇钾作为碱与苯乙炔类化合物R
4CCH室温反应6h得到化合物K(通式二)，其中R
3和R
4参照上述权利要求说明。
具体实施方式
下面通过具体的制备例和实施例对本发明进行详细说明，但这些例举性实施方式的用途和目的仅用来例举本发明，并非对本发明的实际保护范围构成任何形式的任何限定，更非将本发明的保护范围局限于此。
实施例1：2-溴咪唑[2,1-b][1,3,4]噻二唑(化合物A)
5-溴-2-氨基-1,3,4-噻二唑与氯乙醛在乙醇中回流反应得到化合物A，产率为17.6％，
1H NMR(500MHz,CDCl
3)δ7.76(s,1H),7.36(s,1H).
实施例2：4-(咪唑[2,1-b][1,3,4]噻二唑)苯甲酸甲酯(化合物B)
2-溴咪唑[2,1-b][1,3,4]噻二唑(化合物A)300mg(1.47mmol)与4-甲酸甲酯苯硼酸317mg(1.76mmol)在催化剂作用下，发生Suzuki缩合反应后经硅胶柱层析(PE:EA＝10:1)得白色固体93.2mg(即为化合物B)，产率为24.3％。
1H NMR(500MHz,CDCl
3)δ8.19–8.15(m,2H),7.97–7.93(m,2H),7.81(d,J＝1.4Hz,1H),7.37(d,J＝1.4Hz,1H),3.97(s,3H).
实施例3：4-(5-溴咪唑[2,1-b][1,3,4]噻二唑-2-基)苯甲酸甲酯(化合物C)
4-(咪唑[2,1-b][1,3,4]噻二唑)苯甲酸甲酯350mg(1.35mmol)与286mg(1.62mmol)N-溴代丁二酰亚胺反应后，经硅胶柱层析得淡绿色固体340mg(即为化合物C)，产率为74.7％。
1H NMR(500MHz,CDCl
3)δ8.18(d,J＝8.4Hz,2H),7.99(d,J＝8.4Hz,2H),7.29(s,1H),3.98(s,3H).
13C NMR(125MHz,CDCl
3)δ165.9,161.5,144.2,133.8,133.7,133.1,130.5,126.9,96.3,52.5.
实施例4：4-(5-溴咪唑[2,1-b][1,3,4]噻二唑-2-基)苯甲酸(化合物D)
取4-(5-溴咪唑[2,1-b][1,3,4]噻二唑-2-基)苯甲酸甲酯340mg(1mmol)，424mg(10mmol)的一水氢氧化锂混合于30mL的THF/H
2O(V:V＝1:1)的溶液中，反应结束后经纯化得到320mg白色固体，即为化合物D，产率为98％。
实施例5：4-(2-溴乙酰基)苯甲酸甲酯(化合物G)
将4-乙酰基苯甲酸甲酯(5g,28mmol)溶于乙腈(100mL)中，，加入NBS(6.0g,33.6mmol)和TsOH(482mg,2.8mmol)反应后，经柱层析纯化(PE:EA＝10:1)，得白色固体4.6g(即为化合物G)，收率：63.9％。
1H NMR(400MHz,CDCl
3)δ8.13(d,J＝8.1Hz,2H),8.02(d,J＝8.1Hz,2H),4.46(s,2H),3.94(s,3H)；
13C NMR(100MHz,CDCl
3)δ190.84,165.95,137.16,134.62,130.01,128.87,52.58,30.71.
实施例6：4-(2-(2-氨基-1,3,4-噻二唑)乙酰基)苯甲酸甲酯(化合物H)
在250mL茄型瓶中加入4-(2-溴乙酰基)苯甲酸甲酯(4g,15.6mmol)，2-氨基-1,3,4-噻二唑(1.6g,16mmol)，乙醇(100mL)，磁力搅拌下，80℃下回流反应6h。TLC检测原料反应完全。将反应瓶冷却至室温，抽滤，用乙醇洗涤滤饼3次，得白色固体3.2g(即为化合物H)，收率：74％。
1H NMR(400MHz,CDCl
3)δ8.15(d,J＝8.1Hz,2H),8.05(d,J＝8.1Hz,2H),7.67(s,1H),5.41(s,2H),3.96(s,3H)；
13C NMR(100MHz,CDCl
3)δ192.06,166.05,161.55,137.93,134.56,133.53,130.03,128.07,53.71,52.55。
实施例7：4-(咪唑[2,1-b][1,3,4]噻二唑)苯甲酸(化合物I)
在100mL茄型瓶中加入4-(2-(2-氨基-1,3,4-噻二唑)乙酰基)苯甲酸甲酯(3g,10.8mmol)，2N盐酸(60mL)，100℃下回流反应6h。TLC检测原料反应完全。将反应瓶冷却至室温，冰浴下加入1N氢氧化钠调节pH至9-10，加入乙酸乙酯，转移至分液漏斗中，摇匀静止，分离出水层，水层用1N盐酸调节pH至2-3，产生土黄色固体，抽滤得固体2.2g(即为化合物I)，收率：83％。
1H NMR(400MHz,DMSO-d
6)δ9.24(s,1H),8.87(s,1H),7.98–7.92(m,4H)；
13C NMR(100MHz,DMSO-d
6)δ167.62,151.69,145.50,145.26,138.49,130.38,129.83,125.12,112.39.
实施例8:4-(5-4-氰基苯基)咪唑并[2,1-b][1,3,4]噻二唑-2-基)苯甲酸甲酯(化合物L)
在100mL茄型瓶中加入化合物C(50mg,0.12mmol)，4-氰基苯硼酸(35.2mg,0.24mmol)，Pd(PPh
3)
4(28mg,0.025mmol)，CsF(51mg,0.24mmol)，二氧六环(40mmol)和水(10mL)，N
2保护下，100℃反应6h。TLC检测原料反应完全,冷却至室温后过滤得黄色固体16mg(即为化合物L)，收率30％。
1H NMR(400MHz,DMSO-d6)δ8.14(m,9H),3.91(s,3H)。
实施例9：4-(5-溴咪唑并[2,1-b][1,3,4]噻二唑)-2-苯甲酰吗啉(中间体1)
取化合物D(2g,6.2mmol),EDCI(2.4g,12.4mmol),NHS(1.4g,12.4mmol),吗啉(2.7g,31mmol)溶于DMF(50mL)中，室温反应直至TLC检测原料反应完全,旋蒸除去DMF后，经柱层析纯化(CH
2Cl
2:CH
3OH＝50:1),得白色固体1.8g(即为中间体1)，收率：75％。
1H NMR(400MHz,CDCl
3)δ7.97(d,J＝8.3Hz,2H),7.58(d,J＝8.3Hz,2H),7.39(s,1H),3.61(s,4H),3.51(s,2H),3.30(s,2H).
13C NMR(101MHz,CDCl
3)δ168.95,161.56,144.10,138.68,133.74,131.25,128.14,127.24,96.26,66.82,48.17,42.65。
实施例10：4-(5-溴咪唑并[2,1-B][1,3,4]噻二唑)-2-(4-二甲氨基苯甲酰胺哌啶)(中间体2)
取化合物D(2g,6.2mmol),EDCI(2.4g,12.4mmol),NHS(1.4g,12.4mmol),4-二甲氨基哌啶(1.6g,12.4mmol)溶于DMF(50mL)中，室温反应直至TLC检测原料反应完全,旋蒸除去DMF后，经柱层析纯化 (CH
2Cl
2:CH
3OH＝50:1),得白色固体1.6g(即为中间体2)，收率：59.3％。
1H NMR(400MHz,DMSO-d
6)δ8.01(d,J＝8.4Hz,2H),7.60(d,J＝8.0Hz,2H),7.46(s,1H),4.45(d,J＝13.1Hz,1H),3.56(d,J＝13.6Hz,1H),3.06(t,J＝12.9Hz,1H),2.83(t,J＝12.6Hz,1H),2.47–2.37(m,1H),2.21(s,6H),1.86(d,J＝12.9Hz,1H),1.70(d,J＝12.6Hz,1H),1.39(q,J＝13.5Hz,2H)；
13C NMR(101MHz,DMSO-d
6)δ168.13,162.63,144.34,140.26,133.98,130.48,128.44,127.58,96.51,61.73,46.71,41.78,28.74,28.10。
实施例11：(N-甲基哌嗪)-4-(5-溴咪唑[2,1-b][1,3,4]噻二唑-2-基)苯甲酰胺(中间体3)
取化合物D 8mg(0.18mmol)，(1-乙基-3(3-二甲基丙胺)碳二亚胺)69mg(0.36mmol)，N-羟基丁二酰亚胺42mg(0.36mmol)混合于10mL的DMF中，室温搅拌反应10h后加入99μL N-甲基哌嗪，继续搅拌1h后，水洗，氯仿萃取后柱层析，得50mg的黄色固体(即为中间体3)，产率68％。
1H NMR(400MHz,CDCl
3)δ7.97–7.93(m,1H),7.57–7.52(m,2H),7.25(s,1H),3.84–3.77(m,2H),3.52–3.34(m,2H),2.57–2.45(m,2H),2.35(s,2H),2.31(s,3H).
13C NMR(100MHz,CDCl
3)δ168.8,161.7,144.1,139.2,133.7,131.0,128.1,127.2,96.2,55.2,54.6,47.6,46.0,42.1.
实施例12：6-(4-吗啉基羰基苯基)咪唑[2,1-b][1,3,4]噻二唑(中间体4)
取化合物I(2g,8.2mmol)，EDCI(3.2g,16.4mmol)，NHS(1.9g,16.4mmol)，吗啉(3.6g,41mmol)溶于DMF(50mL)中，室温反应直至TLC检测原料反应完全。旋蒸除去DMF后，经柱层析纯化(CH
2Cl
2:CH
3OH＝50:1)，得白色固体1.8g(即为中间体4)，收率：69.8％。
1H NMR(400MHz,CDCl
3)δ8.57(s,1H),8.14(s,1H),7.88(d,J＝8.1Hz,2H),7.47(d,J＝8.0Hz,2H),3.72(s,6H),3.56(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.22,147.03,146.49,144.67,135.43,134.24,127.80,125.18,110.13,66.89,48.27,42.68.
实施例13：6-(4-(N-甲基哌嗪基羰基苯基)咪唑[2,1-b][1,3,4]噻二唑(中间体5)
以化合物I(2g,8.2mmol)和N-甲基哌嗪(1.6g,16.4mmol)为原料按照中间体4的合成方法得到白色固体(1.6g)，收率：59.6％。
1H NMR(400MHz,CDCl
3)δ8.56(s,1H),8.14(s,1H),7.87(d,J＝8.3Hz,2H),7.47(d,J＝8.3Hz,2H),3.82(s,2H),3.51(s,2H),2.50(s,2H),2.39(s,2H),2.34(s,3H)；
13C NMR(100MHz,CDCl
3)δ170.13,146.80,146.70,144.61,135.22,134.82,127.76,125.15,110.08,55.18,47.73,46.04,42.15.
实施例14：6-(4-(4-二甲氨基)哌啶基羰基苯基)咪唑[2,1-b][1,3,4]噻二唑(中间体6)
以化合物I(2g,8.2mmol)和4-二甲氨基哌啶(2.1g,16.4mmol)为原料按照中间体4的合成方法得到白色固体(1.5g)，收率：51.5％。
1H NMR(400MHz,CDCl
3)δ8.66(s,1H),8.17(s,1H),7.87(d,J＝8.2Hz,2H),7.46(d,J＝8.2Hz,2H),4.76(s,1H),3.92(s,1H),3.06(s,1H),2.82(s,1H),2.53(ddt,J＝11.4,7.5,3.6Hz,1H),2.35(s,6H),1.87(s,2H),1.52(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.52,147.55,146.49,144.95,135.26,134.73,127.62,125.29,110.34,62.19,47.17,41.66,41.27,28.78,27.63.
实施例15：6-(4-吗啉哌啶基羰基苯基)咪唑[2,1-b][1,3,4]噻二唑(中间体7)
以化合物I(2g,8.2mmol)和4-吗啉哌啶盐酸盐(3.4g,16.4mmol)为原料按照中间体4的合成方法得到白色固体(900mg)，收率：27.6％。
1H NMR(400MHz,CDCl
3-CD
3OD)δ8.59(s,1H),8.10(s,1H),7.80(d,J＝8.2Hz,2H),7.40(d,J＝8.2Hz,2H),4.67(s,1H),3.85(s,1H),3.71(t,J＝4.7Hz,4H),3.01(s,1H),2.75(s,1H),2.59(t,J＝4.8Hz,4H),2.52(s,1H),1.97(s,1H),1.83(s,1H),1.46(s,2H)；
13C NMR(100MHz,CDCl
3-CD
3OD)δ172.74,170.12,147.22,146.08,144.60,134.86,134.34,127.27,124.95,109.98,66.36,61.72,49.24,46.70,41.26,25.06.
实施例16:4-(5-4-氰基苯基)咪唑并[2,1-b][1,3,4]噻二唑-2-基)苯甲酸(中间体8)
将化合物L(340mg,1.01mmol)和LiOH·H2O(420mg,10mmol)混合在30ml THF/H2O(V:V＝1:1)中，在室温下搅拌12小时。用HCl将pH调至2-3后，过滤得到白色固体化合物M(即中间体8)，无需进一步纯化即可用于下一步。
实施例17：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-氰基苯基)(化合物1)
在100mL茄型瓶中加入4-(5-溴咪唑并[2,1-b][1,3,4]噻二唑)-2-苯甲酰吗啉(中间体1)(200mg,0.5mmol)，4-氰基苯硼酸(150mg,1mmol)，Pd(PPh
3)
4(120mg,0.1mmol)，CsF(380mg,2.5mmol)，二氧六环(40mmol)和水(10mL)，N
2保护下，100℃反应6h。TLC检测原料反应完全，减压蒸馏除去二氧六环，加入二氯甲烷和水，转移至分液漏斗中，摇匀静止，分离出有机层，水层用二氯甲烷萃取2次，合并有机层，有机层用饱和NaCl溶液洗2次，无水Mg(SO
4)
2干燥，过滤，旋干滤液，柱层析纯化(CH
2Cl
2:CH
3OH＝50:1)，得白色固体40mg，收率：19.2％。
1H NMR(500MHz,CDCl
3)δ8.14(d,J＝6.9Hz,2H),8.02(d,J＝7.2Hz,2H),7.77(d,J＝7.8Hz,3H),7.62(d,J＝7.3Hz,2H),3.82(s,4H),3.68(s,2H),3.48(s,2H)；
13C NMR(125MHz,CDCl
3)δ168.85,162.00,146.97,138.84,132.76,132.52,132.06,131.13,128.58,128.25,127.21,124.83,118.78,110.66,66.81,48.18,42.62；HRMS calcd for(C
22H
18O
2N
5S+H)
+416.1176,found 416.1168.
实施例18：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-氟苯基)(化合物2)
在100mL茄型瓶中加入4-(5-溴咪唑并[2,1-b][1,3,4]噻二唑)-2-苯甲酰吗啉(中间体1)(200mg,0.5mmol)，4-氟苯硼酸(140mg,1mmol)，Pd(PPh
3)
4(120mg,0.1mmol)，CsF(380mmol,2.5mmol)，二氧六环(40mmol)和水(10mL)，N
2保护下，100℃反应6h。TLC检测原料反应完全，旋蒸除去二氧六环，加入二氯甲烷和水，转移至分液漏斗中，摇匀静止，分离出有机层，水层用二氯甲烷萃取2次，合并有机层，有机层用饱和NaCl溶液洗2次，无水Mg(SO
4)
2干燥，过滤，旋干滤液，柱层析纯化(CH
2Cl
2:CH
3OH＝50:1)，得白色固体56mg，收率：27.5％。
1H NMR(500MHz,CDCl
3)δ8.00(d,J＝6.4Hz,2H),7.98–7.94(m,2H),7.59(d,J＝6.4Hz,3H),7.20(t,J＝7.8Hz,2H),3.82(s,4H),3.68(s,2H),3.48(s,2H)；
13C NMR(125MHz,CDCl
3)δ168.92,163.29,161.50,144.92,138.62,135.70,131.33,129.69,128.17,127.16,126.99,124.36,116.08,114.45, 66.82,48.12,42.64；HRMS calcd for(C
21H
18O
2N
4FS+H)
+409.1129,found 409.1119.
实施例19：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-羟基苯基)(化合物3)
在100mL茄型瓶中加入4-(5-溴咪唑并[2,1-b][1,3,4]噻二唑)-2-苯甲酰吗啉(中间体1)(200mg,0.5mmol)，4-羟基苯硼酸(140mg,1mmol)，Pd(PPh
3)
4(120mg,0.1mmol)，CsF(380mmol,2.5mmol)，二氧六环(40mmol)和水(10mL)，N
2保护下，100℃反应6h。TLC检测原料反应完全，旋蒸除去二氧六环，加入二氯甲烷和水，转移至分液漏斗中，摇匀静止，分离出有机层，水层用二氯甲烷萃取2次，合并有机层，有机层用饱和NaCl溶液洗2次，无水Mg(SO
4)
2干燥，过滤，旋干滤液，柱层析纯化(CH
2Cl
2:CH
3OH＝50:1)，得白色固体60mg，收率：29.5％。
1H NMR(500MHz,DMSO-d
6)δ9.69(s,1H),8.08(d,J＝7.9Hz,2H),7.87(d,J＝8.2Hz,2H),7.64(d,J＝8.2Hz,3H),6.91(d,J＝8.8Hz,2H),3.65(s,4H),3.57(s,2H),3.36(s,2H)；
13C NMR(125MHz,DMSO-d
6)δ168.41,161.20,157.55,139.21,131.02,129.93,128.65,128.05,127.47,126.71,119.54,116.22,66.48,48.08,42.48；HRMS calcd for(C
21H
19O
3N
4S+H)
+407.1172,found 407.1172.
实施例20：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-甲氧羰基苯基)(化合物4)
以中间体1(200mg,0.5mmol)和4-甲氧羰基苯硼酸(180mg,1mmol)为原料按照化合物1的合成方法得到白色固体78mg，收率：34.8％。
1H NMR(400MHz,CDCl
3)δ8.15(d,J＝8.5Hz,3H),8.08(d,J＝8.6Hz,3H),8.02(d,J＝8.4Hz,2H),7.77(s,1H),7.60(d,J＝8.4Hz,2H),3.95(s,3H),3.82(s,4H),3.66(s,2H),3.48(s,2H)；
13C NMR(100MHz,CDCl
3)δ169.02,166.77,161.97,146.13,138.83,133.72,132.34,131.25,130.40,129.11,128.79,128.35,127.36,124.63,66.93,52.37,48.28,42.75；HRMS calcd for(C
23H
21O
4N
4S+H)
+499.1278,found 499.1269.
实施例21：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-三氟甲基苯基)(化合物5)
以中间体1(200mg,0.5mmol)和4-三氟甲基苯硼酸(190mg,1mmol)为原料按照化合物1的合成方法得到白色固体80mg，收率：34.9％。
1H NMR(400MHz,CDCl
3)δ8.12(d,J＝8.1Hz,2H),8.01(d,J＝8.1Hz,2H),7.73(d,J＝8.1Hz,3H),7.59(d,J＝8.2Hz,2H),3.82(s,4H),3.66(s,2H),3.48(s,2H)；
13C NMR(100MHz,CDCl
3)δ168.98,161.50,146.46,138.67,132.29,131.80,131.41,129.44,128.24,127.20,125.92,124.85,122.76,66.85,48.22,42.77；HRMS calcd for(C
22H
18O
2N
4F
3S+H)
+459.1097,found 459.1086.
实施例22：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-氯苯基)(化合物6)
以中间体1(200mg,0.5mmol)和4-氯苯硼酸(160mg,1mmol)为原料按照化合物1的合成方法得到白色固体76mg，收率：35.8％。
1H NMR(400MHz,CDCl
3)δ8.00(d,J＝8.6Hz,2H),7.93(d,J＝8.7Hz,2H),7.61(s,1H),7.58(d,J＝8.6Hz,2H),7.45(d,J＝8.7Hz,2H),3.80(s,4H),3.67(s,2H),3.51(s,2H),3.47(s,2H)；
13C NMR(100MHz,CDCl
3)δ169.02,161.15,145.70,138.53,133.34,131.54,131.23,129.14,128.20,127.17,126.94,126.18,66.85,48.23,42.58；HRMS calcd for(C
21H
18O
2N
4ClS+H)
+425.0834,found 425.0823.
实施例23：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-甲基苯基)(化合物7)
以中间体1(200mg,0.5mmol)和4-甲基苯硼酸(140mg,1mmol)为原料按照化合物1的合成方法得到白色固体64mg，收率：31.7％。
1H NMR(400MHz,CDCl
3)δ8.00(d,J＝8.6Hz,2H),7.87(d,J＝8.2Hz,2H),7.58(m,3H),7.30(d,J＝7.9Hz,3H),3.80(s,4H),3.67(s,2H),3.50(s,2H),2.42(s,3H)；
13C NMR(100MHz,CDCl
3)δ169.11,160.63,145.06,138.33,137.64,131.79,130.55,129.59,128.33,128.13,127.14,125.63,125.09,66.86,48.14,42.67,21.36；HRMS calcd for(C
22H
21O
2N
4S+H)
+405.1380,found 405.1374.
实施例24：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(4-羟甲基苯基)(化合物8)
以中间体1(200mg,0.5mmol)和4-羟甲基苯硼酸(152mg,1mmol)为原料按照化合物1的合成方法得到白色固体54mg，收率：25.7％。
1H NMR(400MHz,CDCl
3)δ7.95(dd,J＝8.4,5.1Hz,4H),7.58(s,1H),7.54(d,J＝8.4Hz,2H),7.46(d,J＝8.2Hz,2H),4.74(s,2H),3.81(s,4H),3.65(s,2H),3.46(s,2H),2.40(s,1H)；
13C NMR(100MHz,CDCl
3)δ169.19,161.00,145.43,140.62,138.36,131.65,130.86,128.21,128.01,127.58,127.19,125.19,66.92,65.02,48.31,42.72；HRMS calcd for(C
22H
21O
3N
4S+H)
+421.1329,found 421.1322.
实施例25：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(3-氟-4-三氟甲基苯基)(化合物9)
以中间体1(200mg,0.5mmol)和3-氟-4-三氟甲基苯硼酸(208mg,1mmol为原料按照化合物1的合成方法得到白色固体78mg，收率：32.8％。
1H NMR(400MHz,CDCl
3)δ8.01(d,J＝8.2Hz,2H),7.92(dd,J＝11.8,1.6Hz,1H),7.83(d,J＝8.3Hz,1H),7.74(s,1H),7.69(t,J＝7.8Hz,1H),7.60(d,J＝8.2Hz,2H),3.81(s,4H),3.67(s,2H),3.47(s,2H)；
13C NMR(100MHz,CDCl
3)δ168.91,161.95,147.00,138.85,134.21,133.03,131.18, 128.29,127.80,127.24,125.74,119.84,112.71,66.84,48.24,42.67；HRMS calcd for(C
22H
17O
2N
4F
4S+H)
+477.1003,found 477.0989.
实施例26：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(3-氟-4-羟基苯基)(化合物10)
以中间体1(200mg,0.5mmol)和3-氟-4-羟基苯硼酸(156mg,1mmol)为原料按照化合物1的合成方法得到白色固体98mg，收率：46.2％。
1H NMR(400MHz,CDCl
3-CD
3OD)δ7.94(d,J＝8.3Hz,2H),7.66(dd,J＝12.2,2.1Hz,1H),7.51(dd,J＝8.6,2.5Hz,3H),7.41(s,1H),6.98(t,J＝8.7Hz,1H),3.75(s,4H),3.60(s,2H),3.42(s,2H)；
13C NMR(100MHz,CDCl
3-CD
3OD)δ169.60,161.23,152.93,150.54,144.95,138.31,131.76,129.74,128.24,127.41,121.70,120.44,118.34,113.07,66.91,42.84；HRMS calcd for(C
21H
18O
3N
4FS+H)
+425.1078,found 425.1066.
实施例27：2-(4-(苯甲酰吗啉基))咪唑[2,1-b][1,3,4]噻二唑-5-(3,4-二氟苯基)(化合物11)
以中间体1(200mg,0.5mmol)和3,4-二氟苯硼酸(160mg,1mmol)为原料按照化合物1的合成方法得到白色固体68mg，收率：31.9％。
1H NMR(400MHz,CDCl
3)δ8.00(d,J＝8.3Hz,2H),7.87(ddd,J＝11.6,7.5,2.2Hz,1H),7.68(dddd,J＝8.7,3.9,2.2,1.4Hz,1H),7.59(m,3H),7.26(dt,J＝10.1,8.5Hz,1H),3.80(s,4H),3.67(s,2H),3.48(s,2H)；
13C NMR(100MHz,CDCl
3)δ169.00,161.50,151.90,150.99,149.43,148.50,145.76,138.63,131.38,128.23,127.20,126.29,125.49,121.11,118.03,114.14,66.84,48.21,42.69；HRMS calcd for(C
21H
17O
2N
4F
2S+H)
+427.1035,found 427.1024.
实施例28：2-(4-(4-二甲氨基哌啶甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氰基苯基)(化合物12)
以中间体2(300mg,0.7mmol)和4-氰基苯硼酸(200mg,1.4mmol)为原料按照化合物1的合成方法得到白色固体50mg，收率：15.6％。
1H NMR(400MHz,CDCl
3)δ8.14(d,J＝8.1Hz,2H),8.01(d,J＝7.9Hz,2H),7.80–7.73(m,3H),7.60(d,J＝7.9Hz,2H),4.82(s,1H),3.86(s,1H),3.12(s,1H),2.80(m,1H),2.71(s,1H),2.50(s,6H),2.06(s,2H)1.62(s,2H)；
13C NMR(100MHz,CDCl
3)δ168.82,161.88,147.05,139.18,133.01,132.78,132.64,131.13,130.45,128.06,127.20,126.58,126.37,124.79,118.86,110.53,62.29,46.59,41.28,40.89,28.62,26.98；HRMS calcd for(C
25H
25ON
6S+H)
+457.1805,found 457.1792.
实施例29：2-(4-(4-二甲氨基哌啶甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氟苯基)(化合物13)
以中间体2(300mg,0.7mmol)和4-氟苯硼酸(200mg,1.4mmol)为原料按照化合物1的合成方法得到白色固体40mg，收率：12.7％。
1H NMR(400MHz,DMSO-d
6)δ8.09(m,4H),7.82(s,1H),7.61(d,J＝8.0Hz,2H),7.36(d,J＝7.9Hz,2H),4.46(s,1H),3.56(s,1H),3.06(s,1H),2.83(s,1H),2.26(s,6H),1.89(s,1H),1.74(s,1H),1.41(s,2H)；
13C NMR(100MHz,DMSO-d
6)δ168.29,161.80,160.64,145.44,139.58,131.69,130.92,128.45,127.57,127.18,126.78,125.23,116.59,116.37,62.21,55.06,29.51,26.30；HRMS calcd for(C
24H
25ON
5FS+H)
+450.1758,found 450.1750.
实施例30：2-(4-(4-二甲氨基哌啶甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-羟基苯基)(化合物14)
以中间体2(300mg,0.7mmol)和4-羟基苯硼酸(190mg,1.4mmol)为原料按照化合物1的合成方法得到白色固体50mg，收率：15.9％。
1H NMR(400MHz,DMSO-d
6)δ9.71(s,1H),8.04(d,J＝8.2Hz,2H),7.84(d,J＝8.7Hz,2H),7.63(s,1H),7.59(d,J＝8.2Hz,2H),6.88(d,J＝8.7Hz,2H),4.46(s,1H),3.53(s,1H),3.03(s,1H),2.82(s,1H),2.51(m,1H),2.24(s,6H),1.84(s,1H),1.69(s,1H),1.38(s,2H)；
13C NMR(100MHz,DMSO-d
6)δ168.17,161.26,157.60,144.25,139.90,130.85,129.92,128.34,128.06,127.45,126.71,119.54,116.25,61.73,46.60,41.54,41.05,28.54,27.89；HRMS calcd for(C
24H
26O
2N
5S+H)
+448.1802,found 448.1798.
实施例31：2-(4-(4-二甲氨基哌啶甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-甲氧基苯基)(化合物15)
以中间体2(300mg,0.7mmol)和4-甲氧基苯硼酸(210mg,1.4mmol)为原料按照化合物1的合成方法得到淡黄色固体40mg，收率：12.4％。
1H NMR(400MHz,CDCl
3)δ7.98(d,J＝8.4Hz,2H),7.90(d,J＝8.9Hz,2H),7.55(d,J＝8.5Hz,2H),7.51(s,1H),7.02(d,J＝8.9Hz,2H),4.78(s,1H),3.87(s,4H),2.85(s,1H),2.70(m,1H),2.44(s,6H),2.00(s,2H),1.54(s,2H)；
13C NMR(101MHz,CDCl
3)δ169.05,160.73,159.24,144.76,138.81,132.58,131.70,129.93,127.98,127.14,126.65,121.23,114.40,62.37,55.47,41.11,29.80；HRMS calcd for(C
25H
28O
2N
5S+H)
+462.1958,found 462.1947.
实施例32：2-(4-(4-二甲氨基哌啶甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-三氟甲基苯基)(化合物16)
以中间体2(300mg,0.7mmol)和4-三氟甲基苯硼酸(260mg,1.4mmol)为原料按照化合物1的合成方法得到白色固体32mg，收率：9.2％。
1H NMR(400MHz,CDCl
3)δ8.11(d,J＝8.1Hz,2H),7.99(d,J＝8.0Hz, 2H),7.72(d,J＝9.7Hz,3H),7.57(d,J＝8.6Hz,2H),4.76(s,1H),3.80(s,1H),3.07(s,2H),2.58(m,1H),2.39(s,6H),2.00(s,2H),1.56(m,2H)；
13C NMR(100MHz,CDCl
3)δ168.87,161.55,146.44,139.10,132.24,131.79,131.28,128.01,127.15,126.83,125.94,124.84,62.31,46.67,41.04,31.93,29.71,29.37；HRMS calcd for(C
25H
25ON
5F
3S+H)
+500.1726,found 500.1718.
实施例33：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氰基苯基)(化合物17)
以中间体3(200mg,0.5mmol)和4-氰基苯硼酸(150mg,1mmol)为原料按照化合物1的合成方法得到白色固体45mg，收率：21％。
1H NMR(400MHz,CDCl
3)δ8.13(d,J＝8.3Hz,2H),7.99(d,J＝7.9Hz,2H),7.75(d,J＝8.3Hz,3H),7.59(d,J＝8.0Hz,2H),3.83(s,2H),3.45(s,2H),2.51(s,2H),2.36(s,2H),2.33(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.78,161.94,147.06,139.34,133.01,132.77,132.65,131.01,128.20,127.15,126.37,124.79,118.85,110.55,55.23,54.64,47.65,46.02,42.18；HRMS calcd for(C
23H
21ON
6S+H)
+429.1492,found 429.1485.
实施例34：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氟苯基)(化合物18)
以中间体3(200mg,0.5mmol)和4-氟苯硼酸(140mg,1mmol)为原料按照化合物1的合成方法得到白色固体60mg，收率：28.6％。
1H NMR(400MHz,CDCl
3)δ7.97(m,4H),7.56(m,3H),7.17(m,2H),3.82(s,2H),3.45(s,2H),2.52(s,2H),2.37(s,2H),2.37(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.99,163.51,161.27,161.05,145.36,139.06,131.43,130.65,128.20,127.42,127.17,126.94,124.77,116.17,115.95,55.32,54.71,47.70,46.12,42.18；HRMS calcd for(C
22H
21ON
5FS+H)
+422.1445,found 422.1437.
实施例35：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-甲氧羰基苯基)(化合物19)
以中间体3(200mg,0.5mmol)和4-甲氧羰基苯硼酸(180mg,1mmol)为原料按照化合物1的合成方法得到白色固体46mg，收率：20％。
1H NMR(400MHz,CDCl
3)δ8.14(d,J＝8.6Hz,2H),8.08(d,J＝8.7Hz,2H),8.00(d,J＝8.3Hz,2H),7.73(s,1H),7.58(d,J＝8.3Hz,2H),3.94(s,3H),3.83(s,2H),3.46(s,2H),2.52(s,2H),2.38(s,2H),2.34(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.95,166.83,161.54,146.61,139.20,132.73,132.56,131.30,130.37,128.81,128.24,127.27,127.22,124.42,55.33,52.33,47.73,46.15,42.25,29.80；HRMS calcd for(C
24H
24O
3N
5S+H)
+462.1594,found 462.1582.
实施例36：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-吡啶)(化合物20)
以中间体3(200mg,0.5mmol)和吡啶-4-硼酸(120mg,1mmol)为原料按照化合物1的合成方法得到白色固体50mg，收率：24.7％。
1H NMR(400MHz,CDCl
3)δ8.67(d,J＝6.3Hz,2H),7.99(d,J＝8.4Hz,2H),7.89(d,J＝6.3Hz,2H),7.81(s,1H),7.57(d,J＝8.5Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.36(s,2H),2.32(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.86,162.03,150.51,147.41,139.33,135.55,133.49,131.07,128.27,127.23,125.53,118.44,55.30,54.68,47.69,46.11,42.20；HRMS calcd for(C
21H
20ON
6S+H)
+405.1458,found 405.1465.
实施例37：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-三氟甲基苯基)(化合物21)
以中间体3(200mg,0.5mmol)和4-三氟甲基苯硼酸(190mg,1mmol)为原料按照化合物1的合成方法得到白色固体54mg，收率：23％。
1H NMR(400MHz,CDCl
3)δ8.10(d,J＝8.1Hz,2H),7.98(d,J＝8.4Hz,2H),7.71(d,J＝8.7Hz,3H),7.57(d,J＝8.4Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.36(s,2H),2.33(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.93,161.71,146.51,139.25,132.25,131.83,131.23,128.25,127.21,126.88,125.99,124.91,55.34,54.72,47.74,46.15,42.24；HRMS calcd for(C
23H
21ON
5F
3S+H)
+472.1413,found 472.1407.
实施例38：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氯苯基)(化合物22)
以中间体3(200mg,0.5mmol)和4-氯苯硼酸(160mg,1mmol)为原料按照化合物1的合成方法得到白色固体56mg，收率：25.6％。
1H NMR(400MHz,CDCl
3)δ7.98(d,J＝8.3Hz,2H),7.93(d,J＝8.6Hz,2H),7.61(s,1H),7.57(d,J＝8.3Hz,2H),7.45(d,J＝8.6Hz,2H),3.83(s,2H),3.46(s,2H),2.52(s,2H),2.38(s,2H),2.34(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.99,161.37,145.83,139.18,133.42,131.43,131.30,129.24,128.23,127.26,127.20,127.07,126.28,55.38,54.78,47.78,46.17,42.30；HRMS calcd for(C
22H
21ON
5ClS+H)
+438.1150,found 438.1145.
实施例39：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(3-氟-4-三氟甲基苯基)(化合物23)
以中间体3(200mg,0.5mmol)和3-氟-4-三氟甲基苯硼酸(210mg,1mmol)为原料按照化合物1的合成 方法得到白色固体78mg，收率：31.8％。
1H NMR(600MHz,CDCl
3)δ8.00–7.89(m,3H),7.83(d,J＝8.2Hz,1H),7.73(d,J＝2.2Hz,1H),7.68(t,J＝7.9Hz,1H),7.57(m,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.37(m,2H),2.33(m,3H)；
13C NMR(150MHz,CDCl
3)δ168.86,162.14,147.09,139.44,134.28,133.77,133.07,131.06,128.29,128.16,127.25,119.95,112.59,55.31,54.72,47.70,46.09,42.22；HRMS calcd for(C
23H
20ON
5F
4S+H)
+490.1319,found 490.1307.
实施例40：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(3-氟-4-氰基苯基)(化合物24)
以中间体3(200mg,0.5mmol)和3-氟-4-氰基苯硼酸(160mg,1mmol)为原料按照化合物1的合成方法得到白色固体66mg，收率：29.6％。
1H NMR(600MHz,CDCl
3)δ7.99(d,J＝8.3Hz,2H),7.96(dd,J＝10.4,1.6Hz,1H),7.85(dd,J＝8.1,1.6Hz,1H),7.78(s,1H),7.69(dd,J＝8.2,6.7Hz,1H),7.59(d,J＝8.3Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.37(s,2H),2.33(s,3H)；
13C NMR(150MHz,CDCl
3)δ168.79,162.50,147.71,139.60,135.22,134.00,130.87,128.34,127.28,120.44,114.11,111.73,55.33,54.71,47.70,46.10,42.22；HRMS calcd for(C
23H
20ON
6FS+H)
+477.1398,found 477.1400.
实施例41：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-硝基苯基)(化合物25)
以中间体3(200mg,0.5mmol)和4-硝基苯硼酸(170mg,1mmol)为原料按照化合物1的合成方法得到白色固体88mg，收率：39.3％。
1H NMR(400MHz,CDCl
3)δ8.35(d,J＝8.9Hz,2H),8.20(d,J＝8.6Hz,2H),8.02(d,J＝8.0Hz,2H),7.83(s,1H),7.61(d,J＝8.0Hz,2H),3.84(s,2H),3.48(s,2H),2.53(s,2H),2.39(s,2H),2.35(s,3H)；
13C NMR(100MHz,CDCl
3)δ167.43,160.80,146.13,145.11,138.12,133.23,132.28,129.64,126.91,125.86,124.84,123.44,123.17,53.92,53.37,46.36,44.72,40.83；HRMS calcd for(C
22H
21O
3N
6S+H)
+449.1390,found 449.1386.
实施例42：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(2,4-二氟苯基)(化合物26)
以中间体3(200mg,0.5mmol)和3,4-二氟-苯硼酸(160mg,1mmol)为原料按照化合物1的合成方法得到白色固体78mg，收率：35.6％。
1H NMR(400MHz,CDCl
3)δ8.39–7.90(m,3H),7.75–7.50(m,3H),7.25(s,1H)7.09–6.92(m,1H),3.81(s,2H),3.44(s,2H),2.50(s,2H),2.36(s,3H),2.32(d,J＝1.0Hz,5H)；
13C NMR(100MHz,CDCl
3)δ168.86,161.68,161.11,144.13,139.23,139.09,134.16,133.71,131.31,131.05,128.09,127.17,111.78,104.67,55.23,54.67,47.64,46.03,42.18；HRMS calcd for(C
22H
20ON
5F
2S+H)
+440.1351,found 440.1348.
实施例43：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氰基-3-吡啶)(化合物27)
以中间体3(200mg,0.5mmol)和2-氰基-5-吡啶硼酸(150mg,1mmol)为原料按照化合物1的合成方法得到白色固体76mg，收率：35％。
1H NMR(400MHz,CDCl
3)δ9.40(d,J＝2.3Hz,1H),8.46(ddd,J＝8.2,2.3,0.8Hz,1H),7.99(d,J＝8.5Hz,2H),7.82–7.76(m,2H),7.59(d,J＝8.6Hz,2H),3.83(s,2H),3.46(s,2H),2.52(s,2H),2.38(s,2H),2.34(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.70,162.68,147.88,146.78,139.59,133.72,131.37,130.72,128.62,128.27,127.80,127.20,123.53,117.34,55.20,54.60,47.63,46.01,42.15；HRMS calcd for(C
22H
20ON
7S+H)
+430.1445,found 430.1435.
实施例44：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氟-3-吡啶)(化合物28)
以中间体3(200mg,0.5mmol)和2-氟-5-吡啶硼酸(140mg,1mmol)为原料按照化合物1的合成方法得到白色固体65mg，收率：30.8％。
1H NMR(400MHz,CDCl
3)δ8.88(d,J＝2.5Hz,1H),8.36(ddd,J＝8.6,7.5,2.5Hz,1H),7.98(d,J＝8.5Hz,2H),7.65(s,1H),7.58(d,J＝8.5Hz,2H),7.07(ddd,J＝8.6,3.1,0.7Hz,1H),3.83(s,2H),3.46(s,2H),2.50(d,J＝5.9Hz,2H),2.38(s,2H),2.34(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.83,163.91,161.87,161.52,146.18,144.13,139.25,137.46,131.39,131.09,128.18,127.12,124.19,122.98,110.08,109.71,55.21,54.65,47.60,46.00,42.13；HRMS calcd for(C
21H
20ON
6FS+H)
+423.1398,found 423.1393.
实施例45：2-(4-(N-甲基哌嗪甲酰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-三氟甲基-3-吡啶)(化合物29)
以中间体3(200mg,0.5mmol)和2-(三氟甲基)吡啶-5-硼酸(190mg,1mmol)为原料按照化合物1的合成方法得到白色固体75mg，收率：31.8％。
1H NMR(400MHz,CDCl
3)δ9.35(dd,J＝2.3,0.9Hz,1H),8.45(dd,J＝8.2,2.3Hz,1H),7.98(d,J＝8.3Hz,2H),7.83(s,1H),7.78(dd,J＝8.2,0.8Hz,1H),7.58(d,J＝8.4Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.38(s,2H),2.33(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.75,162.34,147.31,145.88,139.48,132.99,132.37,130.88,128.22,127.46,127.14,123.86,120.66,55.26,54.61,47.64,46.03,42.16；HRMS calcd for(C
22H
20ON
6F
3S+H)
+473.1366,found 473.1355.
实施例46：4-(2-(4-吡咯烷基-1-羰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5)-(苯基氰)(化合物30)
将中间体8(65mg,0.18mmol)、EDCI(69mg,0.36mmol)和NHS(42mg,0.36mmol)与10mL DMF的混合物在室温下搅拌10h。然后加入吡咯烷啶(65μL,0.9mmol)，再反应1h。TLC检测原料反应完全，用水淬灭，DCM萃取3次，有机层用饱和NaCl溶液洗3次，无水Mg(SO
4)
2干燥，过滤，旋干滤液。柱层析纯化(DCM:MeOH＝15:1)，得到白色固体(50mg)，收率：68％。
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝8.3Hz,2H),8.08–8.02(m,3H),7.91(d,J＝8.3Hz,2H),7.71(d,J＝8.1Hz,2H),3.46(t,J＝6.6Hz,2H),3.37(t,J＝6.2Hz,2H),1.89-1.76(m,4H)。
13C NMR(100MHz,DMSO-d6)δ167.5,162.5,147.3,141.0,134.3,133.5,132.8,130.8,128.7,127.4,126.1,124.9,119.4,109.7,49.3,46.6,26.5,24.5。HRMS calculated for(M+H)+400.1227,found 400.1217。
实施例47：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)-(2-(吡咯烷基)乙基)苯甲酰酯(化合物31)
以1-(2-羟基乙基)吡咯烷(104mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到白色固体，收率：60％。
1H NMR(400MHz,DMSO-d6)δ,8.29(d,J＝8.2Hz,2H),8.16–8.09(m,3H),8.05(d,J＝8.2Hz,2H),7.96(d,J＝8.2Hz,2H),4.42(dd,J＝12.5,6.3Hz,2H),2.80(t,J＝6.8Hz,2H),2.51–2.47(m,4H),1.64–1.74(m,4H)。HRMS calculated for(M+H)+443.1449,found 443.1452。
实施例48：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)-(正戊基)苯甲酰酯(化合物32)
以正戊硫醇(91.8mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：53％。
1H NMR(400MHz,DMSO-d6)δ8.08(d,J＝8.4Hz,2H),8.04(d,J＝9.7Hz,3H),8.01(d,J＝8.4Hz,2H),7.96(d,J＝8.4Hz,2H),3.53(t,J＝5.1Hz,1H),1.97(dd,J＝11.5,6.1Hz,2H),1.82–1..77(m,4H),1.32(p,J＝6.5Hz,2H)，0.8(p,J＝6.5Hz,2H).。HRMS calculated for(M+H)+432.1176,found 432.1163。
实施例49：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)-(3-(吗啉基)丙基)苯甲酰酯(化合物33)
以N-(3-羟基丙基)吗啉(131mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料按照化合物30的合成方法得到黄色固体，收率为45％。
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝8.4Hz,2H),8.03–8.09(m,3H),7.82(d,J＝8.4Hz,2H),7.71(d,J＝8.4Hz,2H),3.50(t,J＝4.3Hz,4H),3.35–3.30(m,2H),2.41–2.31(m,2H),1.72(p,J＝7.0Hz,2H)。HRMS calculated for(M+H)+473.1528,found 473.1542
实施例50：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)-(5-羟戊基)苯甲酰酯(化合物34)
以1,5-戊二醇(94mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：45％。
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝8.5Hz,2H),8.10(d,J＝9.5Hz,3H),7.96(d,J＝8.4Hz,2H),7.87(d,J＝8.5Hz,2H),3.21(t,J＝5.1Hz,2H),3.41(dd,J＝11.6,6.3Hz,2H),1.69(dd,J＝12.9,6.7Hz,2H),1.31–1.22(m,2H),1.06(m,2H)。HRMS calculated for(M+H)+432.1347,found 432.1356。
实施例51：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)-(2-羟乙基)苯甲酰硫酯(化合物35)
以2-巯基乙醇(70.2mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：35％。1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝8.4Hz,2H),8.10–8.01(m,3H),7.90(d,J＝8.5Hz,2H),7.81(d,J＝8.4Hz,2H),4.80(t,J＝5.6Hz,1H),3.66(q,J＝6.0Hz,2H),3.28(dd,J＝11.7,5.8Hz,2H)。HRMS calculated for(M+H)+406.0622,found 406.0635。
实施例52：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)N-(2-(二甲氨基)乙基)苯甲酰胺(化合物36)
以N,N-二甲基-1,2-乙二胺(80mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：35％。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.26(d,J＝7.8Hz,2H),8.10(d,J＝10.0Hz,3H),8.03(d,J＝7.5Hz,2H),7.94(d,J＝7.8Hz,2H),3.37(t,J＝4.0Hz,2H),2.43(t,J＝8.0Hz,2H),2.20(s,6H)。
13C NMR(100MHz,DMSO-d6)δ162.5,147.4,138.1,134.4,133.5,132.9,132.1,128.9,127.5,126.1,125.1,119.5,109.8,100.00,58.6,45.8,38.1。HRMS calculated for(M+H)+417.1492,found 417.1488。
实施例53：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)N-(3-(吗啉基)丙基)苯甲酰胺(化合物37)
以N-(3-氨基丙基)吗啉(130mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料按照化合物30的合成方法得到黄色固体，收率为47％。
1H NMR(400MHz,DMSO-d6)δ8.72(t,J＝5.4Hz,1H),8.27(d,J＝8.4Hz,2H),8.08–8.14(m,3H),8.04(d,J＝8.4Hz,2H),7.95(d,J＝8.4Hz,2H),3.58(t,J＝4.3Hz,4H),3.35–3.30(m,2H),2.41–2.31(m,6H),1.72(p,J＝7.0Hz,2H)。
13C NMR(100MHz,DMSO-d6)δ165.5,162.4,147.3,138.1,134.3,133.4,132.8,131.9,128.7,127.4,126.0,124.9,119.4,109.7,66.7,56.5,53.8,38.4,26.4。HRMS calculated for(M+H)+473.1730,found 473.1742。
实施例54：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)N-(2-(吡咯烷基)乙基)苯甲酰胺(化合物38)
以1-(2-氨基乙基)吡咯烷(102mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到白色固体，收率：62％。
1H NMR(400MHz,DMSO-d6)δ8.69(t,J＝5.2Hz,1H),8.29(d,J＝8.2Hz,2H),8.16–8.09(m,3H),8.05(d,J＝8.2Hz,2H),7.96(d,J＝8.2Hz,2H),3.42(dd,J＝12.5,6.3Hz,2H),2.60(t,J＝6.8Hz,2H),2.51–2.47(m,4H),1.64–1.74(m,4H)。
13C NMR(100MHz,DMSO-d6)δ165.5,162.4,147.2,138.0,134.4,133.5,132.9,132.0,128.8,127.4,126.1,125.0,119.4,109.7,55.3,54.2,23.6。HRMS calculated for(M+H)+443.1649,found 473.1642。
实施例55：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)N-(3-羟丙基)苯甲酰胺(化合物39)
以3-氨基丙醇(68mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：28％。
1H NMR(400MHz,DMSO-d6)δ8.70(t,J＝5.4Hz,1H),8.28(d,J＝8.4Hz,2H),8.12(d,J＝9.7Hz,3H),8.05(d,J＝8.4Hz,2H),7.96(d,J＝8.4Hz,2H),4.53(t,J＝5.1Hz,1H),3.50(dd,J＝11.5,6.1Hz,2H),3.40–3.35(m,2H),1.72(p,J＝6.5Hz,2H).。
13C NMR(100MHz,DMSO-d6)δ165.5,162.3,147.2,138.1,134.3,133.4,132.8,131.9,128.7,127.3,126.0,124.9,119.4,109.7,59.1,37.3,32.8。HRMS calculated for(M+H)+404.1176,found 404.1173。
实施例56：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)N-(2-羟乙基)苯甲酰胺(化合物40)
以乙醇胺(55mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：36％。
1H NMR(400MHz,DMSO-d6)δ8.71(t,J＝5.5Hz,1H),8.28(d,J＝8.4Hz,2H),8.15–8.10(m,3H),8.07(d,J＝8.5Hz,2H),7.96(d,J＝8.4Hz,2H),4.80(t,J＝5.6Hz,1H),3.56(q,J＝6.0Hz,2H),3.38(dd,J＝11.7,5.8Hz,2H)。
13C NMR(100MHz,DMSO-d6)δ165.7,162.4,147.3,138.0,134.3,133.5,132.9,131.9,128.8,127.3,126.0,124.9,119.4,109.7,60.1,42.8。HRMS calculated for(M+H)+390.1019,found 390.1018。
实施例57：4-(2-(4-甲基哌啶基-1-羰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-5-(4-氰基苯基)(化合物41)
以2-甲基哌啶(89mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：46％。
1H NMR(400MHz,DMSO-d6)δ8.28(d,J＝8.5Hz,2H),8.09(d,J＝8.6Hz,3H),7.96(d,J＝8.5Hz,2H),7.60(d,J＝8.1Hz,2H),5.03–3.59(m,2H),2.99(d,J＝37.9Hz,1H),1.75–1.33(m,6H),1.22(d,J＝6.8Hz,3H)。
13C NMR(100MHz,DMSO-d6)δ168.4,162.5,147.2,140.9,134.3,133.4,132.9,130.3,127.8,127.7,126.0,124.9,119.4,109.7,30.2,25.9,18.9.HRMS calculated for(M+H)+428.1540,found 428.1533。
实施例58：4-(5-(4-氰基苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)N-(5-羟戊基)苯甲酰胺(化合物42)
以5-氨基-1-戊醇(93mg,0.9mmol)和中间体8(65mg,0.18mmol)为原料，按照化合物30的合成方法得到黄色固体，收率：48％。
1H NMR(400MHz,DMSO-d6)δ8.70(t,J＝5.4Hz,1H),8.29(d,J＝8.5Hz,2H),8.13(d,J＝9.5Hz,3H),8.06(d,J＝8.4Hz,2H),7.97(d,J＝8.5Hz,2H),4.39(t,J＝5.1Hz,1H),3.41(dd,J＝11.6,6.3Hz,2H),3.29(dd,J＝12.9,6.7Hz,2H),1.61–1.52(m,2H),1.46(dd,J＝13.9,6.8Hz,2H),1.40–1.31(m,2H)。
13C NMR(100MHz,DMSO-d6)δ165.4,162.4,147.3,138.2,134.3,133.5,132.8,131.9,128.8,127.4,126.0,125.0,119.4,109.7,61.1,32.7,29.5,23.6.HRMS calculated for(M+H)+432.1489,found 432.1479。
实施例59：6-(4-吗啉基羰基苯基)-3-(4-氰基苯基)咪唑[2,1-b]噻唑(化合物43)
在50mL茄型瓶中加入中间体4(500mg,1.6mmol)，4-氰基苯乙炔(240mg,1.9mmol)，叔丁醇钾(540mg,4.8mmol)，DMF(40mL)。磁力搅拌下，室温反应6h。TLC检测原料反应完全。向反应瓶中加入二氯甲烷和水，转移至分液漏斗中，摇匀静止，分离出有机层，水层用二氯甲烷萃取2次，合并有机层，有机层用饱和NaCl溶液洗2次，无水Mg(SO
4)
2干燥，过滤，旋干滤液，柱层析纯化(CH
2Cl
2:CH
3OH＝50:1)，得白色固体(200mg)，收率：30.2％。
1H NMR(400MHz,CDCl
3)δ7.94(s,1H),7.89(m,1H),7.87(m,3H),7.81(m,2H),7.46(d,J＝8.3Hz,2H),6.98(s,1H),3.76(s,6H),3.52(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.29,150.45,147.16,135.21,134.26,133.86,133.28,130.78,127.84,127.29,125.39,117.98,113.43,111.64,107.75,66.91,48.08,42.57；HRMS calcd for(C
23H
19O
2N
6S+H)
+415.1223,found 415.1226.
实施例60：6-(4-吗啉基羰基苯基)-3-(4-氟苯基)咪唑[2,1-b]噻唑(化合物44)
以中间体4(500mg,1.6mmol)和4-氟苯乙炔(230mg,1.9mmol)为原料按照化合物30的合成方法得到白色固体(170mg)，收率：26％。
1H NMR(400MHz,CDCl
3)δ7.88(m,3H),7.65(dd,J＝8.8,5.1Hz,2H),7.45(d,J＝8.3Hz,2H),7.24(m,2H),6.77(s,1H),3.75(s,6H),3.51(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.36,164.64,162.14,150.41,146.96,135.73,133.99,131.57,129.04,128.96,127.78,126.03,126.00,125.25,116.76,116.54, 108.72,107.71,66.93,48.10,42.46；HRMS calcd for(C
22H
19O
2N
3FS+H)
+408.1177,found 408.1178。
实施例61：6-(4-吗啉基羰基苯基)-3-(4-甲氧基苯基)咪唑[2,1-b]噻唑(化合物45)
以中间体4(500mg,1.6mmol)和4-甲氧基苯乙炔(250mg,1.9mmol)为原料按照化合物30的合成方法得到白色固体(280mg)，收率：41.7％。
1H NMR(400MHz,DMSO-d
6)δ8.56(s,1H),8.00(d,J＝8.2Hz,2H),7.77(d,J＝8.4Hz,2H),7.44(d,J＝8.2Hz,2H),7.35(d,J＝1.2Hz,1H),7.13(d,J＝8.5Hz,2H),3.85(s,3H),3.73–3.47(m,8H)；
13C NMR(100MHz,DMSO-d
6)δ169.53,162.85,161.52,160.58,149.93,146.21,135.86,134.35,132.17,128.84,128.07,125.20,122.03,115.17,110.04,108.62,67.19,66.21,55.87,45.58；HRMS calcd for(C
23H
22O
3N
3S+H)
+420.1376,found 420.1370.
实施例62：6-(4-吗啉基羰基苯基)-3-(4-三氟甲基苯基)咪唑[2,1-b]噻唑(化合物46)
以中间体4(500mg,1.6mmol)和4-三氟甲基苯乙炔(320mg,1.9mmol)为原料按照化合物30的合成方法得到白色固体(220mg)，收率：30.1％。
1H NMR(400MHz,CDCl
3)δ7.93(s,1H),7.89(d,J＝8.3Hz,2H),7.82(m,4H),7.46(d,J＝8.3Hz,2H),6.93(s,1H),3.76(s,6H),3.52(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.31,150.45,147.19,135.53,134.15,133.22,131.19,127.81,127.22,126.53,125.30,110.52,107.73,66.93,48.32,42.60；HRMS calcd for(C
23H
19O
2N
3S+H)
+458.1145,found 458.1144.
实施例63：6-(4-吗啉基羰基苯基)-3-(4-氯苯基)咪唑[2,1-b]噻唑(化合物47)
以中间体4(500mg,1.6mmol)和4-氯苯乙炔(260mg,1.9mmol)为原料按照化合物30的合成方法得到白色固体(265mg)，收率：39.1％。
1H NMR(400MHz,CDCl
3)δ7.88(d,J＝4.4Hz,2H),7.85(s,1H),7.59(d,J＝8.6Hz,2H),7.51(d,J＝8.6Hz,2H),7.44(d,J＝8.4Hz,2H),6.80(s,1H),3.73(s,6H),3.51(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.32,150.40,146.95,135.77,135.66,134.01,131.44,129.71,128.17,127.78,125.24,109.22,107.80,66.92,48.30,42.71；HRMS calcd for(C
22H
19O
2N
3ClS+H)
+424.0881,found 424.0870.
实施例64：6-(4-(N-甲基哌嗪基羰基)苯基)-3-(4-氰基苯基)咪唑[2,1-b]噻唑(化合物48)
以中间体5(500mg,1.5mmol)和4-氰基苯乙炔(230mg,1.8mmol)为原料按照化合物30的合成方法得到白色固体(280mg)，收率：43.7％。
1H NMR(400MHz,CDCl
3)δ7.92(s,1H),7.88-7.84(m,4H),7.80(d,J＝8.7Hz,2H),7.45(d,J＝8.6Hz,2H),6.97(s,1H),3.80(s,2H),3.49(s,2H),2.48(s,2H),2.36(s,2H),2.32(s,3H)；
13C NMR(100MHz,CDCl
3)δ170.15,150.41,147.48,135.24,134.71,133.99,133.26,130.77,127.77,127.26,125.26,118.00,113.37,111.39,107.63,55.05,47.56,45.96,41.99；HRMS calcd for(C
24H
22ON
5S+H)
+428.1540,found 428.1535.
实施例65：6-(4-(N-甲基哌嗪基羰基)苯基)-3-(4-氟苯基)咪唑[2,1-b]噻唑(化合物49)
以中间体5(500mg,1.5mmol)和4-氟苯乙炔(220mg,1.8mmol)为原料按照化合物30的合成方法得到白色固体(220mg)，收率：34.9％。
1H NMR(400MHz,CDCl
3)δ7.85(d,J＝8.0Hz,3H),7.64(dd,J＝8.8,5.1Hz,2H),7.43(d,J＝8.5Hz,2H),7.22(d,J＝8.8Hz,2H),6.75(s,1H),3.79(s,2H),3.49(s,2H),2.48(s,2H),2.35(s,2H),2.31(s,3H)；
13C NMR(100MHz,CDCl
3)δ170.24,164.61,162.11,150.35,147.03,135.51,134.48,131.55,129.02,127.71,126.04,125.17,116.51,108.65,107.65,55.21,54.82,47.70,46.02,42.15；HRMS calcd for(C
23H
22ON
4FS+H)
+421.1493,found 421.1490.
实施例66：6-(4-(N-甲基哌嗪基羰基)苯基)-3-(4-三氟甲基苯基)咪唑[2,1-b]噻唑(化合物50)
以中间体5(500mg,1.5mmol)和4-三氟甲基苯乙炔(310mg,1.8mmol)为原料按照化合物30的合成方法得到白色固体(300mg)，收率：42.5％。
1H NMR(400MHz,CDCl
3)δ7.92(s,1H),7.86(d,J＝8.6Hz,2H),7.80(m,4H),7.44(d,J＝8.6Hz,2H),6.91(s,1H),3.79(s,2H),3.49(s,2H),2.47(s,2H),2.36(s,2H),2.32(s,3H)；
13C NMR(100MHz,CDCl
3)δ168.66,148.87,145.72,133.82,133.04,131.68,129.63,126.19,125.66,124.97,123.68,108.92,106.15,53.55,46.07,44.43,40.52；HRMS calcd for(C
24H
22ON
4F
3S+H)
+471.1461,found 471.1452.
实施例67：6-(4-(N-甲基哌嗪基羰基)苯基)-3-(4-氯苯基)咪唑[2,1-b]噻唑(化合物51)
以中间体5(500mg,1.5mmol)和4-氯苯乙炔(245mg,1.8mmol)为原料按照化合物30的合成方法得到白色固体(264mg)，收率：40.3％。
1H NMR(400MHz,CDCl
3)δ7.87(s,1H),7.84(d,J＝8.5Hz,2H),7.58(d,J＝8.7Hz,2H),7.50(d,J＝8.7Hz,2H),7.42(d,J＝8.5Hz,2H),6.78(s,1H),3.78(s,2H),3.48(s,2H),2.46(s,2H),2.35(s,2H),2.30(s,3H)；
13C NMR(101MHz,CDCl
3)δ170.22,150.37,147.04,135.77,135.45,134.47,131.44,129.70,128.23,128.17,127.70,125.17,109.15,107.72,55.18,54.86,47.68,46.00,42.09；HRMS calcd for(C
23H
22ON
4ClS+H)
+437.1197,found 437.1197.
实施例68：6-(4-(4-吗啉哌啶基羰基)苯基)-3-(4-氟苯基)咪唑[2,1-b]噻唑(化合物52)
以中间体6(500mg,1.3mmol)和4-氟苯乙炔(190mg,1.6mmol)为原料按照化合物30的合成方法得到白色固体(280mg)，收率：43.9％。
1H NMR(400MHz,CDCl
3)δ7.85(m,3H),7.64(dd,J＝8.8,5.1Hz,2H),7.42(d,J＝8.6Hz,2H),7.23(d,J＝8.7Hz,2H),6.75(s,1H),4.71(s,1H),3.88(s,1H),3.71(t,J＝4.6Hz,4H),3.02(s,1H),2.81(s,1H),2.55(t,J＝4.6Hz,4H),2.43(m,1H),1.96(s,1H),1.82(s,1H),1.58(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.19,164.62,162.13,150.36,147.07,135.44,134.75,131.56,129.03,128.95,127.53,126.02,125.18,116.75,116.52,108.64,107.62,67.14,61.98,49.81,46.93,41.55,28.96,28.15；HRMS calcd for(C
27H
28O
2N
4FS+H)
+491.1912,found 491.1908.
实施例69：6-(4-(4-二甲氨基)哌啶基羰基)苯基)-3-(4-氟苯基)咪唑[2,1-b]噻唑(化合物53)
以中间体7(500mg,1.4mmol)和4-氟苯乙炔(200mg,1.7mmol)为原料按照化合物30的合成方法得到白色固体(215mg)，收率：34.2％。
1H NMR(400MHz,CDCl
3)δ7.85(d,J＝9.1Hz,3H),7.64(dd,J＝8.8,5.1Hz,2H),7.42(d,J＝8.4Hz,2H),7.22(d,J＝8.6Hz,2H),6.75(s,1H),4.73(s,1H),3.87(s,1H),3.01(s,1H),2.80(s,1H),2.48(m,1H),2.34(s,6H),2.03–1.78(m,2H),1.48(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.22,164.61,162.12,150.35,147.05,135.47,134.69,131.56,129.02,128.94,127.54,126.04,126.01,125.18,116.73,116.52,108.64,107.65,62.26,46.93,41.38,28.88,27.86；HRMS calcd for(C
25H
26ON
4FS+H)
+499.1806,found 499.1795.
实施例70：6-(4-(4-二甲氨基)哌啶基羰基)苯基)-3-(4-三氟甲基苯基)咪唑[2,1-b]噻唑(化合物54)
以中间体7(500mg,1.4mmol)和4-三氟甲基苯乙炔(290mg,1.7mmol)为原料按照化合物30的合成方法得到白色固体(284mg)，收率：40.7％。
1H NMR(400MHz,CDCl
3)δ7.91(s,1H),7.85(d,J＝8.3Hz,2H),7.79(m,4H),7.42(d,J＝8.3Hz,2H),6.91(s,1H),4.73(s,1H),3.87(s,1H),3.01(s,1H),2.80(s,1H),2.49(m,1H),2.34(s,6H),1.97(s,2H),1.49(m,2H)；
13C NMR(100MHz,CDCl
3)δ170.17,150.40,147.25,135.31,134.81,133.22,131.17,127.56,127.20,126.50,125.22,122.33,110.49,107.72,62.26,46.96,41.36,28.88,27.77；HRMS calcd for(C
26H
26ON
4F
3S+H)
+499.1774,found 499.1783.
实施例71：6-(4-(4-二甲氨基)哌啶基羰基)苯基)-3-(4-氯苯)咪唑[2,1-b]噻唑(化合物55)
以中间体7(500mg,1.4mmol)和4-氯苯乙炔(230mg,1.7mmol)为原料按照化合物30的合成方法得到白色固体(254mg)，收率：39％。
1H NMR(400MHz,CDCl
3)δ7.87(s,1H),7.84(d,J＝8.3Hz,2H),7.59(d,J＝8.6Hz,2H),7.50(d,J＝8.6Hz,2H),7.41(d,J＝8.3Hz,2H),6.79(s,1H),4.73(s,1H),3.88(s,1H),3.01(s,1H),2.79(s,1H),2.52(m,1H),2.35(s,6H),1.88(s,2H),1.49(s,2H)；
13C NMR(100MHz,CDCl
3)δ170.21,150.38,147.08,135.79,135.44,134.66,131.46,129.72,128.25,128.18,127.55,125.19,109.13,107.71,62.29,46.89,41.27,28.70,27.68；HRMS calcd for(C
25H
26ON
4ClS+H)
+465.1510,found 465.1501。
实施例72:化合物56-61的制备
以硫代氨基脲与对甲酰苯甲酸甲酯为原料，在甲醇中室温搅拌2小时。然后加入溶于甲醇的FeCl
3·6H
2O，75℃加热搅拌30min，冷却至室温，过滤固体并用甲醇冲洗至滤液无色，得到化合物O。随后与2-溴-1-苯基酮、2-溴-1-(4-氟苯基)酮或2-溴-1-(4-氰苯基)酮的混合在乙腈中回流搅拌12h，通过柱层析得到黄色中间体，将中间体在醋酸中回流搅拌5小时；然后将混合物倒入冰水中，过滤得到相应化合物P1或P2或P3。将P1或P2或P3分别和LiOH·H
2O的混合物在THF/H
2O(1:1)中室温搅拌12小时；用HCl将pH调至2-3后，过滤得到黄色固体Q1或Q2或Q3，无需进一步纯化即可用于下一步。将Q1、Q2或Q3与EDCI、NHS和相应的胺加入DMF溶剂，混合搅拌，室温下搅拌12h得到化合物51-56。
N-(3-(二甲氨基)-2,2-二甲丙基)-4-(6-苯基咪唑基[2,1-b][1,3,4]噻二唑-2-基)苯甲酰胺(化合物56)
在圆底烧瓶中加入Q2(0.5mmol)、EDCI(1mmol)、NHS(1mmol)和N,N,2,2-四甲基-1,3-丙二胺(2.5mmol)，再加入溶剂DMF，室温下搅拌12h。薄层色谱(TLC)判断反应完成后，用水稀释反应混合物，用乙酸乙酯(20mL)萃取3次。结合的有机层用水和盐水洗涤，在无水MgSO
4上干燥，过滤，并在真空中浓缩。粗产物经层析(DCM:MeOH＝10:1)纯化得到白色固体化合物51，收率45％。.
1H NMR(500MHz,DMSO-d
6)δ8.78(s,1H),8.08(s,4H),7.90(d,J＝7.2Hz,2H),7.43(t,J＝7.7Hz,2H),7.30(t,J＝7.4Hz,1H),3.30(s,2H),3.01(s,2H),2.88(s,6H),1.07(s,6H).
13C NMR(125MHz,DMSO-d
6)δ166.9,161.1,159.1,158.8,158.5,158.1,145.9,145.0,137.3,133.7,132.4,129.1(d,J＝3.4Hz),128.0,127.0,125.2,118.8,116.5,114.2,111.9,111.2,65.6,47.2,46.7,36.3,24.2。HRMS calculated for(M+H)
+434.2009,found 434.2010。
4-(6-苯基咪唑[2,1-b][1,3,4]噻二唑-2-基)-N-(3-(四氢吡咯基)丙基)苯甲酰胺(化合物57)
以Q2和1-(3-氨基丙基)四氢吡咯为原料，按照化合物51的合成方法，得到白色固体化合物52，收率49％。
1H NMR(500MHz,DMSO-d
6)δ8.82–8.77(m,2H),8.05(q,J＝8.4Hz,4H),7.91(d,J＝7.6Hz,2H),7.43(t,J＝7.7Hz,2H),7.30(t,J＝7.3Hz,1H),3.37–3.34(m,2H),2.81(d,J＝86.5Hz,6H),1.83(s,6H).
13C NMR(125MHz,DMSO-d
6)δ165.8,160.9,146.3,145.02,137.5,134.1,132.3,129.2,128.8,127.9,127.1,125.2,111.1,53.9,52.9,37.4,26.9,23.2。HRMS calculated for(M+H)
+432.1853,found 432.1855。
4-(6-(4-氟苯基)咪唑[2,1-b][1,3,4]噻二唑-2-基)-N-(2-(吡啶-4-基)乙基)苯甲酰胺(化合物58)
以Q1和4-(2-氨基乙基)吡啶为原料，按照化合物51的合成方法，得到白色固体化合物53，收率31％。
1H NMR(500MHz,DMSO-d
6)δ8.79(t,J＝5.6Hz,1H),8.77(s,1H),8.47(d,J＝5.9Hz,2H),8.05(d,J＝8.4Hz,2H),7.99(d,J＝8.4Hz,2H),7.96–7.91(m,2H),7.27(dd,J＝15.5,6.7Hz,4H),3.57(dd,J＝12.9,6.9Hz,2H),2.90(dd,J＝11.9,4.7Hz,2H).
13C NMR(125MHz,DMSO-d6)δ165.6,162.1(d,J＝244.2Hz),160.9,149.8,148.9,145.2(d,J＝29.8Hz),137.6,132.2,130.7(d,J＝2.8Hz),128.7,127.2(d,J＝6.9Hz),124.7,116.1(d,J＝21.6Hz),111.0,109.9,40.56,34.57。HRMS calculated for(M+H)
+444.1289,found 444.1291。
N-(2-羟乙基)-4-(6-苯基咪唑基[2,1-b][1,3,4]噻二唑-2-基)苯甲酰胺(化合物59)
以Q2和乙醇胺为原料，按照化合物51的合成方法得到白色固体化合物54，收率51％。
1H NMR(500MHz,DMSO-d
6)δ8.78(s,1H),8.66(t,J＝5.5Hz,1H),8.05(s,4H),7.91(d,J＝7.3Hz,2H),7.43(t,J＝7.7Hz,2H),7.30(t,J＝7.3Hz,1H),4.76(s,1H),3.53(t,J＝6.2Hz,2H),3.36(d,J＝5.0Hz,2H).
13C NMR(125MHz,DMSO-d
6)δ165.7,160.9,146.2,145.0,137.7,134.1,132.2,129.2,128.8,127.9,127.0,125.2,111.2,60.1,42.8。HRMS calculated for(M+H)
+365.1067,found 365.1065。
4-(2-(4-(四氢吡咯基-1-羰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-6基)氰基苯(化合物60)
以Q3和四氢吡咯为原料按照化合物51的合成方法得到白色固体化合物55，收率51％。
1H NMR(400MHz,TFA-d1)δ8.47(s,1H),8.19(d,J＝7.9Hz,2H),7.92(d,J＝8.8Hz,4H),7.86(d,J＝7.9Hz,2H),3.93(s,2H),3.70(s,2H),2.18(d,J＝6.3Hz,2H),2.10(d,J＝5.9Hz,2H)。
13C NMR(400MHz,TFA-d1)166.4,145.3,137.6,133.5,131.1,130.2,128.6,128.1,126.6,51.8,49.3,24.8,23.5。
4-(2-(4-(4-甲基哌嗪-1-羰基)苯基)咪唑[2,1-b][1,3,4]噻二唑-6-基)氰基苯(化合物61)
以Q3和N-甲基哌嗪为原料按照化合物51的合成方法得到绿色固体化合物56，收率63％。
1H NMR(400MHz,TFA-d1)δ8.47(s,1H),8.15(d,J＝8.1Hz,2H),7.96–7.89(m,4H),7.73(d,J＝8.1Hz,2H),5.04(d,J＝14.5Hz,1H),4.08(d,J＝14.0Hz,1H),3.85(d,J＝6.8Hz,2H),3.73(d,J＝12.0Hz,1H),3.57(t,J＝13.0Hz,1H),3.32(dt,J＝37.8,11.3Hz,2H),3.11(s,3H)。
13C NMR(100MHz,DMSO-d6)δ168.2,161.9,145.8,144.3,139.7,138.7,133.3,130.7,128.6,127.5,125.7,119.5,113.4,109.9,55.0,46.0。
实施例73：本发明化合物对MNKs蛋白酶抑制活性测试
使用PerkinElmer公司研发的的LANCE Ultra激酶活性分析技术进行MNK1和MNK2激酶抑制活性试验。星形孢菌素Staurosporine(STSP)作为本次试验的阳性对照。试验步骤为：25℃下，1.00ng MNK1或0.05ng MNK2与不同浓度(10000、1000、100、10、1nM)的待检化合物配制成总体积为10μL反应混合物(MNK1:12.5nM CREB,450μM ATP,2mM DTT,1×buffer；MNK2:12.5nM CREB,100μM ATP,2mM DTT,1×buffer)，孵育60min；然后加入5μL EDTA/Detection buffer和5μL Eu-CREB/Detection buffer终止反应；孵育60min后检测615nm和665nm的HTRF信号的比值。先测1000nM的待测化合物，计算抑制率；当抑制率>75％、50％、25％时，分别记为+++、++、+，见表1.
然后测五个不同浓度(10000、1000、100、10、1nM)的待检化合物，根据抑制率拟合曲线计算IC
50值。在体外测试化合物对MNK1/2的IC
50的结果见表2，其中IC
50＜0.05uM(****),0.05-0.2uM(***)，0.2-0.8uM(**)以及0.8-1.5uM(*)。
表1、1μM化合物对MNKs蛋白酶抑制活性
表2.化合物对MNKs蛋白酶的IC
50值
我们测试了上述化合物对不同小鼠疾病模型的作用，以下以化合物12为具体实施例说明。
实施例74：高脂喂养肥胖模型减重试验
选用C57BL/6J雄性小鼠，分别用高脂饲料(含60kcal％)和低脂饲料(含10kcal％)进行喂养，16周后肥胖模型建立成功(高脂喂养的体重高于低脂喂养体重的20％)。并对其进行分组，分别为：空白组，12高剂量组(100mg/kg)，12低剂量组(50mg/kg)以及奥利司他组(50mg/kg)。每日下午灌胃给药，空白组以生理盐水作为对照，连续给药4周，期间定期测量小鼠的饮食量以及体重变化结果显示，给药组1个月之后体重明显的发生下降并且饮食量没有出现降低。
实施例75：STZ+高脂喂养糖尿病小鼠模型降血糖试验
雄性昆明种小鼠50只，恒温25℃环境饲养，自由进食饮水，适应性喂养5天后，第一次分组，分为2组，第一组10只，为空白组(C)进食普通饲料，其余为第二组40只，进食60％高脂饲料诱导高脂模型，自由进水，喂养4周。在第五周的时候第二组的小鼠注射链脲佐菌素(STZ)，诱导2型糖尿病模型，分三次注射，注射期间隔1天，注射总剂量为150mg/kg，饲养条件不变，1周后利用血糖仪及一次性血糖试纸测定小鼠的空腹血糖，血糖值高于11mmol/L的为2型糖尿病小鼠，并对其进行第二次分组，每组10只，分别为模型组(M，蒸馏水)、二甲双胍组(Meft,225mg/kg/d)、化合物12低剂量组(2A-L,50mg/kg/d)、化合物12高剂量组(2A-H,100mg/kg/d)。每天早上灌胃给药，M组给予蒸馏水灌胃，给药剂量分别为Meft：225mg/kg；2A-L：50mg/kg；2A-H：100mg/kg。灌胃剂量为0.2mL/g，灌胃给药8周，期间定期测量小鼠的体重、空腹血糖。
结果显示(图1)，化合物12在低剂量组(50mg/kg)和高剂量组(100mg/kg)均可显著降低小鼠体内的血糖。低剂量组与阳性对照组(二甲双胍，225mg/kg)降血糖效果相当，高剂量组表现出比阳性对照更好的降血糖效果。
化合物12具有改善葡萄糖耐量的作用(图2)。胰岛素耐受实验结果说明，腹腔注射胰岛素后，血糖逐渐下降，并在55min中后达到最低值。与模型组相比，化合物12低剂量组和高剂量对胰岛素的敏感性都比模型组低，说明化合物12可恢复小鼠对胰岛素的敏感性。由此说明化合物12具有降低血糖，恢复胰岛素敏感性的作用。
化合物12可显著降低血清中AST水平(图3)。与模型组相比，化合物12给药组小鼠血清TG和TC都有显著降低，表明化合物12有一定的降脂作用。化合物12降低TG效果与二甲双胍相似，甚至降TC效果优于二甲双胍。血肌酐值高出正常值多数意味肾脏受损。与对照组相比，模型组CREA显著升高，表明模型对肾脏造成损伤。给药后，CREA显著下降，说明化合物12可修复糖尿病肾脏损伤。
实施例76：雄性db/db小鼠模型胰岛素耐受及肝功能改善试验
6周龄的雄性db/db小鼠，随机分为6组，每组12只，分别为：模型组(M，蒸馏水)、二甲双胍组(Meft,200mg/kg/d)、洛伐他汀组(6mg/kg)、化合物12低剂量组(20mg/kg/d)、化合物12中剂量组(40mg/kg/d)、化合物12高剂量组(80mg/kg/d)。恒温25℃环境饲养，自由进食饮水；灌胃剂量为0.2mL/g，灌胃给药6周，期间定期测量小鼠的体重、空腹血糖。
胰岛素耐受实验(ITT)用生理盐水配制浓度1.0U/ml，用量1.0U/kg，上午禁食4h，正常饮水。下午实验，称体重，注射胰岛素前测血糖，胰岛素按体重计算注射量，在15min，30min，45min，60min分别测血糖。实验完毕，每笼补充上饲料。由胰岛素耐量检测可观察到(图4)，各组药物处理均可以显著改善db/db小鼠的胰岛素敏感性，特别是12高剂量组最为显著。
肝功能血清生化指标中(图5)，与模型组相比，高剂量给药组ALT和AST以及总胆汁酸含量显著下降，表明药物可以减弱db/db小鼠肝脏损伤和缓解肝脏炎症反应。
血清活性蛋白指标中(图6)高剂量给药后，可使胰岛素INS含量显著增加，说明本化合物对于胰岛细胞分泌胰岛素起促进作用；使血中GLP-1这种脑肠肽水平增加，这表明了药物的有益治疗效果；同时血浆中衡量心衰的指标BNP以及炎症因子TNF和IL-6在低剂量给药时显著下降，进一步证实了药物对于小鼠机体内的炎症消除效果很好。
上述试验结果表明，本发明化合物具有良好的MNK1/2蛋白激酶的抑制作用，并且在细胞中表现出良好的安全性。以实例化合物12为代表，该类化合物可在糖尿病小鼠模型和肥胖小鼠模型上表现出明显的控制血糖、降低体重、改善各类血生化指标、保护肝脏等重要脏器的作用，具有很好的药物开发应用前景。
以上对本发明进行了详细的介绍，本文中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例只是用于帮助理解本发明的方法及其核心思想，包括最佳方式，并且也使得本领域的任何技术人员都能够实践本发明，包括制造和使用任何装置或系统，和实施任何结合的方法。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定，并可包括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有不是不同于权利要求文字表述的结构要素，或者如果它们包括与权利要求的文字表述无实质差异的等同结构要素，那么这些其他实施例也应包含在权利要求的范围内。
Claims (20)
- 一种咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐，其特征在于所述咪唑并噻唑衍生物具有式(I)所示结构：
式(I)包括通式一和通式二，R 1、R 3各自独立地选自任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷基胺基、C1-C6烷氧基、5元至6元杂环、卤素、羟基、氰基、硝基、氨基、羰基等基团取代的含有1-2个氮原子的5元至6元杂环基，或者R 1选自任选被一个或多个羟基、卤素、氨基、二甲氨基、5元至6元杂环取代的C1-C6烷氧基，R 1选自任选被一个或多个羟基、卤素、氨基、二甲氨基、5元至6元杂环取代的C1-C6烷硫基，R 1选自任选被一个或多个羟基、卤素、氨基、二甲氨基、5元至6元杂环取代的C1-C6烷胺基，R 2、R 4各自独立地选自任选被一个或多个C1-C6烷基、C1-C6卤代烷基、C1-C6烷基胺基、C1-C6烷氧基、C1-C6烷氧基羰基、羟基取代的C1-C6烷基、卤素、羟基、氰基、硝基、氨基、羰基等基团取代的芳基或杂芳基。 - 权利要求1所述的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐，其特征在于所述5元至6元杂环基选自哌嗪环基、吗啉环基、哌啶环基、六氢吡喃环基、四氢呋喃环基、四氢噻吩环基、吡咯基、四氢吡咯基。
- 权利要求1-2任一项所述的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐，其特征在于芳基选自苯基、萘基，杂芳基选自呋喃基、噻吩基、吡啶基、噻唑基、咪唑基。
- 权利要求1-3任一项所述的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐，其特征在于所述C1-C6烷基胺基是指氨基(-NH 2)中的一个或两个氢原子被相同或不同的“C1-C6烷基”取代；即可表示为-NR 1R 2，R 1、R 2各自独立地选自H、C1-C6烷基，且R 1、R 2不能同时为H。
- 权利要求1-4任一项所述的式(I)结构的咪唑并噻唑衍生物选自说明书中表格化合物1-55或其立体异构体、互变异构体、几何异构体或其药学上可接受的盐。
- 权利要求1-5任一项所述式(I)结构的咪唑并噻唑衍生物的制备方法，其特征在于包括如下步骤：通式一的合成方法：
式(II)化合物与相应的硼酸衍生物(B(OH) 2R 2)发生Suzuki缩合反应得到通式一化合物，其中R 1、R 2的定义与权利要求1-5任一项相同，X为卤素，优选氯、溴、碘；通式二的合成方法：
式(III)化合物与相应的乙炔衍生物在碱性条件下反应得到通式二化合物，其中R 3、R 4的定义与权利要求1-5任一项相同。
- 权利要求6所述的制备方法，其特征在于包括如下步骤：通式一的合成方法包括由式(IV)化合物制备式(II)化合物的步骤：
通式二的合成方法包括由式(V)化合物制备式(III)化合物的步骤：
- 权利要求1-5任一项所述式(I)结构的咪唑并噻唑衍生物的制备方法，其特征在于式(I)结构的咪唑并噻唑衍生物选自R 2为4-氰基苯基时的通式一，以化合物N表示，包括如下步骤：
化合物M与R 1H发生缩合反应得到化合物N，R 1的定义与权利要求1-5任一项相同。 - 一种制备权利要求1-5任一项所述式(I)结构的咪唑并噻唑衍生物的中间体，其特征在于所述中间体具有式(II)、式(III)、式(IV)、式(V)所示结构：
R 1、R 3的定义与权利要求1-5任一项相同，X为卤素，优选氯、溴、碘。
- 一种制备权利要求1-5任一项所述式(I)结构的咪唑并噻唑衍生物的中间体，其特征在于所述中间体具有如下结构：
- 权利要求9所述的式(II)、式(III)、式(IV)、式(V)化合物或权利要求10所述的中间体在制备权利要求1-5任一项所述的式(I)结构的咪唑并噻唑衍生物中的应用。
- 权利要求1-5任一项所述的式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐在抑制MNK1或者MNK2或其变体的激酶活性中的应用。
- 权利要求1-5任一项所述的式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐制备用于预防和/或治疗与MNK活性相关的代谢类疾病的药物中的应用。
- 权利要求11所述的应用，其特征在于所述与MNK活性相关的代谢类疾病选自1型糖尿病、2型糖尿病、高血脂、肥胖症、脂肪肝病，及其并发症和与其有关的病症。
- 权利要求求1-5任一项所述的式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐在制备用于预防和/或治疗由MNK1和/或MNK2水平失常引起的的癌症的药物中的应用。
- 权利要求1-5任一项所述的式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐在制备MNK1和/或MNK2抑制剂中的应用。
- 一种药物组合物，其特征在于该药物组合物以权利要求1-5任一项所述的式(I)结构的咪唑并噻唑衍生物、其立体异构体、互变异构体、几何异构体或其药学上可接受的盐作为有效成分。
- 权利要求17所述的药物组合物，其特征在于该药物组合物还可包括药学上可接受的辅料。
- 权利要求17-18任一项所述的药物组合物，其特征在于该药物组合物还可包括其他MNK1和/或MNK2抑制剂。
- 权利要求17-19任一项所述的药物组合物，其特征在于该药物组合物的剂型可以为固体制剂、液体制剂或半固体制剂，优选片剂、胶囊、注射剂等。
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