CN108178760B - 一种嘧啶并吡唑杂环化合物、制备方法、用途 - Google Patents
一种嘧啶并吡唑杂环化合物、制备方法、用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种如结构通式I的所示的嘧啶并吡唑杂环化合物、制备方法、用途。
Description
技术领域
本发明涉及一种嘧啶并吡唑，尤其涉及的是一种嘧啶并吡唑杂环化合物、制备方法、用途。
背景技术
吡唑和嘧啶类衍生物是具有广泛生物学活性的结构骨架，事实上，通过将这两种杂环骨架通过杂环融合设计得到的吡唑并嘧啶衍生物也具有广泛的生物活性。
正是由于这种广泛的生物活性存在，药物化学家合成了大量的杂环拼合嘧啶衍生物。目前已知的几种稠合嘧啶衍生物，如噻吩并嘧啶，吡咯并嘧啶，噻唑并嘧啶和咪唑并嘧啶已显示出良好的抗菌活性。
吡唑并嘧啶骨架及其生物电子等排体为杂环类化合物，该类衍生物的骨架与嘌呤的结构相仿，该类衍生物具有系列重要的生物学活性，在医药领域具有的活性比如抗肿瘤活性、抗菌、抗炎、治疗心血管疾病等；此外，该类结构骨架在农药上作为除草剂具有高效、低毒、广谱、施用期长、对后茬作物安全等特点，故此类骨架的衍生化成为医药和农药化学的研究热点。
因而，基于吡唑并嘧啶骨架的结构修饰具有重要潜在的药用价值。
发明内容
本发明的目的在于克服现有技术的不足，提供了一种嘧啶并吡唑杂环化合物、制备方法、用途。
本发明是通过以下技术方案实现的：一种如结构通式I的所示的嘧啶并吡唑杂环化合物，其盐、前药、非对映异构体混合物、对映异构体、互变异构体、外消旋混合物或者任意组合：
其中：R1，R2，R3相同或不相同，分别选自H、卤素、C1-C5烷基、硝基、C1-C3烷氧基、C1-C3烷胺基、甲硫基、苯基、苯氧基、羟基、乙酰胺基、三氟甲基中的任一种，
R1，R2，R3每个都含有最多3个相同的Cl,、Br、I、甲基、乙基、三氟甲基、硝基、甲氧基、乙氧基、苯基、羟基。
所述如结构通式I所述的嘧啶并吡唑杂环化合物，为如结构通式II的化合物，其盐、前药、非对映异构体混合物、对映异构体、互变异构体、外消旋混合物或者其任意组合：
其中R5选自氢、烷基或取代烷基、烷氧基或取代的烷氧基，环烷基或取代的环烷基，哌嗪基或取代的哌嗪基中的一种。
所述如结构通式I所述的嘧啶并吡唑杂环化合物，为如结构通式III的化合物或其盐、前药、非对映异构体混合物、对映异构体、互变异构体、外消旋混合物或者其任意组合：
其中：R4选自氢、烷基或取代烷基、烷氧基或取代的烷氧基、环烷基或取代的环烷基、派嗪基或取代的哌嗪基中的一种。所述盐包括药学上可接受的盐，“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的盐，包括与酸成盐，通过母体化合物的反应碱与无机酸或有机酸的反应而得，无机酸，有机酸例；存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属离子，有机碱。
无机酸如：盐酸、氢溟酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氛酸等。
有机酸如：乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
适合的盐如：乙酸盐、盐酸盐、硫酸盐或磷酸盐等。
金属离子如：碱金属离子、碱土金属离子或铝离子。
有机碱如：乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺。
一种制备如结构通式I的所示的嘧啶并吡唑杂环化合物，其盐、前药、非对映异构体混合物、对映异构体、互变异构体、外消旋混合物或者任意组合的方法，具体过程如下：
将3,4,5-三甲氧基苯甲酸用氯化亚砜制备成相应酰氯，然后和氨基吡唑中间体1发生缩合反应，制得中间体2，然后在碱性条件下，中间体2发生关环缩合，制得相应中间体3，中间体3用过量三氯氧磷发生氯化反应，制得关键中间体4，该中间体4和相应胺的衍生物发生取代反应制得相应具有结构通式I的化合物。
所述如结构通式II的所示的嘧啶并吡唑杂环化合物，其盐、前药、非对映异构体混合物、对映异构体、互变异构体、外消旋混合物或者任意组合的制备具体过程如下：
以中间体4为原料，与相应胺的衍生物反应，制得相应具有结构通式II的化合物。
所述如结构通式III的所示的嘧啶并吡唑杂环化合物，其盐、前药、非对映异构体混合物、对映异构体、互变异构体、外消旋混合物或者任意组合的制备具体过程如下：
以中间体4为原料，和对氨基苯甲酸甲酯发生取代反应，制得相应中间体5，该中间体在碱性条件下发生水解反应，制得相应中间体6，中间体6和相应胺的衍生物，在edci和hobt催化条件下，发生缩合反应，制得相应具有结构通式III的化合物。
一种药物组合物，其包括活性化合物以及一种或多种药学上可接受的载体或赋形剂，所述活性化合物为所述的如结构通式I的所示的嘧啶并吡唑杂环化合物，其盐、前药、非对映异构体混合物、对映异构体、互变异构体、外消旋混合物或者任意组合。
所述赋形剂包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
所述药学上可接受的载体包括稀释剂、崩解剂、粘合剂、润滑剂。
所述药物组合物的剂型为片剂、胶囊、锭剂、液体溶液、悬浮液、直肠剂型、肌内、静脉、皮内或皮下给药以及脂质体。
所述药物化合物的剂量为0.01～500 mg/kg。也可根据病情的轻重偏离这个范围。
一种所述的药物组合物在制备抗肿瘤药物中的应用。
一种所述的药物组合物在制备除草剂中的应用。
本发明相比现有技术具有以下优点：本发明的吡唑并嘧啶骨架及其生物电子等排体为杂环类化合物，整体制备方法简单，能够快速制得吡唑并嘧啶的化合物。
具体实施方式
下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
实施例1
中间体2的制备：
反应瓶中加入二氯甲烷10ml，三甲氧基苯甲酸(0.5g，2.36mmol)，冰浴条件下，加入氯化亚砜(1.404g，11.8mmol)，催化量DMF,然后于室温搅拌至反应完全，约8-12h，TLC监控，反应完全后，减压蒸出溶剂与过量氯化亚砜，蒸馏至干。
反应瓶中加入氨基吡唑1(0.429g，2.36mmol)，加入10ml二氯甲烷，加入3ml三乙胺，搅拌均匀后，冰浴条件下，滴加入上步反应残留物的二氯甲烷溶液，然后于室温反应过夜，约8～12h，TLC监控，反应完成后，加入适量二氯甲烷，用水，饱和碳酸氢钠洗涤，干燥，浓缩至干，用适量乙醇重结晶，得到白色固体即中间体2。
中间体3的制备：
干燥条件下，反应瓶中加入20ml无水乙醇，加入金属钠(365mg，15.8mmol)，干燥条件下，搅拌至金属钠溶解，成为溶液，然后加入中间体2(500mg，1.33mmol)，隔绝湿气条件下，回流搅拌反应6～12h，TLC监控反应完全后，浓缩部分乙醇，用稀盐酸调节PH＝7，析出白色固体，过滤，洗涤，干燥，得到中间体3。
中间体4的制备：
反应瓶中，加入干燥中间体3(0.5g，1.4mmol)，加入三氯氧磷(POCl3)(5ml，53.75mmol)，隔绝湿气条件下，反应约6～12h，TLC监控，反应完成后，冷却至室温，然后将反应溶液倾入约50g冰水混合物中，充分搅拌待碎冰完全消失，用乙酸乙酯萃取，有机层用水，饱和碳酸氢钠洗涤，干燥，浓缩干，得到中间体4。
实施例2
1-甲基-3-丙基-N-(3-(三氟甲基)苯基)-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(Ia)的制备：
反应瓶中，加入中间体4(100mg，0.266mmol)，加入10ml异丙醇，再加入间三氟甲基苯胺(52mg，0.32mmol)，回流反应约6-12h，TLC监控，反应完成后，冷却至室温，减压浓缩至干，用异丙醇重结晶，得到黄色固体。
Mp：165℃,1H NMR(300MHz,CDCl3)δ8.10(s,1H,ArH),7.92(d,J＝8.0Hz,1H,ArH),7.72(s,2H,ArH),7.52(t,J＝7.9Hz,1H,ArH),7.43(d,J＝7.7Hz,1H,ArH),7.02(s,1H,NH),4.36(s,3H,OCH3),3.95(s,6H,2X OCH3),3.91(s,3H,NCH3),3.02(t,J＝7.6Hz,2H,CH2),2.03–1.84(m,2H,CH2),1.06(t,J＝7.4Hz,3H,CH3).HR-MS:calcd for C25H26F3N5O3[M+H]+,502.2058；found 502.20583.
实施例3
1-甲基-3-丙基-N-(3-(甲基)苯基)-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(Ib)的制备：
反应瓶中，加入中间体4(100mg，0.266mmol)，加入10ml异丙醇，再加入间甲基苯胺(52mg，0.32mmol)，回流反应约6-12h，TLC监控，反应完成后，冷却至室温，减压浓缩至干，用乙醇重结晶，得到白色固体。
Mp：203℃,1H NMR(300MHz,CDCl3)δ7.77(s,2H,ArH),7.63(d,J＝8.1Hz,1H,ArH),7.50(s,1H,ArH),7.30(d,J＝7.8Hz,1H,ArH),6.99(d,J＝7.5Hz,1H,ArH),6.86(s,1H,NH),4.31(s,3H,OCH3),3.97(s,6H,2X OCH3),3.90(s,3H,NCH3),3.02(t,J＝7.6Hz,2H,CH2),2.40(s,3H,CH3),1.93(dd,J＝15.0,7.5Hz,2H,CH2),1.06(t,J＝7.4Hz,3H,,CH3).HR-MS:calcd for C25H30N5O3[M+H]+,448.2039；found448.2039.
实施例4
1-甲基-3-丙基-N-苯基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(Ic)的制备：
按照实施例2的操作方法，残余物用异丙醇重结晶，得到白色固体。
1H NMR(300MHz,CDCl3)δ7.76(d,4H,ArH),7.41(t,J＝7.9Hz,2H,ArH),7.18(t,J＝7.4Hz,1H,ArH),6.89(s,1H,NH),4.32(s,3H,OCH3),3.97(s,6H,2X OCH3),3.90(s,3H,NCH3),3.02(t,J＝7.6Hz,2H,CH2),1.93(dd,J＝15.0,7.5Hz,2H,CH2),1.06(t,J＝7.4Hz,3H,CH3).HR-MS:calcd for C24H28N5O3[M+H]+,434.21496；found 434.21496.
实施例5
N-(4-氯苯乙基)-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(Id)的制备：
按照实施例2的操作方法，残余物用异丙醇重结晶，得到类白色固体。
Mp：147℃,1H NMR(600MHz,cdcl3)δ7.80(s,2H,ArH),7.31(d,J＝8.2Hz,2H,ArH),7.21(d,J＝8.2Hz,2H,ArH),5.12(s,1H,NH),4.09(s,3H,OCH3),3.99(m,8H,2X OCH3+CH2),3.91(s,3H,NCH3),3.09(t,J＝6.9Hz,2H,NCH2),2.98(t,J＝7.6Hz,2H,CH2),1.97–1.85(m,2H,CH2),1.04(t,J＝7.4Hz,3H,CH3).HR-MS:calcd for C26H31ClN5O3[M+H]+,496.2110；found 496.2112.
实施例6
N-(4-甲氧基苯乙基)-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(Ie)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(10:1,v/v)，得到白色固体。
Mp：148℃,1H NMR(300MHz,CDCl3)δ7.81(s,2H,ArH),7.18(d,J＝8.5Hz,2H,ArH),6.87(d,J＝8.6Hz,2H,ArH),5.16(t,J＝5.3Hz,1H,NH),4.04(s,3H,OCH3),3.99(s,6H,2XOCH3),3.95(d,J＝5.9Hz,2H,NCH2),3.91(s,3H,NCH3),3.79(s,3H,OCH3),3.12–2.88(m,4H,2X CH2),1.90(m,2H,CH2),1.04(t,J＝7.4Hz,3H,CH3).HR-MS:calcd for C27H34N5O4[M+H]+,492.25700；found 492.25700.
实施例7
N-异丁基-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(IIa)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(10:1,v/v)，得到类白色固体。
Mp：138℃,1H NMR(300MHz,CDCl3)δ7.79(s,2H,ArH),5.24(t,J＝5.5Hz,1H,NH),4.25(s,3H,OCH3),3.99(s,6H,2X OCH3),3.90(s,3H,NCH3),3.58(t,J＝6.2Hz,2H,NCH2),2.98(t,J＝7.6Hz,2H,CH2),2.19(m,1H,CH),1.89(m,2H,CH2),1.05(t,9H,CH3).HR-MS:calcd for C22H32N5O3[M+H]+,414.2500；found 414.2505.
实施例8
N,1-二甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(IIb)的制备：
反应瓶中，加入中间体4(100mg，0.266mmol)，加入10ml异丙醇，再加入甲胺水溶液(2ml)，回流反应约6-12h，TLC监控，反应完成后，冷却至室温,减压浓缩至干，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(10:1,v/v)，得类白色固体。
Mp：185℃,HR-MS:calcd for C19H26N5O3[M+H]+,372.20302；found 372.20122.1HNMR(600MHz,cdcl3)δ7.80(s,2H,ArH),5.15(d,J＝4.2Hz,1H,NH),4.22(s,3H,OCH3),3.99(s,6H,2X OCH3),3.90(s,3H,NCH3),3.27(d,J＝4.8Hz,3H,NCH3),2.98(t,J＝7.6Hz,2H,CH2),1.95–1.86(m,2H,CH2),1.04(t,J＝7.4Hz,3H,CH3).
实施例9
N-苯乙基-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(If)的制备：
按照实施例2的操作方法，残余物用乙醇重结晶，得到微黄色固体。
Mp：136℃,1H NMR(600MHz,cdcl3)δ7.81(s,2H,ArH),7.35(t,J＝7.5Hz,2H,ArH),7.28(d,J＝7.3Hz,3H,ArH),5.11(t,J＝5.2Hz,1H,NH),4.06–4.01(m,5H,OCH3+NCH2),3.99(s,6H,2X OCH3),3.91(s,3H,NCH3),3.10(t,J＝6.8Hz,2H,NCH2),2.97(t,J＝7.6Hz,2H,CH2),1.94–1.86(m,2H,CH2),1.04(t,J＝7.4Hz,3H,CH3).HR-MS:calcd for C26H32N5O3[M+H]+,462.2500；found 462.2502.
实施例10
N,N,1-三甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(IIc)的制备：
反应瓶中，加入中间体4(100mg，0.266mmol)，加入10ml DMF，回流反应约6-12h，TLC监控，反应完成后，冷却至室温，减压浓缩至干，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(10:1,v/v)，得到白色固体。
Mp：123℃,1H NMR(600MHz,cdcl3)δ7.80(s,2H,ArH),4.13(s,3H,OCH3),3.99(s,6H,2X OCH3),3.91(s,3H,NCH3),3.20(s,6H,2X CH3),3.02(t,J＝7.6Hz,2H,CH2),2.00–1.86(m,2H,CH2),1.06(t,J＝7.3Hz,3H,CH3).HR-MS:calcd for C20H28N5O3[M+H]+,386.2187；found 386.2189.
实施例11
N-异丙基-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(IId)的制备：
按照实施例2的操作方法，残余物用乙醇重结晶，得到微黄色固体。
1H NMR(600MHz,cdcl3)δ7.79(s,2H,ArH),4.87(d,J＝6.5Hz,1H,NH),4.62(dq,J＝13.0,6.5Hz,1H,2X CH3),4.23(s,3H,OCH3),3.99(s,6H,2X OCH3),3.90(s,3H,NCH3),2.98(t,J＝7.6Hz,2H,CH2),1.95–1.85(m,2H,CH2),1.42(d,J＝6.5Hz,6H,2X CH3),1.04(t,J＝7.3Hz,3H,CH3).HR-MS:calcd for C21H30N5O3[M+H]+,400.2343；found 400.2345.
实施例12
4-(1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)吗啉(IIe)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(10:1,v/v)，得到白色固体。
Mp：146℃,1H NMR(600MHz,cdcl3)δ7.78(s,2H,ArH),4.12(s,3H,OCH3),4.00(s,6H,2X OCH3),3.98–3.93(m,4H,2X OCH2),3.91(s,3H,NCH3),3.66–3.57(m,4H,2X NCH2),3.03(t,J＝7.6Hz,2H,CH2),1.93(m,2H,CH2),1.06(t,J＝7.3Hz,3H,CH3).13C NMR(151MHz,cdcl3)δ156.41,153.86,153.25,147.75,145.67,139.58,134.18,124.41,105.30,66.52,61.08,56.29,50.11,38.60,28.02,22.18,14.29.HR-MS:calcd for C22H30N5O4[M+H]+,428.2292；found 428.2292.
实施例13
4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯甲酸甲酯(IIIa)的制备：
反应瓶中，加入中间体4(200mg，0.53mmol)，加入10ml异丙醇，再加入对氨基苯甲酸甲酯(96mg，0.64mmol)，回流反应约6-12h，TLC监控，反应完成后，冷却至室温，减压浓缩至干，用乙醇重结晶，得到黄色固体。
Mp：243℃,1H NMR(600MHz,cdcl3)δ8.05(d,J＝8.6Hz,2H,ArH),7.86(d,J＝8.6Hz,2H,ArH),7.74(s,2H,ArH),7.04(s,1H,NH),4.32(s,3H,OCH3),3.97(s,6H,2X OCH3),3.93(s,3H,OCH3),3.91(s,3H,NCH3),3.01(t,J＝7.6Hz,2H,CH2),1.92(dd,J＝15.0,7.5Hz,2H,CH2),1.06(t,J＝7.4Hz,3H,CH3).13C NMR(151MHz,cdcl3)δ166.63,156.52,153.25,146.50,146.12,145.24,142.92,139.74,133.95,130.78,125.37,120.96,119.95,105.19,61.08,56.19,52.23,39.28,27.88,22.14,14.26.HR-MS:calcd for C26H30N5O5[M+H]+,492.2241；found 492.2243.
实施例14
N1-(1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)苯基-1,4-二胺(Ig)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为氯仿：甲醇(10:1,v/v)，得到黄色固体。
Mp：240-241℃,1H NMR(600MHz,dmso)δ10.42(brs,2H,NH2),9.51(brs,1H,NH),7.92(d,J＝7.9Hz,2H,ArH),7.66(s,2H,ArH),7.47(d,J＝7.6Hz,2H,ArH),4.36(s,3H,OCH3),3.85(s,6H,2X OCH3),3.73(s,3H,NCH3),2.98(s,2H,CH2),1.84(dd,J＝14.3,7.1Hz,2H,CH2),0.99(t,J＝7.3Hz,3H,CH3).HR-MS:calcd for C24H29N6O3[M+H]+,449.2296；found449.2302.
实施例15
4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯酚(Ih)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为氯仿：甲醇(10:1,v/v)，得到微黄色固体。
Mp：242℃,1H NMR(600MHz,dmso)δ9.34(d,J＝3.3Hz,1H,NH),8.70(brs,1H,OH),7.65(d,J＝2.1Hz,2H,ArH),7.58(d,J＝6.7Hz,2H,ArH),6.84(d,J＝6.6Hz,2H,ArH),4.31(d,J＝2.4Hz,3H,OCH3),3.84(d,J＝2.1Hz,6H,2X OCH3),3.72(d,J＝2.2Hz,3H,NCH3),2.90(s,2H,CH2),1.85(dd,J＝7.0,5.0Hz,2H,CH2),1.04–0.95(m,3H,CH3).13C NMR(151MHz,dmso)δ154.96,154.14,152.59,147.60,143.97,143.10,138.74,133.88,130.11,125.09,120.81,114.64,104.60,60.05,55.58,39.20,27.19,21.37,13.92.HR-MS:calcd forC24H28N5O4[M+H]+,450.2136；found 450.2136.
实施例16
4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯甲酸(IIIb)的制备：
反应瓶中加入原料A(100mg)，2N NaOH水溶液(0.5ml)，甲醇5ml，室温搅拌过夜，TLC监控，反应完成后，减压除去部分甲醇溶液，用1N HCl调节PH＝3-4，析出大量白色固体，过滤，干燥后得到白色固体。
Mp：276℃,1H NMR(600MHz,dmso)δ12.76(brs,1H,OH),9.19(s,1H,NH),7.99(q,J＝8.9Hz,4H,ArH),7.68(s,2H,ArH),4.32(s,3H,OCH3),3.86(s,6H,2XOCH3),3.73(s,3H,NCH3),2.93(t,J＝7.4Hz,2H,CH2),1.87(h,J＝7.4Hz,2H,CH2),1.00(t,J＝7.4Hz,3H,CH3).13C NMR(151MHz,dmso)δ167.03,154.85,152.76,146.48,144.30,143.93,143.56,138.95,133.50,129.85,125.02,121.21,120.97,104.57,60.11,55.57,48.62,27.18,21.38,13.97.HR-MS:calcd for C25H28N5O5[M+H]+,478.2085；found 478.2085.
实施例17
1-甲基-7-(4-甲基哌嗪-1-基)-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶(IIf)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为洗脱剂为石油醚：乙酸乙酯(10:1,v/v)，得到微黄色固体。
Mp：118℃,1H NMR(600MHz,cdcl3)δ7.79(s,2H,ArH),4.11(s,3H,OCH3),3.99(s,6H,2X OCH3),3.91(s,3H,NCH3),3.65(s,4H,2X NCH2),3.03(t,J＝7.6Hz,2H,CH2),2.69(s,4H,2X NCH2),2.41(s,3H,NCH3),1.93(dd,J＝15.0,7.5Hz,2H,CH2),1.06(t,J＝7.4Hz,3H,CH3).13C NMR(151MHz,cdcl3)δ156.37,153.89,153.23,147.65,145.63,139.76,134.33,124.51,105.42,61.04,56.28,54.58,49.45,46.27,38.64,28.03,22.16,14.25.HR-MS:calcd for C23H33N6O3[M+H]+,441.2609；found 441.2613.
实施例18
1-(1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)哌啶-4-醇(IIg)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(20:1,v/v)，得到白色固体。
1H NMR(600MHz,dmso)δ7.73(s,2H,ArH),4.84(s,1H,OH),4.07(s,3H,OCH3),3.88(m,8H,2X OCH3+CH2),3.81(s,1H,OCH),3.74(s,3H,NCH3),3.30(s,2H,CH2),2.91(d,J＝3.1Hz,2H,CH2),1.95(s,2H,CH2),1.85(s,2H,NCH2),1.63(d,J＝8.2Hz,2H,NCH2),1.02–0.96(m,3H,CH3).13C NMR(151MHz,dmso)δ154.87,153.44,152.75,145.28,144.20,139.05,133.71,123.57,104.80,65.60,60.13,55.79,46.70,38.72,33.67,27.27,21.32,13.99.HR-MS:calcd for C23H32N5O4[M+H]+,442.2449；found442.2447.
实施例19
N-异丁基-4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯甲酰胺(IIIc)的制备：
反应瓶中加入羧酸(50mg 0.105mmol)，二氯甲烷(5ml)，EDCI(30mg，0.157mmol)，HOBt(21mg,0.157mmol)，再加入异丁胺(11mg，0.157mmol)，三乙胺(0.5ml)，室温搅拌过夜，反应完全后，加适量饱和NaHCO3溶液，用EtOAc萃取2-3次，至水层无紫外吸收，合并有机层，用无水Na2SO4干燥后旋干，乙醇重结晶，得微黄色固体。
1H NMR(600MHz,cdcl3)δ7.66(d,J＝8.6Hz,4H,ArH),7.53(s,2H,ArH),6.99(s,1H,NH),6.65(s,1H,NH),4.16(s,3H,OCH3),3.88(s,3H,NCH3),3.82(s,6H,2X OCH3),3.27(d,J＝5.4Hz,2H,NCH2),2.94(t,J＝6.8Hz,2H,CH2),1.97–1.84(m,3H,CH2+CH),1.05(t,J＝6.6Hz,3H,CH3),0.98(d,J＝5.7Hz,6H,2X CH3).13C NMR(151MHz,cdcl3)δ167.39,155.73,152.89,145.94,145.83,144.51,141.43,139.21,133.86,129.76,127.63,120.60,120.04,104.73,60.98,55.90,47.55,38.97,28.75,27.78,22.03,20.30,14.29.HR-MS:calcd forC29H37N6O4[M+H]+,533.2871；found533.2874.
实施例20
1-甲基-3-丙基-7-(吡咯烷-1-基)-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶(IIh)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(20:1,v/v)，得到白色固体。
1H NMR(600MHz,cdcl3)δ7.78(s,2H,ArH),4.17(s,3H,OCH3),3.99(s,6H,2XOCH3),3.90(s,3H,NCH3),3.87(Brs,4H,2X NCH2),3.01(t,J＝7.6Hz,2H,CH2),2.04(Brs,4H,2X CH2),1.91(dt,J＝14.7,7.4Hz,2H,CH2),1.06(t,J＝7.3Hz,3H,CH3).13C NMR(151MHz,cdcl3)δ155.99,153.07,151.09,146.56,145.09,139.42,134.78,123.30,105.27,61.00,56.21,50.36,41.47,27.94,25.71,22.18,14.28.HR-MS:calcd forC22H30N5O3[M+H]+,412.2343；found 412.2346.
实施例21
1-甲基-7-(哌啶-1-基)-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶(IIi)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(20:1,v/v)，得到白色固体。
1H NMR(600MHz,cdcl3)δ7.80(s,2H,ArH),4.11(s,3H,OCH3),4.00(s,6H,2XOCH3),3.91(s,3H,NCH3),3.55(s,4H,2X NCH2),3.02(t,J＝7.6Hz,2H,CH2),1.97–1.88(m,2H,CH2),1.82(d,J＝4.9Hz,4H,2X CH2),1.75(d,J＝4.6Hz,2H,CH2),1.06(t,J＝7.3Hz,3H,CH3).13C NMR(151MHz,cdcl3)δ156.34,154.55,153.17,147.38,145.28,139.56,134.54,124.62,105.30,61.03,56.24,50.66,38.58,28.02,25.61,24.59,22.20,14.27.HR-MS:calcd for C23H32N5O3[M+H]+,426.2500；found 426.2503.
实施例22
1-甲基-N-(3-吗啉基丙基)-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(IIj)的制备：
按照实施例2的操作方法，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(20:1,v/v)，得到白色固体。
1H NMR(600MHz,cdcl3)δ7.78(s,2H,ArH),6.20(s,1H,NH),4.27(s,3H,OCH3),3.99(s,6H,2X OCH3),3.90(s,3H,NCH3),3.84(dd,J＝11.6,5.9Hz,2H,CH2),3.77–3.68(m,4H,2XCH2),2.98(t,J＝7.6Hz,2H,CH2),2.59(dd,J＝12.6,6.4Hz,2H,CH2),2.52(s,4H,2X CH2),1.99(p,J＝6.1Hz,2H,CH2),1.95–1.87(m,2H,CH2),1.04(t,J＝7.4Hz,3H,CH3).13C NMR(151MHz,cdcl3)δ156.94,153.07,149.73,146.02,143.32,139.49,134.87,121.32,105.34,66.71,61.02,58.38,56.24,54.21,41.06,39.35,27.91,24.59,22.24,14.25.
实施例23
N-正丁基-4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯甲酰胺(IIId)的制备：
反应瓶中加入羧酸(50mg，0.105mmol)，二氯甲烷(5ml)，EDCI(30mg，0.157mmol)，HOBt(21mg,0.157mmol)，再加入丁胺(11mg，0.157mmol)，三乙胺(0.5ml)，室温搅拌过夜，反应完全后，加适量饱和NaHCO3溶液，用EtOAc萃取2-3次，至水层无紫外吸收，合并有机层，用无水Na2SO4干燥后旋干，乙醇重结晶，得微黄色固体。
1H NMR(600MHz,cdcl3+dmso)δ8.74(s,1H,NH),7.92(brs,1H,NH),7.86(s,4H,ArH),7.66(s,2H,ArH),4.29(s,3H,OCH3),3.86(s,6H,2X OCH3),3.76(s,3H,NCH3),3.31(dd,J＝13.2,6.7Hz,2H,NCH2),2.92(t,J＝7.5Hz,2H,CH2),1.84(dd,J＝14.9,7.4Hz,2H,CH2),1.61–1.46(m,2H,CH2),1.34(dd,J＝14.9,7.5Hz,2H,CH2),0.98(t,J＝7.4Hz,3H,CH3),0.90(t,J＝7.4Hz,3H,CH3).13C NMR(151MHz,cdcl3+dmso)δ165.37,154.44,151.72,145.75,144.13,143.24,140.93,137.90,133.04,128.38,126.50,120.36,119.90,103.74,59.42,54.80,38.34,38.16,30.56,26.48,20.78,18.99,12.99,12.79.HR-MS:calcd forC29H37N6O4[M+H]+,533.2871；found533.2869.
实施例24
7-(4-乙基哌嗪-1-基)-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶(IIk)的制备：
按照实施例2的操作方法，残余物用乙醇溶解后，加入少量盐酸PH＝3-4，浓缩干，再用乙醇重结晶，得到黄色固体。
1H NMR(600MHz,cdcl3)δ12.65(s,1H,H),7.71(s,2H,ArH),4.47(d,J＝11.0Hz,2H,NCH2),4.27(t,J＝11.9Hz,2H,NCH2),4.14(s,3H,OCH3),3.96(s,6H,2X OCH3),3.88(s,3H,NCH3),3.62(d,J＝9.3Hz,2H,CH2),3.52(Brs,2H,CH2),3.21(Brs,2H,CH2),3.14(t,J＝7.5Hz,2H,CH2),1.80(dd,J＝14.7,7.3Hz,2H,CH2),1.46(t,J＝6.8Hz,3H,CH3),1.02(t,J＝7.3Hz,3H,CH3).HR-MS:calcd for C24H35N6O3[M+H]+,455.2765；found 455.2766.
实施例25
N-(2-(二甲基胺基)乙基)-4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯甲酰胺(IIIe)的制备：
反应瓶中加入羧酸(50mg 0.105mmol)，二氯甲烷(5ml)，EDCI(30mg，0.157mmol)，HOBt(21mg,0.157mmol)，再加入N,N-二甲基乙二胺(14mg，0.157mmol)，三乙胺(0.5ml)，室温搅拌过夜，反应完全后，加适量饱和NaHCO3溶液，用EtOAc萃取2-3次，至水层无紫外吸收，合并有机层，用无水Na2SO4干燥后旋干，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(20:1,v/v)，得微黄色固体。
1H NMR(600MHz,cdcl3)δ9.09(t,J＝5.4Hz,1H,NH),8.19(d,J＝8.5Hz,2H,ArH),7.89(d,J＝8.5Hz,2H,ArH),7.69(s,2H,ArH),4.51(s,3H,OCH3),3.92(s,6H,2X OCH3),3.87–3.82(m,5H,NCH3+NCH2),3.43(dd,J＝10.8,5.3Hz,2H,NCH2),3.21(t,J＝7.5Hz,2H,CH2),2.95(s,3H,NCH3),2.94(s,3H,NCH3),1.84(dd,J＝14.9,7.4Hz,2H,CH2),1.05(t,J＝7.3Hz,3H,CH3).HR-MS:calcd for C29H38N7O4[M+H]+,548.2980；found 548.2976.
实施例26
2-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)硫基)苯并[d]噻唑(Ii)的制备：
按照实施例2的操作方法，残余物用乙醇重结晶，得到黄色固体。
1H NMR(600MHz,cdcl3)δ8.13(d,J＝7.8Hz,1H,ArH),7.90(d,J＝7.8Hz,1H,ArH),7.60(s,2H,ArH),7.55(dd,J＝11.2,4.1Hz,1H,ArH),7.49(dd,J＝10.7,4.4Hz,1H,ArH),4.38(s,3H,OCH3),3.86(s,3H,NCH3),3.68(s,6H,2X OCH3),3.06(t,J＝7.5Hz,2H,CH2),1.94(dd,J＝14.7,7.4Hz,2H,CH2),1.06(t,J＝7.3Hz,3H,CH3).13C NMR(151MHz,cdcl3)δ156.11,153.18,152.52,149.41,146.72,143.87,139.75,137.45,132.86,128.44,126.76,126.27,123.68,121.18,105.17,61.01,55.86,39.48,27.87,22.14,14.21.HR-MS:calcdfor C25H26N5O3S2[M+H]+,508.1472；found508.1472.
实施例27
2-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯酚(Ij)的制备：
按照实施例2的操作方法，残余物用异丙醇重结晶，得到类白色固体。
1H NMR(600MHz,cdcl3+dmso)δ7.95(s,1H,OH),7.68(s,2H,ArH),7.12(t,J＝7.5Hz,1H,ArH),7.07(d,J＝8.0Hz,2H,ArH),6.90(t,J＝7.5Hz,1H,ArH),4.43(s,3H,OCH3),3.90(s,6H,2X OCH3),3.83(s,3H,NCH3),3.13(t,J＝7.2Hz,2H,CH2),1.89–1.80(m,2H,CH2),1.05(t,J＝7.3Hz,3H,CH3).HR-MS:calcd for C24H28N5O4[M+H]+,450.2136；found450.2134.
实施例28
3-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯酚(Ik)的制备：
按照实施例2的操作方法，残余物用异丙醇重结晶，得到类白色固体。
1H NMR(600MHz,dmso)δ9.76(s,1H,OH),7.74(s,2H,ArH),7.31(s,1H,ArH),7.25(t,J＝8.0Hz,1H,ArH),7.18(d,J＝8.0Hz,1H,ArH),6.71(d,J＝8.0Hz,1H,ArH),4.37(s,3H,OCH3),3.87(s,6H,2X OCH3),3.74(s,3H,NCH3),3.08(t,J＝7.5Hz,2H,CH2),1.84–1.75(m,2H,CH2),0.99(t,J＝7.3Hz,3H,CH3).13C NMR(151MHz,dmso)δ157.66,153.99,152.77,148.30,141.69,140.29,138.65,129.13,121.32,114.77,112.50,111.26,106.97,106.22,99.25,60.24,56.01,27.44,25.55,21.93,13.84.HR-MS:calcd for C24H28N5O4[M+H]+,450.2136；found 450.2137.
实施例29
2-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯硫酚(Il)的制备：
按照实施例2的操作方法，残余物用异丙醇重结晶，得到类白色固体。
1H NMR(600MHz,dmso)δ11.85(s,1H,H),10.22(s,1H,SH),9.17(s,1H,NH),8.23(d,J＝8.1Hz,1H,ArH),8.15(d,J＝8.2Hz,1H,ArH),7.62(t,J＝7.7Hz,1H,ArH),7.53(m,3H,ArH),4.34(s,3H,OCH3),3.96(s,6H,2X OCH3),3.81(s,3H,NCH3),2.57(m,2H,CH2),1.69(dd,J＝14.8,7.4Hz,2H,CH2),0.97(t,J＝7.3Hz,3H,CH3).13C NMR(151MHz,dmso)δ164.50,154.12,153.01,152.10,147.76,142.26,133.76,131.97,127.19,126.30,123.27,122.64,121.84,114.74,106.72,60.35,56.53,40.56,27.23,21.40,14.02.HR-MS:calcd forC24H28N5O3S[M+H]+,466.1907；found466.1910.
实施例30
4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)-N-(3-吗啉基丙基)苯甲酰胺(IIIf)的制备：
反应瓶中加入羧酸(50mg，0.105mmol)，二氯甲烷(5ml)，EDCI(30mg，0.157mmol)，HOBt(21mg,0.157mmol)，再加入N-(3-氨丙基)吗啉(23mg，0.157mmol)，三乙胺(0.5ml)，室温搅拌过夜，反应完全后，加适量饱和NaHCO3溶液，用EtOAc萃取2-3次，至水层无紫外吸收，合并有机层，用无水Na2SO4干燥后旋干，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(20:1,v/v)，得白色泡沫状固体。
1H NMR(600MHz,dmso)δ9.08(s,1H,NH),8.44(t,J＝5.3Hz,1H,NH),7.98–7.90(m,4H,ArH),7.68(s,2H,ArH),4.33(s,3H,OCH3),3.86(s,6H,2X OCH3),3.73(s,3H,NCH3),3.58(brs,4H,2X OCH2),3.32(dd,J＝12.8,6.6Hz,2H,CH2),2.93(t,J＝7.4Hz,2H,CH2),2.47–2.26(m,6H,3X NCH2),1.86(dd,J＝14.8,7.4Hz,2H,CH2),1.71(p,J＝7.0Hz,2H,CH2),0.99(t,J＝7.4Hz,3H,CH3).13C NMR(151MHz,dmso)δ165.53,154.92,152.76,146.72,144.24,143.76,141.85,138.92,133.64,129.17,127.46,121.12,104.59,66.25,60.13,56.19,55.68,53.42,37.78,27.19,26.11,21.41,13.97.HR-MS:calcd for C32H42N7O5[M+H]+,604.3242；found 604.3240.
实施例31
N-(4-甲氧基苯乙基)-4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯甲酰胺(IIIg)的制备：
反应瓶中加入羧酸(50mg 0.105mmol)，二氯甲烷(5ml)，EDCI(30mg，0.157mmol)，HOBt(21mg,0.157mmol)，再加入4-甲氧基苯乙胺(24mg，0.157mmol)，三乙胺(0.5ml)，室温搅拌过夜，反应完全后，加适量饱和NaHCO3溶液，用EtOAc萃取2-3次，至水层无紫外吸收，合并有机层，用无水Na2SO4干燥后旋干，残余物用乙醇重结晶，得微黄色固体。
1H NMR(600MHz,cdcl3)δ7.76(d,J＝8.2Hz,2H,ArH),7.65(d,J＝8.2Hz,2H,ArH),7.61(s,2H,ArH),7.14(d,J＝8.1Hz,2H,ArH),7.03(s,1H,NH),6.85(d,J＝8.1Hz,2H,ArH),6.48(s,1H,NH),4.24(s,3H,OCH3),3.90(s,3H,OCH3),3.87(s,6H,2X OCH3),3.78(s,3H,NCH3),3.72–3.61(m,2H,NCH2),2.98(t,J＝7.5Hz,2H,CH2),2.88(t,J＝6.7Hz,2H,NCH2),1.91(dd,J＝14.4,7.3Hz,2H,CH2),1.08–0.99(m,3H,CH3).13C NMR(151MHz,cdcl3)δ167.06,158.39,156.04,153.02,146.06,144.72,141.57,139.35,133.92,130.91,129.82,129.60,127.76,120.73,120.08,114.17,104.87,61.03,56.01,55.36,41.55,39.10,34.91,27.81,22.10,14.29.HR-MS:calcd for C34H39N6O5[M+H]+,611.2976；found 611.2977.
实施例32
(4-乙基哌嗪-1-基)(4-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)苯基)甲酮(IIIh)的制备：
反应瓶中加入羧酸(50mg，0.105mmol)，二氯甲烷(5ml)，EDCI(30mg，0.157mmol)，HOBt(21mg,0.157mmol)，再加入N-乙基哌嗪(18mg，0.157mmol)，三乙胺(0.5ml)，室温搅拌过夜，反应完全后，加适量饱和NaHCO3溶液，用EtOAc萃取2-3次，至水层无紫外吸收，合并有机层，用无水Na2SO4干燥后旋干，残余物用乙醇重结晶，得微黄色固体。
1H NMR(600MHz,dmso+cdcl3)δ9.00(s,1H),7.92(d,J＝8.4Hz,2H),7.70(s,2H),7.43(d,J＝8.4Hz,2H),4.34(s,3H),3.89(s,6H),3.77(s,3H),3.73–3.41(m,4H),2.95(t,J＝7.4Hz,2H),2.41(dd,J＝14.3,7.1Hz,6H),1.89(dd,J＝14.8,7.4Hz,2H),1.06(t,J＝7.2Hz,3H),1.03(t,J＝7.4Hz,3H).13C NMR(151MHz,dmso+cdcl3)δ168.81,154.82,152.45,146.52,144.36,143.77,140.40,138.64,133.57,130.15,127.14,121.16,121.02,104.39,59.92,56.14,55.35,51.47,38.97,27.12,21.38,13.77,11.69.HR-MS:calcd forC31H40N7O4[M+H]+,573.3136；found574.3138.
实施例33
4-(2-((1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-基)胺基)乙基)苯酚(Im)的制备：
按照实施例2的操作方法，残余物用异丙醇重结晶，得到类白色固体。
1H NMR(300MHz,DMSO)δ9.24(s,1H,OH),7.77(s,2H),7.44(t,J＝5.6Hz,1H,NH),7.13(d,J＝8.3Hz,2H),6.72(d,J＝8.3Hz,2H),4.18(s,3H),3.88(s,6H),3.85–3.76(m,2H),3.74(s,3H),2.99–2.90(m,2H),2.87(t,J＝7.4Hz,2H),2.04–1.71(m,2H),0.98(t,J＝7.4Hz,3H).13C NMR(75MHz,DMSO)δ155.67,155.40,152.60,149.15,143.72,142.10,138.83,134.39,129.56,129.36,120.75,115.14,104.74,60.07,55.67,42.39,38.97,33.92,27.18,21.37,13.91.
实施例34
N-(2-甲氧基苯基)-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(In)的制备：
按照实施例2的操作方法，残余物用残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(20:1,v/v)，得到类白色固体。
1H NMR(600MHz,dmso)δ8.46(s,1H),8.32(d,J＝7.5Hz,1H),7.62(s,2H),7.21–7.15(m,2H),7.08–7.03(m,1H),4.33(s,3H),3.88(s,3H),3.83(s,6H),3.71(s,3H),2.90(t,J＝7.4Hz,2H),1.89–1.81(m,2H),0.99(t,J＝7.4Hz,3H).HR-MS:calcd for C25H30N5O4[M+H]+,464.2292；found 464.2296.
实施例35
N-(2-氯苯基乙基)-1-甲基-3-丙基-5-(3,4,5-三甲氧基苯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(Io)的制备：
按照实施例2的操作方法，残余物用乙醇重结晶，得到类白色固体。
1H NMR(600 MHz,cdcl3)δ7.80(s,2H),7.44–7.39(m,1H),7.28(m,1H),7.22(m,2H),5.17(t,J＝5.7 Hz,1H),4.13(s,3H),4.08(td,J＝6.8,5.5 Hz,2H),4.00(s,6H),3.91(s,3H),3.26(t,J＝6.8 Hz,2H),3.00–2.96(m,2H),1.90(m,2H),1.04(t,J＝7.4 Hz,3H).
实施例36
测试方法
本发明的化合物经活性评价表明其具有抗肿瘤活性。下面是本发明部分化合物的活性评价试验及结果。
以抗肿瘤活性体外筛选的方法测试化合物的活性，测定按常规采用溴化四氮唑蓝(MTT)法，这是一种检测细胞存活和增殖的方法。其检测原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲瓒(Formazan)并沉积在细胞中，而死细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中的甲瓒，用酶联免疫检测仪在492nm波长处测定其光吸收值，可间接反映活细胞数量。在一定细胞数范围内，MTT结晶形成的量与细胞数成正比。该方法已广泛用于一些生物活性因子的活性检测、大规模的抗肿瘤药物筛选、细胞毒性试验以及肿瘤放射敏感性测定等。它的特点是灵敏度高、经济。
筛选了三种细胞株：人肝癌细胞(SMMC-7721)，人胃癌细胞(SGC-7901)，人神经胶质瘤细胞(u87MG)。
实验步骤：
1.1接种：收集对数期细胞并计数，接种于96孔板中，每孔种5000个，边缘孔用无菌PBS填充。
1.2培养：在5％CO2，37℃条件下孵育过夜。
1.3初筛加药：用DMEM培养基作溶剂配置带测化合物和阳性药的工作液，设5个梯度，100μΜ，50μΜ，25μΜ，12.5μΜ，6.25μΜ。每孔加入100μL待测化合物，培养48小时。该实验设3个平行孔，并重复操作3次。
1.4染色：
1.4.1避光条件下，加入MTT溶液20ul/孔，继续放入培养箱中培养4小时。
1.4.2终止培养，小心用带针医用注射器吸出吸去孔内培养液。加入二甲基亚砜150ul/孔，置摇床上振荡15min，使结晶物充分溶解。
1.5测定：在酶标仪波长492nm处测量各孔的OD吸光值。记录结果并计算抑制率，以判断受试药物的抗肿瘤活性。
1.6复筛加药：初筛抗肿瘤IC50较小的化合物，降低给药剂量复筛，浓度依次设置为10μΜ、5μΜ、2.5μΜ、1.25μΜ、0.625μΜ。培养48小时。每组设3个平行孔，重复3次。
细胞抑制率的计算：
抑制率＝[(1-(实验组OD均值-空白组OD均值)/(对照组OD均值-空白组OD均值)]*100％数据用SPSS 17.0处理，并用回归分析得出IC50值。
部分化合物活性数据
IC50值单位为：μmol/L，“-”表示没有测试数据，“--”表示IC50值大于50μmol/L，没有进行复筛。作为阳性对照的是替莫唑胺(TMZ)，阿霉素(ADR)。TMZ是针对u87细胞的阳性药，ADR是临床广泛使用的抗肿瘤药物。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (7)
1.一种嘧啶并吡唑杂环化合物，其特征在于，包括结构如下所示化合物：
2.一种药物组合物，其特征在于，包括活性化合物以及一种或多种药学上可接受的载体或赋形剂；
其中，所述活性化合物为权利要求1中所示嘧啶并吡唑杂环化合物中的任意一种化合物。
3.权利要求2所述的药物组合物，其特征在于，所述赋形剂包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
4.根据权利要求3所述的药物组合物，其特征在于，所述药学上可接受的载体包括稀释剂、崩解剂、粘合剂、润滑剂。
5.根据权利要求4所述的药物组合物，其特征在于，所述药物组合物的剂型为片剂、胶囊、锭剂、液体溶液、悬浮液、直肠剂型、肌内、静脉、皮内或皮下给药以及脂质体。
6.根据权利要求5所述的药物组合物，其特征在于，所述药物组合物的剂量为0.01～500mg/kg。
7.一种如权利要求6所述的药物组合物在制备抗肿瘤药物中的应用。
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