CN109503496B - 丙酮酸脱氢酶系抑制剂类化合物及其制备方法和应用 - Google Patents
丙酮酸脱氢酶系抑制剂类化合物及其制备方法和应用 Download PDFInfo
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
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- A—HUMAN NECESSITIES
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
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- 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
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
- A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明提供了一种丙酮酸脱氢酶系抑制剂类化合物及其制备方法和应用，特别是式I所示化合物或其立体异构体、几何异构体、互变异构体、消旋体、氮氧化物、水合物、溶剂化物、药学上可接受的盐，其中，R1和R2各自独立的选自氢、烷基、氨基或碳环基；R3为苯环任意位置上的单取代或多取代基，所述取代基可以相同或不同；X为酰腙基或腙基。该类化合物具有抑制丙酮酸脱氢酶的活性，能够预防和/或治疗植物疾病和抑制藻类生长
Description
技术领域
本发明涉及化学领域，具体的，本发明涉及化合物、制备方法及其应用，更具体的，本发明涉及式Ι所示化合物以及衍生物及其制备方法和应用。
背景技术
探索、发现不仅具有新结构，而且具有新靶标的农药活性化合物，是目前新农药创制研究关注的焦点。在生物的代谢过程中，丙酮酸脱氢酶复合体可以催化生物体内的丙酮酸转变成乙酰辅酶A，其是连接糖酵解与柠檬酸循环的关键酶，也是生物体内能量代谢过程的关键酶。因此，丙酮酸脱氢酶复合体是一个具有重要农学意义的作用靶标，针对此靶标进行农药分子的合理设计也具有很高的研究价值。目前已有一些丙酮酸脱氢酶系抑制剂的报道，例如，焦磷酸硫胺素类似物T-1与T-2，是针对微生物中丙酮酸脱氢酶系的高效抑制剂。
但该类化合物结构复杂，合成难度大，而且此类焦磷酸硫胺素类似物尚未显示出在农业方面的应用价值。因此，具有应用价值的丙酮酸脱氢酶系抑制剂类化合物仍有待研究发现。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一或至少提供一种有用的商业选择。为此，本发明的目的在于提出一类具有抑制丙酮酸脱氢酶活性、抗菌和抑藻活性的化合物。
在本发明的第一方面，提供了一种化合物。根据本发明的实施例，该化合物为式I所示丙酮酸脱氢酶系抑制剂类化合物或其立体异构体、几何异构体、互变异构体、消旋体、氮氧化物、水合物、溶剂化物、药学上可接受的盐，
其中，
R1和R2各自独立的选自氢、烷基、氨基或碳环基；
R3为苯环任意位置上的单取代或多取代基，例如可以为对位或间位取代；所述取代基可以相同或不同；
X为酰腙基或腙基。
发明人惊奇地发现，本发明实施例的化合物具有有效抑制丙酮酸脱氢酶系的活性、抗菌和抑制藻类生长的生物活性。
根据本发明的实施例，上述化合物还可以具有下列附加技术特征：
根据本发明的实施例，所述取代基R1和R2可以自由排列组合。
根据本发明的实施例，所述取代基R1和R2各自独立的选自氢、C1-10烷基、氨基或3至5元的碳环基。
根据本发明的实施例，所述取代基R1为氢、甲基、氨基或环丙基。
根据本发明的实施例，所述取代基R2为氢或甲基。
根据本发明的实施例，所述取代基R3选自卤素、C1-10烷基、烷氧基、卤代烷基、卤代烷氧基、硝基、氨基、羟基。
根据本发明的实施例，所述取代基R3选自取代或未取代的苯甲酰胺基、烷基酰胺基、苯基脲基、呋喃酰胺基，例如所述取代可以为卤代或烷氧基取代，进一步的，所述卤代可以为1-2个卤素或卤代烷基取代。
根据本发明的实施例，所述卤素为氟、氯、溴、碘。
根据本发明的实施例，所述烷基酰胺基为C1-4烷基酰胺基。
根据本发明的实施例，所述取代基R3选自C1-4烷基。
根据本发明的实施例，所述烷氧基为C1-6烷氧基。
根据本发明的实施例，所述卤代烷基为氟代C1-4烷基。
根据本发明的实施例，所述卤代烷氧基为氟代C1-6烷氧基。
根据本发明的实施例，所述X为-CONHN＝或-NHN＝。
根据本发明的具体实施例，所述化合物为下列化合物或者所述下列化合物的立体异构体、几何异构体、互变异构体、消旋体、氮氧化物、水合物、溶剂化物、药学上可接受的盐：
在本发明的第二方面，本发明提供了一种制备前面所述化合物的方法，根据本发明的实施例，该方法包括：
使式II所示化合物与式III所示化合物进行接触，以便获得式I所示化合物。
Y＝-CONHNH2-或者-NHNH2-
其中R1、R2、R3、X具有上文所述的定义，Y为式III所示化合物的结构单元，具体可以为酰肼结构单元(-CONHNH2)或肼结构单元(-NHNH2)。
根据本发明的实施例，在催化剂存在下，将式II所示化合物与式III所示化合物溶于第一有机溶剂中，加热搅拌。
根据本发明的实施例，所述式II所示化合物与式III所示化合物以及催化剂的摩尔比为1：(1-1.5)：(0.01-0.15)。在此条件下，可以使II所示化合物反应完全，后处理简单，从而以更高的产率获得目标化合物。
根据本发明的实施例，所述催化剂为选自抗坏血酸、乙酸、酒石酸、三氟乙酸、甲酸、水杨酸、苹果酸、乙酸酐中的至少一种。在使用催化剂的条件下，可以提升反应效率。
根据本发明的实施例，所述第一有机溶剂为选自乙腈、乙醇、1,2-二氯乙烷、丙酮、叔丁醇、水、甲苯、苯、二甲苯、乙酸乙酯、甲醇、正己烷、二氯甲烷、三氯甲烷、四氢呋喃、二甲基亚砜和N,N-二甲基甲酰胺中的至少一种。
根据本发明的实施例，所述加热反应的温度为20～90摄氏度，优选为64～78摄氏度。由此可以提高反应速率，以较高产率获得目标化合物。如果反应温度过低，会导致反应不能发生或反应很慢，导致反应失败或产率很低。而反应最优的温度在64-78摄氏度之间，反应温度过高，则会提高反应成本,或增加副产物。
根据本发明的实施例，所述加热反应的时间为0.5～60小时，优选为3～48小时。由此可以保证反应物充分反应，以较高产率获得目标化合物。如果反应时间太短，反应不完全，不仅降低了产率，而且增加了后处理的难度。如果反应时间太长，超过了最优时间，对产率的影响不大，在相似的产率下，不仅提高了成本，而且浪费了时间。还可能增加副产物。
本发明的第三方面，本发明提供了一种农药，包括本发明化合物(包括式I所示的化合物、其立体异构体、几何异构体、互变异构体、消旋体、氮氧化物、水合物、溶剂化物、药学上可接受的盐)。发明人发现本发明化合物能够有效地用于抑制丙酮酸脱氢酶系活性、抗菌和抑制藻类生长。根据发明人实验发现，本发明的代表性化合物1-151表现出对大肠杆菌丙酮酸脱氢酶系优异的抑制活性，最高可达纳摩尔级，表明该类化合物具有潜在的农药活性和应用价值，值得进一步的研究。同时代表性化合物80-118表现优异杀真菌活性；代表性化合物89-118表现优异的抑藻活性；代表性化合物119-151表现优异杀细菌活性。
在本发明的第四方面，本发明提供了前面所述的化合物或农药预防和/或治疗植物疾病的方法，所述植物疾病是由下列至少之一引起的：水稻纹枯病菌，稻曲病菌，苹果轮纹，桃褐腐病菌，辣椒疫霉，灰霉病菌，炭疽病菌。根据本发明的实施例，所述植物为水稻，苹果，桃子或辣椒。
在本发明的第五方面，本发明提供了前面所述的化合物或农药在抑制藻类生长的用途。根据本发明的实施例，所述藻类为蓝藻。
术语定义和解释
“C1-10烷基”应理解为优选表示具有1～10个碳原子的直链或支链饱和一价烃基，优选为C1-4烷基。“C1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2、3、4、5或6个碳原子(“C1-6烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(“C1-3烷基”)，例如甲基、乙基、正丙基或异丙基。
除非另有说明，当本文中使用“本发明化合物”或“本发明的化合物”时，旨在涵盖式(I)所示的化合物、其立体异构体、几何异构体、互变异构体、消旋体、氮氧化物、水合物、溶剂化物、药学上可接受的盐。
在本发明中所使用的术语，将本发明化合物的所有立体异构体(无论是混合物形式还是纯的形式或基本纯的形式)都考虑在内。在本发明中所使用的术语“立体异构体”可包括通过拥有一个或多个手性原子而为光学异构体的化合物，以及通过围绕一个或多个键受限旋转而为光学异构体的化合物。本发明化合物的定义涵盖所有可能的立体异构体和它们的混合物。非常具体地涵盖外消旋形式和具有特定活性的经分离的光学异构体。可通过物理方法拆分外消旋形式，所述物理方法包括但不限于分级结晶、非对映异构衍生物的分离或结晶或通过手性柱色谱法分离。可通过常规方法由外消旋体获得单独的光学异构体，所述常规方法包括但不限于与光学活性酸形成盐，然后结晶。
在本发明中所使用的术语，式I所示化合物及其盐可按它们的互变异构形式存在，在所述互变异构形式中氢原子转移到分子的其它部分，并且分子中原子之间的化学键因此发生重排。应该理解的是，所有互变异构形式(只要它们可以存在)，就包括在本发明中。此外，本发明式I所示化合物可具有反式异构体和顺式异构体。
在本发明中所使用的术语，“化学上可接受上的盐”为式I所示化合物与无机酸或有机酸反应形成的盐。
在本文中所使用的术语“接触”应做广义理解，其可以是任何能使得至少两种反应物发生化学反应的方式，例如可以是将两种反应物在适当的条件下进行混合。在本文中，“化合物N”在本文中有时也称为“式N所示化合物”，在本文中N为1-151的任意整数，例如“化合物2”在本文中也可以称为“式2所示化合物”。
在本发明的描述中，需要理解的是，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。在本发明的描述中，“多个”的含义是两个或两个以上，除非另有明确具体的限定。
根据本发明实施例的本发明的化合物可以实现下列优点至少之一：
1、本发明的化合物尚未见报道。本申请人以微生物中丙酮酸脱氢酶系为靶标，设计并实际合成出新型高效抑制剂，且发明人意外发现本发明化合物能够有效地抑制丙酮酸脱氢酶系活性，抑制农业细菌和藻类生长。对于开发新型高效杀菌剂具有重要的研究意义和应用价值。
2、本发明提出的制备本发明化合物的方法，起始原料廉价易得，采用一锅法，反应条件温和，合成效率高，产品纯度高、收率高，生产成本低，有利于大量制备。并且反应操作过程简便易控制，未涉及特殊的反应设备，符合安全生产及绿色化学需求。其终产品纯化分离操作简便，适于工业化大生产。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
具体实施方式
下文将结合具体实施例对本发明的通式化合物及其制备方法和应用做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，实施例中使用的原料和试剂均为市售商品。
一般方法
将2,6-取代-4-氨基-5-醛基嘧啶化合物(式II所示)和苯甲酰肼化合物(式III-1所示)溶于第一有机溶剂中，加入催化剂，加热搅拌反应，反应完毕后加水，搅拌有固体析出，抽滤，干燥得到产品。
实施例1
化合物1的制备
将1mmol 2-甲基4-氨基-5-醛基嘧啶和1.5mmol苯甲酰肼溶于15mL甲醇溶剂中，加入0.02mmol冰醋酸，加热搅拌反应3-5h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率78％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.53(s,2H,NH2),7.58(s,1H,Ar-H),7.92(d,2H,Ar-H,J＝4.9Hz),8.07(s,1H,pyrimidine-H),8.42(s,1H,CH＝N),8.42(s,2H,Ar-H),12.08(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.99,163.17,160.01,158.30,146.27,133.16,132.06,128.69,127.84,107.31,25.78；
ESI-MS m/z:256.2[M+1]+。
化合物2-22按化合物1类似方法制得，其结构鉴定数据如实施例2-22。
实施例2
所得化合物2纯品为白色固体，产率为89％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.38(s,2H,NH2),7.99(s,1H,pyrimidine-H),7.99(s,2H,Ar-H),8.41(s,1H,CH＝N),8.41(s,2H,Ar-H),12.08(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.92,163.10,161.96,159.88,158.27,146.24,130.49,129.47,115.73,115.52,107.15,25.67；
ESI-MS m/z:274.3[M+1]+。
实施例3
所得化合物3纯品为黄色固体，产率为68％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.35(d,3H,CH3,J＝34.5Hz),7.46(s,2H,NH2),7.52(d,1H,Ar-H,J＝6.4Hz),7.58(d,1H,Ar-H,J＝6.4Hz),8.03(s,1H,pyrimidine-H),8.19(s,1H,CH＝N),8.25(s,2H,Ar-H),8.29(s,2H,Ar-H),12.14(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.50,159.94,159.43,158.63,146.60,134.99,131.73,130.61,129.95,129.56,127.50,106.95,25.78；
ESI-MS m/z:290.1[M+1]+。
实施例4
所得化合物4纯品为黄色固体，产率为75％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.59(d,1H,Ar-H,J＝7.2Hz),7.67(s,1H,Ar-H),7.88(d,1H,Ar-H,J＝6.6Hz),7.96(s,1H,Ar-H),8.07(s,1H,pyrimidine-H),8.32(s,1H,CH＝N),8.41(s,2H,NH2),12.15(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.00,161.58,159.88,158.38,146.76,135.03,133.43,131.77,130.61,127.40,126.52,107.04,25.68；
ESI-MS m/z:290.2[M+1]+。
实施例5
所得化合物5纯品为黄色固体，产率为79％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.63(s,2H,NH2),7.94(d,2H,Ar-H,J＝7.2Hz),8.07(s,1H,pyrimidine-H),8.30(s,1H,CH＝N),8.41(s,2H,Ar-H),12.14(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.00,161.98,159.94,158.40,146.53,136.92,131.75,129.69,128.77,107.17,25.76；
ESI-MS m/z:290.1[M+1]+。
实施例6
所得化合物6纯品为黄色固体，产率为76％，m.p.236-246℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.35(d,3H,CH3,J＝30.2Hz),7.53-7.65(m,2H,NH2),7.75(d,1H,Ar-H,J＝27.0Hz),8.05(s,1H,pyrimidine-H),8.24(s,2H,Ar-H),8.30(s,1H,CH＝N),12.17(s,1H,NH)；
ESI-MS m/z:324.3[M+1]+。
实施例7
所得化合物7纯品为白色固体，产率为69％，m.p.250-251℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.35(d,3H,CH3,J＝34.9Hz),7.44(s,2H,NH2),7.46-7.56(m,1H,Ar-H),7.70(dd,1H,Ar-H,J＝7.6,7.5Hz),8.03(s,1H,pyrimidine-H),8.19(s,1H,CH＝N),8.24(s,1H,Ar-H),8.29(s,1H,Ar-H),12.12(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.07,163.33,159.91,158.51,146.54,137.11,132.98,131.77,129.49,127.89,119.62,106.92,25.73；
ESI-MS m/z:334.3[M+1]+。
实施例8
所得化合物8纯品为白色固体，产率为80％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.53(d,1H,Ar-H,J＝7.4Hz),7.82(d,1H,Ar-H,J＝6.8Hz),7.92(d,1H,Ar-H,J＝6.8Hz),8.10(s,2H,NH2),8.33(s,1H,pyrimidine-H),8.41(s,1H,Ar-H),8.41(s,1H,CH＝N),12.16(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):161.53,159.92,146.80,135.24,134.77,130.97,130.28,127.00,121.95,106.06,25.77；
ESI-MS m/z:334.2[M+1]+。
实施例9
所得化合物9纯品为黄色固体，产率为78％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.77(s,2H,NH2),7.86(s,2H,Ar-H),8.06(s,1H,pyrimidine-H),8.34(s,1H,CH＝N),8.41(s,2H,Ar-H),12.13(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.06,162.11,159.94,158.41,146.57,132.11,131.73,129.86,125.90,107.17,25.77；
ESI-MS m/z:334.2[M+1]+。
实施例10
所得化合物10纯品为白色固体，产率为83％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),5.83(s,2H,NH2),6.60(d,2H,NH2,J＝8.1Hz),7.66(d,2H,Ar-H,J＝7.8Hz),7.96(s,1H,pyrimidine-H),8.25(s,1H,CH＝N),8.36(s,2H,Ar-H),11.66(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.57,163.02,159.90,157.76,152.68,144.34,129.58,119.10,112.86,107.62,25.75；
ESI-MS m/z:271.4[M+1]+。
实施例11
所得化合物11纯品为白色固体，产率为79％，m.p.234-236℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),5.87(s,2H,NH2),6.54(d,1H,Ar-H,J＝8.2Hz),6.65(s,1H,Ar-H),7.27(d,1H,Ar-H,J＝8.3Hz),8.00(s,1H,pyrimidine-H),8.23(s,1H,CH＝N),8.23(s,2H,NH2),11.77(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.84,162.94,159.92,158.05,151.99,145.29,132.13,131.01,120.58,113.99,111.83,107.28,25.67；
ESI-MS m/z:305.3[M+1]+。
实施例12
所得化合物12纯品为白色固体，产率为78％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),8.14(s,1H,pyrimidine-H),8.16(s,2H,NH2),8.32(s,1H,CH＝N),8.39(d,2H,Ar-H,J＝8.0Hz),8.43(s,2H,Ar-H),12.36(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.15,161.36,159.89,158.59,149.42,147.35,138.68,129.23,123.76,106.93,25.69；
ESI-MS m/z:301.2[M+1]+。
实施例13
所得化合物13纯品为红色固体，产率为67％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.85(t,1H,Ar-H,J＝7.6Hz),8.10(s,1H,pyrimidine-H),8.32(s,2H,NH2),8.36(d,1H,Ar-H,J＝7.3Hz),8.44(s,1H,CH＝N),8.44(s,1H,Ar-H),8.76(s,1H,Ar-H),12.38(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.15,160.89,159.91,158.63,147.90,147.26,134.41,134.26,130.50,126.62,122.39,106.97,25.75；
ESI-MS m/z:301.1[M+1]+。
实施例14
所得化合物14纯品为红色固体，产率为78％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),8.58(s,1H,Ar-H),8.75(s,1H,Ar-H),8.89(s,1H,Ar-H),9.06(s,2H,NH2),9.48(s,1H,pyrimidine-H),8.80(s,1H,CH＝N),13.35(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):160.94,160.37,159.60,148.23,146.59,144.77,135.03,128.27,121.68,107.69,21.35；
ESI-MS m/z:346.4[M+1]+。
实施例15
所得化合物15纯品为红色固体，产率为65％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),6.16(s,2H,NH2),7.48(s,1H,Ar-H),7.56(s,1H,Ar-H),7.88(s,1H,Ar-H),8.08(s,1H,pyrimidine-H),8.30(s,2H,NH2),8.44(s,1H,CH＝N),12.22(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.07,161.73,159.95,158.46,150.49,148.88,146.91,134.90,119.00,110.06,108.51,107.14,25.76；
ESI-MS m/z:316.1[M+1]+。
实施例16
所得化合物16纯品为白色固体，产率为65％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),6.86(s,2H,NH2),7.80(d,2H,Ar-H,J＝6.7Hz),8.01(s,1H,pyrimidine-H),8.38(s,1H,CH＝N),8.38(s,2H,Ar-H),10.20(s,1H,OH),11.86(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.68,162.73,160.96,159.88,157.91,145.20,129.81,123.54,115.24,107.39,25.67；
ESI-MS m/z:272.3[M+1]+。
实施例17
所得化合物17纯品为白色固体，产率为82％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),6.97(s,2H,NH2),7.44(s,1H,Ar-H),7.87(d,1H,Ar-H,J＝6.7Hz),8.08(s,1H,pyrimidine-H),8.31(s,2H,Ar-H),8.45(s,1H,CH＝N),12.00(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.09,164.70,159.97,159.21,158.48,147.10,134.07,128.75,119.13,117.48,115.79,107.13,25.76；
ESI-MS m/z:272.2[M+1]+。
实施例18
所得化合物18纯品为白色固体，产率为76％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),2.50(s,3H,CH3),7.77(s,2H,NH2),7.86(s,2H,Ar-H),8.16(s,1H,pyrimidine-H),8.25(s,1H,CH＝N),8.42(s,2H,Ar-H),12.16(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.57,162.07,159.93,157.65,146.30,136.21,13.32.00,131.67,129.82,127.68,125.86,107.14,25.49,20.86；
ESI-MS m/z:270.2[M+1]+。
实施例19
所得化合物19纯品为白色固体，产率为81％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,6H,2CH3),7.41(s,2H,NH2),7.73(s,2H,Ar-H),8.05(s,1H,pyrimidine-H),8.28(s,1H,CH＝N),8.41(s,2H,Ar-H),12.03(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.89,163.18,159.92,158.19,146.12,137.99,133.07,132.61,128.54,128.17,124.90,107.23,25.69,21.07；
ESI-MS m/z:270.2[M+1]+。
实施例20
所得化合物20纯品为白色固体，产率为78％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,6H,2CH3),7.33(s,2H,NH2),7.83(d,2H,Ar-H,J＝6.5Hz),8.04(s,1H,pyrimidine-H),8.28(s,1H,CH＝N),8.41(s,2H,Ar-H),12.00(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.87,162.91,159.95,158.21,145.92,142.16,130.19,129.22,127.80,107.30,25.75,21.21；
ESI-MS m/z:270.2[M+1]+。
实施例21
所得化合物21纯品为白色固体，产率为70％，m.p.246-248℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.34(s,6H,2CH3),2.38(s,3H,CH3),7.23(s,1H,Ar-H),7.52(s,2H,NH2),,8.14(s,1H,pyrimidine-H),8.23(s,1H,CH＝N),8.41(s,2H,Ar-H),12.00(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.67,163.21,159.89,157.83,145.84,137.80,133.27,133.03,125.38,107.24,25.57,20.94；
ESI-MS m/z:284.1[M+1]+。
实施例22
所得化合物22纯品为白色固体，产率为79％，m.p.235-237℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),3.83(s,3H,OCH3),7.17(d,1H,Ar-H,J＝5.6Hz),7.45(s,2H,NH2),7.48(d,1H,Ar-H,J＝6.6Hz),8.06(s,1H,pyrimidine-H),8.29(s,1H,CH＝N),8.42(s,2H,Ar-H),12.04(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.96,162.85,159.97,159.38,158.31,146.33,134.48,129.89,119.98,117.68,113.09,107.24,55.49,25.77；
ESI-MS m/z:286.1[M+1]+。
实施例23
化合物23的制备
将1mmol 4-氨基-5-醛基嘧啶和1mmol苯甲酰肼溶于10ml甲醇溶剂中，加入0.01mmol冰醋酸，加热搅拌反应3-4h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率为64％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):7.55(s,2H,NH2),7.60(s,1H,Ar-H),7.92(s,2H,Ar-H),8.15(s,1H,Ar-H),8.42(s,1H,Ar-H),8.42(s,1H,pyrimidine-6-H),8.45(s,1H,CH＝N),8.45(s,1H,pyrimidine-2-H),8.87(s,1H,Ar-H),12.15(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):163.07,159.73,157.87,157.80,145.95,132.87,132.04,128.61,127.70,109.77；
ESI-MS m/z:242.4[M+1]+。
化合物24-29按化合物23类似方法制得，其结构鉴定数据如实施例24-29。
实施例24
所得化合物24纯品为白色固体，产率为74％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):7.40(s,2H,NH2),8.01(s,2H,Ar-H),8.17(s,1H,pyrimidine-6-H),8.44(s,1H,CH＝N),8.44(s,1H,pyrimidine-2-H),8.44(s,2H,Ar-H),12.18(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):165.56,163.07,161.98,159.71,157.84,146.01,130.48,129.32,115.73,115.51,109.73；
ESI-MS m/z:260.4[M+1]+。
实施例25
所得化合物25纯品为白色固体，产率为64％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):7.78(s,2H,NH2),7.81(s,2H,Ar-H),8.17(s,1H,pyrimidine-6-H),8.42(s,1H,CH＝N),8.42(s,1H,pyrimidine-2-H),8.44(s,2H,Ar-H),12.22(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):161.94,159.57,157.78,146.12,131.76,131.51,129.64,125.74,109.53；
ESI-MS m/z:320.4[M+1]+。
实施例26
所得化合物26纯品为黄色固体，产率为56％，m.p.239-240℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):7.47(s,2H,NH2),7.53(s,1H,Ar-H),7.59(d,2H,Ar-H,J＝7.4Hz),8.28(s,1H,pyrimidine-6-H),8.31(s,1H,CH＝N),8.39(s,1H,Ar-H),8.43(s,1H,pyrimidine-2-H),12.21(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):168.43,162.52,159.75,158.13,146.38,143.20,134.80,131.69,130.54,129.87,129.48,127.40,109.51；
ESI-MS m/z:276.2[M+1]+。
实施例27
所得化合物27纯品为白色固体，产率为51％，m.p.236-238℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.29(s,1H,Ar-H),7.32(s,2H,NH2),7.41(d,1H,Ar-H,J＝6.9Hz),7.47(d,1H,Ar-H,J＝7.0Hz),8.30(s,1H,Ar-H),8.30(s,1H,pyrimidine-6-H),8.36(s,1H,CH＝N),8.41(s,1H,pyrimidine-2-H),12.05(s,1H,NH)；13C NMR(100MHz,DMSO-d6)δ(ppm):165.18,159.74,157.89,145.64,136.18,134.71,130.78,130.23,127.63,126.36,125.77,109.72,19.47；
ESI-MS m/z:256.3[M+1]+。
实施例28
所得化合物28纯品为白色固体，产率为76％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.35(s,6H,2CH3),7.24(s,1H,Ar-H),7.53(s,2H,NH2),8.15(s,1H,pyrimidine-6-H),8.44(s,1H,CH＝N),8.44(s,1H,pyrimidine-2-H),8.44(s,2H,Ar-H),12.06(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):163.20,159.70,157.83,157.72,145.68,137.80,133.34,132.86,125.37,109.80,20.92；
ESI-MS m/z:270.4[M+1]+。
实施例29
所得化合物29纯品为白色固体，产率为77％，m.p.235-236℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):7.57(s,2H,NH2),7.65(s,1H,Ar-H),7.77(d,1H,Ar-H,J＝26.5Hz),8.27(s,1H,pyrimidine-6-H),8.27(s,1H,CH＝N),8.27(s,1H,Ar-H),8.44(s,1H,pyrimidine-2-H),8.44(s,2H,Ar-H),12.06(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):161.62,159.72,157.98,146.51,134.85,133.39,131.85,130.64,127.39,126.54,109.63；
ESI-MS m/z:310.3[M+1]+。
实施例30
化合物30的制备
将1mmol 2,4-二氨基-5-醛基嘧啶和1.1mmol苯甲酰肼溶于25ml乙醇溶剂中，加入0.15mmol三氟乙酸，加热搅拌反应6-8h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到黄色固体。产率为79％，m.p.250-252℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):6.55(s,2H,NH2),7.51(s,2H,NH2),7.53(s,1H,pyrimidine-H),7.57(d,1H,Ar-H,J＝6.5Hz),7.89(d,2H,Ar-H,J＝6.7Hz),7.95(s,1H,CH＝N),8.26(s,2H,Ar-H),11.73(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.63,161.01,160.45,147.55,133.37,131.67,128.53,127.52,101.06；
ESI-MS m/z:257.3[M+1]+。
化合物31-38按化合物30类似方法制得，其结构鉴定数据如实施例31-38。
实施例31
所得化合物31纯品为黄色固体，产率为79％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):6.60(s,2H,NH2),7.50(s,1H,pyrimidine-H),7.83(s,H,NH2),7.99(s,H,NH2),8.17(s,1H,CH＝N),8.29(s,1H,Ar-H),8.34(s,1H,Ar-H),8.43(s,2H,Ar-H),8.74(s,1H,Ar-H),12.05(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.86,161.14,160.88,160.43,148.62,147.90,134.89,134.08,130.39,126.26,122.27,101.00；
ESI-MS m/z:302.2[M+1]+。
实施例32
所得化合物32纯品为黄色固体，产率为87％，m.p.238-240℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):5.76(s,2H,NH2),6.48(s,2H,NH2),6.58(s,2H,NH2),7.39(s,1H,pyrimidine-H),7.63(d,2H,Ar-H,J＝5.4Hz),7.91(s,1H,CH＝N),8.20(s,2H,Ar-H),11.32(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.57,162.33,160.94,159.61,152.18,145.70,129.19,119.50,112.72,101.43；
ESI-MS m/z:272.2[M+1]+。
实施例33
所得化合物33纯品为黄色固体，产率为87％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):5.82(s,2H,NH2),6.52(s,2H,NH2),6.52(s,1H,NH2),6.63(s,1H,NH2),7.22(d,1H,Ar-H,J＝7.8Hz),7.42(s,1H,pyrimidine-H),7.89(s,1H,CH＝N),8.07(s,2H,Ar-H),11.42(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.60,162.34,160.96,160.26,151.64,146.44,131.79,130.75,121.01,113.70,111.68,101.03；
ESI-MS m/z:306.2[M+1]+。
实施例34
所得化合物34纯品为黄色固体，产率为77％，m.p.149-151℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):6.60(s,2H,NH2),7.50-7.57(m,2H,NH2),7.61(d,1H,Ar-H,J＝8.1Hz),7.77(s,1H,pyrimidine-H),7.88(d,2H,Ar-H,J＝8.2Hz),7.96(s,1H,CH＝N),8.07(s,2H,Ar-H),11.81(s,1H,NH)；
ESI-MS m/z:325.1[M+1]+。
实施例35
所得化合物35纯品为黄色固体，产率为79％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):6.58(s,2H,NH2),7.49-7.58(m,2H,NH2),7.65(d,1H,Ar-H,J＝7.1Hz),7.86(d,1H,Ar-H,J＝6.8Hz),7.94(s,1H,pyrimidine-H),7.97(s,1H,Ar-H),8.16(s,1H,CH＝N),8.25(s,1H,Ar-H),11.81(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.76,161.06,160.69,158.96,148.03,135.43,133.33,131.47,130.56,127.25,126.39,100.93；
ESI-MS m/z:291.2[M+1]+。
实施例36
所得化合物36纯品为黄色固体，产率为87％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):6.57(s,2H,NH2),6.65(s,1H,Ar-H),7.50(s,1H,pyrimidine-H),7.60(d,2H,NH2,J＝8.0Hz),7.92(d,2H,Ar-H,J＝7.9Hz),8.13(s,1H,CH＝N),8.25(s,1H,Ar-H),11.79(s,1H,NH)；
ESI-MS m/z:291.3[M+1]+。
实施例37
所得化合物37纯品为黄色固体，产率为77％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):6.58(s,2H,NH2),7.49(s,2H,NH2),7.78(d,1H,Ar-H,J＝5.8Hz),7.89(d,1H,Ar-H,J＝6.3Hz),7.96(s,1H,pyrimidine-H),8.07(s,1H,Ar-H),8.18(s,1H,CH＝N),8.25(s,1H,Ar-H),11.81(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):162.60,160.89,160.54,147.89,135.46,134.22,130.66,129.93,126.62,121.68,100.78；
ESI-MS m/z:335.2[M+1]+。
实施例38
所得化合物38纯品为黄色固体，产率为80％，m.p.249-251℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):6.56(s,2H,NH2),7.75(s,2H,NH2),7.47(s,1H,pyrimidine-H),7.84(d,2H,Ar-H,J＝6.9Hz),7.95(s,1H,CH＝N),8.25(s,2H,Ar-H),11.80(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):163.20,159.70,157.83,157.72,145.68,137.80,133.34,132.86,125.37,109.80；
ESI-MS m/z:335.3[M+1]+。
实施例39
化合物39的制备
将1mmol 4-氨基-6-甲基-5-醛基嘧啶和1mmol苯甲酰肼溶于10ml乙醇溶剂中，加入0.01mmol冰醋酸，加热搅拌反应4-6h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率为48％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.44(s,3H),7.53(t,J＝7.4Hz,2H),7.58(d,J＝7.3Hz,1H),7.90(d,J＝7.3Hz,3H),8.25(s,1H),8.69(s,1H),8.81(s,1H),11.97(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.42,111.36,132.43,133.46,136.86,137.68,149.87,162.01,164.70,167.61,169.60；
ESI-MS m/z:256.09[M+1]+。
化合物40-47按化合物39类似方法制得，其结构鉴定数据如实施例40-47。
实施例40
所得化合物40纯品为白色固体，产率为82％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.45(s,3H),7.51(t,J＝7.9Hz,1H),7.80(d,J＝8.1Hz,1H),7.91(d,J＝7.8Hz,1H),7.97(s,1H),8.08(s,1H),8.25(s,1H),8.65(s,1H),8.80(s,1H),12.06(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):24.60,109.33,124.84,129.78,133.01,133.77,137.62,137.93,148.44,160.22,162.80,164.03,167.81；
ESI-MS m/z:334.01[M+1]+。
实施例41
所得化合物41纯品为白色固体，产率为84％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.45(s,3H),7.76(d,J＝8.4Hz,2H),7.85(d,J＝8.4Hz,2H),7.96(s,1H),8.25(s,1H),8.66(s,1H),8.80(s,1H),12.04(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):24.60,109.37,128.81,132.60,134.61,134.86,148.27,160.22,162.81,164.65,167.77；
ESI-MS m/z:334.02[M+1]+。
实施例42
所得化合物42纯品为黄色固体，产率为73％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.47(s,3H),7.85(t,J＝8.0Hz,1H),7.99(s,1H),8.26(s,1H),8.35(d,J＝7.8Hz,1H),8.44(d,J＝8.2Hz,1H),8.66(s,1H),8.75(s,1H),8.83(s,1H),12.29(s,1H)；
ESI-MS m/z:301.14[M+1]+。
实施例43
所得化合物43纯品为黄色固体，产率为86％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.46(s,3H),8.03(s,1H),8.15(d,J＝8.7Hz,2H),8.27(s,1H),8.38(d,J＝8.7Hz,2H),8.64(s,1H),8.83(s,1H),12.26(s,1H)；
ESI-MS m/z:301.03[M+1]+。
实施例44
所得化合物44纯品为黄色固体，产率为80％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.45(s,3H),6.13(s,2H),7.48(s,1H),7.55(s,1H),7.85(s,1H),7.96(s,1H),8.25(s,1H),8.66(s,1H),8.83(s,1H),12.11(s,1H)；
ESI-MS m/z:316.05[M+1]+。
实施例45
所得化合物45纯品为黄色固体，产率为89％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.49(s,3H),8.02(s,1H),8.27(s,1H),8.62(s,1H),8.83(s,1H),8.98(s,1H),9.09(d,J＝1.6Hz,2H),12.54(s,1H)；
ESI-MS m/z:346.08[M+1]+。
实施例46
所得化合物46纯品为白色固体，产率为67％，m.p.253-255℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.44(s,3H),6.86(d,J＝8.5Hz,2H),7.78(d,J＝8.4Hz,2H),7.89(s,1H),8.23(s,1H),8.75(d,J＝20.8Hz,2H),10.16(s,1H),11.77(s,1H)；13C NMR(100MHz,DMSO-d6)δ(ppm):24.55,109.60,118.19,126.29,132.61,146.94,159.96,162.76,163.79,165.30,167.36；
ESI-MS m/z:272.05[M+1]+。
实施例47
所得化合物47纯品为白色固体，产率为73％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H),2.44(s,3H),7.33(d,J＝7.9Hz,2H),7.82(d,J＝8.0Hz,2H),7.92(s,1H),8.24(s,1H),8.70(s,1H),8.81(s,1H),11.91(s,1H)；13C NMR(100MHz,DMSO-d6)δ(ppm):26.35,26.56,111.51,132.54,134.07,134.93,147.01,149.61,162.07,164.80,167.42,169.54；
ESI-MS m/z:270.09[M+1]+。
实施例48
化合物48的制备
将1mmol 2-环丙基-4-氨基-5-醛基嘧啶和1.2mmol苯甲酰肼溶于20ml乙醇溶剂中，加入0.03mmol乙酸酐，加热搅拌反应8-12h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率为71％，m.p.247-248℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.85-1.05(m,4H),1.96(ddd,J＝12.4,7.7,5.1Hz,1H),7.51(t,J＝7.3Hz,2H),7.54-7.62(m,1H),7.90(t,J＝13.3Hz,3H),8.20(s,1H),8.32(s,1H),8.37(s,1H),11.96(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):15.08,23.24,112.11,132.58,133.48,136.80,137.99,151.15,162.97,164.58,167.76,175.48；
ESI-MS m/z:282.09[M+1]+。
化合物49-56按化合物48类似方法制得，其结构鉴定数据如实施例49-56。
实施例49
所得化合物49纯品为白色固体，产率为77％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.85-1.10(m,4H),1.96(ddd,J＝12.7,7.7,5.0Hz,1H),7.35(t,J＝8.8Hz,2H),7.96(dd,J＝8.7,5.5Hz,3H),8.21(s,1H),8.35(s,1H),11.97(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):12.65,20.80,109.63,117.98,118.19,132.00,132.81,132.89,148.79,160.58,162.14,164.24,165.42,167.89,173.07；19F NMR(376MHz,DMSO-d6)δ(ppm):-108.10；
ESI-MS m/z:300.06[M+1]+。
实施例50
所得化合物50纯品为白色固体，产率为83％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.96 0.85-1.10(m,4H),1.96(ddd,J＝12.7,7.7,5.0Hz,1H),7.59(d,J＝8.4Hz,2H),7.91(d,J＝8.4Hz,2H),7.99(s,1H),8.22(s,1H),8.29(s,1H),8.36(s,1H),12.03(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):15.10,23.24,112.02,133.60,134.48,136.67,141.67,151.47,163.09,164.57,166.65,175.56；
ESI-MS m/z:316.03[M+1]+。
实施例51
所得化合物51纯品为白色固体，产率为88％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.85-1.11(m,4H),1.97(ddd,J＝12.7,7.7,5.0Hz,1H),7.74(d,J＝8.5Hz,2H),7.84(d,J＝8.5Hz,2H),7.96(s,1H),8.22(s,1H),8.37(s,1H),12.03(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):15.14,23.26,112.02,130.68,134.67,136.56,137.03,151.50,163.13,164.57,166.78,175.58；
ESI-MS m/z:360.02[M+1]+。
实施例52
所得化合物52纯品为黄色固体，产率为87％，m.p.256-258℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.87-1.05(m,4H),1.96(ddd,J＝12.7,7.7,5.0Hz,1H),7.82(t,J＝7.9Hz,1H),8.00(s,1H),8.23(s,1H),8.33(d,J＝7.8Hz,1H),8.37-8.47(m,2H),8.72(s,1H),12.26(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):12.71,20.82,109.44,124.80,128.92,132.81,136.59,136.83,149.74,150.23,160.84,162.13,163.05,173.27；
ESI-MS m/z:327.11[M+1]+。
实施例53
所得化合物53纯品为黄色固体，产率为85％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.87-1.05(m,4H),1.96(ddd,J＝12.7,7.7,5.0Hz,1H),8.01(s,1H),8.13(d,J＝7.5Hz,2H),8.24(s,1H),8.43–8.31(m,3H),12.24(s,1H)；13C NMR(100MHz,DMSO-d6)δ(ppm):15.15,23.25,111.86,128.60,134.07,143.49,152.25,154.15,163.29,164.56,165.94,175.73；
ESI-MS m/z:327.10[M+1]+。
实施例54
所得化合物54纯品为黄色固体，产率为89％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.87-1.05(m,4H),1.96(ddd,J＝12.7,7.7,5.0Hz,1H),8.04(s,2H),8.25(s,1H),8.41(s,1H),8.96(t,J＝2.0Hz,1H),9.08(d,J＝2.0Hz,2H),12.51(s,1H)；
ESI-MS m/z:372.05[M+1]+。
实施例55
所得化合物55纯品为黄色固体，产率为82％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.87-1.05(m,4H),1.96(ddd,J＝12.6,7.3,5.0Hz,1H),6.11(s,2H),7.46(s,1H),7.54(s,1H),7.85(s,1H),7.99(s,1H),8.21(s,1H),8.39(s,1H),12.09(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):12.70,20.81,109.57,110.95,112.49,121.42,137.35,149.39,151.23,152.80,160.71,162.15,163.95,173.19；
ESI-MS m/z:342.07[M+1]+。
实施例56
所得化合物56纯品为白色固体，产率为76％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.89-1.03(m,4H),1.96(ddd,J＝12.6,7.3,5.0Hz,1H),2.38(s,3H),7.32(d,J＝8.0Hz,2H),7.81(d,J＝8.1Hz,2H),7.93(s,1H),8.20(s,1H),8.34(s,1H),8.37(s,1H),11.89(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):15.09,23.24,26.35,112.18,132.60,134.01,135.09,146.86,150.83,162.88,164.58,167.56,175.41；
ESI-MS m/z:296.10[M+1]+。
实施例57
化合物57的制备
将1mmol 2,6-二甲基-4-氨基-5-醛基嘧啶和1mmol苯甲酰肼溶于25ml甲醇溶剂中，加入0.08mmol冰醋酸，加热搅拌反应8-10h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率为61％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),7.52(t,J＝7.3Hz,2H),7.58(t,J＝7.2Hz,1H),7.83(s,1H),7.89(d,J＝7.1Hz,2H),8.62(s,1H),8.79(s,1H),11.89(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.44,30.72,108.83,132.49,133.52,136.86,137.93,150.13,165.07,167.56,169.89,170.95；
ESI-MS m/z:270.08[M+1]+。
化合物58-74按化合物57类似方法制得，其结构鉴定数据如实施例58-74所示。
实施例58
所得纯品为黄色固体，产率为69％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),7.36(t,J＝8.7Hz,2H),7.83(s,1H),7.96(dd,J＝8.4,5.6Hz,2H),8.60(s,1H),8.77(s,1H),11.90(s,1H)；
19F NMR(376MHz,DMSO-d6)δ(ppm):-108.06；
ESI-MS m/z:288.06[M+1]+。
实施例59
所得化合物59纯品为白色固体，产率为65％，m.p.209-211℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.41(s,3H),7.40–7.58(m,4H),7.88(s,1H),8.52(s,1H),8.63(s,1H),11.94(s,1H)；
ESI-MS m/z:304.03[M+1]+。
实施例60
所得化合物60纯品为白色固体，产率为69％，m.p.248-250℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),7.56(t,J＝7.7Hz,1H),7.65(d,J＝8.2Hz,1H),7.85(d,J＝7.2Hz,2H),7.93(s,1H),8.58(s,1H),8.78(s,1H),11.97(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.47,30.74,108.70,131.37,132.16,135.55,136.68,138.33,139.85,150.66,165.06,166.07,170.07,171.07；
ESI-MS m/z:304.05[M+1]+。
实施例61
所得化合物61纯品为白色固体，产率为75％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),7.60(d,J＝8.4Hz,2H),7.83(s,1H),7.91(d,J＝8.3Hz,2H),8.60(s,1H),8.78(s,1H),11.95(s,1H)；
ESI-MS m/z:304.05[M+1]+。
实施例62
所得化合物62纯品为白色固体，产率为71％，m.p.198-200℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.35(s,3H),7.43(d,J＝7.6Hz,1H),7.48(t,J＝7.2Hz,1H),7.54(d,J＝7.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.88(s,1H),8.51(s,1H),8.62(s,1H),11.91(s,1H)；
ESI-MS m/z:347.97[M+1]+。
实施例63
所得化合物63纯品为白色固体，产率为77％，m.p.218-221℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),7.49(t,J＝8.0Hz,1H),7.79(d,J＝7.7Hz,1H),7.84(s,1H),7.89(d,J＝7.8Hz,1H),8.06(s,1H),8.58(s,1H),8.77(s,1H),11.97(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.47,30.74,108.70,126.81,131.74,134.97,135.78,139.55,140.06,150.65,165.06,165.98,170.05,171.06；
ESI-MS m/z:347.97[M+1]+。
实施例64
所得化合物64纯品为白色固体，产率为82％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.40(s,3H),7.75(d,J＝8.5Hz,2H),7.79(s,1H),7.85(d,J＝8.4Hz,2H),8.60(s,1H),8.78(s,1H),11.96(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.46,30.74,108.75,130.67,134.54,136.53,136.94,150.41,165.05,166.54,169.96,171.00；
ESI-MS m/z:347.97[M+1]+。
实施例65
所得化合物65纯品为白色固体，产率为67％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.39(s,3H),5.80(s,2H),6.58(d,J＝8.6Hz,2H),7.63(d,J＝8.5Hz,2H),7.74(s,1H),8.68(s,1H),8.73(s,1H),11.50(s,1H)；13C NMR(100MHz,DMSO-d6)δ(ppm):26.39,30.65,109.05,117.65,123.90,134.17,148.16,157.30,164.91,167.38,169.26,170.49；
ESI-MS m/z:285.07[M+1]+。
实施例66
所得化合物66纯品为黄色固体，产率为73％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.34(s,3H),2.43(s,3H),7.84(t,J＝8.0Hz,1H),7.88(s,1H),8.34(d,J＝7.8Hz,1H),8.43(dd,J＝7.8,1.8Hz,1H),8.60(s,1H),8.77–8.71(m,1H),8.81(s,1H),12.21(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.50,30.72,108.63,127.06,131.37,135.27,138.95,139.18,151.00,152.66,165.05,165.25,170.14,171.12；
ESI-MS m/z:315.04[M+1]+。
实施例67
所得化合物67纯品为黄色固体，产率为81％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.41(s,3H),7.88(s,1H),8.13(d,J＝8.8Hz,2H),8.37(d,J＝8.8Hz,2H),8.57(s,1H),8.81(s,1H),12.17(s,1H)；
ESI-MS m/z:315.05[M+1]+。
实施例68
所得化合物68纯品为黄色固体，产率为87％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.44(s,3H),7.92(s,1H),8.55(s,1H),8.81(s,1H),8.97(s,1H),9.08(s,2H),12.45(s,1H)；
ESI-MS m/z:360.06[M+1]+。
实施例69
所得化合物69纯品为棕色固体，产率为83％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.41(s,3H),6.11(s,2H),7.47(s,1H),7.54(s,1H),7.84(s,2H),8.59(s,1H),8.80(s,1H),12.02(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.46,30.71,108.74,113.19,114.94,123.82,139.74,150.77,153.69,155.28,165.08,166.20,170.07,171.06；
ESI-MS m/z:330.05[M+1]+。
实施例70
所得化合物70纯品为白色固体，产率为71％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.39(s,3H),6.85(d,J＝8.6Hz,2H),7.77(d,J＝8.5Hz,3H),8.56-8.71(m,1H),8.75(s,1H),10.12(s,1H),11.68(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.44,30.72,108.97,120.14,128.42,134.54,149.11,165.02,165.70,167.20,169.56,170.72；
ESI-MS m/z:286.06[M+1]+。
实施例71
所得化合物71纯品为白色固体，产率为58％，m.p.228-230℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.35(s,3H),2.38(s,3H),7.29(d,J＝8.5Hz,2H),7.35-7.41(m,1H),7.44(d,J＝7.5Hz,1H),7.83(s,1H),8.58(s,1H),8.66(s,1H),11.76(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):24.72,26.37,30.77,108.72,130.69,132.44,135.11,135.72,139.70,141.10,149.86,165.08,169.68,169.93,170.99；
ESI-MS m/z:284.07[M+1]+。
实施例72
所得化合物72纯品为白色固体，产率为64％，m.p.236-238℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.40(d,J＝3.4Hz,6H),7.40(d,J＝4.5Hz,2H),7.70(d,J＝7.4Hz,2H),7.82(s,1H),8.63(s,1H),8.79(s,1H),11.85(s,1H)；13CNMR(100MHz,DMSO-d6)δ(ppm):26.29,26.47,30.74,108.84,129.70,132.92,133.44,137.47,137.89,142.86,150.00,165.06,167.62,169.87,170.92；
ESI-MS m/z:284.08[M+1]+。
实施例73
所得化合物73纯品为白色固体，产率为71％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.33(s,3H),2.38(s,3H),2.40(s,3H),7.33(d,J＝8.0Hz,2H),7.81(d,J＝8.1Hz,3H),8.64(s,1H),8.79(s,1H),11.83(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.34,26.46,30.74,108.88,132.50,134.04,135.05,146.90,149.80,165.05,167.33,169.78,170.86；
ESI-MS m/z:284.07[M+1]+。
实施例74
所得化合物74纯品为白色固体，产率为73％，m.p.222-225℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),3.83(s,3H),7.06(d,J＝8.7Hz,2H),7.81(s,1H),7.88(d,J＝8.7Hz,2H),8.65(s,1H),8.77(s,1H),11.78(s,1H)；13C NMR(100MHz,DMSO-d6)δ(ppm):26.45,30.72,60.63,108.93,118.82,129.96,134.40,149.42,165.04,167.00,169.67,170.79,184.81；
ESI-MS m/z:300.06[M+1]+。
实施例75
化合物75的制备
将1mmol 2-甲基-4-氨基-5-醛基嘧啶和1mmol苯肼溶于20ml乙醇溶剂中，加入0.02mmol冰醋酸，加热搅拌反应3-5h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到黄色固体。产率为85％，m.p.249-251℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),6.75(s,1H,Ar-H),6.91(d,2H,Ar-H,J＝7.1Hz),7.22(s,2H,Ar-H),7.75(s,2H,NH2),7.90(s,1H,pyrimidine-H),8.16(s,1H,CH＝N),11.22(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):164.95,163.16,159.19,155.65,144.85,136.37,129.35,119.04,108.45,25.42；
ESI-MS m/z:228.2[M+1]+。
化合物76-88按化合物75类似方法制得，其结构鉴定数据如实施例76-88所示。
实施例76
所得化合物76纯品为黄色固体，产率为79％，m.p.242-243℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),6.95-7.10(m,3H,Ar-H),7.25(d,1H,Ar-H,J＝1.8Hz),7.73(s,2H,NH2),7.95(s,1H,pyrimidine-H),8.20(s,1H,CH＝N),10.59(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):165.33,159.19,156.20,146.28,137.77,131.33,127.27,119.87,111.19,108.15,95.58,25.50；
ESI-MS m/z:354.1[M+1]+。
实施例77
所得化合物77纯品为红色固体，产率为76％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),7.01(d,2H,Ar-H,J＝8.4Hz),7.70(s,2H,NH2),8.03(s,1H,pyrimidine-H),8.09(d,2H,Ar-H,J＝8.8Hz),8.23(s,1H,CH＝N),11.22(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):166.24,159.31,157.50,149.94,141.71,138.45,126.29,111.05,107.48,25.55；
ESI-MS m/z:273.4[M+1]+。
实施例78
所得化合物78纯品为黄色固体，产率为71％，m.p.240-241℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),6.93(d,2H,Ar-H,J＝8.7Hz),7.27(d,2H,Ar-H,J＝8.6Hz),7.73(s,2H,NH2),7.92(s,1H,pyrimidine-H),8.20(s,1H,CH＝N),10.49(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):165.27,159.20,156.13,143.79,137.36,129.14,122.24,113.22,108.24,25.49；
ESI-MS m/z:262.3[M+1]+。
实施例79
所得化合物79纯品为黄色固体，产率为69％，m.p.239-241℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.26(s,1H,Ar-H),7.31(s,1H,Ar-H),7.47(s,1H,Ar-H),7.73(s,2H,NH2),8.17(s,1H,pyrimidine-H),8.37(s,1H,CH＝N),10.03(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):165.86,159.34,156.81,141.39,140.15,128.83,128.22,122.44,117.02,114.28,107.89,25.53；
ESI-MS m/z:296.3[M+1]+。
实施例80
所得化合物80纯品为黄色固体，产率为77％，m.p.237-238℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),6.89(d,2H,Ar-H,J＝7.8Hz),7.38(d,2H,Ar-H,J＝7.8Hz),7.75(s,2H,NH2),7.93(s,1H,pyrimidine-H),8.20(s,1H,CH＝N),10.51(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):165.14,163.29,159.27,155.80,144.14,137.35,131.96,113.75,108.29,25.38；
ESI-MS m/z:306.2[M+1]+。
实施例81
所得化合物81纯品为黄色固体，产率为71％，m.p.222-224℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),7.02(s,1H,Ar-H),7.22(d,2H,Ar-H,J＝8.7Hz),7.74(s,2H,NH2),8.15(s,1H,pyrimidine-H),8.15(s,1H,CH＝N),10.20(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):165.40,163.15,159.28,156.15,139.45,130.07,113.73,111.67,111.47,108.12,104.40,104.16,103.90,25.43；
ESI-MS m/z:264.1[M+1]+。
实施例82
所得化合物82纯品为黄色固体，产率为79％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.35(s,3H,CH3),7.64(s,2H,Ar-H),7.72(s,2H,NH2),8.13(s,1H,pyrimidine-H),8.20(s,1H,CH＝N),9.69(s,1H,NH)；
ESI-MS m/z:330.1[M+1]+。
实施例83
所得化合物83纯品为黄色固体，产率为84％，m.p.252-254℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.06(d,2H,Ar-H,J＝8.4Hz),7.56(d,2H,Ar-H,J＝8.5Hz),7.75(s,2H,NH2),8.00(s,1H,pyrimidine-H),8.24(s,1H,CH＝N),10.83(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):165.67,159.31,156.67,147.77,138.99,126.68,123.72,119.17,118.86,118.54,118.22,111.48,107.99,25.50；
ESI-MS m/z:295.9[M+1]+。
实施例84
所得化合物84纯品为黄色固体，产率为80％，m.p.246-248℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),6.78(d,1H,Ar-H,J＝7.7Hz),6.87(d,1H,Ar-H,J＝8.3Hz),7.24(t,1H,Ar-H,J＝8.0Hz),7.74(s,2H,NH2),7.94(s,1H,pyrimidine-H),8.22(s,1H,CH＝N),10.56(s,1H,NH)；
ESI-MS m/z:262.3[M+1]+。
实施例85
所得化合物85纯品为黄色固体，产率为79％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.37(s,3H,CH3),6.92(dd,2H,Ar-H,J＝8.0,2.0Hz),7.06(t,2H,Ar-H,J＝2.0Hz),7.19(t,1H,Ar-H,J＝8.0Hz),7.74(s,2H,NH2),7.94(s,1H,pyrimidine-H),8.22(s,1H,CH＝N),10.55(s,1H,NH)；
ESI-MS m/z:306.2[M+1]+。
实施例86
所得化合物86纯品为绿色固体，产率为82％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),6.77(t,1H,Ar-H,J＝7.5Hz),7.23(d,1H,Ar-H,J＝8.0Hz),7.33(t,1H,Ar-H,J＝7.7Hz),7.52(d,1H,Ar-H,J＝7.9Hz),7.77(s,2H,NH2),8.17(s,1H,pyrimidine-H),8.38(s,1H,CH＝N),9.66(s,1H,NH)；
ESI-MS m/z:306.0[M+1]+。
实施例87
所得化合物87纯品为黄色固体，产率为79％，m.p.255-257℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.35(d,1H,Ar-H,J＝7.9Hz),7.50(t,1H,Ar-H,J＝8.0Hz),7.58(d,1H,Ar-H,J＝8.0Hz),7.68(s,1H,Ar-H),7.76(s,2H,NH2),8.00(s,1H,pyrimidine-H),8.26(s,1H,CH＝N),10.89(s,1H,NH)；
ESI-MS m/z:273.1[M+1]+。
实施例88
所得化合物88纯品为黄色固体，产率为56％，m.p.220-228℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.57(s,3H,CH3),7.00(s,1H,Ar-H),7.73(dd,2H,Ar-H,J＝6.6,8.0Hz),8.12(d,1H,Ar-H,J＝8.1Hz),8.57(d,2H,NH2,J＝6.6,15.2Hz),8.69(s,1H,pyrimidine-H),9.68(s,1H,CH＝N),11.28(s,1H,NH)；
ESI-MS m/z:273.1[M+1]+。
实施例89
化合物89的制备
将1mmol 4-氨基-6-甲基-5-醛基嘧啶和1.1mmol苯肼溶于10ml甲醇溶剂中，加入0.01mmol冰醋酸，加热搅拌反应3-4h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到黄色固体。产率为51％，m.p.208-209℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.42(s,3H),6.76(t,J＝7.2Hz,1H),6.90(d,J＝8.1Hz,2H),7.23(t,J＝7.7Hz,2H),7.87(s,2H),8.17(s,1H),8.25(s,1H),10.41(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.71,112.67,116.64,124.11,134.35,140.05,149.53,160.53,164.05,166.90；
ESI-MS m/z:228.10[M+1]+。
化合物90-102按化合物89类似方法制得，其结构鉴定数据如实施例90-102所示。
实施例90
所得化合物90纯品为黄色固体，产率为63％，m.p.206-208℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.45(s,3H),6.75(t,J＝7.4Hz,1H),7.19(d,J＝8.1Hz,1H),7.31(t,J＝7.6Hz,1H),7.51(d,J＝7.8Hz,1H),7.95(s,2H),8.23(s,1H),8.78(s,1H),9.75(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.51,111.29,112.40,118.43,125.69,133.83,137.87,144.39,146.70,160.61,164.32,167.56；
HRMS(ESI):calcd.for C12H12BrN5[M+H]+306.03488,found:306.03501。
实施例91
所得化合物91纯品为黄色固体，产率为69％，m.p.193-195℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.46(s,3H),6.99–6.90(m,2H),7.08(t,J＝1.9Hz,1H),7.23(t,J＝8.0Hz,1H),7.94(s,2H),8.25(s,1H),8.31(s,1H),10.67(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):21.75,107.73,111.18,114.14,121.81,123.00,131.74,137.00,146.55,156.22,159.66,162.81；
ESI-MS m/z:306.02[M+1]+。
实施例92
所得化合物92纯品为黄色固体，产率为79％，m.p.196-198℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.42(s,3H),6.86(d,J＝8.6Hz,2H),7.38(d,J＝8.6Hz,2H),7.82(s,2H),8.18(s,1H),8.25(s,1H),10.53(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.70,112.47,114.90,118.59,136.94,141.04,148.81,160.69,164.08,167.24；
ESI-MS m/z:306.04[M+1]+。
实施例93
所得化合物93纯品为黄色固体，产率为81％，m.p.181-182℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.45(s,3H),6.93(d,J＝8.7Hz,2H),7.27(d,J＝8.7Hz,2H),8.19(s,2H),8.23(s,1H),8.29(s,1H),10.67(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):25.58,112.58,118.19,127.49,134.09,140.04,148.28,159.04,164.31,165.00；
ESI-MS m/z:262.07[M+1]+。
实施例94
所得化合物94纯品为黄色固体，产率为74％，m.p.176-178℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.44(s,3H),7.03(d,J＝8.4Hz,2H),7.55(d,J＝8.5Hz,2H),7.85(s,2H),8.20(s,1H),8.33(s,1H),10.83(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):167.80,164.18,161.01,152.39,142.59,131.71,123.89,123.57,116.35,112.23,26.70；
19F NMR(376MHz,DMSO-d6)δ(ppm):-59.30；
ESI-MS m/z:296.09[M+1]+。
实施例95
所得化合物95纯品为黄色固体，产率为79％，m.p.249-251℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.43(s,3H),7.21(d,J＝8.8Hz,1H),7.33(d,J＝8.8Hz,1H),7.49(d,J＝2.0Hz,1H),7.81(s,2H),8.21(s,1H),8.77(s,1H),10.04(s,1H)；
ESI-MS m/z:296.05[M+1]+。
实施例96
所得化合物96纯品为黄色固体，产率为84％，m.p.213-214℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.41(s,3H),7.01(t,J＝8.3Hz,1H),7.12-7.30(m,2H),7.82(s,2H),8.19(s,1H),8.55(s,1H),10.19(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):20.80,104.30,104.52,104.57,104.79,107.79,111.83,111.86,112.05,112.08,113.78,113.82,113.87,113.91,130.04,130.06,130.13,130.16,137.95,147.71,147.83,150.13,150.25,154.08,154.19,154.98,156.44,156.55,159.86,161.24；
19F NMR(376MHz,DMSO-d6)δ(ppm):-122.69,-128.92；
ESI-MS m/z:264.06[M+1]+。
实施例97
所得化合物97纯品为黄色固体，产率为61％，m.p.199-201℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.47(s,3H),6.80-6.90(m,1H),7.28(dtd,J＝9.8,8.2,1.4Hz,2H),7.39(dd,J＝8.0,1.2Hz,1H),8.24(s,2H),8.34(s,1H),8.78(s,1H),10.09(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):20.71,107.83,113.40,116.88,120.44,128.61,129.99,138.97,140.93,154.83,159.97,161.37；
HRMS(ESI):calcd.for C12H12ClN5[M+H]+262.0854,found:262.08581。
实施例98
所得化合物98纯品为黄色固体，产率为67％，m.p.196-198℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.44(s,3H),6.74-6.98(m,3H),7.26(s,1H),7.87(s,2H),8.22(s,1H),8.29(s,1H),10.64(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):21.75,107.72,110.79,111.26,118.86,131.35,134.40,136.92,146.39,156.24,159.61,162.88；
HRMS(ESI):calcd.for C12H12ClN5[M+H]+262.0854,found:262.08580。
实施例99
所得化合物99纯品为黄色固体，产率为71％，m.p.170-172℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.49(s,3H),6.96(dd,J＝8.9,4.6Hz,2H),7.13(t,J＝8.8Hz,2H),8.24(s,1H),8.39(s,1H),8.50(s,2H),10.73(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):19.66,108.15,113.24,113.32,116.18,116.41,133.92,141.40,141.42,152.98,155.41,157.75,158.27,160.01；
19F NMR(376MHz,DMSO-d6)δ(ppm):-124.95；
HRMS(ESI):calcd.for C12H12FN5[M+H]+246.11495,found:246.11534。
实施例100
所得化合物100纯品为黄色固体，产率为75％，m.p.169-171℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.47(s,3H),7.01(d,J＝9.0Hz,2H),7.27(d,J＝8.8Hz,2H),8.24(s,2H),8.29(s,1H),8.33(s,1H),10.78(s,1H)；
19F NMR(376MHz,DMSO-d6)δ(ppm):-57.18；
HRMS(ESI):calcd.for C13H12F3N5O[M+H]+312.10667,found:312.10738。
实施例101
所得化合物101纯品为黄色固体，产率为81％，m.p.205-207℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.23(s,3H),2.56(s,3H),6.90(d,J＝8.4Hz,2H),7.10(d,J＝8.3Hz,2H),8.18(s,1H),8.62(s,1H),9.32(d,J＝114.1Hz,2H),10.92(s,1H)；
HRMS(ESI):calcd.for C13H13N5[M+H]+242.14002,found:242.14029。
实施例102
所得化合物102纯品为黄色固体，产率为80％，m.p.208-210℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.57(s,3H),3.71(s,3H),6.90(d,J＝9.1Hz,2H),6.96(d,J＝9.1Hz,2H),8.19(s,1H),8.58(s,1H),9.25(d,J＝74.5Hz,2H),10.88(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):17.09,55.69,108.61,113.53,115.17,130.59,138.25,149.08,152.78,153.73,160.47；
HRMS(ESI):calcd.for C13H13N5O[M+H]+258.13494,found:258.13535。
实施例103
化合物103的制备
将1mmol 2-环丙基-4-氨基-5-醛基嘧啶和1.1mmol苯肼溶于20ml乙醇溶剂中，加入0.1mmol冰醋酸，加热搅拌反应4-6h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到黄色固体。产率为59％，m.p.214-216℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.86-1.00(m,4H),1.94(ddd,J＝12.8,7.8,5.0Hz,1H),6.73(t,J＝7.3Hz,1H),6.88(d,J＝7.6Hz,2H),7.16-7.26(m,2H),7.69(s,2H),7.87(s,1H),8.10(s,1H),10.27(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):12.39,20.64,110.95,114.23,121.45,131.83,139.08,147.34,158.22,161.48,171.24；
ESI-MS m/z：254.09[M+1]+。
化合物104-110按化合物103类似方法制得，其结构鉴定数据如实施例104-110所示。
实施例104
所得化合物104纯品为白色固体，产率为73％，m.p.180-182℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.86-1.00(m,4H),1.94(ddd,J＝13.3,8.1,5.3Hz,1H),6.72(t,J＝7.6Hz,1H),7.17(d,J＝8.1Hz,1H),7.28(t,J＝7.7Hz,1H),7.47(d,J＝7.8Hz,1H),7.67(s,2H),8.08(s,1H),8.32(s,1H),9.56(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.96,23.13,111.37,112.98,118.55,125.47,133.74,137.78,145.86,146.91,161.45,164.06,174.36；
ESI-MS m/z:332.02[M+1]+。
实施例105
所得化合物105纯品为白色固体，产率为76％，m.p.220-222℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.86-1.04(m,4H),1.94(ddd,J＝13.3,8.1,5.3Hz,1H),6.95(dd,J＝7.9,2.0Hz,2H),7.09(d,J＝1.8Hz,1H),7.22(t,J＝8.0Hz,1H),7.95(s,1H),8.08(s,2H),8.28(s,1H),10.64(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):10.02,18.21,108.38,111.13,114.18,121.55,122.92,131.69,138.57,146.80,156.74,159.46,169.66；
ESI-MS m/z:332.01[M+1]+。
实施例106
所得化合物106纯品为黄色固体，产率为79％，m.p.223-225℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.86-1.06(m,4H),1.93(ddd,J＝13.3,8.1,5.3Hz,1H),6.84(d,J＝8.7Hz,2H),7.35(d,J＝8.6Hz,2H),7.63(s,2H),7.87(s,1H),8.11(s,1H),10.40(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.90,23.09,113.14,114.65,118.59,136.86,142.53,149.04,160.99,163.91,173.94；
ESI-MS m/z:332.03[M+1]+。
实施例107
所得化合物107纯品为黄色固体，产率为81％，m.p.232-234℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.86-0.97(m,4H),1.93(ddd,J＝13.0,8.0,5.2Hz,1H),6.89(d,J＝8.8Hz,2H),7.23(d,J＝8.8Hz,2H),7.64(s,2H),7.87(s,1H),8.11(s,1H),10.39(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.89,23.07,113.16,118.08,127.06,134.03,142.40,148.67,160.89,163.92,173.88；
ESI-MS m/z:288.03[M+1]+。
实施例108
所得化合物108纯品为黄色固体，产率为77％，m.p.253-255℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.84-1.00(m,4H),1.94(ddd,J＝12.7,7.7,4.8Hz,1H),7.01(d,J＝8.5Hz,2H),7.52(d,J＝8.6Hz,2H),7.67(s,2H),7.94(s,1H),8.15(s,1H),10.72(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.87,23.08,112.87,116.34,123.36,123.68,128.62,131.30,131.57,144.03,152.62,161.47,163.99,174.30；19F NMR(376MHz,DMSO-d6)δ(ppm):-59.28；
ESI-MS m/z:322.08[M+1]+。
实施例109
所得化合物109纯品为黄色固体，产率为83％，m.p.225-227℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.86-1.00(m,4H),1.94(ddd,J＝12.5,7.7,4.8Hz,1H),7.20(d,J＝8.8Hz,1H),7.30(dd,J＝8.7,2.3Hz,1H),7.45(d,J＝2.3Hz,1H),7.64(s,2H),8.09(s,1H),8.31(s,1H),9.92(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.94,23.11,112.79,119.12,121.87,127.27,133.13,133.73,145.03,146.47,161.66,164.03,174.51；
ESI-MS m/z:322.00[M+1]+。
实施例110
所得化合物110纯品为黄色固体，产率为75％，m.p.216-218℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.82-1.01(m,4H),1.93(ddd,J＝12.6,7.8,4.9Hz,1H),6.99(t,J＝8.1Hz,1H),7.26–7.10(m,2H),7.65(s,2H),8.07(s,1H),8.10(s,1H),10.10(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.87,23.06,108.80,109.03,109.29,113.05,116.32,116.54,118.43,134.99,135.08,144.50,152.19,152.31,154.60,154.71,158.40,158.51,160.75,160.86,161.05,163.98,174.10；
19F NMR(376MHz,DMSO-d6)δ(ppm):-123.58,-128.85；
ESI-MS m/z:290.05[M+1]+。
实施例111
化合物111的制备
将1mmol 2，6-二甲基-4-氨基-5-醛基嘧啶和1mmol苯肼溶于25ml乙醇溶剂中，加入0.05mmol冰醋酸，加热搅拌反应6-8h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到黄色固体。产率为58％，m.p.244-246℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H),2.38(s,3H),6.74(t,J＝7.3Hz,1H),6.88(d,J＝7.6Hz,2H),7.16-7.26(m,2H),7.79(s,2H),8.24(s,1H),10.30(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.58,30.58,109.99,116.57,123.88,134.29,140.44,149.71,164.35,167.21,169.10；
ESI-MS m/z:242.06[M+1]+。
化合物112-118按化合物111类似方法制得，其结构鉴定数据如实施例112-118所示。
实施例112
所得化合物112纯品为黄色固体，产率为63％，m.p.235-236℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),6.73(td,J＝7.6,1.5Hz,1H),7.17(dd,J＝8.1,1.3Hz,1H),7.29(t,J＝7.7Hz,1H),7.49(dd,J＝7.9,1.3Hz,1H),7.78(s,2H),8.77(s,1H),9.63(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.71,30.63,109.73,111.15,118.27,125.33,133.76,137.79,144.97,146.86,164.53,168.48,169.72；
ESI-MS m/z:319.97[M+1]+。
实施例113
所得化合物113纯品为黄色固体，产率为71％，m.p.249-250℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H),2.46(s,3H),6.94(t,J＝8.4Hz,2H),7.07(s,1H),7.20(t,J＝8.0Hz,1H),8.26(s,1H),8.36(s,2H),10.77(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):21.76,25.76,105.04,111.08,114.01,121.54,123.00,131.68,137.45,146.70,159.92,163.34,165.05；
ESI-MS m/z:319.96[M+1]+。
实施例114
所得化合物114纯品为黄色固体，产率为78％，m.p.244-246℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H),2.38(s,3H),6.84(d,J＝8.8Hz,2H),7.36(d,J＝8.8Hz,2H),7.74(s,2H),8.24(s,1H),10.43(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.54,30.52,109.70,114.55,118.40,136.85,141.34,148.86,164.27,167.49,169.26；
ESI-MS m/z:319.97[M+1]+。
实施例115
所得化合物115纯品为黄色固体，产率为86％，m.p.235-236℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.34(s,3H),2.40(s,3H),6.89(d,J＝8.5Hz,2H),7.25(d,J＝8.6Hz,2H),7.92(s,2H),8.23(s,1H),10.48(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):25.94,30.04,109.94,118.04,127.17,134.09,140.79,148.50,164.44,166.26,168.55；
ESI-MS m/z:276.00[M+1]+。
实施例116
所得化合物116纯品为黄色固体，产率为82％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.40(s,3H),7.01(d,J＝8.5Hz,2H),7.54(d,J＝8.6Hz,2H),7.78(s,2H),8.32(s,1H),10.74(s,1H)；
19F NMR(376MHz,DMSO-d6)δ(ppm):-59.27；
ESI-MS m/z:310.04[M+1]+。
实施例117
所得化合物117纯品为白色固体，产率为86％，m.p.251-253℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.32(s,3H),2.39(s,3H),7.19(d,J＝8.8Hz,1H),7.32(dd,J＝8.8,2.4Hz,1H),7.47(d,J＝2.4Hz,1H),7.74(s,2H),8.76(s,1H),9.95(s,1H)；ESI-MS m/z:309.99[M+1]+。
实施例118
所得化合物118纯品为白色固体，产率为54％，m.p.232-233℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.31(s,3H),2.36(s,3H),7.04–6.95(m,1H),7.26–7.10(m,2H),7.73(s,2H),8.54(s,1H),10.08(s,1H)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.55,30.58,108.87,109.10,109.36,109.70,116.42,116.63,118.14,118.18,134.99,135.06,143.70,152.11,152.24,154.52,154.64,158.33,158.44,160.68,160.79,164.43,167.93,169.53；
19F NMR(376MHz,DMSO-d6)δ(ppm):-123.70,-129.35；
ESI-MS m/z:278.04[M+1]+。
实施例119
化合物119的制备
将1mmol 2-甲基-4-氨基-5-醛基嘧啶和1.1mmol 3-苯甲酰胺-苯甲酰肼溶于25ml乙醇溶剂中，加入0.1mmol三氟乙酸，加热搅拌反应16-24h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率为71％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.56(ddd,J＝25.0,18.3,8.0Hz,5H,Ar-H),7.98(t,J＝7.4Hz,4H,Ar-H),8.26(s,1H,CH＝N),8.30(s,1H,NH2),8.41(s,1H,pyrimidine-H),10.44(s,1H,NH),12.03(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.91,112.17,125.02,127.56,128.74,132.73,133.42,133.78,136.72,138.61,139.64,144.49,151.17,163.08,164.73,167.88,170.63,171.70；
ESI-MS m/z：375.07[M+1]+。
化合物120-133按化合物119类似方法制得，其结构鉴定数据如实施例120-133所示。
实施例120
所得化合物120纯品为白色固体，产率为83％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.51(t,J＝7.6Hz,1H,Ar-H),7.57-7.69(m,3H,Ar-H),8.00(d,J＝7.1Hz,3H,Ar-H),8.09(s,1H,Ar-H),8.28(d,J＝8.4Hz,2H,NH2,CH＝N),8.41(s,1H,pyrimidine-H),10.51(s,1H,NH),12.04(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.88,112.14,125.07,127.69,128.78,133.50,133.82,134.66,138.26,138.57,141.61,144.26,151.20,163.06,164.70,167.81,169.51,171.69；
ESI-MS m/z:409.05[M+1]+。
实施例121
所得化合物121纯品为白色固体，产率为75％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.46-7.61(m,2H,Ar-H),7.66(s,2H,Ar-H),7.93(d,J＝7.0Hz,1H,Ar-H),7.97-8.07(m,3H,Ar-H),8.28(d,J＝7.5Hz,2H,NH2,CH＝N),8.41(s,1H,pyrimidine-H),10.53(s,1H,NH),12.04(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.88,112.14,125.08,127.77,128.77,131.54,132.47,133.84,135.40,136.55,138.28,138.59,141.52,144.19,151.22,163.06,164.70,167.81,169.13,171.70；
ESI-MS m/z:409.07[M+1]+。
实施例122
所得化合物122纯品为白色固体，产率为71％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.48(dt,J＝19.5,7.1Hz,3H,Ar-H),7.54-7.61(m,2H,Ar-H),7.63(d,J＝7.3Hz,1H,Ar-H),7.89(d,J＝7.7Hz,1H,Ar-H),8.05(s,1H,Ar-H),8.27(s,2H,NH2,CH＝N),8.41(s,1H,pyrimidine-H),10.70(s,1H,NH),12.05(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.92,112.17,124.20,127.74,127.94,132.28,133.98,134.70,134.99,136.20,138.86,141.72,144.20,151.24,163.09,164.74,167.88,170.09,171.72；ESI-MS m/z:409.07[M+1]+。
实施例123
所得化合物123纯品为黄色固体，产率为77％，m.p.238-241℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),7.37(t,J＝8.8Hz,2H,Ar-H),7.51(t,J＝7.9Hz,1H,Ar-H),7.64(d,J＝7.7Hz,1H,Ar-H),7.93(s,1H,Ar-H),7.99(d,J＝7.5Hz,1H,Ar-H),8.06(dd,J＝5.5,8.5Hz,2H,Ar-H),8.27(s,1H,CH＝N),8.29(s,1H,NH2),8.42(s,1H,pyrimidine-H),10.45(s,1H,NH),12.03(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.88,112.14,120.31,120.53,125.04,127.59,128.75,133.80,135.42,135.51,136.04,138.57,144.37,151.17,163.04,164.70,167.82,169.48,170.24,170.31,170.39,171.68；
19F NMR(376MHz,DMSO-d6)δ(ppm):-108.43；
ESI-MS m/z:393.10[M+1]+。
实施例124
所得化合物124纯品为白色固体，产率为71％，m.p.148-150℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),7.34(dd,J＝16.5,8.7Hz,2H,Ar-H),7.51(t,J＝7.9Hz,1H,Ar-H),7.58(dd,J＝13.3,6.1Hz,1H,Ar-H),7.62-7.73(m,2H,Ar-H),7.91(d,J＝7.8Hz,1H,Ar-H),8.06(s,1H,Ar-H),8.27(s,2H,CH＝N,NH2),8.41(s,1H,pyrimidine-H),10.61(s,1H,NH),12.05(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.90,112.15,121.13,121.34,124.36,127.78,128.11,129.59,129.83,133.98,134.93,137.62,137.70,138.77,144.11,151.23,162.61,163.08,164.71,165.08,167.84,167.94,171.70；
19F NMR(376MHz,DMSO-d6)δ(ppm):-114.52；
ESI-MS m/z:393.10[M+1]+。
实施例125
所得化合物125纯品为白色固体，产率为83％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),7.51(t,J＝7.8Hz,1H,Ar-H),7.65(d,J＝7.6Hz,1H,Ar-H),7.71-7.78(m,2H,Ar-H),7.93(d,J＝8.4Hz,2H,Ar-H),7.99(d,J＝8.1Hz,1H,Ar-H),8.04(s,1H,Ar-H),8.27(s,1H,CH＝N),8.30(s,1H,NH2),8.42(s,1H,pyrimidine-H),10.51(s,1H,NH),12.04(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.92,112.16,125.08,127.69,128.76,130.59,133.80,134.83,136.43,138.59,138.64,144.27,151.18,163.06,164.71,167.78,169.60,171.68；
ESI-MS m/z:453.03[M+1]+。
实施例126
所得化合物126纯品为白色固体，产率为64％，m.p.246-248℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),7.42(td,J＝7.7,1.6Hz,1H,Ar-H),7.50(td,J＝7.6,3.6Hz,2H,Ar-H),7.57(d,J＝6.3Hz,1H,Ar-H),7.64(d,J＝7.7Hz,1H,Ar-H),7.72(d,J＝7.9Hz,1H,Ar-H),7.89(d,J＝8.1Hz,1H,Ar-H),8.04(s,1H,Ar-H),8.26(d,J＝4.7Hz,2H,CH＝N,NH2),8.42(s,1H,pyrimidine-H),10.68(s,1H,NH),12.05(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.93,112.15,124.03,124.18,127.69,127.92,132.75,133.89,133.97,136.30,137.76,138.84,143.86,144.22,151.22,163.09,164.72,167.85,170.95,171.70；
ESI-MS m/z:453.01[M+1]+。
实施例127
所得化合物127纯品为白色固体，产率为69％，m.p.231-233℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,6H,2CH3),7.33(d,J＝8.0Hz,2H,Ar-H),7.50(t,J＝7.9Hz,1H,Ar-H),7.63(d,J＝7.7Hz,1H,Ar-H),7.90(d,J＝8.0Hz,2H,Ar-H),8.00(d,J＝8.1Hz,1H,Ar-H),8.10(s,1H,Ar-H),8.27(s,1H,CH＝N),8.31(s,1H,NH2),8.42(s,1H,pyrimidine-H),10.35(s,1H,NH),12.03(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.34,30.89,112.17,125.00,127.46,128.74,132.75,133.76,133.95,136.72,138.56,144.54,146.77,151.17,163.05,164.71,167.91,170.45,171.70；
ESI-MS m/z:389.11[M+1]+。
实施例128
所得化合物128纯品为白色固体，产率为80％，m.p.231-233℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.40(s,3H,CH3),7.53(t,J＝7.8Hz,1H,Ar-H),7.67(d,J＝7.7Hz,1H,Ar-H),7.92(d,J＝8.2Hz,2H,Ar-H),8.01(d,J＝8.0Hz,1H,Ar-H),8.06(s,1H,Ar-H),8.17(d,J＝8.1Hz,2H,Ar-H),8.27(s,1H,CH＝N),8.31(s,1H,NH2),8.42(s,1H,pyrimidine-H),10.66(s,1H,NH),12.05(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.90,112.13,125.10,127.57,127.87,128.79,130.27,130.46,133.66,133.88,136.37,136.68,138.62,143.38,144.13,151.21,163.10,164.70,167.74,169.44,171.70；
19F NMR(376MHz,DMSO-d6)δ(ppm):-61.25；
ESI-MS m/z:443.09[M+1]+。
实施例129
所得化合物129纯品为白色固体，产率为79％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.50(dt,J＝15.6,7.8Hz,2H,Ar-H),7.58(d,J＝6.9Hz,1H,Ar-H),7.65(d,J＝6.9Hz,1H,Ar-H),7.76(d,J＝7.7Hz,1H,Ar-H),7.88(d,J＝7.4Hz,1H,Ar-H),8.04(s,1H,Ar-H),8.26(d,J＝10.4Hz,2H,CH＝N,NH2),8.42(s,1H,pyrimidine-H),10.79(s,1H,NH),12.06(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.91,112.14,124.18,127.90,132.40,133.20,133.69,134.05,136.44,137.18,138.87,143.92,143.98,151.25,163.09,164.72,167.78,169.27,171.70；ESI-MS m/z:443.02[M+1]+。
实施例130
所得化合物130纯品为白色固体，产率为86％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.46-7.59(m,2H,Ar-H),7.64(d,J＝7.8Hz,2H,Ar-H),7.77(s,1H,Ar-H),7.88(d,J＝7.7Hz,1H,Ar-H),8.01(s,1H,Ar-H),8.23(s,1H,NH2),8.27(s,1H,CH＝N),8.41(s,1H,pyrimidine-H),10.74(s,1H,NH),12.06(s,1H,NH)；13C NMR(100MHz,DMSO-d6)δ(ppm):30.88,112.14,124.22,127.87,127.97,132.50,134.05,134.25,135.37,136.27,138.82,140.03,140.45,143.98,151.29,163.07,164.71,167.80,169.17,171.72；
ESI-MS m/z:443.05[M+1]+。
实施例131
所得化合物131纯品为白色固体，产率为64％，m.p.259-261℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.07(s,3H,CH3),2.39(s,3H,CH3),7.43(t,J＝7.6Hz,1H,Ar-H),7.55(d,J＝7.4Hz,1H,Ar-H),7.79(d,J＝7.7Hz,1H,Ar-H),8.02(d,J＝39.3Hz,2H,Ar-H,NH2),8.26(s,1H,CH＝N),8.39(s,1H,pyrimidine-H),10.12(s,1H,NH),11.99(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):29.29,30.86,112.13,123.58,126.84,127.35,133.86,138.60,144.55,151.15,163.03,164.69,167.90,171.68,173.53；
ESI-MS m/z:313.07[M+1]+。
实施例132
所得化合物132纯品为白色固体，产率为73％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):1.10(t,J＝6.8Hz,3H,CH3).2.39(s,3H,CH3),2.34(s,2H,CH2),7.44(d,J＝7.5Hz,1H,Ar-H),7.55(d,J＝7.0Hz,1H,Ar-H),7.81(d,J＝7.4Hz,1H,Ar-H),8.02(s,1H,Ar-H),8.09(s,1H,NH2),8.26(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.04(s,1H,NH),11.99(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.96,30.88,34.85,112.15,123.60,126.76,127.34,133.80,138.62,144.62,151.09,163.03,164.70,167.89,171.66,177.13；
ESI-MS m/z:327.10[M+1]+。
实施例133
所得化合物133纯品为白色固体，产率为87％，m.p.242-243℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):0.93(dd,J＝9.7,5.0Hz,3H,CH3),1.63(dd,J＝14.6,7.3Hz,2H,CH2),2.31(t,J＝7.3Hz,2H,CH2),2.39(s,3H,CH3),7.43(t,J＝7.8Hz,1HAr-H),7.55(d,J＝7.7Hz,1H,Ar-H),7.81(d,J＝7.7Hz,1H,Ar-H),7.99(s,1H,Ar-H),8.09(s,1H,NH2),8.26(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.05(s,1H,NH),11.99(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):18.97,23.87,30.88,43.60,112.15,123.61,126.80,127.36,133.80,138.62,144.58,151.09,163.03,164.70,167.89,171.66,176.29；
ESI-MS m/z:341.08[M+1]+。
实施例134
化合物134的制备
将1mmol 2-甲基-4-氨基-5-醛基嘧啶和1mmol 4-苯甲酰胺-苯甲酰肼溶于35ml乙醇溶剂中，加入0.15mmol三氟乙酸，加热搅拌反应24-36h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率为52％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.57(dd,J＝19.5,6.8Hz,3H,Ar-H),7.83-8.05(m,7H,Ar-H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.49(s,1H,NH),11.95(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.76,108.41,109.58,109.84,110.09,116.89,117.10,123.63,123.77,136.78,136.85,160.30,166.76,167.58,170.40,174.04；
ESI-MS m/z:375.18[M+1]+；
化合物135-148按化合物134类似方法制得，其结构鉴定数据如实施例135-148所示。
实施例135
所得化合物135纯品为白色固体，产率为78％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.62(d,J＝8.3Hz,2H,Ar-H),7.92(s,5H,Ar-H),7.99(d,J＝8.3Hz,3H,Ar-H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.55(s,1H,NH),11.95(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.87,112.21,124.65,132.74,133.48,134.65,134.78,138.23,141.68,147.23,150.67,162.90,164.67,167.21,169.61,171.55；
ESI-MS m/z:409.14[M+1]+。
实施例136
所得化合物136纯品为白色固体，产率为69％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.57(t,J＝7.7Hz,1H,Ar-H),7.67(d,J＝7.6Hz,1H,Ar-H),7.92(s,6H,Ar-H),8.01(s,1H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.58(s,1H,NH),11.96(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.89,112.19,124.58,124.67,131.60,132.41,132.57,132.85,133.42,135.42,136.62,138.23,141.51,147.11,164.65,167.18,169.25,171.56；
ESI-MS m/z:409.12[M+1]+。
实施例137
所得化合物137纯品为白色固体，产率为64％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.52(ddd,J＝22.6,17.2,7.0Hz,4H,Ar-H),7.83(d,J＝7.9Hz,2H,Ar-H),7.92(d,J＝7.9Hz,2H,Ar-H),8.03(s,1H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.77(s,1H,NH),11.95(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.86,112.19,123.95,132.29,132.80,133.61,133.96,134.69,134.90,136.30,141.56,147.04,162.75,162.97,164.66,167.17,170.16,171.55；
ESI-MS m/z:409.10[M+1]+。
实施例138
所得化合物138纯品为黄色固体，产率为76％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.37(t,J＝8.3Hz,2H,Ar-H),7.92(s,4H,Ar-H),7.99-8.13(m,3H,Ar-H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.50(s,1H,NH),11.95(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):25.59,106.96,115.02,115.23,119.35,127.39,128.15,130.21,130.30,130.73,142.08,145.35,157.61,159.41,161.98,162.59,164.35,165.07,166.29；
19F NMR(376MHz,DMSO-d6)δ(ppm):-108.23；
ESI-MS m/z:393.15[M+1]+。
实施例139
所得化合物139纯品为白色固体，产率为69％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.75(s,1H,Ar-H),7.77(s,1H,Ar-H),7.81(s,1H,Ar-H),7.92(s,7H,Ar-H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.55(s,1H,NH),11.95(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.91,112.23,124.67,130.69,132.78,133.46,134.89,136.44,138.63,147.24,150.64,162.92,164.69,167.23,169.77,171.58；
ESI-MS m/z:453.01[M+1]+。
实施例140
所得化合物140纯品为白色固体，产率为71％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.43(t,J＝7.4Hz,1H,Ar-H),7.50(t,J＝7.3Hz,1H,Ar-H),7.57(d,J＝7.5Hz,1H,Ar-H),7.72(d,J＝7.8Hz,1H,Ar-H),7.84(d,J＝8.0Hz,2H,Ar-H),7.93(d,J＝7.7Hz,2H,Ar-H),8.05(s,1H,NH2),8.27(s,1H,CH＝N),8.41(s,1H,pyrimidine-H),10.76(s,1H,NH),11.95(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.91,112.23,124.01,132.76,132.85,133.63,133.90,136.38,137.76,143.76,147.10,150.72,162.94,164.70,167.22,171.07,171.61；
ESI-MS m/z:453.03[M+1]+。
实施例141
所得化合物141纯品为黄色固体，产率为80％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,6H,2CH3),7.34(d,J＝7.6Hz,2H,Ar-H),7.77-7.99(m,7H,Ar-H,NH2),8.07(s,1H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.40(s,1H,NH),11.94(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):26.33,30.88,112.25,124.56,132.47,132.81,133.42,133.93,136.71,146.85,147.57,150.58,162.88,164.70,167.29,170.57,171.56；
ESI-MS m/z:389.15[M+1]+。
实施例142
所得化合物142纯品为黄色固体，产率为81％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),3.85(s,3H,OCH3),7.07(d,J＝7.3Hz,2H,Ar-H),7.80(s,1H,Ar-H),7.87-8.00(m,7H,Ar-H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.33(s,1H,NH),11.94(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.89,60.64,112.26,118.69,124.52,131.61,132.62,133.40,134.77,147.69,150.56,162.90,164.69,167.01,167.30,170.11,171.57；
ESI-MS m/z:405.08[M+1]+。
实施例143
所得化合物143纯品为白色固体，产率为75％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.92(d,J＝9.6Hz,7H,Ar-H),8.15(d,J＝7.3Hz,2H,Ar-H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.70(s,1H,NH),11.96(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):25.59,106.94,119.45,125.13,127.71,128.20,128.42,131.14,131.45,138.09,141.79,145.39,157.65,159.41,161.92,164.32,166.30；
19F NMR(376MHz,DMSO-d6)δ(ppm):-61.27；
ESI-MS m/z:443.11[M+1]+。
实施例144
所得化合物144纯品为白色固体，产率为81％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.49(t,J＝7.7Hz,1H,Ar-H),7.59(d,J＝7.2Hz,1H,Ar-H),7.80(dd,J＝21.0,8.0Hz,3H,Ar-H),7.94(d,J＝8.2Hz,2H,Ar-H),8.03(s,1H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.86(s,1H,NH),11.96(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.90,112.22,124.02,132.41,133.04,133.18,133.69,136.51,137.19,143.81,146.83,150.74,162.94,164.69,167.16,169.36,171.60；
ESI-MS m/z:443.11[M+1]+。
实施例145
所得化合物145纯品为白色固体，产率为76％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),7.56(d,J＝8.3Hz,1H,Ar-H),7.66(d,J＝8.0Hz,1H,Ar-H),7.77(s,1H,Ar-H),7.82(d,J＝7.9Hz,2H,Ar-H),7.93(d,J＝8.0Hz,2H,Ar-H),8.01(s,1H,NH2),8.27(s,1H,CH＝N),8.40(s,1H,pyrimidine-H),10.81(s,1H,NH),11.96(s,1H,NH)；
ESI-MS m/z:443.11[M+1]+。
实施例146
所得化合物146纯品为白色固体，产率为60％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.39(s,3H,CH3),6.71(s,1H,furan-H),7.37(s,1H,Ar-H),7.93(d,J＝19.1Hz,5H,Ar-H,furan-H),8.07(s,1H,NH2),8.27(s,1H,CH＝N),8.39(s,1H,pyrimidine-H),10.42(s,1H,NH),11.94(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):25.60,106.94,112.03,115.09,119.33,127.42,128.16,141.57,145.35,145.67,146.89,156.01,157.63,159.40,161.99,166.29；
ESI-MS m/z:365.15[M+1]+。
实施例147
所得化合物147纯品为白色固体，产率为80％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.09(s,3H,CH3),2.39(s,3H,CH3),7.69(d,J＝8.1Hz,2H,Ar-H),7.86(d,J＝7.9Hz,2H,Ar-H),7.98(s,1H,NH2),8.26(s,1H,CH＝N),8.38(s,1H,pyrimidine-H),10.20(s,1H,NH),11.90(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):29.42,30.83,112.22,123.28,131.98,133.55,147.47,150.52,162.82,164.65,167.29,171.52,173.72；
ESI-MS m/z:313.12[M+1]+。
实施例148
所得化合物148纯品为白色固体，产率为82％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):1.10(t,J＝7.4Hz,3H,CH3),2.28-2.44(m,5H,CH2CH3),7.71(d,J＝8.0Hz,2H,Ar-H),7.86(d,J＝7.9Hz,2H,Ar-H),7.99(s,1H,NH2),8.26(s,1H,CH＝N),8.38(s,1H,pyrimidine-H),10.13(s,1H,NH),11.90(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):14.82,30.81,34.90,112.22,123.31,131.85,133.53,147.55,150.52,162.80,164.64,167.30,171.52,177.39；
ESI-MS m/z:327.23[M+1]+。
实施例149
化合物149的制备
将1mmol 2-甲基-4-氨基-5-醛基嘧啶和1mmol 4-苯脲-苯甲酰肼溶于40ml乙醇溶剂中，加入0.15mmol冰醋酸，加热搅拌反应36-48h，TLC监测反应进程，反应完毕后加50ml水，搅拌有固体析出，抽滤，干燥得到白色固体。产率为75％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),6.98(d,J＝7.1Hz,1H,Ar-H),7.27(t,J＝7.5Hz,2H,Ar-H),7.44(d,J＝7.9Hz,2H,Ar-H),7.57(d,J＝8.3Hz,2H,Ar-H),7.85(d,J＝8.2Hz,2H,Ar-H),8.01(s,1H,NH2),8.25(s,1H,CH＝N),8.38(s,1H,pyrimidine-H),8.76(s,1H,NH),9.00(s,1H,NH),11.89(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):30.92,112.26,122.30,123.41,127.18,130.69,133.74,133.84,144.33,148.18,150.32,157.20,162.87,164.66,167.30,171.52；
ESI-MS m/z:390.25[M+1]+。
化合物150-151按化合物149类似方法制得，其结构鉴定数据如实施例150-151所示。
实施例150
所得化合物150纯品为白色固体，产率为79％，m.p.>260℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.25(s,3H,CH3),2.38(s,3H,CH3),7.08(d,J＝8.2Hz,2H,Ar-H),7.33(d,J＝8.3Hz,2H,Ar-H),7.56(d,J＝8.6Hz,2H,Ar-H),7.85(d,J＝8.5Hz,2H,Ar-H),7.99(s,1H,NH2),8.25(s,1H,CH＝N),8.38(s,1H,pyrimidine-H),8.65(s,1H,NH),8.96(s,1H,NH),11.88(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):23.67,28.90,110.26,120.22,121.50,128.57,131.72,132.20,133.99,139.74,146.26,148.29,155.21,160.83,162.66,165.30,169.50；
ESI-MS m/z:404.21[M+1]+。
实施例151
所得化合物151纯品为白色固体，产率为69％，m.p.252-254℃；
1H NMR(400MHz,DMSO-d6)δ(ppm):2.38(s,3H,CH3),7.33(dd,J＝8.8,2.4Hz,1H,Ar-H),7.52(d,J＝8.8Hz,1H,Ar-H),7.58(d,J＝8.6Hz,2H,Ar-H),7.86(d,J＝7.8Hz,3H,Ar-H),8.00(s,1H,NH2),8.26(s,1H,CH＝N),8.38(s,1H,pyrimidine-H),9.09(s,1H,NH),9.15(s,1H,NH),11.90(s,1H,NH)；
13C NMR(100MHz,DMSO-d6)δ(ppm):21.86,110.23,120.56,121.48,122.47,126.45,129.05,131.69,133.52,134.06,142.57,145.71,148.35,154.97,160.80,162.65,165.23,169.48；
ESI-MS m/z:458.15[M+1]+。
药理活性筛选实验
实施例152
大肠杆菌丙酮酸脱氢酶抑制活性实验
试验材料：大肠杆菌丙酮酸脱氢酶
(1)本申请通过DCIP法测试代表性化合物对酶的抑制作用，由此来筛选高效的丙酮酸脱氢酶(PDHc-E1)抑制剂，初筛待测化合物的终浓度设定为100μM。具体筛选方法如下：
①配置95μL反应混合液：0.05μg/μL PDHc-E1，50mM K3PO4(pH＝6.4)，50μM ThDP，0.4mM DCIP，100μM用DMSO溶解的待测化合物(对照组加等量的DMSO)，其余用水补齐(共配置4倍量的反应液于2mL的EP管中)，放置在37℃水浴锅中温育3min。
②酶促反应：分别取95μL温育后的反应液加入到96孔酶标板的3个孔中，迅速加入5μL1mM的底物丙酮酸钠开启反应，置于酶标仪中测600nm处的吸光度值，反应0min时测定OD0min，37℃酶标仪中反应5min后，测定OD5min。然后求5min内的吸光度值改变量△OD600＝OD0min－OD5min。每次测定均做溶剂DMSO的对照实验，每组实验做3～5个平行。
③数据处理：化合物引起的吸光度值的改变需扣除溶剂DMSO的影响，100μM待测化合物的抑制率的计算公式如下：
抑制率＝[(△OD对照-△OD实验)/△OD对照]*100％
(2)化合物对大肠杆菌PDHc-E1抑制活性IC50的测定：
先用溶剂(DMSO)将待测化合物配制成一定梯度，在100μL测活体系中加入50μMThDP，0.4mM 2,6-DCIP，50mM K3P04(pH＝6.4)，5μg PDHc-E1(Cx-ace)和一定梯度的待测化合物2μl。先不加底物丙酮酸钠，在37℃的恒温箱中温育3min，让酶与待测化合物充分结合，然后加入50μM底物开启反应，用酶标仪测600nm处光吸收值，0min时测一次OD0min，在37℃的酶标仪再反应5min，再测OD5min，最后求吸光值的差值△OD600，每次实验均做化合物的溶剂DMSO的空白对照，每组实验做3～5个平行。分别测出每个化合物在梯度浓度下对酶的抑制率。在梯度浓度下测定每个化合物对酶的抑制率(需先扣除DMSO对酶活性的影响)以化合物浓度为横坐标，抑制率为纵坐标，用Orgin7.5软件中的Logistic函数作图，由函数拟合得出的X0即为IC50。其中Logistic函数公式为：y＝[A1-A2/1+(x/x0)p]+A2。
表1代表性化合物对大肠杆菌丙酮酸脱氢酶抑制活性
由表1所示，所合成的化合物中大部分化合物对大肠杆菌丙酮酸脱氢酶表现出优异的抑制活性，其中化合物69对大肠杆菌的抑制活性达到了纳摩尔级别。该部分化合物具有潜在的农药发展价值，值得进一步研究。
实施例153
杀菌活性实验
试验材料：水稻纹枯病菌，稻曲病菌，苹果轮纹，桃褐腐病菌，辣椒疫霉，灰霉病菌，炭疽病菌。
试验方法：将本发明化合物分别溶解于DMSO中配制得系列药液(浓度50ppm)，分别加至融化后冷却到45℃左右的土豆培养基中，制成所需药剂浓度的含药平板。将在PDA平板培养基上预培养的各菌株菌落边缘打取直径5mm的菌饼，接种于含不同浓度的含药平板上，25℃黑暗培养。当对照菌落直径达到培养皿直径的80﹪以上时，采用十字交叉法测量菌落直径，每个处理重复3次，以DMSO溶液作为空白对照。按照下面的公式求出各药剂浓度对菌丝生长的抑制百分率(％)：
表2代表性化合物的活性数据(测试浓度50ppm)
N：表示对此靶标的抑制活性未测
本发明化合物具有优异的杀菌活性，能用于防治水稻纹枯病菌，稻曲病菌，苹果轮纹，桃褐腐病菌，辣椒疫霉，灰霉病菌和炭疽病菌。
实施例154
杀细菌活性测试实验
实验材料：水稻白叶枯，烟草青枯。
试验方法：采用浊度法测试。将本发明化合物分别溶解在DMSO中，用水稀释至100ppm。取DMSO作为空白对照组，商品药三唑酮和叶枯唑作为阳性对照。取1mL样品加入到含4mL无菌NB培养基的试管中，接着向试管中加入40μL已经培养好的细菌培养液(OD597＝0.6～0.8)。对照组和空白组采取相同的操作。将接好菌的试管放入温度处于30℃、转速为180rpm的摇床中振荡，当空白组中的菌液OD597在0.6～0.8之间即可停止振荡。将所有试管中的液体放入分光光度计中测试其在597nm处的光密度。通过下面的公式求出各化合物对细菌的抑制百分率(％)：
表3代表性化合物的细菌抑制活性(测试浓度100ppm)
由表3所示，本发明化合物具有优异的杀菌活性。大部分化合物表现出的杀菌活性要优于对照商品药三唑酮。同时化合物123，124，125，133，149的杀菌活性要明显高于另一对照药叶枯唑。
实施例155
实验材料：型号为PCC6803和FACH905的蓝藻
实验方法：将对数生长期的蓝藻按体积的1％的接种量加入到新鲜的BG11培养液(BG11培养基作为一种细胞培养基)中，培养4-7天后，用紫外分光光度计测X＝680nm处的吸光值，然后用培养液稀释，使藻细胞数约为1×106个/mL，即稀释后PCC6803或FACH905的吸光值为0.015。向96孔板中的每个孔中加入200μL稀释好的藻液，然后再加入lμL一定浓度的化合物(化合物用DMSO配制)，混匀，每种化合物平行做三个。做两组对照，一组是只加200μL藻液，另外一组是加入200μL藻液和10μL DMSO。将96孔板封住，放在人工气候箱培养，每天在摇床上摇30min.每隔24小时，在BIOTECK多功能酶标仪上读取波长为680nm处的各孔吸光值，每次读完后将96孔板封住放入培养箱中继续培养。
抑制率的计算公式：
生长抑制率＝[(OD680对照组第n天-OD680培养基第n天)-(OD680实验组第n天-OD680药物组第n天)/(OD680对照组第n天-OD680培养基第n天)]*100％
OD680对照组第n天：200μL藻液和1μLDMSO第n天的吸光值
OD680培养基第n天：200μL BGll第n天的吸光值
OD680实验组第n天：200μL藻液和lμL化合物第n天的吸光值
OD680药物组第n天：200μL BG11和1μL化合物第n天的吸光值
表4代表性化合物的蓝藻抑制活性(EC50)
由表4所示，本发明化合物具有优异的蓝藻抑制活性，大部分化合物对蓝藻的防治效果可达与对照药剂硫酸铜相当，并且明显优于另外一个对照药剂扑草津。因此，此类化合物在控制水华爆发方面应有巨大的潜力和应用前景。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
尽管已经示出和描述了本发明的实施例，本领域的普通技术人员可以理解：在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。
Claims (19)
1.式I所示丙酮酸脱氢酶系抑制剂类化合物及其药学上可接受的盐，
其中，
R1独立的选自氢、C1-10烷基或3至5元的碳环基；
R2独立的选自氢、C1-10烷基或3至5元的碳环基；
R3为苯环任意位置上的单取代或多取代基，所述取代基可以相同或不同，所述R3选自取代或未取代的苯甲酰胺基、C1-4烷基酰胺基、苯基脲基、呋喃酰胺基；
所述取代为苯甲酰胺基、烷基酰胺基、苯基脲基、呋喃酰胺基被1-2个卤素、氟代C1-4烷基或C1-6烷氧基取代；
X为-CONHN＝。
2.式I所示丙酮酸脱氢酶系抑制剂类化合物及其药学上可接受的盐，
其中，
R1独立的选自氢、C1-10烷基、氨基或3至5元的碳环基；
R2独立的选自氢、C1-10烷基、氨基或3至5元的碳环基；
R3为苯环任意位置上的单取代或多取代基，所述取代基可以相同或不同，所述R3选自卤素、C1-10烷基、C1-6烷氧基、氟代C1-4烷基、氟代C1-6烷氧基、氨基、羟基；
X为-NHN＝。
3.根据权利要求2所述的丙酮酸脱氢酶系抑制剂类化合物及其药学上可接受的盐，其特征在于，所述R3选自C1-4烷基。
4.根据权利要求1或2所述的丙酮酸脱氢酶系抑制剂类化合物及其药学上可接受的盐，其特征在于，所述R1为氢、甲基或环丙基；所述R2为氢或甲基。
5.根据权利要求1所述的丙酮酸脱氢酶系抑制剂类化合物及其药学上可接受的盐，其特征在于，所述卤素为氟、氯、溴、碘。
6.具有以下结构的化合物及其药学上可接受的盐，其特征在于，结构如下，
7.一种制备权利要求1-5任一项所述化合物的方法，其特征在于，包括：使式II所示化合物与式III所示化合物进行接触，以便获得式I所示化合物，
其中R1、R2、R3、X具有权利要求1-5任一项所述相应基团的定义，Y为-CONHNH2或-NHNH2。
8.根据权利要求7所述的方法，其特征在于，在催化剂存在下，将所述式II所示化合物与所述式III所示化合物溶于第一有机溶剂中，加热搅拌；
所述式II所示化合物与所述式III所示化合物以及催化剂的摩尔比为1：1-1.5：0.01-0.15；所述催化剂为选自抗坏血酸、乙酸、酒石酸、三氟乙酸、甲酸、水杨酸、苹果酸、乙酸酐中的至少一种。
9.根据权利要求8所述的方法，其特征在于，所述第一有机溶剂为选自乙腈、乙醇、1,2-二氯乙烷、丙酮、叔丁醇、甲苯、苯、二甲苯、乙酸乙酯、甲醇、正己烷、二氯甲烷、三氯甲烷、四氢呋喃、二甲基亚砜和N,N-二甲基甲酰胺中的至少一种。
10.根据权利要求8所述的方法，其特征在于，所述加热的温度为20～90摄氏度。
11.根据权利要求8所述的方法，其特征在于，所述加热的温度为64～78摄氏度。
12.根据权利要求8所述的方法，其特征在于，所述加热的时间为0.5～60小时。
13.根据权利要求8所述的方法，其特征在于，所述加热的时间为3～48小时。
14.一种农药，其特征在于，包括权利要求1-5任一项所述的化合物及其药学上可接受的盐，所述化合物具有抑制丙酮酸脱氢酶系的活性。
15.一种预防和/或治疗植物疾病的方法，其特征在于，为所述植物施加权利要求1-5任一项所述的化合物或者权利要求14所述的农药。
16.根据权利要求15所述的方法，其特征在于，所述植物为水稻、苹果、桃子、辣椒或烟草。
17.根据权利要求15所述的方法，其特征在于，所述植物疾病由水稻纹枯病菌、稻曲病菌、苹果轮纹、桃褐腐病菌、辣椒疫霉、灰霉病菌、炭疽病菌、水稻白叶枯、烟草青枯中至少之一引起。
18.一种抑制藻类生长的方法，其特征在于，为所述藻类施加权利要求1-5任一项所述的化合物或者权利要求14所述的农药。
19.根据权利要求18所述的方法，其特征在于，所述藻类为蓝藻。
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