CN111848612A - 含稠杂环结构的化合物及其制备方法和应用以及杀菌剂 - Google Patents
含稠杂环结构的化合物及其制备方法和应用以及杀菌剂 Download PDFInfo
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- CN111848612A CN111848612A CN202010760478.XA CN202010760478A CN111848612A CN 111848612 A CN111848612 A CN 111848612A CN 202010760478 A CN202010760478 A CN 202010760478A CN 111848612 A CN111848612 A CN 111848612A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—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)
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- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及农药杀菌剂领域，公开了含稠杂环结构的化合物及其制备方法和应用以及杀菌剂，该含稠杂环结构的化合物具有式(1)所示的结构。本发明的化合物对致病疫霉、大豆疫霉、辣椒疫霉、荔枝霜疫霉、黄瓜霜霉病菌等多种卵菌病原菌引起的植物病害具有优异的防治效果，明显优于常规卵菌病害防治药剂烯酰吗啉，具有很好的市场开发前景。
Description
技术领域
本发明涉及农药杀菌剂领域，具体涉及一种含稠杂环结构的化合物及其制备方法、该含稠杂环结构的化合物在防治植物卵菌病害中的应用、该含稠杂环结构的化合物作为农药杀菌剂的应用以及一种杀菌剂。
背景技术
卵菌是引起植物病害的重要病原菌之一，具有寄生范围广、破坏性强、为害性大、发展迅速等特点，其可以危害大多数主要经济作物如马铃薯、番茄、辣椒、葡萄、烟草、辣椒等。同时，其引起的病害也较难防治，因此给农业生产带来极大的损失。
卵菌主要的植物病原菌有致病疫霉、大豆疫霉、辣椒疫霉、终极腐霉、荔枝霜疫霉、黄瓜霜霉病菌等。其中致病疫霉是一种典型的病原菌，其引发的马铃薯晚疫病爆发曾导致历史上著名的爱尔兰大饥馑的发生。其它植物病原菌也能导致病害的严重发生，例如辣椒疫霉容易引起辣椒、番茄、茄子和瓜类等作物的疫病，黄瓜霜霉病菌引起的瓜果类霜霉病等。
卵菌病害防治日益困难，目前，化学防治依旧是防治举措中最为简便和有效的方法，生产上主要使用的是多作用位点的保护性杀菌剂和单作用位点的内吸性杀菌剂。但随着这些杀菌剂使用时间的延长和长期的不合理使用，使得很多病原菌出现了严重的抗药性。
因此，开发新型无交互抗性的卵菌杀菌剂成为目前该领域所亟需的发展方向。
发明内容
本发明的目的是提供一种新的含稠杂环结构的化合物以在低浓度下实现良好的防治卵菌病害的效果。
为了实现上述目的，第一方面，本发明提供了一种式(1)所示结构的含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物，
在式(1)中，
R选自氢、甲基、正丙基、C4-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C4烷基羰基、醛基、醛肟基、硝基、氨基、氰基、氟、溴、C2-C6醛肟醚基、C2-C6含氧环烷基、C3-C6环烷基、C4-C10环烷基烷基、C4-C10烷基环烷基、C5-C10烷基环烷基烷基、C3-C6卤代环烷基、羟基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4卤代烷硫基、C1-C4卤代烷基亚磺酰基、C1-C4卤代烷基磺酰基、C1-C4烷基氨基、C2-C8二烷基氨基、C3-C6环烷基氨基、C2-C4烷基羰基氨基、羟胺基、C1-C4烷氧氨基、C2-C4卤代烷基羰基氨基、C2-C4烷基羰基、C2-C6烷氧羰基、C2-C6烷基羰氧基、C2-C6烷基羰硫基、C2-C6烷基氨基羰基、C3-C8二烷基氨基羰基或C3-C6三烷基甲硅烷基；
R1、R2和R3各自独立地选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C4烷基羰基、醛基、醛肟基、硝基、氨基、氰基、卤素、C2-C6醛肟醚基、C2-C6含氧环烷基、C3-C6环烷基、C4-C10环烷基烷基、C4-C10烷基环烷基、C5-C10烷基环烷基烷基、C3-C6卤代环烷基、羟基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4卤代烷硫基、C1-C4卤代烷基亚磺酰基、C1-C4卤代烷基磺酰基、C1-C4烷基氨基、C2-C8二烷基氨基、C3-C6环烷基氨基、C2-C4烷基羰基氨基、羟胺基、C1-C4烷氧氨基、C2-C4卤代烷基羰基氨基、C2-C4烷基羰基、C2-C6烷氧羰基、C2-C6烷基羰氧基、C2-C6烷基羰硫基、C2-C6烷基氨基羰基、C3-C8二烷基氨基羰基和C3-C6三烷基甲硅烷基；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
以下针对本发明的部分基团提供一些示例性的解释，在没有特别说明的情况下，未列举的部分参照如下示例性的解释进行解释。
“C4-C6烷基”表示碳原子总数为4-6的烷基，包括直链烷基、支链烷基，例如可以为碳原子总数为4、5或6的直链烷基、支链烷基，例如可以为正丁基、异丁基、叔丁基、正戊基、异戊基、正己基等。“C1-C6卤代烷基”的定义与“C4-C6烷基”的定义相似，不同的是，“C1-C6卤代烷基”上的至少一个H被卤素原子取代，且碳原子总数不同，例如可以有1、2、3、4、5或6个H由选自氟、氯、溴、碘的至少一种卤素原子取代，且该C1-C6卤代烷基的碳原子总数为1-6。“C1-C4羟基烷基”的定义与“C4-C6烷基”的定义相似，不同的是，“C1-C4羟基烷基”上的至少一个H被羟基取代，例如可以有1、2或3个H由羟基取代，且该C1-C4羟基烷基的碳原子总数为1-4。“C2-C4烷氧基烷基”的定义与“C4-C6烷基”的定义相似，不同的是，“C2-C4烷氧基烷基”上的至少一个H被烷氧基取代，例如可以有1、2或3个H由烷氧基取代，且该C2-C4烷氧基烷基的碳原子总数为2-4，该C2-C4烷氧基烷基例如可以表示为R1O-R2-，其中，R1O即为该C2-C4烷氧基烷基中的烷氧基，R2即为该C2-C4烷氧基烷基中的烷基。
“C2-C6烯基”表示碳原子总数为2-6的烯基，例如可以为乙烯基、丙烯基、丁烯基等。“C2-C6卤代烯基”的定义与“C2-C6烯基”的定义相似，不同的是，“C2-C6卤代烯基”上的至少一个H被卤素原子取代，例如可以有1、2、3、4、5或6个H由选自氟、氯、溴、碘的至少一种卤素原子取代。
“C2-C6炔基”表示碳原子总数为2-6的炔基，例如可以为乙炔基、丙炔基、丁炔基等。“C2-C6卤代炔基”的定义与“C2-C6炔基”的定义相似，不同的是，“C2-C6卤代炔基”上的至少一个H被卤素原子取代，例如可以有1、2、3、4、5或6个H由选自氟、氯、溴、碘的至少一种卤素原子取代。
“C2-C6烷基氨基烷基”表示碳原子总数为2-6的基团，该C2-C6烷基氨基烷基例如可以表示为R3-NH-R4-，且R3和R4的碳原子总数为2-6。“C3-C6二烷基氨基烷基”的定义与“C2-C6烷基氨基烷基”的定义相似，该C3-C6二烷基氨基烷基例如可以表示为R5-N(R6)-R7-，且R5、R6、R7的碳原子总数为3-6。
“C3-C8环烷氨基烷基”表示碳原子总数为3-8的基团，该C3-C8环烷氨基烷基例如可以表示为R8-R9-，其中，R8为含有N原子的环基，以及该R8中的N原子与R9直接连接。
“C2-C4烷基羰基”表示碳原子总数为2-4的基团，该C2-C4烷基羰基例如可以表示为R10-CO-，R10即为C2-C4烷基羰基中的烷基。
“醛肟基”表示为HON＝CH-。
“C2-C6醛肟醚基”表示碳原子总数为2-6的基团，该C2-C6醛肟醚基例如可以表示为R11-ON＝CH-，该R11表示烷基。
“C2-C6含氧环烷基”表示碳原子总数为2-6的基团，且该基团中的成环的原子中含有至少一个氧原子。“C3-C6环烷基”的定义与“C2-C6含氧环烷基”的定义类似，不同的是，“C3-C6环烷基”的成环原子均为C原子，且该基团的碳原子总数为3-6。“C4-C10环烷基烷基”的定义与“C2-C6含氧环烷基”的定义类似，但“C4-C10环烷基烷基”的成环原子均为C原子，该基团的碳原子总数为4-10，该“C4-C10环烷基烷基”例如可以表示为R12-R13-，其中，R12为环烷基，R13为连接环烷基和式(1)所示结构的化合物中的母核结构基团。“C4-C10烷基环烷基”的定义与“C4-C10环烷基烷基”的定义类似，该C4-C10烷基环烷基例如可以表示为R14-R15-，其中，R15为环烷基，且R14为取代该R15中的H的烷基。
“C5-C10烷基环烷基烷基”表示碳原子总数为5-10的基团，该基团例如可以表示为R16-R17-R18-，其中，R17为环烷基，该环烷基连接作为烷基的R16和R18，且R18直接与式(1)所示结构的化合物中的母核结构连接。
“C3-C6卤代环烷基”的定义与“C3-C6环烷基”的定义相似，不同的是，该C3-C6卤代环烷基中的成环的碳原子上的至少一个H由选自氟、氯、溴、碘的卤素原子取代。
根据一种优选的具体实施方式，在式(1)中，
R选自H、甲基、正丙基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C1-C4酰基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C6烷基氨基、C3-C6二烷基氨基、羟胺基、C1-C4烷氧胺基、C1-C4烷氧基、C2-C4烷基羰基、C1-C4烷基磺酰基、醛基、C1-C4醛肟基、羟基、硝基、氨基、氰基、卤素、C2-C6醛肟醚基、1,3-二氧环戊基；
R1、R2和R3各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C1-C4酰基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C6烷基氨基、C3-C6二烷基氨基、羟胺基、C1-C4烷氧胺基、C1-C4烷氧基、C2-C4烷基羰基、C1-C4烷基磺酰基、醛基、醛肟基、羟基、硝基、氨基、氰基、氟、氯、溴、碘、C2-C6醛肟醚基和1,3-二氧环戊基；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
根据另一种优选的具体实施方式，在式(1)中，
R选自H、甲基、正丙基、正丁基、叔丁基、乙烯基、丙烯基、乙炔基、丙炔基、氯甲基、二氯甲基、三氯甲基、溴甲基、二溴甲基、三溴甲基、氟甲基、二氟甲基、三氟甲基、1-氯乙基、2-氯乙基、1-氟乙基、2-氟乙基、1,1-二氟乙基、2,2-二氟乙基、1,2-二氟乙基、2,2,2-三氟乙基、1,1,2,2,2-五氟乙基、乙酰基甲基、1-氯-乙烯基、2-氯-乙烯基、2,2-二氯乙烯基、1,2-二氯乙烯基、1-氟-乙烯基、2-氟-乙烯基、2,2-二氟乙烯基、1,2-二氟乙烯基、氟代乙炔基、氯代乙炔基、碘代乙炔基、羟基甲基、1-羟基乙基、2-羟基乙基、羟基正丙基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、3-甲氧基正丙基、乙氧基甲基、1-乙氧基乙基、2-乙氧基乙基、3-乙氧基正丙基、甲基氨基甲基、1-甲基氨基乙基、2-甲基氨基乙基、甲基氨基正丙基、二甲基氨基甲基、1-二甲基氨基乙基、2-二甲基氨基乙基、二甲基氨基正丙基、
甲氨基、二甲氨基、甲基乙基氨基、羟胺基、甲氧胺基、甲氧基、乙氧基、乙酰基、丙酰基、甲基磺酰基、醛基、-CH＝NOH、-CH＝NOCH3、羟基、硝基、氨基、氰基、氟、溴或1,3-二氧环戊基；
R1、R2和R3各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基、正丁基、叔丁基、乙烯基、丙烯基、乙炔基、丙炔基、氯甲基、二氯甲基、三氯甲基、溴甲基、二溴甲基、三溴甲基、氟甲基、二氟甲基、三氟甲基、1-氯乙基、2-氯乙基、1-氟乙基、2-氟乙基、1,1-二氟乙基、2,2-二氟乙基、1,2-二氟乙基、2,2,2-三氟乙基、1,1,2,2,2-五氟乙基、乙酰基甲基、1-氯-乙烯基、2-氯-乙烯基、2,2-二氯乙烯基、1,2-二氯乙烯基、1-氟-乙烯基、2-氟-乙烯基、2,2-二氟乙烯基、1,2-二氟乙烯基、氟代乙炔基、氯代乙炔基、碘代乙炔基、羟基甲基、1-羟基乙基、2-羟基乙基、羟基正丙基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、3-甲氧基正丙基、乙氧基甲基、1-乙氧基乙基、2-乙氧基乙基、3-乙氧基正丙基、甲基氨基甲基、1-甲基氨基乙基、2-甲基氨基乙基、甲基氨基正丙基、二甲基氨基甲基、1-二甲基氨基乙基、2-二甲基氨基乙基、二甲基氨基正丙基、
甲氨基、二甲氨基、甲基乙基氨基、羟胺基、甲氧胺基、甲氧基、乙氧基、乙酰基、丙酰基、甲基磺酰基、醛基、-CH＝NOH、-CH＝NOCH3、羟基、硝基、氨基、氰基、氟、氯、溴、碘和1,3-二氧环戊基；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
特别优选情况下，在式(1)中，
R选自-CHO、-CH2OH、-CH(OH)CH3、-CH2CH2OH、-CH2OCH3、-CH(CH3)OCH3、-CH2CH2OCH3、-CH＝NOH、-CH＝NOCH3、-CH2NHCH3、-CH2N(CH3)2、
-CH3、-CH2Cl、-CHClCH3、-CH2CH2Cl、-CH2F、-CHF2、-CF3、-CHFCH3、-CH2CH2F、-CHFCH2F、-CF2CH3、-CH2CHF2、-CH2CF3、-CF2CF3、-CH2CH2CH3、-C(CH3)3、-COCH3、-CH2COCH3、-COCH2CH3、-CH＝CH2、-CH＝CF2、-CH＝CHCH3、-C≡CH、-C≡C-I、-C≡CCH3、-OCH3、-OH、-NO2、-NH2、-NHCH3、-N(CH3)2、-N(CH2CH3)CH3、-NHOH、-NHOCH3、-C≡N、-Br或-H；
R1、R2和R3均为H；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
进一步优选地，在式(1)中，
R选自-CHO、-CH2OH、-CH(OH)CH3、-CH2CH2OH、-CH2OCH3、-CH(CH3)OCH3、-CH2CH2OCH3、-CH＝NOH、-CH＝NOCH3、-CH2NHCH3、-CH2N(CH3)2、
-CH3、-CH2Cl、-CHClCH3、-CH2CH2Cl、-CH2F、-CHF2、-CF3、-CHFCH3、-CH2CH2F、-CHFCH2F、-CF2CH3、-CH2CHF2、-CH2CF3、-CF2CF3、-CH2CH2CH3、-C(CH3)3、-COCH3、-CH2COCH3、-COCH2CH3、-CH＝CH2、-CH＝CF2、-CH＝CHCH3、-C≡CH、-C≡C-I、-C≡CCH3、-OCH3、-OH、-NO2、-NH2、-NHCH3、-N(CH3)2、-N(CH2CH3)CH3、-NHOH、-NHOCH3、-C≡N、-Br或-H；
R1、R2和R3均为H；
R4为2,6-二氟苯基。
另一种优选情况下，在式(1)中，
R选自-CHO、-CH2OH、-CH(OH)CH3、-CH2CH2OH、-CH2OCH3、-CH(CH3)OCH3、-CH2CH2OCH3、-CH＝NOH、-CH＝NOCH3、-CH2NHCH3、-CH2N(CH3)2、
-CH3、-CH2Cl、-CHClCH3、-CH2CH2Cl、-CH2F、-CHF2、-CF3、-CHFCH3、-CH2CH2F、-CHFCH2F、-CF2CH3、-CH2CHF2、-CH2CF3、-CF2CF3、-CH2CH2CH3、-C(CH3)3、-COCH3、-CH2COCH3、-COCH2CH3、-CH＝CH2、-CH＝CF2、-CH＝CHCH3、-C≡CH、-C≡C-I、-C≡CCH3、-OCH3、-OH、-NO2、-NH2、-NHCH3、-N(CH3)2、-N(CH2CH3)CH3、-NHOH、-NHOCH3、-C≡N、-Br或-H；
R1、R2和R3均为H；
R4为2-氯-6-[(甲基磺酰基)氧基]苯基。
本发明对制备前述化合物的方法没有特别的限制，本领域技术人员在了解本发明的技术方案以后能够结合有机合成领域内的常规手段获得合适的制备本发明的化合物的方法。
本发明在如下示例性地提供了制备本发明的前述化合物的方法，本领域技术人员不应理解为对本发明的限制。
制备式(1)所示结构的含稠杂环结构的化合物的方法，该方法包括：在亲核取代反应条件下，将式(2-1)所示的化合物与式(2-2)所示的化合物进行接触反应，
其中，式(2-1)所示的化合物中的R4和式(2-2)所示的化合物中的R、R1、R2、R3的定义与式(1)所示结构的含稠杂环结构的化合物中的R、R1、R2、R3、R4的定义相同。
本发明的所述亲核取代反应在碱性条件下进行时，所述碱性条件也可以由例如四氢呋喃等溶剂来提供。优选地，所述亲核取代反应在碱性试剂的存在且无水环境下进行。优选情况下，所述碱性试剂为氢化钠、碳酸钾和碳酸铯中的至少一种。
优选地，所述接触反应在溶剂存在下进行，所述溶剂优选选自二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈和丙酮中的至少一种。
优选地，所述接触反应的条件包括：反应温度为0～60℃，反应时间为2～48h。
在本发明中，所述式(2-1)和式(2-2)所示的化合物可以来自商购，也可以根据结构式而采用现有技术的方法合成得到。本发明在实施例中示例性地提供了制备式(2-1)所示的化合物的方法，本领域技术人员不应理解为对本发明的限制。
优选地，式(2-1)所示的化合物与式(2-2)所示的化合物的用量摩尔比为1：(1-3)；更优选为1：(1.2-2.4)。
在本发明的第二方面中，还可以对接触反应后获得的产物进行本领域内常规应用的后处理方法进行后处理以获得纯度更高的产物，例如，所述后处理操作方法包括：萃取、洗涤、旋转蒸发、柱层析、重结晶等，本发明对此没有特别的限制，只要能够获得本发明前述含稠杂环结构的化合物即可。
本发明的第二方面提供了前述含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物在防治植物卵菌病害中的应用。
优选情况下，所述植物卵菌病害选自致病疫霉、大豆疫霉、辣椒疫霉、终极腐霉、烟草疫霉、荔枝霜疫霉和黄瓜霜霉病菌中的至少一种病菌导致的病害。
本发明的第三方面提供了前述含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物作为农药杀菌剂的应用。
本发明的第四方面提供了一种杀菌剂，该杀菌剂由活性成分和辅料组成，所述活性成分包括本发明前述的式(1)所示结构的含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物中的至少一种。
优选情况下，所述活性成分的含量为1-99.9重量％，更优选所述活性成分的含量为5-95重量％。
优选情况下，该杀菌剂的剂型选自乳油、悬浮剂、可湿性粉剂、粉剂、粒剂、水剂、毒饵、母液和母粉中的至少一种。
在本发明中，所述辅料可以为本领域内常规使用的各种辅料，例如可以为表面活性剂、溶剂等。
本发明的实验表明，本发明的化合物对致病疫霉、辣椒疫霉、荔枝霜疫霉、黄瓜霜霉病菌等多种卵菌病原菌引起的植物病害具有优异的防治效果，明显优于常规卵菌病害防治药剂烯酰吗啉，具有很好的市场开发前景。
本发明提供的化合物还能够有效防治对现有杀菌剂产生抗性的突变菌株。因此，本发明的化合物对开发新型无交互抗性的卵菌杀菌剂具有重要意义。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
以下将通过实例对本发明进行详细描述。
以下实例中，在没有特别说明的情况下，使用的各种原料均来自商购，纯度为化学纯。
实施例1
本实施例用于说明式(2-1)所示化合物的制备方法。其中，式(2-1)所示化合物中的R4为2,6-二氟苯基。
(1)25℃下，将1,3-二氯丙酮(1mol)加入到1L的2M的盐酸乙醚溶液中，再加入亚硝酸特丁酯(1mol)，25℃继续反应10h，反应完毕后除去乙醚，冷却后得到式(2-4)所示的化合物的粗品，并且以1-氯丁烷洗涤，过滤，收集滤饼；并且将滤液重结晶，过滤，滤饼干燥后也获得式(2-4)所示的化合物，合并两批后得到式(2-4)所示的化合物的纯品。
(2)25℃下，将碳酸氢钠(5mol)加入到1L的式(2-4)所示的化合物(1mol)乙腈溶液中，再将2,6-二氟苯乙烯(1mol)缓慢加入，继续搅拌反应4h，反应完毕，过滤，除去滤液中的溶剂，得到式(2-5)所示的化合物，直接用于下一步反应。
(3)将式(2-5)所示的化合物(1mol)、4-氨基硫代羰基四氢吡啶-1(2H)-甲酸叔丁酯(1.1mol)和溴化钠(0.1mol)依次加入到2.5L丙酮中，该反应体系加热回流反应12h，反应完毕，除去丙酮，加入2L水，以500mL*3乙酸乙酯萃取，合并有机相，干燥浓缩后得到式(2-6)所示的化合物的粗品，进一步以硅胶与石油醚和乙酸乙酯形成的洗脱体系进行柱层析纯化，最终得到式(2-6)所示的化合物纯品；
(4)将式(2-6)所示的化合物(0.5mol)溶于500mL甲醇中，加入100mL氯化氢/甲醇溶液(4M)，25℃搅拌反应6h，反应完毕后，缓慢滴加2M氢氧化钠水溶液调节至pH＝7，以500mL*5的乙酸乙酯萃取，合并有机相，干燥浓缩后得到式(2-7)所示的化合物。
(5)向式(2-7)所示的化合物(0.1mol)的500mL无水二氯甲烷溶液中滴入氯乙酰氯(0.15mol)，保持温度在-5～0℃，继续缓慢加入碳酸钾水溶液(0.12mol，w/v 20％)，并且继续保持温度在-5～0℃，滴加完毕，升温至室温，反应完毕，分液除去水相，有机相以饱和食盐水洗涤，无水硫酸钠干燥，并且减压浓缩后，得到式(2-1)所示的化合物粗品，然后加入乙酸乙酯，搅拌成均匀的浆液后过滤，滤饼干燥后，得到式(2-1)所示的化合物纯品。
实施例2
本实施例用于说明式(2-1)所示化合物的制备方法。其中，式(2-1)所示化合物中的R4为2-氯-6-[(甲基磺酰基)氧基]苯基。
(1)0℃，氮气保护条件下，将甲基溴化镁(1.1mol)缓慢滴加入到3-氯-2-乙烯基苯酚(1mol)的无水四氢呋喃溶液中，滴加完毕，缓慢升至室温后，继续反应10h，反应完毕，加入饱和氯化铵淬灭，以乙酸乙酯萃取，有机相经干燥、浓缩后得到3-氯-2-(1-羟基乙基)-苯酚粗品，直接用于下一步反应；
将以上化合物3-氯-2-(1-羟基乙基)-苯酚(1mol)溶于N,N-二甲基乙酰胺，升温至160℃，缓慢加入甲基磺酸(1mol)，继续搅拌反应2h，反应完毕，加入1L水，乙酸乙酯萃取，有机相以饱和碳酸氢钠洗涤，经过干燥浓缩后得到化合物3-氯-2-乙烯基-苯酚；
将以上化合物3-氯-2-乙烯基-苯酚(1mol)溶于四氢呋喃中，并且加入三乙胺(1.2mol)，温度降至0-5℃，继续缓慢加入甲基磺酰氯(1.2mol)并且保持温度在0-5℃，滴加完毕后，继续搅拌反应30min，反应完毕，加入250mL 1N稀盐酸，并且以乙酸乙酯萃取，有机相经过干燥、过滤和柱层析纯化后得到式(2-8)所示的化合物。
(2)25℃下，将碳酸氢钠(5mol)加入到1L的式(2-4)所示的化合物(1mol)乙腈溶液中，再将式(2-8)所示的化合物(1mol)缓慢加入，继续搅拌反应4h，反应完毕，过滤，除去滤液中的溶剂，得到式(2-9)所示的化合物，直接用于下一步反应。
(3)将式(2-9)所示的化合物(1mol)、4-氨基硫代羰基四氢吡啶-1(2H)-甲酸叔丁酯(1.1mol)和溴化钠(0.1mol)依次加入到2.5L丙酮中，该反应体系加热回流反应12h，反应完毕，除去丙酮，加入2L水，以500mL*3乙酸乙酯萃取，合并有机相，干燥浓缩后得到式(2-10)所示的化合物的粗品，进一步以硅胶与石油醚和乙酸乙酯形成的洗脱体系进行柱层析纯化，最终得到式(2-10)所示的化合物纯品；
(4)将式(2-10)所示的化合物(0.5mol)溶于500mL甲醇中，加入100mL氯化氢/甲醇溶液(4M)，25℃搅拌反应6h，反应完毕后，缓慢滴加2M氢氧化钠水溶液调节至pH＝7，以500mL*5的乙酸乙酯萃取，合并有机相，干燥浓缩后得到式(2-11)所示的化合物。
(5)向式(2-11)所示的化合物(0.1mol)的500mL无水二氯甲烷溶液中滴入氯乙酰氯(0.15mol)，保持温度在-5～0℃，继续缓慢加入碳酸钾水溶液(0.12mol，w/v 20％)，并且继续保持温度在-5～0℃，滴加完毕，升温至室温，反应完毕，分液除去水相，有机相以饱和食盐水洗涤，无水硫酸钠干燥，并且减压浓缩后，得到式(2-1)所示的化合物粗品，然后加入乙酸乙酯，搅拌成均匀的浆液后过滤，滤饼干燥后，得到式(2-1)所示的化合物纯品。
实施例3
本实施例用于说明式(3-1)、式(3-12)、式(3-15)、式(3-17)、式(3-18)、式(3-19)、式(3-20)、式(3-23)、式(3-25)、式(3-27)、式(3-28)、式(3-29)、式(3-30)、(3-31)、式(3-32)、式(3-33)、式(3-34)、式(3-35)、式(3-36)、式(3-37)、式(3-38)、式(3-39)、式(3-40)、式(3-41)、式(3-42)、式(3-43)、式(3-44)、式(3-45)、式(3-46)、式(3-47)、式(3-48)、式(3-49)、式(3-50)、式(3-51)、式(3-52)、式(3-53)所示的化合物的制备方法。
具体地，以式(3-1)所示的化合物的制备为例
0℃下，将氢化钠(1.5mmol)加入到1H-吡唑并[3,4-b]吡啶-3-羧醛(1.2mmol)的10mL的无水四氢呋喃溶液中，0℃下反应0.5h，再加入式(2-1)所示化合物(1mmol)，0℃继续反应6h。反应完毕后经过萃取、洗涤、浓缩，柱层析纯化得到式(3-1)所示的化合物。
另外，以式(3-36)所示的化合物的制备为例
0℃下，将氢化钠(1.5mmol)加入到1H-吡唑并[3,4-b]吡啶-3-羧醛(1.2mmol)的10mL的无水四氢呋喃溶液中，0℃下反应0.5h，再加入式(2-1)所示化合物(1mmol)，0℃继续反应6h。反应完毕后经过萃取、洗涤、浓缩，柱层析纯化得到式(3-36)所示的化合物。
式(3-1)：白色固体，收率70％，m.p.173-174℃,1H NMR(400MHz,CDCl3)δ10.20(s,1H),8.67–8.54(m,2H),7.68(s,1H),7.39–7.28(m,2H),6.92(t,J＝8.4Hz,2H),6.15–6.02(m,1H),5.56(s,2H),4.60(d,J＝13.2Hz,1H),4.08(d,J＝13.6Hz,1H),3.82(dd,J＝17.2,12.0Hz,1H),3.64(dd,J＝17.2,9.2Hz,1H),3.46–3.32(m,2H),2.99–2.87(m,1H),2.32(d,J＝12.8Hz,1H),2.20(d,J＝12.8Hz,1H),2.02–1.78(m,2H).13C NMR(100MHz,CDCl3)δ186.79,174.22,174.15,164.05,162.58(d,J＝8.1Hz,1H),160.08(d,J＝8.1Hz,1H),152.22,150.01,145.18,142.59,131.62,130.62(t,J＝10.1Hz,1H),120.07,117.97,115.70(t,J＝16.2Hz,1H),113.77,111.97(d,J＝6.1Hz,1H),,111.78(d,J＝6.1Hz,1H),72.87,49.14,44.73,42.09,41.53,40.18,32.46,31.74.HRMS计算值C27H22F2N6O2S[M+Na]+559.13344.实测值559.13344.
式(3-12)：白色固体，收率87％，m.p.143-145℃,1H NMR(600MHz,CDCl3)δ8.50(d,J＝4.8Hz,1H),8.01(d,J＝7.8Hz,1H),7.67(s,1H),7.28-7.32(m,1H),7.10(dd,J＝7.8,4.8Hz,1H),6.92(t,J＝8.1Hz,2H),6.08(dd,J＝12.0,9.0Hz,1H),5.37(s,2H),4.61(d,J＝13.8Hz,1H),4.06(d,J＝13.8Hz,1H),3.81(dd,J＝17.4,12.0Hz,1H),3.64(dd,J＝17.4,9.0Hz,1H),3.29-3.34(m,2H),2.85(t,J＝12.6Hz,1H),2.59(s,3H),2.24(d,J＝13.8Hz,1H),2.15(d,J＝13.8Hz,1H),1.80-1.75(m,2H)；13C NMR(150MHz,CDCl3)δ174.15,164.86,161.65(d,J＝4.5Hz),160.00(d,J＝4.5Hz),151.86,151.15,148.24,144.58,141.25,130.25(t,J＝9.1Hz),129.32,117.76,115.77,115.25(t,J＝16.2Hz),114.96,111.50(d,J＝3.0Hz),111.36(d,J＝3.0Hz),72.37,47.64,44.12,41.45,41.03,39.80,32.00,31.38,12.11.HRMS计算值C26H24F2N6O2S[M+H]+523.17223.实测值523.17055.
式(3-15)：白色固体，收率78％，m.p.146-147℃,1H NMR(400MHz,DMSO-d6)δ8.72(dd,J＝4.4,1.6Hz,1H),8.36(d,J＝8.0Hz,1H),8.04(s,1H),7.43-7.54(s,2H),7.15(t,J＝8.4Hz,2H),6.02(dd,J＝12.0,8.4Hz,1H),5.70(q,J＝16.8Hz,2H),4.34(d,J＝13.2Hz,1H),4.13(d,J＝13.6Hz,1H),3.91(dd,J＝17.2,12.0Hz,1H),3.55(dd,J＝17.2,8.8Hz,1H),3.45-3.35(m,2H),2.85(t,J＝11.6Hz,1H),2.17(d,J＝12.0Hz,1H),2.09(d,J＝12.0Hz,1H),1.95-1.83(m,1H),1.66-1.53(m,1H).13C NMR(100MHz,CDCl3)δ174.22,163.96,162.55(d,J＝8.1Hz),160.05(d,J＝8.1Hz),152.25,151.06,150.17,145.11,133.72(q,J＝39.4Hz),130.58(t,J＝10.1Hz),129.54,122.58,119.90,118.90,117.92,115.68(t,J＝16.2Hz),112.32,111.93(t,J＝6.1Hz),111.74(t,J＝6.1Hz),72.84,48.99,44.62,41.98,41.51,40.16,32.41,31.74.HRMS计算值C26H21F5N6O2S[M+Na]+599.12591.实测值599.12602.
式(3-17)：白色固体，收率71％，m.p.141-143℃,1H NMR(400MHz,CDCl3)8.51(dd,J＝4.8,1.6Hz,1H),8.05(dd,J＝8.0,1.6Hz,1H),7.68(s,1H),7.35–7.27(m,1H),7.10(dd,J＝8.0,4.8Hz,1H),6.92(t,J＝8.4Hz,2H),6.08(dd,J＝12.0,9.2Hz,1H),5.40(s,2H),4.61(d,J＝13.6Hz,1H),4.06(d,J＝13.6Hz,1H),3.81(dd,J＝17.2,12.0Hz,1H),3.64(dd,J＝17.2,9.2Hz,1H),3.38–3.25(m,2H),2.96(t,J＝7.6Hz,2H),2.85(t,J＝12.0Hz,1H),2.19(dd,J＝28.0,13.2Hz,2H),1.88–1.74(m,4H),1.00(t,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3)δ174.46,173.92,165.21,162.61(d,J＝7.1Hz),160.11(d,J＝7.1Hz),152.29,151.44,148.44,146.04,145.13,130.59(d,J＝10.1Hz),130.17,117.82,116.16,115.77(d,J＝16.2Hz),115.20,111.97(d,J＝5.1Hz),111.78(d,J＝6.1Hz),72.87(t,J＝3.0Hz),48.34,44.65,41.97,41.59,41.57,40.35,32.49,31.86,29.63,22.46,20.92,14.08.HRMS计算值C28H28F2N6O2S[M+H]+551.20353.实测值551.20533.
式(3-18)：白色固体，收率88％，m.p.138-139℃,1H NMR(600MHz,CDCl3)δ8.45(s,1H),8.16(d,J＝8.4Hz,1H),7.64(s,1H),7.09–6.98(m,2H),6.88(t,J＝8.4Hz,2H),6.04(t,J＝10.8Hz,1H),5.36(d,J＝15.6Hz,1H),5.32(d,J＝16.8Hz,1H),4.58(d,J＝13.8Hz,1H),4.05(d,J＝13.8Hz,1H),3.77(t,J＝14.8Hz,1H),3.61(dd,J＝17.4,9.0Hz,1H),3.32–3.22(m,2H),2.81(t,J＝13.2Hz,1H),2.14(dd,J＝26.8,13.2Hz,2H),1.75(t,J＝12.6Hz,2H),1.48(s,9H).13C NMR(150MHz,CDCl3)δ174.47,165.37,162.27,160.61,152.98,152.36,151.98,148.22,145.21,131.37,130.61,117.77,115.82,113.42,111.99,111.84,72.91,48.43,44.79,41.99,41.64,40.40,34.23,32.52,31.94,30.11.HRMS计算值C29H30F2N6O2S[M+H]+565.21918.实测值565.21901.
式(3-19)：白色固体，收率90％，m.p.155-156℃,1H NMR(400MHz,CDCl3)δ8.67(d,J＝7.6Hz,1H),8.57(d,J＝4.4Hz,1H),7.66(s,1H),7.36–7.27(m,2H),6.91(t,J＝8.4Hz,2H),6.08(dd,J＝12.0,9.6Hz,1H),5.52(s,2H),4.60(d,J＝13.6Hz,1H),4.07(d,J＝13.6Hz,1H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.50–3.28(m,2H),2.98–2.80(m,1H),2.71(s,3H),2.31(d,J＝12.4Hz,1H),2.19(d,J＝12.4Hz,1H),2.02–1.76(m,2H).13C NMR(150MHz,CDCl3)δ194.39,174.10,164.09,161.95,160.28,152.05,151.48,149.26,144.94,141.89,132.16,130.50(t,J＝7.1Hz),119.48,117.93,115.49(t,J＝10.1Hz),114.29,111.78,111.63,72.67,48.92,44.52,41.84,41.32,40.01,32.27,31.59,26.27.HRMS计算值C27H24F2N6O3S[M+Na]+573.14909.实测值573.14878.
式(3-20)：白色固体，收率87％，m.p.149-150℃,1H NMR(400MHz,CDCl3)δ8.53(d,J＝4.5Hz,1H),8.26(d,J＝8.0Hz,1H),7.67(s,1H),7.35–7.28(m,1H),7.17(dd,J＝8.0,4.8Hz,1H),7.00(dd,J＝18.0,11.6Hz,1H),6.92(t,J＝8.4Hz,2H),6.13–6.01(m,2H),5.56(d,J＝11.6Hz,1H),5.40(s,2H),4.60(d,J＝13.2Hz,1H),4.06(d,J＝13.2Hz,1H),3.81(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.32(t,J＝11.6Hz,2H),2.86(t,J＝12.0Hz,1H),2.23(d,J＝13.2,1H),2.16(d,J＝13.2,1H),1.92–1.74(m,2H).13C NMR(100MHz,CDCl3)δ174.38,164.91,162.61(d,J＝8.1Hz),160.12(d,J＝8.1Hz),152.29,151.77,148.86,145.15,142.67,130.60(t,J＝10.1Hz),130.56,129.08,117.85,117.61,117.30,115.76(t,J＝16.2Hz),113.80,111.98(d,J＝6.1Hz),111.79(t,J＝6.1Hz),72.87(t,J＝3.0Hz),48.42,44.67,41.99,41.56,40.31,32.50,31.82.HRMS计算值C27H24F2N6O2S[M+H]+535.17223.实测值535.17301.
式(3-23)：白色固体，收率89％，m.p.215-217℃,1H NMR(400MHz,CDCl3)δ8.55(d,J＝3.6Hz,1H),8.13(d,J＝8.0Hz,1H),7.67(s,1H),7.35–7.25(m,1H),7.23–7.13(m,1H),6.91(t,J＝8.0Hz,2H),6.12–5.92(m,1H),5.44(s,2H),4.57(d,J＝12.8Hz,1H),4.05(d,J＝13.2Hz,1H),3.87–3.71(dd,J＝17.2,8.4Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.40(s,1H),3.37–3.20(m,2H),2.87(t,J＝11.6Hz,1H),2.26–2.11(m,2H),1.95–1.72(m,2H).13CNMR(100MHz,CDCl3)δ174.28,164.44,162.64(d,J＝7.1Hz),160.14(d,J＝7.1Hz),152.32,150.76,149.65,145.20,130.58(t,J＝11.1Hz),129.83,127.41,117.98,117.81,117.44,115.79(t,J＝16.2Hz),111.98(d,J＝5.1Hz),111.78(d,J＝5.1Hz),81.80,74.79,72.89,48.81,44.69,42.01,41.59,40.25,32.48,31.80.HRMS计算值C27H22F2N6O2S[M+H]+533.15658.实测值533.15512.
式(3-25)：浅黄色固体，收率78％，m.p.131-132℃,1H NMR(600MHz,DMSO-d6)δ8.79(d,J＝4.2Hz,1H),8.63(d,J＝8.4Hz,1H),8.05(s,1H),7.68–7.61(m,1H),7.55–7.43(m,1H),7.17(t,J＝9.0Hz,2H),6.01(t,J＝10.8Hz,1H),5.84(d,J＝16.8Hz,1H),5.77(d,J＝16.8Hz,1H),4.33(d,J＝13.8Hz,1H),4.12(d,J＝13.8Hz,1H),3.91(dd,J＝17.4,13.2Hz,1H),3.55(dd,J＝17.4,8.4Hz,1H),3.46–3.38(m,2H),2.87(t,J＝12.6Hz,1H),2.18(d,J＝13.2Hz,1H),2.10(d,J＝13.8Hz,1H),1.96–1.86(m,1H),1.64–1.56(m,1H).13C NMR(100MHz,DMSO-d6)δ175.11,163.84,162.04(d,J＝8.1Hz),159.56(d,J＝8.1Hz),152.25,151.41,150.87,145.61,144.42,131.53(t,J＝10.1Hz),130.54,121.99,120.15,115.73(t,J＝16.2Hz),112.43(d,J＝6.1Hz),112.24(d,J＝6.1Hz),108.59,72.16,49.87,44.15,41.49,41.26,39.46,32.29,31.86.HRMS计算值C25H21F2N7O4S[M+Na]+576.1236.实测值576.12505.
式(3-27)：白色固体，收率66％，m.p.155-157℃,1H NMR(600MHz,CDCl3)δ8.67(dd,J＝8.4,1.6Hz,1H),8.57(dd,J＝4.8,1.6Hz,1H),7.66(s,1H),7.33–7.27(m,2H),6.92(t,J＝8.4Hz,2H),6.08(dd,J＝12.0,9.0Hz,1H),5.46(s,2H),4.60(d,J＝13.8Hz,1H),4.07(d,J＝13.8Hz,1H),3.88–3.73(m,2H),3.63(dd,J＝17.4,9.0Hz,1H),3.39–3.35(m,1H),2.91(t,J＝12.0Hz,1H),2.27(d,J＝13.2Hz,1H),2.18(d,J＝13.2Hz,1H),1.98–1.86(m,2H).13CNMR(100MHz,CDCl3)δ174.28,164.46,162.49(d,J＝8.1Hz),159.99(d,J＝8.1Hz),152.15,151.53,149.43,145.01,132.20,130.57(t,J＝10.1Hz),118.97,118.05,115.59(t,J＝16.2Hz),114.79,111.93,111.69,72.79,48.80,44.70,41.99,41.41,40.09,32.36,31.71.HRMS计算值C26H21F2N7O2S[M+H]+566.21443.实测值566.21471.
式(3-28)：白色固体，收率83％，m.p.123-124℃,1H NMR(600MHz,CDCl3)δ8.58(d,J＝4.8Hz,1H),7.99(d,J＝8.4Hz,1H),7.68(s,1H),7.33-7.28(m,1H),7.22(dd,J＝8.4,4.8Hz,1H),6.92(t,J＝8.4Hz,2H),6.09(dd,J＝12.0,9.0Hz,1H),5.43(s,2H),4.59(d,J＝13.7Hz,1H),4.04(d,J＝13.8Hz,1H),3.82(dd,J＝17.4,12.0Hz,1H),3.64(dd,J＝17.4,9.0Hz,1H),3.34(t,J＝12.0Hz,2H),2.87(t,J＝12.6Hz,1H),2.28(d,J＝12.8Hz,1H),2.17(d,J＝13.6Hz,1H),1.90(q,J＝12.6Hz,1H),1.80(q,J＝12.6Hz,1H)；13C NMR(150MHz,CDCl3)δ174.14,164.21,161.82(d,J＝7.6Hz),160.15(d,J＝7.6Hz),152.00,151.07,149.87(d,J＝7.6Hz),144.74,130.38(d,J＝10.6Hz),129.34,119.82,117.87,117.49,115.79,115.38(d,J＝15.2Hz),111.65(d,J＝4.5Hz),111.51(d,J＝4.5Hz),72.52,48.31,44.28,41.64,41.20,39.88,32.13,31.48.HRMS计算值C25H21BrF2N6O2S[M+Na]+609.04904.实测值609.04743.
式(3-29)：白色固体，收率53％，m.p.120-121℃,1H NMR(600MHz,CDCl3)δ8.53(s,1H),8.10(s,1H),8.09(d,J＝10.8Hz,1H),7.66(s,1H),7.33–7.25(m,1H),7.14(dd,J＝8.4,4.8Hz,1H),6.91(t,J＝8.4Hz,2H),6.07(t,J＝10.6Hz,1H),5.44(s,2H),4.60(d,J＝13.8Hz,1H),4.07(d,J＝13.8Hz,1H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.0Hz,1H),3.32(t,J＝12.0Hz,2H),2.85(t,J＝12.6Hz,1H),2.23(d,J＝13.8Hz,1H),2.15(d,J＝13.8Hz,1H),1.90–1.81(m,2H).13C NMR(100MHz,CDCl3)δ174.21,164.78,162.31(d,J＝8.1Hz),159.81(d,J＝8.1Hz),152.05,150.59,148.56,144.83,132.85,130.40(t,J＝11.1Hz),130.20,117.81,116.81,115.48,115.47(t,J＝16.2Hz),111.72(d,J＝5.1Hz),111.53(d,J＝5.1Hz),72.59(t,J＝3.0Hz),48.24,44.37,41.66,41.27,40.00,32.22,31.56.HRMS计算值C25H22F2N6O2S[M+H]+509.15658.实测值509.15668.
式(3-30)：白色固体，收率82％；m.p.110-111℃.1H NMR(600MHz,DMSO-d6)δ8.40(d,J＝5.4Hz,1H),8.21(s,1H),8.04(s,1H),7.55(d,J＝4.8Hz,1H),7.53-7.46(m,1H),7.17(t,J＝8.4Hz,2H),6.01(dd,J＝12.0,8.4Hz,1H),5.58(d,J＝16.8Hz,1H),5.50(d,J＝16.8Hz,1H),4.33(d,J＝13.2Hz,1H),4.13(d,J＝13.2Hz,1H),3.91(dd,J＝17.2,12.0Hz,1H),3.55(dd,J＝17.2,8.4Hz,1H),3.45-3.35(m,2H),2.83(t,J＝12.6Hz,1H),2.15(d,J＝13.2Hz,1H),2.09(d,J＝13.2Hz,1H),1.88-1.80(m,1H),1.57(d,J＝12.0Hz,1H).13C NMR(150MHz,CDCl3)δ174.16,164.58,162.13,160.51,152.21,151.11,148.95,145.16,132.98,130.52,126.80,120.24,117.75,111.90,111.75,72.83,48.81,44.62,41.94,41.52,40.21,32.44,31.73.HRMS计算值C25H21BrF2N6O2S[M+Na]+609.04904,实测值609.04777.
式(3-31)：白色固体，收率89％；m.p.143-144℃.1H NMR(600MHz,DMSO-d6)δ8.62(s,1H),8.56(s,1H),8.17(s,1H),8.04(s,1H),7.55-7.45(m,1H),7.17(t,J＝8.4Hz,2H),6.02(dd,J＝12.0,8.4Hz,1H),5.57(d,J＝16.8,1H),5.47(d,J＝16.8,1H),4.33(d,J＝13.2Hz,1H),4.13(d,J＝13.2Hz,1H),3.91(dd,J＝17.4,12.0Hz,1H),3.55(dd,J＝17.4,8.4Hz,1H),3.47-3.35(m,1H),3.34-3.26(m,1H),2.83(t,J＝12.6Hz,1H),2.15(d,J＝13.2Hz,1H),2.09(d,J＝13.2Hz,1H),1.90-1.75(m,1H),1.65-1.50(m,1H).13C NMR(100MHz,DMSO)δ175.12,164.77,162.03(d,J＝8.0),159.56(d,J＝8.0),152.25,149.07,144.41,132.58,132.21,131.54(t,J＝10.0),120.12,116.93,115.74(d,J＝16.2),112.43(d,J＝5.0),112.25(d,J＝5.0),112.00,72.16,48.72,44.05,41.36,41.27,32.37,31.90.HRMS计算值C25H21BrF2N6O2S[M+Na]+609.04904,实测值609.04935.
式(3-32)：白色固体，收率92％；m.p.165-166℃.1H NMR(600MHz,DMSO-d6)δ8.23(d,J＝4.8Hz,1H),8.22(s,1H),8.05(d,J＝3.6Hz,1H),7.55-7.48(m,1H),7.43(d,J＝8.4Hz,1H),7.17(t,J＝8.4Hz,2H),6.02(t,J＝10.8Hz,1H),5.54(d,J＝16.8Hz,1H),5.45(d,J＝16.8Hz,1H),4.35(d,J＝13.2Hz,1H),4.14(d,J＝13.2Hz,1H),4.06-3.98(m,1H),3.92(dd,J＝17.4,12.0Hz,1H),3.55(dd,J＝17.4,8.4Hz,1H),3.44-3.39(m,1H),2.85(t,J＝13.2Hz,1H),2.16(d,J＝13.2Hz,1H),2.10(d,J＝13.2Hz,1H),1.94-1.82(m,1H),1.68-1.57(m,1H).13C NMR(100MHz,DMSO)δ175.05,164.70,161.99(d,J＝8.0),159.51(d,J＝8.0),152.22,150.34,144.36,140.62,133.42,133.20,131.46(t,J＝10.0),120.76,119.96,115.68(t,J＝16.2),114.39,112.37(d,J＝5.0),112.17(d,J＝5.0),72.11,48.62,44.03,41.33,41.24,32.33,31.81.HRMS计算值C25H21BrF2N6O2S[M+Na]+609.04904,实测值609.04888.
式(3-33)：白色固体，收率86％；m.p.87-88℃.1H NMR(600MHz,CDCl3)δ8.67(d,J＝8.4,1H),8.57(d,J＝4.8,1H),7.66(s,1H),7.33-7.27(m,2H),6.92(t,J＝8.4Hz,2H),6.08(dd,J＝12.0,9.6Hz,1H),5.46(s,2H),4.60(d,J＝13.2Hz,1H),4.07(d,J＝13.2Hz,1H),3.88-3.73(m,2H),3.66-3.60(m,1H),3.39-3.35(m,1H),2.93-2.87(m,1H),2.27(d,J＝13.2Hz,1H),2.18(d,J＝13.2Hz,1H),1.98-1.86(m,2H).13C NMR(100MHz,CDCl3)δ174.28,164.46,162.52,162.45,160.02,159.95,152.15,151.53,149.43,145.01,132.20,130.68,130.57,130.47,118.97,118.05,115.75,115.59,115.43,114.79,111.93,111.69,72.79,48.80,44.70,41.99,41.41,40.09,32.36,31.71.HRMS计算值C26H21F5N6O2S[M+Na]+599.12591,实测值599.12602.
式(3-34)：白色固体，收率92％；m.p.154-155℃.1H NMR(600MHz,DMSO-d6)δ8.91(s,1H),8.79(s,1H),8.39(s,1H),8.06(s,1H),7.55-7.46(m,1H),7.18(t,J＝8.4Hz,2H),6.03(dd,J＝12.0,8.4Hz,1H),5.67(d,J＝16.8,1H),5.58(d,J＝16.8,1H),4.35(d,J＝13.2Hz,1H),4.16(d,J＝13.2Hz,1H),3.93(dd,J＝17.2,12.0Hz,1H),3.46-3.38(m,1H),3.37-3.33(t,J＝12.6Hz,2H),2.84(t,J＝12.0Hz,1H),2.17(d,J＝13.2Hz,1H),2.10(d,J＝13.2Hz,1H),1.91-1.85(m,1H),1.61-1.55(m,1H).13C NMR(100MHz,CDCl3)δ174.14,164.46,162.59(d,J＝8.0),160.09(d,J＝8.0),152.21,151.81,145.93(t,J＝3.0),134.80,134.08,130.56(t,J＝10.0),128.44(q,J＝4.0),124.16(q,J＝135.0),120.37(q,J＝33.0),117.80,115.72(t,J＝16.2),114.45,111.94(d,J＝6.0),111.75(d,J＝6.0),72.86(t,J＝3.0),48.69,44.65,42.00,41.52,41.49,40.21,32.47,31.73.HRMS计算值C26H21F5N6O2S[M+Na]+599.12591,实测值599.12565.
式(3-35)：白色固体，收率78％；m.p.128-129℃.1H NMR(600MHz,DMSO-d6)δ8.61(d,J＝8.4Hz,1H),8.42(s,1H),8.06(s,1H),7.73(d,J＝8.4Hz,1H),7.53-7.49(m,1H),7.17(t,J＝8.4Hz,2H),6.01(t,J＝10.8Hz,1H),5.65(d,J＝16.8Hz,1H),5.55(d,J＝16.8Hz,1H),4.34(d,J＝13.2Hz,1H),4.18(d,J＝13.2Hz,1H),3.93-3.88(m,1H),3.57-3.52(m,1H),3.45-3.39(m,1H),3.34(s,1H),2.85(t,J＝13.2Hz,1H),2.17(d,J＝9.6Hz,1H),2.11(d,J＝9.6Hz,1H),1.65-1.50(m,2H).13C NMR(150MHz,CDCl3)δ174.20,164.69,162.20,160.53,152.29,149.99,145.16,133.27,133.10,131.88,130.54,117.81,117.28,113.25,111.92,111.76,72.85,48.24,44.76,42.00,41.54,40.24,36.80,32.47,31.75,20.34.HRMS计算值C26H21F5N6O2S[M+Na]+599.12591,实测值599.12762.
式(3-36)：白色固体，收率84％；m.p.161-163℃.1H NMR(400MHz,CDCl3)δ9.99(s,1H),8.58–8.44(m,1H),8.38–8.25(m,1H),8.04(d,J＝4.0Hz,1H),7.64(d,J＝4.0Hz,1H),7.50–7.46(m,1H),7.38–7.30(m,2H),6.29(td,J＝11.6,4.0Hz,1H),5.28(s,2H),4.60(d,J＝13.2Hz,1H),4.15(d,J＝13.6Hz,1H),3.84(ddd,J＝16.8,12.0,4.0Hz,1H),3.66(ddd,J＝16.4,10.4,4.0Hz,1H),3.37(q,J＝12.4,11.2Hz,2H),3.25(d,J＝4.0Hz,3H),2.91(t,J＝13.2Hz,1H),2.29(d,J＝13.2Hz,1H),2.19–2.13(m,1H),1.95–1.85(m,1H),1.81–1.76(m,1H).13C NMR(100MHz,CDCl3)δ185.03,174.34,164.78,152.89,148.63,148.36,145.00,144.76,140.09,135.25,130.94,130.29,129.73,129.14,121.26,119.10,118.45,117.44,116.95,45.33,44.90,42.15,41.91,40.19,37.99,32.48,31.79.HRMS(ESI)计算值C27H25ClN6O6S2[M+Na]+:651.0858,实测值651.0832.
式(3-37)：白色固体，收率83％；m.p.157-158℃.1H NMR(400MHz,CDCl3)δ8.52(t,J＝3.6Hz,1H),8.04(d,J＝8.8Hz,1H),7.66(d,J＝3.2Hz,1H),7.57–7.49(m,1H),7.46–7.29(m,2H),7.12(dt,J＝8.0,3.6Hz,1H),6.37–6.22(m,1H),5.39(d,J＝3.2Hz,2H),4.63(d,J＝13.2Hz,1H),4.09(d,J＝13.6Hz,1H),3.86(ddd,J＝16.4,12.4,3.2Hz,1H),3.67(ddd,J＝17.2,11.2,3.2Hz,1H),3.40–3.30(m,2H),3.25(d,J＝3.2Hz,3H),2.87(t,J＝12.8Hz,1H),2.61(d,J＝3.2Hz,3H),2.22(q,J＝14.0,13.2Hz,2H),1.82(dt,J＝24.4,12.8Hz,2H).13C NMR(100MHz,CDCl3)174.61,165.27,152.96,151.60,148.70,144.95,141.87,135.22,130.19,129.82,128.99,121.24,118.22,116.19,115.57,48.17,44.64,42.00,41.95,40.35,38.02,32.51,32.45,31.86,31.80,29.67,12.55.HRMS(ESI)计算值C27H27ClN6O5S2[M+Na]+:637.1065,实测值637.1062.
式(3-38)：白色固体，收率75％；m.p.148-150℃.1H NMR(400MHz,CDCl3)δ8.67(d,J＝4.4Hz,1H),8.24(d,J＝8.0Hz,1H),7.68(s,1H),7.52(d,J＝8.0Hz,1H),7.44–7.27(m,3H),6.31(t,J＝11.6Hz,1H),5.54(s,2H),4.61(d,J＝13.6Hz,1H),4.08(d,J＝13.6Hz,1H),3.88(dd,J＝17.2,12.4Hz,1H),3.68(dd,J＝17.2,10.8Hz,1H),3.40(td,J＝12.4,10.8,4.8Hz,2H),3.27(s,3H),2.92(t,J＝12.8Hz,1H),2.32(d,J＝13.2Hz,1H),2.21(d,J＝11.2Hz,1H),1.96(d,J＝12.0Hz,1H),1.84(q,J＝12.4,11.6Hz,1H).13C NMR(100MHz,CDCl3)174.36,163.99,152.96,151.15,150.20,148.71,145.01,135.24,133.87(q,J＝39.3Hz),130.21,129.74,129.61,129.02,125.29,122.61,121.24,119.93,118.91,118.25,117.26,112.41,49.02,44.69,42.01,40.24,38.01,32.44(d,J＝5.6Hz),31.78(d,J＝5.1Hz).HRMS(ESI)计算值C27H24ClF3N6O5S2[M+Na]+:691.0782,实测值691.0794.
式(3-39)：白色固体，收率83％；m.p.177-179℃.1H NMR(600MHz,CDCl3)δ8.50(d,J＝4.8Hz,1H),8.07(d,J＝7.8Hz,1H),7.63(s,1H),7.50(d,J＝8.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.33(t,J＝8.4Hz,1H),7.11(dd,J＝7.8,4.8Hz,1H),6.28(t,J＝11.4Hz,1H),5.41(s,2H),4.60(d,J＝14.4Hz,1H),4.06(d,J＝14.4Hz,1H),3.83(dd,J＝17.2,12.0Hz,1H),3.64(dd,J＝17.2,10.8Hz,1H),3.34–3.28(m,2H),3.22(s,3H),2.95(t,J＝7.6Hz,2H),2.85(t,J＝12.6Hz,1H),2.22(d,J＝12.6Hz,1H),2.15(d,J＝15.0Hz,1H),1.84(q,J＝7.2Hz,4H),1.00(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ182.13,174.69,165.25,152.99,151.56,148.70,148.53,146.04,144.93,135.25,130.23,129.73,129.02,121.27,118.28,116.17,115.15,66.83,59.08,48.32,44.67,42.00,40.38,38.00,32.45,31.88,29.66,22.46,14.08.HRMS(ESI)计算值C29H31ClN6O5S2[M+Na]+:665.1378,实测值665.1383.
式(3-40)：白色固体，收率80％；m.p.181-183℃.1H NMR(400MHz,CDCl3)δ8.55–8.39(m,1H),8.23–8.11(m,1H),7.66(d,J＝5.6Hz,1H),7.52–7.49(m,1H),7.44–7.33(m,2H),7.09(m,1H),6.37–6.20(m,1H),5.39(t,J＝4.8Hz,2H),4.64(d,J＝13.6Hz,1H),4.11(d,J＝13.6Hz,1H),3.86–3.72(m,1H),3.67–3.51(m,1H),3.39–3.29(m,2H),3.25(d,J＝5.6Hz,3H),2.85–2.74(m,1H),2.20(q,J＝13.2,9.6Hz,2H),1.83–1.71(m,2H),1.53(d,J＝5.6Hz,9H).13C NMR(100MHz,CDCl3)δ174.72,165.33,160.00,152.99,151.82,148.69,148.07,144.92,139.33,135.24,131.49,130.24,129.74,129.04,121.28,118.28,117.25,115.79,113.49,59.40,48.45,44.75,42.00,41.28,40.39,38.01,34.20,32.43,31.90,30.08.HRMS(ESI)计算值C30H33ClN6O5S2[M+Na]+:679.1535,实测值679.1537.
式(3-41)：白色固体，收率46％；m.p.170-172℃.1H NMR(400MHz,CDCl3)δ8.56(d,J＝7.2Hz,1H),8.46(d,J＝4.4Hz,1H),7.81(s,1H),7.43–7.34(m,2H),6.84(t,J＝8.0Hz,2H),6.13(dd,J＝12.4,9.2Hz,1H),5.64(s,2H),4.71(d,J＝13.2Hz,1H),4.22(d,J＝13.2Hz,1H),3.83(dd,J＝17.6,12.4Hz,1H),3.71(dd,J＝17.6,9.2Hz,1H),3.61–3.32(m,2H),3.27(s,3H),2.91–2.73(m,1H),2.67(s,3H),2.45(d,J＝12.0Hz,1H),2.23(d,J＝12.0Hz,1H),2.14–1.80(m,2H).13C NMR(100MHz,CDCl3)δ190.42,176.33,165.45,163.25,161.81,154.25,153.60,150.24,146.11,142.07,134.37,131.16(t,J＝7.2Hz),121.51,118.56,116.35(t,J＝10.7Hz),114.58,112.30,111.79,73.06,50.49,45.78,42.15,41.87,40.83,37.50,34.59,32.57,28.38.
式(3-42)：白色固体，收率78％；m.p.166-168℃.1H NMR(400MHz,CDCl3)δ8.74(d,J＝4.0Hz,1H),7.76(d,J＝8.4Hz,1H),7.69(s,1H),7.29–7.04(m,2H),6.99(dd,J＝16.8,10.4Hz,1H),6.89(t,J＝8.0Hz,2H),6.72(d,J＝16.8Hz,1H),6.32(dd,J＝12.0,9.2Hz,1H),5.68(d,J＝11.2Hz,1H),5.33(d,J＝4.0Hz,2H),4.57(d,J＝13.5Hz,1H),4.13(d,J＝13.9Hz,1H),3.72(dd,J＝17.1,12.0Hz,1H),3.57(dd,J＝17.1,9.2Hz,1H),3.41(td,J＝11.5,5.4Hz,2H),3.11–2.63(m,1H),2.18(t,J＝15.7Hz,2H),1.81(pd,J＝12.1,4.0Hz,2H).13C NMR(100MHz,CDCl3)δ175.44,166.75,163.70(d,J＝8.4Hz),161.18(d,J＝8.4Hz),155.31,152.82,149.92,146.21,142.95,131.54(t,J＝10.0Hz),130.67,129.48,117.91,117.67,117.35,115.84(t,J＝17.6Hz),114.02,111.26(d,J＝7.2Hz),111.03(t,J＝7.2Hz),72.23(t,J＝4.2Hz),50.39,46.72,42.87,42.60,40.64,38.09,33.89,31.99.
式(3-43)：白色固体，收率52％；m.p.180-182℃.1H NMR(400MHz,CDCl3)δ8.62(d,J＝4.4Hz,1H),8.21(d,J＝8.4Hz,1H),7.74(s,1H),7.53–7.43(m,1H),7.28–7.19(m,1H),6.98(t,J＝8.4Hz,2H),6.26–6.06(m,1H),5.50(s,2H),4.61(d,J＝12.8Hz,1H),4.11(d,J＝12.8Hz,1H),3.90–3.75(dd,J＝17.6,8.4Hz,1H),3.66(dd,J＝17.6,8.8Hz,1H),3.60(s,3H),3.49(s,1H),3.35–3.16(m,2H),2.92(t,J＝12.0Hz,1H),2.34–2.19(m,2H),1.98–1.78(m,2H).13C NMR(100MHz,CDCl3)δ175.33,166.74,163.87(d,J＝7.2Hz),161.25(d,J＝7.2Hz),155.42,151.69,150.13,146.15,131.69(t,J＝11.9Hz),130.02,128.51,118.91,118.80,117.65,116.31(t,J＝15.8Hz),112.05(d,J＝5.7Hz),111.84(d,J＝5.7Hz),83.48,75.80,72.97,50.15,46.82,43.21,41.87,40.47,38.11,33.02,32.19.
式(3-44)：白色固体，收率70％；m.p.178-179℃.1H NMR(400MHz,CDCl3)δ8.72(dd,J＝4.4,1.6Hz,1H),8.64(dd,J＝8.4,1.6Hz,1H),7.68(s,1H),7.51(dt,J＝8.4,5.6Hz,2H),7.45–7.34(m,2H),6.32(dd,J＝12.0,10.4Hz,1H),5.62(d,J＝2.0Hz,2H),4.64–4.56(m,1H),4.08(d,J＝13.6Hz,1H),3.89(dd,J＝17.2,12.4Hz,1H),3.69(dd,J＝17.2,10.8Hz,1H),3.49–3.37(m,2H),3.28(s,3H),2.95(t,J＝13.2Hz,1H),2.37(d,J＝13.2Hz,1H),2.22(d,J＝12.8Hz,1H),2.04–1.98(m,1H),1.86(dd,J＝13.6,9.6Hz,1H).13C NMR(100MHz,CDCl3)δ178.65,165.62,157.58,153.78,151.45,147.88,142.26,137.64,135.57,134.25,133.79,132.08,128.06,127.52,124.36,122.97,118.88,115.72,106.51,56.64,49.63,45.47,43.76,37.24,33.68,32.74.HRMS(ESI)计算值C26H24ClN7O7S2[M+Na]+:630.1779,实测值630.1792.
式(3-45)：白色固体，收率48％；m.p.182-184℃.1H NMR(400MHz,CDCl3)δ8.66(dd,J＝4.6,1.4Hz,1H),8.23(dd,J＝8.1,1.5Hz,1H),7.65(s,1H),7.50(dd,J＝8.0,1.4Hz,1H),7.43–7.31(m,3H),6.29(dd,J＝12.2,10.6Hz,1H),5.52(s,2H),4.57(d,J＝13.6Hz,1H),4.04(d,J＝13.8Hz,1H),3.85(dd,J＝17.3,12.2Hz,1H),3.65(dd,J＝17.3,10.6Hz,1H),3.39(qd,J＝11.7,11.2,3.3Hz,2H),3.23(s,3H),2.98–2.84(m,1H),2.37–2.29(m,1H),2.24–2.16(m,1H),1.96(q,J＝12.0Hz,1H),1.83(qd,J＝12.0,4.1Hz,1H).13C NMR(100MHz,CDCl3)δ174.23,163.62,152.94,150.66,148.71,145.04,135.26,130.24,129.73,129.15,129.05,121.25,119.69,118.30,117.93,117.04,112.78,49.35,44.73,42.05(d,J＝11.4Hz),40.19,37.99,32.45(d,J＝5.0Hz),31.73(d,J＝5.0Hz).
式(3-46)：白色固体，收率77％；m.p.169-171℃.1H NMR(400MHz,CDCl3)δ8.59(d,J＝4.4Hz,1H),8.00(d,J＝8.0Hz,1H),7.66(s,1H),7.51(d,J＝8.0Hz,1H),7.38(dt,J＝16.0,8.0Hz,2H),7.23(dd,J＝8.0,4.4Hz,1H),6.30(t,J＝11.2Hz,1H),5.43(s,2H),4.60(d,J＝13.2Hz,1H),4.06(d,J＝13.6Hz,1H),3.86(dd,J＝17.2,12.4Hz,1H),3.67(dd,J＝17.2,10.4Hz,1H),3.36(t,J＝12.0Hz,2H),3.26(s,3H),2.89(t,J＝12.4Hz,1H),2.29(d,J＝13.2Hz,1H),2.18(d,J＝10.4Hz,1H),1.84(dt,J＝38.8,13.2Hz,2H).13C NMR(150MHz,CDCl3)δ170.91,160.88,149.35,147.79,146.53,145.08,141.36,131.64,126.64,126.27,126.14,125.45,117.66,116.79,114.75,114.18,112.71,45.11,41.22–40.88(m),38.41,36.68,34.45,28.88(d,J＝8.5Hz),28.21(d,J＝7.4Hz).HRMS(ESI)计算值C26H24BrClN6O5S2[M+Na]+:701.0014,实测值701.0015.
式(3-47)：白色固体，收率75％；m.p.160-162℃.1H NMR(600MHz,CDCl3)δ8.53(dd,J＝4.8,1.5Hz,1H),8.09(d,J＝7.2Hz,2H),7.62(s,1H),7.49(d,J＝8.2Hz,1H),7.38(d,J＝8.0Hz,1H),7.33(t,J＝8.2Hz,1H),7.15(dd,J＝8.0,4.5Hz,1H),6.27(dd,J＝12.2,10.6Hz,1H),5.44(s,2H),4.60(d,J＝13.6Hz,1H),4.06(d,J＝13.8Hz,1H),3.83(dd,J＝17.2,12.2Hz,1H),3.63(dd,J＝17.2,10.6Hz,1H),3.32(tt,J＝11.1,3.4Hz,2H),3.22(s,3H),2.89–2.82(m,1H),2.24(d,J＝13.4Hz,1H),2.15(d,J＝13.4Hz,1H),1.88–1.74(m,2H).13C NMR(150MHz,CDCl3)δ174.53,164.95,152.93,150.77,148.76,148.64,144.90,135.20,133.17,130.49,130.17,129.67,128.97,121.21,118.22,117.04,115.78,48.49,44.64,41.94,40.31,37.93,32.46(d,J＝9.9Hz),31.78(d,J＝9.8Hz).
式(3-48)：白色固体，收率70％；m.p.166-168℃.1H NMR(600MHz,CDCl3)δ8.31(d,J＝4.8Hz,1H),8.10(s,1H),7.63(s,1H),7.49(d,J＝8.2Hz,1H),7.38(d,J＝8.1Hz,1H),7.33(dd,J＝9.3,6.6Hz,2H),6.30–6.24(m,1H),5.41(s,2H),4.59(d,J＝13.6Hz,1H),4.04(d,J＝13.8Hz,1H),3.83(dd,J＝17.3,12.2Hz,1H),3.64(dd,J＝17.2,10.6Hz,1H),3.36–3.29(m,2H),3.22(s,3H),2.90–2.83(m,1H),2.26(d,J＝13.6Hz,1H),2.16(d,J＝13.6Hz,1H),1.88(t,J＝12.4Hz,1H),1.78(s,1H).13C NMR(150MHz,CDCl3)δ174.38,164.57,152.91,151.13,148.98,148.64,144.93,135.20,133.04,130.18,129.67,128.98,126.83,121.21,120.27,118.23,117.77,48.82,44.63,41.94,40.25,37.93,32.48,32.41,31.78,31.72.
式(3-49)：白色固体，收率65％；m.p.171-173℃.1H NMR(600MHz,CDCl3)δ8.53(d,J＝2.1Hz,1H),8.20(d,J＝2.1Hz,1H),8.03(s,1H),7.62(s,1H),7.48(d,J＝8.2Hz,1H),7.38(d,J＝8.1Hz,1H),7.32(t,J＝8.2Hz,1H),6.29–6.23(m,1H),5.39(s,2H),4.57(d,J＝13.6Hz,1H),4.03(d,J＝13.7Hz,1H),3.82(dd,J＝17.3,12.2Hz,1H),3.63(dd,J＝17.3,10.6Hz,1H),3.32(tt,J＝11.5,3.6Hz,2H),3.21(s,3H),2.89–2.81(m,1H),2.25(d,J＝13.4Hz,1H),2.15(d,J＝13.4Hz,1H),1.86(dd,J＝12.0,6.5Hz,1H),1.77(tt,J＝12.5,6.6Hz,1H).13C NMR(150MHz,CDCl3)δ170.47,160.66,148.95,145.78,145.44,144.70,140.97,131.26,128.43,128.15,126.24,125.72,125.05,117.26,114.30,113.18,108.80,44.69,40.75,40.67,38.00,36.31,36.25,34.02,33.96.
式(3-50)：白色固体，收率63％；m.p.163-165℃.1H NMR(600MHz,CDCl3)δ8.41(d,J＝4.8Hz,1H),8.23(s,1H),7.52(s,1H),7.50(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.35(dd,J＝9.0,6.6Hz,2H),6.53–6.31(m,1H),5.54(s,2H),4.69(d,J＝13.8Hz,1H),4.23(d,J＝13.8Hz,1H),3.61(dd,J＝17.4,12.6Hz,1H),3.60(dd,J＝17.4,10.8Hz,1H),3.42–3.30(m,2H),3.31(s,3H),2.99–2.75(m,1H),2.33(d,J＝13.8Hz,1H),2.21(d,J＝13.7Hz,1H),1.76(t,J＝12.8Hz,1H),1.73(s,1H).13C NMR(150MHz,CDCl3)δ176.44,166.37,153.81,152.16,149.68,148.56,145.67,136.62,134.26,132.31,130.74,129.51,126.66,123.31,121.19,118.57,118.03,50.62,45.33,42.48,41.37,38.06,33.62,33.32,32.19,31.89.
式(3-51)：白色固体，收率62％；m.p.163-165℃.1H NMR(600MHz,CDCl3)δ8.45(d,J＝4.8Hz,1H),8.23(s,1H),7.74(s,1H),7.53(d,J＝8.4Hz,1H),7.41(d,J＝8.0Hz,1H),7.31(dd,J＝9.6,6.0Hz,2H),6.53–6.48(m,1H),5.62(s,2H),4.71(d,J＝12.6Hz,1H),4.32(d,J＝12.8Hz,1H),4.03(dd,J＝17.4,12.0Hz,1H),3.76(dd,J＝17.4,10.4Hz,1H),3.40–3.34(m,2H),3.25(s,3H),2.99–2.92(m,1H),2.38(d,J＝13.8Hz,1H),2.20(d,J＝13.8Hz,1H),1.90(t,J＝12.6Hz,1H),1.81(s,1H).13C NMR(150MHz,CDCl3)δ174.40,166.62,154.81,152.06,149.11,148.76,145.86,137.61,134.63,131.20,130.29,129.05,127.74,122.38,121.37,119.64,118.58,50.31,46.52,43.71,41.52,39.26,34.27,34.20,32.59,31.72.
式(3-52)：白色固体，收率81％；m.p.167-169℃.1H NMR(400MHz,CDCl3)δ8.69(d,J＝2.4Hz,1H),8.30(s,1H),8.14(d,J＝2.4Hz,1H),7.56(d,J＝2.4Hz,1H),7.41(d,J＝8.0Hz,1H),7.32–7.23(m,2H),6.26–6.11(m,1H),5.40(d,J＝2.4Hz,2H),4.50(d,J＝13.6Hz,1H),3.99(d,J＝13.6Hz,1H),3.82–3.70(m,1H),3.57(ddd,J＝17.2,10.8,2.4Hz,1H),3.28(q,J＝11.2,10.0Hz,2H),3.15(d,J＝2.4Hz,3H),2.81(t,J＝12.8Hz,1H),2.22(d,J＝13.2Hz,1H),2.13–2.04(m,1H),1.84(d,J＝11.6Hz,1H),1.73(d,J＝12.4Hz,1H).13CNMR(100MHz,CDCl3)δ205.86,174.43,164.52,152.95,151.85,148.69,145.99,145.00,135.26,134.13,130.26,129.74,129.07,128.52,122.87,121.27,120.44(q,J＝32.6Hz),118.35,114.51,66.96,48.73,44.70,41.98,40.27,38.00,32.47,31.80.HRMS(ESI)计算值C27H24ClF3N6O5S2[M+Na]+:691.0782,实测值691.0781.
式(3-53)：白色固体，收率81％；m.p.171-173℃.1H NMR(400MHz,CDCl3)δ8.35–8.21(m,2H),7.68(q,J＝3.6Hz,1H),7.58–7.53(m,2H),7.45–7.36(m,2H),6.36–6.27(m,1H),5.52(d,J＝3.6Hz,2H),4.63(d,J＝13.2Hz,1H),4.14(d,J＝13.6Hz,1H),3.89(ddd,J＝16.8,12.4,3.6Hz,1H),3.69(ddd,J＝17.2,10.8,3.6Hz,1H),3.48–3.34(m,2H),3.28(d,J＝4.0Hz,3H),3.00–2.86(m,1H),2.34(d,J＝13.2Hz,1H),2.27–2.18(m,1H),2.06–1.78(m,2H).13C NMR(100MHz,CDCl3)δ174.52,164.74,152.99,150.05,148.71,146.91,146.54,144.99,135.27,133.36,131.96,130.26,129.74,129.06,121.28,120.32,118.35,117.36,113.33,59.23,48.29,44.82,42.03,40.33,38.01,32.50,31.84.HRMS(ESI)计算值C27H24ClF3N6O5S2[M+Na]+:691.0782,实测值691.0780.
实施例4
本实施例用于说明式(3-2)所示的化合物的制备方法。
0℃下，将式(3-1)所示的化合物(1.87mmol,1eq)溶于10mL无水四氢呋喃中，缓慢加入NaBH4(2.80mmol,1.5eq)，继续缓慢滴加3mL甲醇，温度升至室温反应1h。反应完毕，加入20mL饱和氯化铵进行淬灭，加入10mL，反应体系以乙酸乙酯萃取，有机相经干燥，浓缩，柱层析得到式(3-2)所示的化合物。
式(3-2)：白色固体，收率95％，m.p.168-170℃,1H NMR(400MHz,DMSO-d6)δ8.51(dd,J＝4.8,1.6Hz,1H),8.32(dd,J＝8.0,1.6Hz,1H),8.04(s,1H),7.50(tt,J＝8.4,6.4Hz,1H),7.22(dd,J＝8.0,4.8Hz,1H),7.17(t,J＝8.4Hz,2H),6.56(s,1H),6.07–5.96(m,1H),5.54–5.34(m,3H),4.79(d,J＝5.2Hz,2H),4.35(d,J＝13.2Hz,1H),4.15(d,J＝13.2Hz,1H),3.92(dd,J＝17.2,12.0Hz,1H),3.55(dd,J＝17.2,8.4Hz,1H),3.45–3.36(m,1H),2.82(t,J＝11.6Hz,1H),2.12(dd,J＝23.6,12.8Hz,2H),1.83(q,J＝10.4,9.6Hz,1H),1.64–1.48(m,1H).13C NMR(100MHz,DMSO-d6)δ175.11,165.09,162.01(d,J＝8.1Hz),159.53(d,J＝8.1Hz),152.23,151.39,148.62,144.64,144.39,131.49(t,J＝11.1Hz),130.58,120.05,116.54,115.71(t,J＝16.2Hz),113.97,112.40(d,J＝6.1Hz),112.20(d,J＝6.1Hz),72.13,59.55,57.20,48.90,48.09,44.02,41.28(d,J＝4.0Hz),32.39,31.91.HRMS计算值C26H24F2N6O3S[M+H]+539.16714.实测值539.17034.
实施例5
本实施例用于说明式(3-3)所示的化合物的制备方法。
0℃下，将式(3-2)所示的化合物(1.00mmol,1eq)溶于10mL无水四氢呋喃中，缓慢加入氢化钠(1.50mmol,1.5eq)，继续反应0.5小时，再滴加碘甲烷(1.20mmol,1.2eq)，反应完毕。升至室温，加入10mL水，体系以乙酸乙酯萃取，有机相经干燥，浓缩，柱层析得到式(3-3)所示的化合物。
式(3-3)：白色固体，收率90％，m.p.147-149℃,1H NMR(400MHz,DMSO-d6)δ8.54(dd,J＝4.8,1.6Hz,1H),8.27(dd,J＝8.0,1.6Hz,1H),8.04(s,1H),7.50(tt,J＝8.4,6.4Hz,1H),7.25(dd,J＝8.0,4.8Hz,1H),7.17(t,J＝8.4Hz,2H),6.02(dd,J＝12.0,8.4Hz,1H),5.53(d,J＝16.8Hz,1H),5.44(d,J＝16.8Hz,1H),4.73(s,2H),4.34(d,J＝13.2Hz,1H),4.15(d,J＝13.2Hz,1H),3.92(dd,J＝17.2,12.0Hz,1H),3.55(dd,J＝17.2,8.4Hz,1H),3.45–3.36(m,1H),3.31(s,3H),3.27–3.37(m,1H),2.82(t,J＝11.6Hz,1H),2.20–2.05(m,2H),1.90–1.75(m,1H),1.64–1.50(m,1H).13C NMR(100MHz,DMSO-d6)δ175.11,165.08,161.99(d,J＝8.1Hz),159.51(d,J＝8.1Hz),151.85,151.33,148.55,144.61,142.54,131.44(t,J＝11.6Hz),130.01,123.11,116.51,115.66(t,J＝16.2Hz),114.00,112.38(d,J＝6.1Hz),112.17(d,J＝6.1Hz),72.09,62.35,58.77,57.14,48.88,48.13,43.98,41.25(d,J＝4.0Hz),32.45,32.03.HRMS计算值C27H26F2N6O3S[M+H]+553.18279.实测值553.18420.
实施例6
本实施例用于说明式(3-4)所示的化合物的制备方法。
室温下，将式(3-1)所示的化合物(1.00mmol,1eq)溶于10mL无水二氯甲烷中，缓慢加入氯化亚砜(5.00mmol,5eq)，加热回流反应3h。反应完毕，将反应体系倒入20mL冰水中进行淬灭，以二氯甲烷萃取，有机相经干燥，浓缩，柱层析得到式(3-4)所示的化合物。
式(3-4)：白色固体，收率85％，m.p.142-143℃,1H NMR(400MHz,CDCl3)δ8.56(s,1H),8.24(d,J＝7.6Hz,1H),7.66(s,1H),7.38–7.28(m,1H),7.24–7.13(m,1H),6.92(t,J＝8.4Hz,2H),6.08(t,J＝10.2Hz,1H),5.43(s,2H),4.95(s,2H),4.59(d,J＝12.6Hz,1H),4.05(d,J＝10.8Hz,1H),3.81(dd,J＝16.8,12.0Hz,1H),3.63(dd,J＝16.8,9.6Hz,1H),3.45–3.20(m,2H),2.87(t,J＝12.0Hz,1H),2.34–2.12(m,2H),1.97–1.75(m,2H).13C NMR(150MHz,CDCl3)δ174.21,164.61,161.97,160.30,152.06,151.39,149.05,144.90,140.86,130.51,130.09,117.94,117.22,115.52,114.07,111.80,111.66,72.68,48.40,44.57,41.85,41.41,40.08,38.24,32.32,31.63.HRMS计算值C26H23ClF2N6O2S[M+H]+557.13326.实测值557.13158.
实施例7
本实施例用于说明式(3-5)所示的化合物的制备方法。
室温下，将式(3-1)所示的化合物(1.00mmol,1eq)溶于10mL无水甲醇中，加入盐酸羟胺(1.50mmol,1.5eq)和三乙胺(2.00mmol,2.0eq)，继续室温反应5h。反应完毕，将反应体系倒入20mL水中，以乙酸乙酯萃取，有机相依次以1N稀盐酸和饱和碳酸氢钠洗涤，硫酸钠干燥，浓缩，柱层析得到式(3-5)所示的化合物。
式(3-5)：白色固体，收率91％，m.p.158-159℃,1H NMR(600MHz,CDCl3)δ9.34(brs,1H),8.56–8.48(m,1H),8.38(d,J＝7.2Hz,1H),8.28(s,1H),7.67(s,1H),7.32–7.27(m,1H),7.20–7.10(m,1H),6.90(t,J＝7.8Hz,2H),6.07(t,J＝10.8Hz,1H),5.44(s,2H),4.59(d,J＝13.8Hz,1H),4.03(d,J＝11.4Hz,1H),3.80(dd,J＝16.8,9.0Hz,1H),3.63(dd,J＝16.8,9.0Hz,1H),3.32(t,J＝11.4Hz,2H),2.88–2.81(m,1H),2.24(d,J＝13.2Hz,1H),2.14(d,J＝13.2Hz,1H),1.89–1.77(m,2H).13C NMR(100MHz,CDCl3)δ174.37,164.80,162.58(d,J＝8.1Hz),160.08(d,J＝8.1Hz),152.29,151.72,149.35,145.09,141.04,130.60(t,J＝10.1Hz),130.10,117.92,117.35,115.72(t,J＝16.2Hz),114.20,111.97(t,J＝6.1Hz),111.78(t,J＝6.1Hz),72.87(t,J＝3.0Hz),48.39,44.65,41.99,41.54,40.22,38.33,32.45,31.78.HRMS计算值C26H23F2N7O3S[M+Na]+574.14434.实测值574.14738.
实施例8
本实施例用于说明式(3-6)所示的化合物的制备方法。
0℃下，将式(3-5)所示的化合物(0.50mmol,1eq)溶于5mL无水四氢呋喃中，缓慢加入氢化钠(0.75mmol,1.5eq)，继续反应0.5小时，再滴加碘甲烷(0.60mmol,1.2eq)，反应完毕。升至室温，加入10mL水，体系以乙酸乙酯萃取，有机相经干燥，浓缩，柱层析得到式(3-6)所示的化合物。
式(3-6)：白色固体，收率74％，m.p.144-145℃,1H NMR(600MHz,CDCl3)δ8.56(d,J＝4.2Hz,1H),8.53(d,J＝7.8Hz,1H),8.35(s,1H),7.67(s,1H),7.32–7.28(m,1H),7.25–7.19(m,1H),6.92(t,J＝8.4Hz,2H),6.08(t,J＝10.8Hz,1H),5.43(s,2H),4.60(d,J＝13.2Hz,1H),4.17–4.01(m,4H),3.81(dd,J＝16.8,12.6Hz,1H),3.63(dd,J＝16.8,9.0Hz,1H),3.34(t,J＝10.2Hz,2H),2.88(t,J＝12.6Hz,1H),2.25(d,J＝12.0Hz,1H),2.17(d,J＝13.2Hz,1H),1.92–1.77(m,2H).13C NMR(100MHz,CDCl3)δ174.30,164.72,162.69(d,J＝8.1Hz),160.19(d,J＝8.1Hz),152.34,151.83,149.65,145.26,143.90,138.50,132.65,130.65(t,J＝10.1Hz),118.24,117.86,115.83(t,J＝16.2Hz),113.64,112.05(d,J＝6.1Hz),111.85(d,J＝6.1Hz),72.94(t,J＝3.0Hz),62.60,48.61,44.75,42.08,41.63,40.34,32.57,31.86.HRMS计算值C27H25F2N7O3S[M+Na]+588.15999.实测值588.16178.
实施例9
本实施例用于说明式(3-7)、式(3-8)、式(3-9)和式(3-10)所示的化合物的制备方法。
具体地，以式(3-7)所示的化合物的制备为例
室温下，将式(3-1)所示的化合物(1.00mmol,1eq)、甲胺溶液(1.50mmol,1.50eq,33重量％乙醇溶液)和三乙酰氧基硼氢化钠(1.50mmol,1.50eq)依次加入到10mL的1,2-二氯乙烷中，搅拌反应5h，反应完毕，加入20mL水，以二氯甲烷萃取，有机相以饱和碳酸氢钠洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-7)所示的化合物。
式(3-7)：白色固体，收率75％，m.p.133-135℃,1H NMR(400MHz,CDCl3)δ8.50(d,J＝4.8Hz,1H),8.25(d,J＝8.0Hz,1H),7.65(s,1H),7.36–7.27(m,1H),7.11(dd,J＝8.0,4.8Hz,1H),6.91(t,J＝8.4Hz,2H),6.07(dd,J＝12.0,9.6Hz,1H),5.41(s,2H),4.57(d,J＝13.2Hz,1H),4.19(s,2H),4.06(d,J＝13.2Hz,1H),3.90(s,1H),3.80(dd,J＝17.2,12.0Hz,1H),3.62(dd,J＝17.2,9.2Hz,1H),3.40–3.25(m,2H),2.84(t,J＝12.4Hz,1H),2.53(s,3H),2.25(d,J＝12.4Hz,1H),2.15(d,J＝12.4Hz,1H),1.94–1.73(m,2H).13C NMR(150MHz,CDCl3)δ174.37,165.07,162.10(d,J＝5.1Hz),160.43(d,J＝5.1Hz),152.20,151.54,149.06,145.04,141.61,130.57(t,J＝7.1Hz),130.22,117.93,116.85,115.66,114.53,111.91,111.75,72.80,48.20,47.24,44.58,41.89,41.46,40.21,35.27,32.42,31.76.HRMS计算值C27H27F2N7O2S[M+H]+552.19878.实测值552.19872.
式(3-8)：白色固体，收率68％，m.p.131-132℃,1H NMR(400MHz,CDCl3)δ8.46(d,J＝4.8Hz,1H),8.21(d,J＝8.4Hz,1H),7.59(s,1H),7.29–7.22(m,1H),7.08(dd,J＝8.0,4.8Hz,1H),6.85(t,J＝8.4Hz,2H),6.00(d,J＝9.6Hz,1H),5.34(s,2H),4.52(d,J＝13.2Hz,1H),4.00(d,J＝13.2Hz,1H),3.90(s,2H),3.74(dd,J＝17.2,9.6Hz,1H),3.56(dd,J＝13.2,8.4Hz,1H),3.27–3.23(m,2H),2.78(t,J＝11.2Hz,1H),2.33(s,6H),2.18(d,J＝14.4Hz,1H),2.09(d,J＝13.2Hz,1H),1.83–1.70(m,2H).13C NMR(150MHz,CDCl3)δ174.25,164.81,161.95(d,J＝5.1Hz),160.28(d,J＝5.1Hz),152.09,151.54,148.85,144.89,141.36,130.46(t,J＝7.1Hz),130.39,117.87,116.74,115.51(t,J＝10.1Hz),115.09,111.78,111.63,72.65,55.70,48.13,44.94,44.42,41.75,41.34,40.07,32.29,31.64.HRMS计算值C28H29F2N7O2S[M+H]+566.21443.实测值566.21471.
式(3-9)：白色固体，收率77％，m.p.123-125℃,1H NMR(400MHz,CDCl3)δ8.36(s,1H),7.95(s,1H),7.60(s,1H),7.37–7.27(m,1H),7.18–6.80(m,3H),6.12–5.98(m,1H),5.16(s,2H),4.50(d,J＝13.2Hz,1H),4.23–3.71(m,4H),3.61(dq,J＝17.6,9.2Hz,1H),3.34–3.08(m,2H),3.00–2.53(m,2H),2.47–2.04(m,5H),1.91–1.39(m,4H).13C NMR(100MHz,CDCl3)δ174.31,174.06,164.37,162.54(d,J＝8.1Hz),160.04(d,J＝8.1Hz),152.24,150.65,149.61,145.07,130.57(t,J＝11.1Hz),129.80,127.31,117.95,117.90,117.37,115.69(t,J＝16.2Hz),111.93(d,J＝6.1Hz),111.74(d,J＝6.1Hz),81.84,74.72,72.81,48.77,44.62,41.96,41.50,40.20,32.44,31.75.HRMS计算值C29H29F2N7O2S[M+H]+578.21443.实测值578.21619.
式(3-10)：白色固体，收率69％，m.p.117-118℃,1H NMR(400MHz,CDCl3)δ8.51(d,J＝4.8Hz,1H),8.26(d,J＝8.4Hz,1H),7.66(s,1H),7.35–7.27(m,1H),7.12(dd,J＝8.4,4.8Hz,1H),6.91(t,J＝8.4Hz,2H),6.07(dd,J＝12.0,9.2Hz,1H),5.39(s,2H),4.59(d,J＝13.6Hz,1H),4.11–4.00(m,3H),3.80(dd,J＝17.2,12.0Hz,1H),3.63(dd,J＝17.2,9.2Hz,1H),3.37–3.24(m,2H),2.84(t,J＝11.8Hz,1H),2.73–2.55(m,4H),2.23(d,J＝12.8Hz,1H),2.15(d,J＝12.8Hz,1H),1.90–1.70(m,6H).13C NMR(150MHz,CDCl3)δ174.21,164.80,161.89(d,J＝6.1Hz),160.23(d,J＝6.1Hz),152.04,151.40,148.70,144.83,142.15,130.41(t,J＝7.1Hz),130.35,117.81,116.55,115.47(t,J＝10.1Hz),114.93,111.71,111.57,72.59,53.91,52.00,48.06,44.37,41.69,41.28,40.03,32.23,31.59,23.31.HRMS计算值C30H31F2N7O2S[M+H]+592.23008.实测值592.23083.
实施例10
本实施例用于说明式(3-11)所示的化合物的制备方法。
室温下，将式(3-1)所示的化合物(1.00mmol,1eq)、乙二醇(1.50mmol,1.5eq)和对甲苯磺酸(0.1mmol,0.1eq)依次加入到10mL三氯甲烷中，升温至回流反应6h，反应完毕，加入20mL水，以二氯甲烷萃取，有机相以饱和食盐水洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-11)所示的化合物。
式(3-11)：白色固体，收率71％，m.p.127-128℃,1H NMR(600MHz,CDCl3)δ8.66–8.57(m,1H),8.54–8.43(m,1H),7.65(s,1H),7.32–7.27(m,1H),7.13(dd,J＝8.4,4.8Hz,1H),6.91(t,J＝7.8Hz,2H),6.07(dd,J＝14.4,6.6Hz,1H),5.64–5.24(m,3H),4.59(d,J＝12.0Hz,1H),4.09–4.03(m,1H),3.82–3.76(m,1H),3.62(dd,J＝16.8,9.6Hz,1H),3.33(dd,J＝19.2,8.4Hz,2H),2.88–2.80(m,1H),2.30–2.26(m,1H),2.14–2.09(m,1H),1.87–1.76(m,2H),1.27–1.17(m,4H).13C NMR(100MHz,CDCl3)δ174.20,164.11,162.63(d,J＝8.1Hz),160.13(d,J＝8.1Hz),152.26,150.06,149.13,145.21,142.66,131.73,130.66(d,J＝10.1Hz),120.13,118.00,115.73(d,J＝16.2Hz),113.85,112.01(d,J＝6.1Hz),111.82(d,J＝6.1Hz),100.22,72.93(t,J＝3.0Hz),65.51,63.71,49.16,44.78,42.14,41.55,40.22,32.49,31.77.HRMS计算值C28H26F2N6O4S[M+H]+581.17771.实测值581.17399.
实施例11
本实施例用于说明式(3-13)所示的化合物的制备方法。
0℃下，将式(3-2)所示的化合物(1.00mmol,1eq)、二乙胺基三氟化硫(1.50mmol,1.5eq)依次加入到10mL二氯甲烷中，升温至室温反应6h，反应完毕，加入20mL水，以二氯甲烷萃取，有机相以饱和食盐水洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-13)所示的化合物。
式(3-13)：白色固体，收率68％，m.p.151-153℃,1H NMR(400MHz,CDCl3)δ8.50(d,J＝4.4Hz,1H),8.14(d,J＝8.0Hz,1H),7.60(s,1H),7.29–7.20(m,1H),7.14(dd,J＝8.0,4.8Hz,1H),6.85(t,J＝8.4Hz,2H),6.01(dd,J＝11.6,9.6Hz,1H),5.66(d,J＝48.0Hz,2H),5.38(s,2H),4.53(d,J＝13.6Hz,1H),3.99(d,J＝12.4Hz,1H),3.74(dd,J＝17.2,12.0Hz,1H),3.56(dd,J＝17.2,9.0Hz,1H),3.33–3.22(m,2H),2.80(t,J＝11.6Hz,1H),2.25–2.05(m,2H),1.87–1.67(m,2H).13C NMR(150MHz,CDCl3)δ174.22,164.57,161.92,160.28,152.06,151.35,149.08,144.86,139.83(t,J＝14.2Hz),130.46(t,J＝7.1Hz),129.74,117.90,117.37,115.48(t,J＝11.1Hz),114.37,111.75,111.60,78.20,72.63,48.24,44.41,41.74,41.29,40.02,32.24,31.58.HRMS计算值C26H23F3N6O2S[M+H]+541.16281.实测值541.16508.
实施例12
本实施例用于说明式(3-14)所示的化合物的制备方法。
0℃下，将式(3-1)所示的化合物(1.00mmol,1eq)、二乙胺基三氟化硫(1.50mmol,1.5eq)依次加入到10mL二氯甲烷中，升温至室温反应6h，反应完毕，加入20mL水，以二氯甲烷萃取，有机相以饱和食盐水洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-14)所示的化合物。
式(3-14)：白色固体，收率70％，m.p.157-158℃,1H NMR(600MHz,CDCl3)δ8.58(d,J＝4.8Hz,1H),8.26(d,J＝8.4Hz,1H),7.65(s,1H),7.31–7.26(m,1H),7.23(dd,J＝8.4,4.8Hz,1H),6.94(t,J＝54.0Hz,1H),6.90(t,J＝8.4Hz,2H),6.07(dd,J＝12.0,9.0Hz,1H),5.43(s,2H),4.57(d,J＝13.8Hz,1H),4.04(d,J＝13.8Hz,1H),3.79(dd,J＝17.4,12.0Hz,1H),3.62(dd,J＝17.4,9.0Hz,1H),3.37–3.28(m,2H),2.88(t,J＝12.6Hz,1H),2.25(d,J＝13.8Hz,1H),2.16(d,J＝10.8Hz,1H),1.93–1.85(m,1H),1.85–1.73(m,1H).13C NMR(150MHz,CDCl3)δ174.18,164.44,162.29,160.63,152.32,151.47,149.91,145.31,138.43(t,J＝30.2Hz),130.62(t,J＝7.1Hz),130.41,118.37,117.81,115.83(t,J＝10.1Hz),112.50,112.19,112.01,111.86,72.94,48.67,44.75,42.07,41.62,40.30,32.54,31.83.HRMS计算值C26H22F4N6O2S[M+H]+559.17858.实测值559.17683.
实施例13
本实施例用于说明式(3-16)所示的化合物的制备方法。
氮气保护条件下，将式(3-1)所示的化合物(1.00mmol,1eq)、(三苯基磷鎓基)二氟乙酸内盐(2.0mmol,2.0eq)依次加入到10mL无水N,N-二甲基甲酰胺中，升温至60℃，反应1h，然后再加入四丁基氟化铵(3mL,3.00mmol,3eq,1M四氢呋喃溶液)，继续搅拌反应30min，反应完毕，加入60mL水，以乙酸乙酯萃取，有机相以饱和食盐水洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-16)所示的化合物。
式(3-16)：白色固体，收率89％，m.p.142-144℃,1H NMR(600MHz,CDCl3)δ8.56(d,J＝4.2Hz,1H),8.09(d,J＝8.4Hz,1H),7.66(s,1H),7.33–7.27(m,1H),7.22–7.15(m,1H),6.91(t,J＝8.4Hz,2H),6.07(t,J＝10.8Hz,1H),5.43(s,2H),4.58(d,J＝13.8Hz,1H),4.05(d,J＝13.8Hz,1H),3.95–3.70(m,3H),3.63(dd,J＝17.4,9.0Hz,1H),3.33(t,J＝12.6Hz,2H),2.87(t,J＝12.6Hz,1H),2.24(d,J＝13.2Hz,1H),2.15(d,J＝13.2Hz,1H),1.90–1.75(m,2H).13C NMR(150MHz,CDCl3)δ174.35,164.92,162.32(d,J＝6.1Hz),160.66(d,J＝6.1Hz),152.38,151.66,149.36,145.31,134.90,130.66(t,J＝10.6Hz),130.07,125.37(q,J＝277.8Hz),117.84,117.53,115.88(t,J＝16.2Hz),115.22,112.06,111.89,72.99,48.58,44.78,42.11,41.68,40.38,33.74(d,J＝31.7Hz),32.57,31.90.HRMS计算值C27H23F5N6O2S[M+H]+591.15961.实测值591.15960.
实施例14
本实施例用于说明式(3-21)所示的化合物的制备方法。
氮气保护条件下，将式(3-1)所示的化合物(1.00mmol,1eq)、(三苯基磷鎓基)二氟乙酸内盐(2.0mmol,2.0eq)依次加入到10mL无水N,N-二甲基甲酰胺中，升温至80℃，反应2h，反应完毕，加入60mL水，以乙酸乙酯萃取，有机相以饱和食盐水洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-21)所示的化合物。
式(3-21)：白色固体，收率65％，m.p.168-169℃,1H NMR(600MHz,DMSO-d6)δ8.55(s,1H),8.32(d,J＝8.4Hz,1H),8.03(d,J＝3.6Hz,1H),7.52–7.45(m,1H),7.27(dd,J＝8.4,4.8Hz,1H),7.15(t,J＝8.4Hz,2H),6.23(d,J＝28.8Hz,1H),6.02(dd,J＝12.6,9.0Hz,1H),5.57(d,J＝17.2Hz,1H),5.48(d,J＝17.2Hz,1H),4.34(d,J＝13.2Hz,1H),4.14(d,J＝13.2Hz,1H),3.91(dd,J＝17.2,12.0Hz,1H),3.57–3.53(m,1H),3.39(t,J＝11.6Hz,1H),3.32(t,J＝12.6Hz,1H),2.81(t,J＝12.6Hz,1H),2.11(dd,J＝39.0,13.2Hz,2H),1.84(q,J＝12.6Hz,1H),1.56(q,J＝12.6,1H).13C NMR(100MHz,DMSO-d6)δ175.06,164.82,162.01(d,J＝8.1Hz),159.53(d,J＝8.1Hz),152.22,151.00,149.19,144.41,133.77(d,J＝6.1Hz),133.67(d,J＝6.1Hz),131.46(t,J＝10.1Hz),130.15(d,J＝6.1Hz),120.02,117.25,115.70(t,J＝16.2Hz),113.58(d,J＝3.0Hz),112.37(d,J＝6.1Hz),112.18(d,J＝6.1Hz),75.11(d,J＝14.2Hz),74.78(d,J＝14.2Hz),72.14(t,J＝3.0Hz),48.46,44.00,41.28(d,J＝6.1Hz),32.34,31.88.HRMS计算值C27H22F4N6O2S[M+H]+571.15338.实测值571.15289.
实施例15
本实施例用于说明式(3-22)所示的化合物的制备方法。
氮气保护条件下，将式(3-1)所示的化合物(1.00mmol,1eq)、乙基三苯基溴化膦(1.2mmol,1.2eq)依次加入到10mL无水四氢呋喃中，-15℃下，缓慢滴加双三甲基硅基胺基锂(1.5mL,1.5eq,1M四氢呋喃溶液)，升至室温，继续反应2h，反应完毕，加入10mL饱和氯化铵淬灭和10mL水，以乙酸乙酯萃取，有机相以饱和食盐水洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-22)所示的化合物。
式(3-22)：白色固体，收率65％，m.p.119-120℃,1H NMR(400MHz,CDCl3)δ8.52(t,J＝4.8Hz,1H),8.26–8.04(m,1H),7.67(s,1H),7.34–7.28(m,1H),7.14(dd,J＝8.0,4.8Hz,1H),6.92(t,J＝8.4Hz,2H),6.74–6.56(m,1H),6.15–5.96(m,2H),5.41(d,J＝19.2Hz,2H),4.61(d,J＝12.4Hz,1H),4.07(t,J＝12.0Hz,1H),3.81(dd,J＝16.8,12.0Hz,1H),3.64(dd,J＝17.2,9.2Hz,1H),3.32(t,J＝11.2Hz,2H),2.87(t,J＝11.6Hz,1H),2.27–2.15(m,2H),2.15–2.10(m,2H),1.97(d,J＝6.0Hz,1H),1.90–1.75(m,2H).13C NMR(100MHz,CDCl3)δ174.45,165.05,165.03,162.68(d,J＝8.1Hz),160.18(d,J＝8.1Hz),152.34,148.43,145.22,142.20,131.52,130.63(t,J＝10.1Hz),123.12,118.25,117.84,116.94,116.70,115.83(t,J＝16.2Hz),112.03(t,J＝6.1Hz),111.84(t,J＝6.1Hz),72.93(t,J＝3.0Hz),48.90,44.80,42.05,41.63,40.42,32.57,31.91,19.07.HRMS计算值C28H26F2N6O2S[M+H]+549.18788.实测值549.18675.
实施例16
本实施例用于说明式(3-24)所示的化合物的制备方法。
室温下，将式(3-23)所示的化合物(1.00mmol,1eq)、四丁基碘化铵(1.10mmol,1.1eq)和硝酸银(0.1mmol,0.1eq)依次加入到10mL丙酮中，搅拌反应3h，反应完毕，加入10mL乙酸乙酯，依次以20mL水和饱和食盐水洗涤，硫酸钠干燥后，浓缩，并进一步以硅胶柱层析纯化，得到式(3-24)所示的化合物。
式(3-24)：白色固体，收率90％，m.p.265-267℃,1H NMR(600MHz,CDCl3)δ8.57(s,1H),8.16(d,J＝7.8Hz,1H),7.68(s,1H),7.33–7.28(m,1H),7.24–7.17(m,1H),6.93(t,J＝7.8Hz,2H),6.13–6.05(m,1H),5.43(s,2H),4.59(d,J＝14.4Hz,1H),4.04(d,J＝13.2Hz,1H),3.87–3.77(dd,J＝17.2,13.2Hz,1H),3.64(dd,J＝17.2,9.0Hz,1H),3.34(t,J＝12.0Hz,2H),2.87(t,J＝12.0Hz,1H),2.27(d,J＝15.6Hz,1H),2.17(d,J＝14.4Hz,1H),1.90–1.78(m,2H).13C NMR(100MHz,DMSO-d6)δ175.43,164.49,161.95(d,J＝8.1Hz),159.47(d,J＝8.1Hz),152.26,150.06,149.63,144.10,131.48(t,J＝10.1Hz),129.47,126.91,120.34,118.29,116.63,115.55(t,J＝16.2Hz),112.34(d,J＝5.1Hz),112.16(d,J＝6.1Hz),84.12,72.27,48.72,43.99,41.29,41.01,32.30,31.81,23.73.HRMS计算值C27H21F2IN6O2S[M+H]+659.05322.实测值659.04904.
实施例17
本实施例用于说明式(3-26)所示的化合物的制备方法。
室温下，将式(3-25)所示的化合物(1.00mmol,1eq)溶于10mL无水甲醇中，加入Pd/C(50.00mg,10重量％)，反应体系以氢气置换3次,继续反应12h。反应完毕，以氮气置换3次，体系经过滤，浓缩得到式(3-26)所示的化合物。
式(3-26)：黄色固体，收率97％，m.p.142-143℃,1H NMR(600MHz,DMSO-d6)δ8.34(s,1H),8.12(d,J＝7.8Hz,1H),8.03(s,1H),7.55–7.43(m,1H),7.16(t,J＝9.0Hz,2H),6.98(s,1H),6.01(t,J＝10.8Hz,1H),5.70(s,2H),5.20–5.00(m,2H),4.33(d,J＝13.2Hz,1H),4.10(d,J＝13.2Hz,1H),3.90(t,J＝15.0Hz,1H),3.54(dd,J＝17.2,8.6Hz,1H),3.35–3.20(m,2H),2.78(t,J＝13.2Hz,1H),2.08(t,J＝13.8Hz,2H),1.76–1.65(m,1H),1.57–1.48(m,1H).13C NMR(100MHz,DMSO-d6)δ175.17,165.68,162.03(d,J＝7.1Hz),159.54(d,J＝7.1Hz),152.25,151.49,148.52,147.67,144.39,131.53(t,J＝10.1Hz),130.03,120.09,115.73(t,J＝16.2Hz),114.08,112.42(d,J＝5.1Hz),112.23(d,J＝5.1Hz),107.27,72.14,47.42,44.05,41.28,32.44,31.95.HRMS计算值C25H23F2N7O2S[M+H]+524.16748.实测值524.16795.
测试例1：抑制黄瓜霜霉病的活体活性
测试和调查方法参照康卓、顾宝根编写的《农药生物活性测试标准操作规范》杀菌剂卷中的SOP-SC-1098黄瓜霜霉病盆栽法。
表1
*90％≦A≦100％；75％≦B＜90％；“-”表示未测试
由表1可知，本发明的大部分化合物对黄瓜霜霉病具有良好的防效。式(3-3)、式(3-4)、式(3-6)～(3-13)、式(3-15)、式(3-18)～(3-20)、式(3-23)、式(3-25)、式(3-28)和式(3-29)所示化合物在给药浓度为20mg/L时，对黄瓜霜霉病的防效均在A级，达到90％以上。
测试例2：抑制卵菌病原菌：辣椒疫霉、致病疫霉、荔枝霜疫霉、大豆疫霉等菌丝生长的离体活性
测试方法采用微孔板法进行药剂室内生物活性的测定
荔枝霜疫霉、大豆疫霉：将靶标菌接种在PDB或V8汁液体培养基内摇培96小时，过滤后收集新鲜的菌丝，然后称取0.1g菌丝体，放入50mL的PDB液体培养基后，用组织捣碎机把菌丝体捣碎成小菌丝段，制成菌丝段悬浮液，置于4℃下备用。
致病疫霉：将致病疫霉接种于V8培养基平板后培养12天，待其产生大量孢子囊后，加入无菌水并将平板转移到4℃冰箱内放置1小时，然后再转移到室温内，诱导游动孢子释放。待游动孢子充分释放后，配置孢子浓度为105个孢子/mL的孢子悬浮液，置于4℃下备用。
将供试药剂用二甲基亚砜配制成2000mg/L的母液，然后用无菌水稀释成0.1mg/L的浓度，置于4℃下备用。
将孢子悬浮液(菌丝段悬浮液)和提前配制的系列梯度药液按100μl+100μl的量依次加入到每个微孔内，然后将96孔微孔板置于25℃(致病疫霉18℃)的培养箱内静置培养，3-4天(致病疫霉7天)后用酶标仪检测各处理的OD595(595nm处的吸光值)值。计算药剂对靶标菌的室内毒力。测试结果如表2所示。
表2
*95％≦A≦100％；90％≦B<95％；85％≦C<90％；75％≦D<85％；E<75％；“-”表示未测试
由表2可知，在0.1mg/L的给药浓度下，本发明的多个化合物对四种疫霉的菌丝生长抑制比较显著，显示为A级，大于95％的抑制率，特别是对荔枝霜疫霉的活性明显具有很大的开发潜力。
式(3-3)、式(3-12)、式(3-14)、式(3-15)、式(3-20)和式(3-29)等6个所示化合物对大豆疫霉的菌丝生长抑制作用为C级及以上，大于85％的抑制率；式(3-12)、式(3-15)、式(3-20)、式(3-25)、式(3-28)等5个所示化合物对辣椒疫霉的菌丝生长抑制作用为A级，抑制率大于95％；式(3-1)、式(3-3)、式(3-4)、式(3-12)、式(3-13)、式(3-15)、式(3-16)、式(3-19)、式(3-20)、式(3-25)、式(3-28)和式(3-29)等所示的12个化合物对致病疫霉的菌丝生长抑制作用为C级及以上，大于85％的抑制率；式(3-1)、式(3-3)、式(3-4)、式(3-12)、式(3-13)、式(3-14)、式(3-16)、式(3-19)、式(3-20)和式(3-28)等所示的10化合物对荔枝霜疫霉的菌丝生长抑制作用为C级及以上，大于85％的抑制率。
综上所述，以上化合物具有很大的开发潜力。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。
Claims (10)
1.一种式(1)所示结构的含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物，
在式(1)中，
R选自氢、甲基、正丙基、C4-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C4烷基羰基、醛基、醛肟基、硝基、氨基、氰基、氟、溴、C2-C6醛肟醚基、C2-C6含氧环烷基、C3-C6环烷基、C4-C10环烷基烷基、C4-C10烷基环烷基、C5-C10烷基环烷基烷基、C3-C6卤代环烷基、羟基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4卤代烷硫基、C1-C4卤代烷基亚磺酰基、C1-C4卤代烷基磺酰基、C1-C4烷基氨基、C2-C8二烷基氨基、C3-C6环烷基氨基、C2-C4烷基羰基氨基、羟胺基、C1-C4烷氧氨基、C2-C4卤代烷基羰基氨基、C2-C4烷基羰基、C2-C6烷氧羰基、C2-C6烷基羰氧基、C2-C6烷基羰硫基、C2-C6烷基氨基羰基、C3-C8二烷基氨基羰基或C3-C6三烷基甲硅烷基；
R1、R2和R3各自独立地选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C4烷基羰基、醛基、醛肟基、硝基、氨基、氰基、卤素、C2-C6醛肟醚基、C2-C6含氧环烷基、C3-C6环烷基、C4-C10环烷基烷基、C4-C10烷基环烷基、C5-C10烷基环烷基烷基、C3-C6卤代环烷基、羟基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4卤代烷硫基、C1-C4卤代烷基亚磺酰基、C1-C4卤代烷基磺酰基、C1-C4烷基氨基、C2-C8二烷基氨基、C3-C6环烷基氨基、C2-C4烷基羰基氨基、羟胺基、C1-C4烷氧氨基、C2-C4卤代烷基羰基氨基、C2-C4烷基羰基、C2-C6烷氧羰基、C2-C6烷基羰氧基、C2-C6烷基羰硫基、C2-C6烷基氨基羰基、C3-C8二烷基氨基羰基和C3-C6三烷基甲硅烷基；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
2.根据权利要求1所述的化合物，其中，在式(1)中，
R选自H、甲基、正丙基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C1-C4酰基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C6烷基氨基、C3-C6二烷基氨基、羟胺基、C1-C4烷氧胺基、C1-C4烷氧基、C2-C4烷基羰基、C1-C4烷基磺酰基、醛基、C1-C4醛肟基、羟基、硝基、氨基、氰基、卤素、C2-C6醛肟醚基、1,3-二氧环戊基；
R1、R2和R3各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C2-C6卤代烯基、C2-C6卤代炔基、C1-C4羟基烷基、C1-C4酰基烷基、C2-C4烷氧基烷基、C2-C6烷基氨基烷基、C3-C6二烷基氨基烷基、C3-C8环烷氨基烷基、C2-C6烷基氨基、C3-C6二烷基氨基、羟胺基、C1-C4烷氧胺基、C1-C4烷氧基、C2-C4烷基羰基、C1-C4烷基磺酰基、醛基、醛肟基、羟基、硝基、氨基、氰基、氟、氯、溴、碘、C2-C6醛肟醚基和1,3-二氧环戊基；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
3.根据权利要求1所述的化合物，其中，在式(1)中，
R选自H、甲基、正丙基、正丁基、叔丁基、乙烯基、丙烯基、乙炔基、丙炔基、氯甲基、二氯甲基、三氯甲基、溴甲基、二溴甲基、三溴甲基、氟甲基、二氟甲基、三氟甲基、1-氯乙基、2-氯乙基、1-氟乙基、2-氟乙基、1,1-二氟乙基、2,2-二氟乙基、1,2-二氟乙基、2,2,2-三氟乙基、1,1,2,2,2-五氟乙基、乙酰基甲基、1-氯-乙烯基、2-氯-乙烯基、2,2-二氯乙烯基、1,2-二氯乙烯基、1-氟-乙烯基、2-氟-乙烯基、2,2-二氟乙烯基、1,2-二氟乙烯基、氟代乙炔基、氯代乙炔基、碘代乙炔基、羟基甲基、1-羟基乙基、2-羟基乙基、羟基正丙基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、3-甲氧基正丙基、乙氧基甲基、1-乙氧基乙基、2-乙氧基乙基、3-乙氧基正丙基、甲基氨基甲基、1-甲基氨基乙基、2-甲基氨基乙基、甲基氨基正丙基、二甲基氨基甲基、1-二甲基氨基乙基、2-二甲基氨基乙基、二甲基氨基正丙基、
甲氨基、二甲氨基、甲基乙基氨基、羟胺基、甲氧胺基、甲氧基、乙氧基、乙酰基、丙酰基、甲基磺酰基、醛基、-CH＝NOH、-CH＝NOCH3、羟基、硝基、氨基、氰基、氟、溴或1,3-二氧环戊基；
R1、R2和R3各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基、正丁基、叔丁基、乙烯基、丙烯基、乙炔基、丙炔基、氯甲基、二氯甲基、三氯甲基、溴甲基、二溴甲基、三溴甲基、氟甲基、二氟甲基、三氟甲基、1-氯乙基、2-氯乙基、1-氟乙基、2-氟乙基、1,1-二氟乙基、2,2-二氟乙基、1,2-二氟乙基、2,2,2-三氟乙基、1,1,2,2,2-五氟乙基、乙酰基甲基、1-氯-乙烯基、2-氯-乙烯基、2,2-二氯乙烯基、1,2-二氯乙烯基、1-氟-乙烯基、2-氟-乙烯基、2,2-二氟乙烯基、1,2-二氟乙烯基、氟代乙炔基、氯代乙炔基、碘代乙炔基、羟基甲基、1-羟基乙基、2-羟基乙基、羟基正丙基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、3-甲氧基正丙基、乙氧基甲基、1-乙氧基乙基、2-乙氧基乙基、3-乙氧基正丙基、甲基氨基甲基、1-甲基氨基乙基、2-甲基氨基乙基、甲基氨基正丙基、二甲基氨基甲基、1-二甲基氨基乙基、2-二甲基氨基乙基、二甲基氨基正丙基、
甲氨基、二甲氨基、甲基乙基氨基、羟胺基、甲氧胺基、甲氧基、乙氧基、乙酰基、丙酰基、甲基磺酰基、醛基、-CH＝NOH、-CH＝NOCH3、羟基、硝基、氨基、氰基、氟、氯、溴、碘和1,3-二氧环戊基；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
4.根据权利要求3所述的化合物，其中，在式(1)中，
R选自-CHO、-CH2OH、-CH(OH)CH3、-CH2CH2OH、-CH2OCH3、-CH(CH3)OCH3、-CH2CH2OCH3、-CH＝NOH、-CH＝NOCH3、-CH2NHCH3、-CH2N(CH3)2、
-CH3、-CH2Cl、-CHClCH3、-CH2CH2Cl、-CH2F、-CHF2、-CF3、-CHFCH3、-CH2CH2F、-CHFCH2F、-CF2CH3、-CH2CHF2、-CH2CF3、-CF2CF3、-CH2CH2CH3、-C(CH3)3、-COCH3、-CH2COCH3、-COCH2CH3、-CH＝CH2、-CH＝CF2、-CH＝CHCH3、-C≡CH、-C≡C-I、-C≡CCH3、-OCH3、-OH、-NO2、-NH2、-NHCH3、-N(CH3)2、-N(CH2CH3)CH3、-NHOH、-NHOCH3、-C≡N、-Br或-H；
R1、R2和R3均为H；
R4为2,6-二氟苯基或2-氯-6-[(甲基磺酰基)氧基]苯基。
5.权利要求1-4中任意一项所述的含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物在防治植物卵菌病害中的应用。
6.根据权利要求5所述的应用，其中，所述植物卵菌病害选自致病疫霉、大豆疫霉、辣椒疫霉、荔枝霜疫霉和黄瓜霜霉病菌中的至少一种病菌导致的病害。
7.权利要求1-4中任意一项所述的含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物作为农药杀菌剂的应用。
8.一种杀菌剂，该杀菌剂由活性成分和辅料组成，所述活性成分包括权利要求1-4中任意一项所述的式(1)所示结构的含稠杂环结构的化合物或其农业化学上可接受的盐、水合物和溶剂化物中的至少一种。
9.根据权利要求8所述的杀菌剂，其中，所述活性成分的含量为1-99.9重量％。
10.根据权利要求9所述的杀菌剂，其中，该杀菌剂的剂型选自乳油、悬浮剂、可湿性粉剂、粉剂、粒剂、水剂、毒饵、母液和母粉中的至少一种。
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