WO2020047716A1 - 吡嗪酰胺类化合物及其制备方法和应用以及杀菌剂 - Google Patents

吡嗪酰胺类化合物及其制备方法和应用以及杀菌剂 Download PDF

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WO2020047716A1
WO2020047716A1 PCT/CN2018/103826 CN2018103826W WO2020047716A1 WO 2020047716 A1 WO2020047716 A1 WO 2020047716A1 CN 2018103826 W CN2018103826 W CN 2018103826W WO 2020047716 A1 WO2020047716 A1 WO 2020047716A1
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compound
formula
halogen
substituted
alkyl
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PCT/CN2018/103826
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English (en)
French (fr)
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杨光富
李华
熊力
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华中师范大学
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Priority to PCT/CN2018/103826 priority Critical patent/WO2020047716A1/zh
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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
    • 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
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to the field of pesticide fungicides, in particular to a pyrazinamide compound, a method for preparing a pyrazinamide compound, and a pyrazinamide compound and a pyrazinamide compound prepared by the method as amber Use of acid dehydrogenase inhibitors and a fungicide.
  • Succinate dehydrogenase inhibitors are fungicides that interfere with breathing through complex II (also called succinate dehydrogenase or succinate ubiquinone reductase) on the mitochondrial respiratory electron transfer chain of pathogenic bacteria.
  • complex II also called succinate dehydrogenase or succinate ubiquinone reductase
  • the succinate dehydrogenase on the electron transfer chain inhibits mitochondrial function, prevents it from generating energy, inhibits the growth of pathogenic bacteria, and eventually causes its death to achieve the purpose of controlling diseases.
  • Succinate dehydrogenase inhibitor fungicides have become the most promising type of fungicides in recent years due to their high-efficiency, broad-spectrum fungicidal activity and environmental friendliness.
  • a new fungicide disclosed in 2014 is the succinate dehydrogenase inhibitor (SDHI) fungicide Pyraziflumid (test code NNF-0721) developed by Japan Pesticide Corporation, which is mainly used to control powdery mildew on rice, fruits and vegetables , Black spot, gray mold, sclerotinia, sclerotinia, fruit spot and money spot, etc.
  • SDHI succinate dehydrogenase inhibitor
  • Pyraziflumid test code NNF-0721
  • the dosage is 100-375g / hm 2 and it is expected to be launched in Japan in 2018.
  • An object of the present invention is to provide a pyrazinamide compound having a broad spectrum of antibacterial and bactericidal activities.
  • Another object of the present invention is to provide a pyrazinamide compound which can be used as a succinate dehydrogenase inhibitor.
  • a third object of the present invention is to provide a pyrazinamide compound which can be used as a main active ingredient of a fungicide.
  • the present invention provides a pyrazinamide compound having a structure represented by formula (I), formula (II), or formula (III):
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, 1-4 halogen A substituted C 1-4 alkyl group and a C 1-4 alkoxy group substituted with 1-4 halogens, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 12 is halogen, R 13 is also halogen; when R 14 is halogen, R 11 is halogen and R 12 and R 13 are H; when R 13 is H, R 14 is halogen or C 1-4 alkyl; when R 13 is CF 3 , R 11 is Br or F; when R 11 , R 12 and R 14 are all H, R 13 is not F; when R 11 is Cl, R 13 is not halogen;
  • R 11 , R 12 and R 13 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C substituted by 1-4 halogen 1-4 alkyl and C 1-4 alkoxy substituted by 1-4 halogens, and R 11 , R 12 and R 13 are not H at the same time;
  • R 32 and R 33 are each independently selected from H, halo, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted by a 1-4 C 1-4 alkyl groups of 1-4 and a halogen substituted C 1-4 alkoxy
  • R 32 and R 33 are not both H; when R 32 or R 33 is a C 1-4 alkyl group, R 11 and R 13 are not the same halogen;
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and 1-4 halogens A substituted C 1-4 alkyl group and a C 1-4 alkoxy group substituted with 1-4 halogens, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 11 is F, R 12 is not H; when R 11 is Br, R 13 is not H; when R 13 is F, R 11 and R 12 are not H at the same time.
  • the present invention provides a method for preparing a pyrazinamide compound, the pyrazinamide compound having a structure represented by formula (I), formula (II) or formula (III), the method comprising: The compound represented by (2-1) is contacted with a compound represented by formula (2-21), formula (2-22) or formula (2-23);
  • R 11 , R 12 , R 13 , R 14 , R 32 and R 33 are as defined in the foregoing description of the present invention.
  • the present invention provides a pyrazinamide compound prepared by the aforementioned method of the present invention.
  • the present invention provides the use of the aforementioned pyrazinamide compound as a succinate dehydrogenase inhibitor.
  • the present invention provides a bactericide, which is composed of an active ingredient and an auxiliary material, the active ingredient including at least one of the aforementioned pyrazinamide compounds of the present invention.
  • a pyrazine ring fragment and a diphenyl ether fragment having extensive biological activity are introduced into NNF-0721 to design a pyrazinamide compound having a completely new structure.
  • the pyrazinamide compound can be used as a novel succinic acid to remove Catalase inhibitor or fungicide.
  • the foregoing pyrazinamide compounds provided by the present invention have significant succinate dehydrogenase inhibitory activity and are effective against rice sheath blight, strawberry gray mold, cucumber downy mildew, melons powdery mildew, soybean rust, corn rust and wheat white powder
  • the diseases all have certain inhibitory activity, and have obvious broad-spectrum advantages over the medicaments in the prior art, wherein the powdery mildew of melons includes, for example, cucumber powdery mildew and the like.
  • the raw materials involved in the method for preparing pyrazinamide compounds provided by the present invention are cheap and readily available, the reaction conditions are mild, and the post-treatment is simple.
  • a first aspect of the present invention provides a compound pyrazinamide, the compound having the structure of formula (I) of formula (II) or Formula (III) shown below:
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, 1-4 halogen A substituted C 1-4 alkyl group and a C 1-4 alkoxy group substituted with 1-4 halogens, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 12 is halogen, R 13 is also halogen; when R 14 is halogen, R 11 is halogen and R 12 and R 13 are H; when R 13 is H, R 14 is halogen or C 1-4 alkyl; when R 13 is CF 3 , R 11 is Br or F; when R 11 , R 12 and R 14 are all H, R 13 is not F; when R 11 is Cl, R 13 is not halogen;
  • R 11 , R 12 and R 13 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C substituted by 1-4 halogen 1-4 alkyl and C 1-4 alkoxy substituted by 1-4 halogens, and R 11 , R 12 and R 13 are not H at the same time;
  • R 32 and R 33 are each independently selected from H, halo, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted by a 1-4 C 1-4 alkyl groups of 1-4 and a halogen substituted C 1-4 alkoxy
  • R 32 and R 33 are not both H; when R 32 or R 33 is a C 1-4 alkyl group, R 11 and R 13 are not the same halogen;
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and 1-4 halogens A substituted C 1-4 alkyl group and a C 1-4 alkoxy group substituted with 1-4 halogens, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 11 is F, R 12 is not H; when R 11 is Br, R 13 is not H; when R 13 is F, R 11 and R 12 are not H at the same time.
  • the aforementioned halogen in the present invention means at least one element selected from the group consisting of fluorine element, chlorine element, bromine element, and iodine element.
  • C 1-4 alkyl means an alkyl group having 1 to 4 carbon atoms, and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. .
  • C 1-4 alkoxy for example, it can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy base.
  • C 1-4 alkyl substituted with 1-4 halogens means an alkyl group having 1-4 carbon atoms, and 1-4 H on the alkyl group are substituted with halogens. A similar definition applies to "C 1-4 alkoxy substituted by 1-4 halogens”.
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkane An oxy group, a C 1-3 alkyl group substituted with 1-4 halogens, and a C 1-3 alkoxy group substituted with 1-4 halogens, and R 11 , R 12 , R 13, and R 14 are not simultaneously Is H; when R 12 is halogen, R 13 is also halogen; when R 14 is halogen, R 11 is halogen and R 12 and R 13 are H; when R 13 is H, R 14 is halogen or C 1-4 Alkyl; when R 13 is CF 3 , R 11 is Br or F; when R 11 , R 12 and R 14 are all H, R 13 is not F; when R 11 is Cl, R 13 is not halogen.
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, methyl, isopropyl, trifluoromethyl, isopropoxy and trifluoromethoxy And R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 12 is halogen, R 13 is also halogen; when R 14 is halogen, R 11 is halogen and R 12 and R 13 are H; R When 13 is H, R 14 is halogen or C 1-4 alkyl; when R 13 is CF 3 , R 11 is Br or F; when R 11 , R 12 and R 14 are all H, R 13 is not F ; When R 11 is Cl, R 13 is not halogen.
  • R 11 , R 12 and R 13 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl substituted with 1-4 halogens and C 1-3 alkoxy substituted with 1-4 halogens, and R 11 , R 12 and R 13 are not both H;
  • R 32 and R 33 is each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-4 alkyl substituted with 1-4 halogens, and C 1-3 alkoxy substituted by 1-4 halogens, and R 32 and R 33 are not H at the same time; when R 32 or R 33 is C 1-3 alkyl, R 11 and R 13 are not The same halogen.
  • R 11 , R 12 and R 13 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, trifluoromethyl and trifluoromethoxy, and R 11 , R 12 and R 13 are not H at the same time;
  • R 32 and R 33 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, isopropoxy, trifluoromethyl, and trifluoro A methoxy group, and R 32 and R 33 are not both H; when R 32 or R 33 is a C 1-3 alkyl group, R 11 and R 13 are not the same halogen.
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkane An oxy group, a C 1-3 alkyl group substituted with 1-4 halogens, and a C 1-3 alkoxy group substituted with 1-4 halogens, and R 11 , R 12 , R 13, and R 14 are not simultaneously Is H; when R 11 is F, R 12 is not H; when R 11 is Br, R 13 is not H; when R 13 is F, R 11 and R 12 are not H at the same time.
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, isopropoxy, methoxy, trifluoromethyl And trifluoromethoxy, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 11 is F, R 12 is not H; when R 11 is Br, R 13 is not H; R When 13 is F, R 11 and R 12 are not H at the same time.
  • C 1-4 alkyl substituted with 1-4 halogens means an alkyl group having 1-4 carbon atoms, and 1-4 H on the alkyl group are selected from F, Cl, Br and Halogen substitution of I.
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, Tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, C 1-4 alkyl substituted with 1-4 halogens selected from F and / or Cl and 1-4 A halogen-substituted C 1-4 alkoxy group selected from F and / or Cl, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 12 is halogen, R 13 is also halogen; When R 14 is halogen, R 11 is halogen and R 12 and R 13 are H; when R 13 is H, R 14 is halogen or C 1-4 alkyl; when R 13 is CF 3 , R 11 is Br or F; when R 11 , R 12 and R 14 are all H, R 13 is not F; when R 11 is Cl
  • R 11 , R 12 and R 13 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, Isopropoxy, tert-butoxy, C 1-4 alkyl substituted with 1-4 halogens selected from F and / or Cl and substituted with 1-4 halogens selected from F and / or Cl C 1-4 alkoxy, and R 11 , R 12 and R 13 are not H at the same time;
  • R 32 and R 33 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl , Tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, C 1-4 alkyl substituted by 1-4 halogens selected from F and / or Cl, and by 1- 4 halogen-substituted C 1-4 alkoxy groups selected from F and / or Cl, and
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethyl Oxy, isopropoxy, tert-butoxy, C 1-4 alkyl substituted with 1-4 halogens selected from F and / or Cl and 1-4 alkyls selected from F and / or Cl Halo-substituted C 1-4 alkoxy, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 11 is F, R 12 is not H; when R 11 is Br, R 13 is not Is H; when R 13 is F, R 11 and R 12 are not H at the same time.
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, methyl, isopropyl, trifluoro Methyl, isopropoxy and trifluoromethoxy, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 12 is halogen, R 13 is also halogen; when R 14 is halogen, R 11 is halogen and R 12 and R 13 are H; when R 13 is H, R 14 is halogen or C 1-4 alkyl; when R 13 is CF 3 , R 11 is Br or F; R 11 and R 12 When R and R 14 are both H, R 13 is not F; when R 11 is Cl, R 13 is not halogen;
  • R 11 , R 12, and R 13 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, trifluoromethyl, and trifluoromethoxy, and R 11 , R 12 and R 13 are not H at the same time;
  • R 32 and R 33 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, isopropoxy, trifluoromethyl And trifluoromethoxy, and R 32 and R 33 are not H at the same time; when R 32 or R 33 is a C 1-3 alkyl group, R 11 and R 13 are not the same halogen;
  • R 11 , R 12 , R 13 and R 14 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, isopropoxy, methoxy, Trifluoromethyl and trifluoromethoxy, and R 11 , R 12 , R 13 and R 14 are not H at the same time; when R 11 is F, R 12 is not H; when R 11 is Br, R 13 is not H; when R 13 is F, R 11 and R 12 are not H at the same time.
  • the pyrazinamide compound is at least one of the following, and compound I1-compound I21 has a structure represented by formula (I), and compound II1-compound II13 has formula (II) ), Compound III1-compound III20 has a structure represented by formula (III):
  • R 12 and R 13 are F; R 11 and R 14 are H;
  • R 12 is Cl, R 13 is F; R 11 and R 14 are H;
  • R 12 is F, R 13 is Cl; R 11 and R 14 are H;
  • R 11 is Cl, R 13 is OCF 3 ; R 12 and R 14 are H;
  • R 11 is Cl, R 14 is F; R 12 and R 13 are H;
  • R 11 is F, R 14 is Cl; R 12 and R 13 are H;
  • R 11 is Br, R 13 is Cl; R 12 and R 14 are H;
  • R 13 is Cl; R 11 , R 12 and R 14 are H;
  • R 13 is OCH (CH 3 ) 2 ;
  • R 11 , R 12 and R 14 are H;
  • R 11 and R 14 are Cl; R 12 and R 13 are H;
  • R 13 is OCF 3 ;
  • R 11 , R 12 and R 14 are H;
  • R 11 is CH 3
  • R 14 is CH (CH 3 ) 2
  • R 12 and R 13 are H
  • R 11 is Br, R 13 is CF 3 ; R 12 and R 14 are H;
  • R 11 is Br, R 13 is CH 2 CH 3 , R 12 and R 14 are H;
  • R 11 is OCH 2 CH 3
  • R 13 is CH 3
  • R 12 and R 14 are H
  • R 11 is F, R 13 is CH 2 Cl, R 12 and R 14 are H;
  • R 11 is CH 2 CF 3
  • R 14 is CH 3
  • R 12 and R 13 are H
  • R 11 and R 13 are Cl, R 12 is H; R 33 is F, and R 32 is H;
  • R 11 is Cl, R 13 is CF 3 ; R 12 is H; R 33 is CH 3 , and R 32 is H;
  • R 11 is Cl, R 13 is CF 3 ;
  • R 12 is H;
  • R 33 is H, and
  • R 32 is CH 3 ;
  • R 11 is Cl, R 13 is CF 3 ; R 12 is H; R 33 is F, and R 32 is H;
  • R 11 is Cl, R 13 is CF 3 ; R 12 is H; R 33 is H, and R 32 is F;
  • R 11 is CH 3 , R 13 is CF 3 ;
  • R 12 is H;
  • R 33 is CH 2 CF 3 , and
  • R 32 is CH 3 ;
  • R 11 is OCF 3 , R 13 is Cl; R 12 is H; R 33 is Cl, and R 32 is CH (CH 3 ) 2 ;
  • R 11 is CH 2 CH 3 , R 13 is F; R 12 is H; R 32 is CHCl 2 , and R 33 is OCH 3 ;
  • R 11 is CHCl 2 , R 13 is Cl; R 12 is H; R 33 is F, and R 32 is CH 2 CH 3 ;
  • R 11 is CH (CH 3 ) 2 , R 13 is Br, R 12 is H; R 33 is Br, and R 32 is CH 3 ;
  • R 11 is OCH 2 CH 3 , R 13 is F, R 12 is H; R 32 is H, and R 33 is CF 3 ;
  • R 11 is H, R 12 is CH 2 CF 3 , R 13 is Cl; R 32 is H, R 33 is OCH 2 CH 3 ;
  • R 11 is H
  • R 12 is OCH 3
  • R 13 is F
  • R 32 is OCF 3
  • R 33 is H
  • R 11 is Cl; R 12 , R 13 and R 14 are H;
  • R 11 and R 12 are F; R 13 and R 14 are H;
  • R 11 is Cl, R 12 is F; R 13 and R 14 are H;
  • R 11 and R 12 are Cl; R 13 and R 14 are H;
  • R 12 and R 13 are F; R 11 and R 14 are H;
  • R 11 and R 13 are Cl; R 12 and R 14 are H;
  • R 11 is Cl, R 13 is F; R 12 and R 14 are H;
  • R 11 is Cl, R 13 is CF 3 ; R 12 and R 14 are H;
  • R 11 is Br, R 13 is Cl; R 12 and R 14 are H;
  • R 11 is Cl, R 14 is F; R 12 and R 13 are H;
  • R 11 is CH 3 , R 13 is Cl; R 12 and R 14 are H;
  • R 11 is F
  • R 12 is CH 2 CH 3
  • R 13 and R 14 are H
  • R 11 is Cl, R 13 is OCF 3 ; R 12 and R 14 are H;
  • R 11 is CF 3 , R 13 is Br; R 12 and R 14 are H;
  • R 11 is CHCl 2 , R 13 is Cl; R 12 and R 14 are H;
  • R 11 is F
  • R 12 is OCH (CH 3 ) 2
  • R 13 and R 14 are H
  • R 11 and R 12 are H, R 13 is OCH (CH 3 ) 2 , and R 14 is Cl;
  • R 11 is Br
  • R 13 is CH 2 CF 3
  • R 12 and R 14 are H
  • R 11 is F
  • R 12 is CH 2 Cl
  • R 13 and R 14 are H
  • R 11 is F
  • R 12 is CH 3
  • R 13 and R 14 are H.
  • a second aspect of the invention provides a method of preparing compound pyrazinamide, pyrazinamide compound having the structural formula (I) of formula (II) or Formula (III) shown, The method includes: contacting a compound represented by formula (2-1) with a compound represented by formula (2-21), formula (2-22) or formula (2-23);
  • R 11 , R 12 , R 13 , R 14 , R 32 and R 32 are as defined in the foregoing description of the present invention.
  • the substituents in the pyrazinamide compounds of the structure represented by the formula (I), the formula (II), and the formula (III) in the second aspect of the present invention and thereafter are the same as those described in the first aspect of the present invention.
  • the amide compounds have the same substituents.
  • the present invention does not repeat the specific types of pyrazinamide compounds, and those skilled in the art should not understand the invention as a limitation.
  • the method of the present invention does not specifically limit the source of the compound represented by the formula (2-1) and the compounds represented by the formula (2-21), (2-22), or (2-23)
  • it can be obtained commercially, or it can be designed and synthesized according to the different conventional substituents in the art.
  • the method for preparing a pyrazinamide compound according to the present invention further includes preparing a compound represented by formula (2-1) according to the following steps:
  • the "first contact” and the “second contact” are only for distinguishing the contact process of different raw materials.
  • the conditions of the first contact include: a temperature of 0-120 ° C and a time of 0.5-48h.
  • the first contacting is performed in the presence of at least one solvent selected from ethyl acetate and water.
  • the molar ratio of the compound represented by the formula (2-3) with ethylenediamine hydrochloride and sodium azide may be 1: (0.8-2.4): (1-10).
  • the amount of the palladium-carbon catalyst there is no particular requirement on the amount of the palladium-carbon catalyst, and it can be a conventionally used amount in the art.
  • the step of first contacting the compound represented by the formula (2-3) with ethylenediamine hydrochloride includes: mixing sodium azide with water and ethylenediamine hydrochloride, and then adding a solvent thereto. There is an ethyl acetate solution of the compound represented by formula (2-3), and then a palladium-carbon catalyst is added, and the mixture is first stirred at 0-50 ° C for 0.5-4h, then heated at 5-50 ° C for 0.5-4h, and finally under reflux conditions. Under reaction for 0.2-40h.
  • the compound represented by the formula (2-4) obtained after the first contact between the compound represented by the formula (2-3) and ethylenediamine hydrochloride is first passed through the conventionally used in the art.
  • the treatment means is post-processed and then introduced into the next step to react with lithium hydroxide.
  • the compound represented by the formula (2-1) is prepared by a process route shown in reaction formula 1, specifically: the compound represented by the formula (2-5) is subjected to a substitution reaction.
  • the compound represented by the formula (2-3) is subjected to a ring-forming reaction with ethylenediamine hydrochloride
  • the compound represented by the formula (2-4) is subjected to a ring-forming reaction with ethylenediamine hydrochloride
  • a compound represented by the formula (2-4) is hydrolyzing the compound represented by the formula (2-4) to obtain a compound represented by the formula (2-1).
  • the step of subjecting the compound represented by the formula (2-4) and lithium hydroxide to a second contact includes: in the presence of tetrahydrofuran and water, combining the compound represented by the formula (2-4) with Lithium hydroxide is subjected to a second contact, and the conditions of the second contact include: a temperature of 0-50 ° C and a time of 0.1-4h.
  • the molar ratio of the compound represented by formula (2-4) to lithium hydroxide is 1: (1-8).
  • the product obtained after the second contact between the compound represented by the formula (2-4) and lithium hydroxide is preferably first adjusted to pH 1-6 with hydrochloric acid, and then extracted and separated to obtain the formula (2-1) ).
  • the conditions for contacting the compound represented by formula (2-1) with the compound represented by formula (2-21), formula (2-22) or formula (2-23) include: the temperature is 0-60 ° C, time is 1-72h.
  • the step of contacting the compound represented by formula (2-1) with the compound represented by formula (2-21), formula (2-22) or formula (2-23) includes: -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt), place the compound represented by formula (2-1) under N , N-dimethylformamide (DMF) is reacted at 0-60 ° C for 0.5-4h, and then the formula (2-21), formula (2-22) or formula (2-23) is added to the system And continue to react for 10-68h.
  • EDCI -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • the present invention provides a pyrazinamide compound prepared by the aforementioned method of the present invention.
  • the present invention provides the use of the aforementioned pyrazinamide compound as a succinate dehydrogenase inhibitor.
  • the pyrazinamide compound can be used for resistance to plant fungal diseases.
  • the plant fungal disease is at least one of rice sheath blight, strawberry gray mold, cucumber downy mildew, melons powdery mildew, soybean rust, corn rust and wheat powdery mildew.
  • the present invention provides a bactericide, which is composed of an active ingredient and an auxiliary material, the active ingredient including at least one of the aforementioned pyrazinamide compounds of the present invention.
  • the content of the active ingredient is 1-99.9% by weight; more preferably 5-95% by weight.
  • the dosage form of the bactericide is at least one selected from the group consisting of emulsifiable concentrate, suspending agent, wettable powder, powder, granule, aqueous preparation, poison bait, mother liquor and mother powder.
  • the auxiliary materials may be various auxiliary materials conventionally used in the art, and may be, for example, surfactants, solvents, and the like.
  • R 12 and R 13 are F; R 11 and R 14 are H; R 33 and R 32 are H; 90 2 R 12 is Cl, R 13 is F; R 11 and R 14 are H; R 33 and R 32 are H; 87 3 R 12 is F, R 13 is Cl; R 11 and R 14 are H; R 33 and R 32 are H; 89 4 R 11 is Cl, R 13 is OCF 3 ; R 12 and R 14 are H; R 33 and R 32 are H; 90 5 R 11 is Cl, R 14 is F; R 12 and R 13 are H; R 33 and R 32 are H; 91 6 R 11 is F, R 14 is Cl; R 12 and R 13 ; R 33 and R 32 are H; 70 7 R 11 is Br, R 13 is Cl; R 12 and R 14 are H; R 33 and R 32 are H; 90 8 R 13 is Cl; R 11 , R 12 and R 14 are H; R 33 and R 32 are H; 82 9 R 13 is OCH (CH 3 ) 2 ; R 11 and R 14 are H; R 33 and R 32 are
  • R 11 is Cl; R 12 , R 13 and R 14 are H 55 2 R 11 and R 12 are F; R 13 and R 14 are H 62 3 R 11 is Cl, R 12 is F; R 13 and R 14 are H 70 4 R 11 and R 12 are Cl; R 13 and R 14 are H 77 5 R 12 and R 13 are F; R 11 and R 14 are H 80 6 R 11 and R 13 are Cl; R 12 and R 14 are H 71 7 R 11 is Cl, R 13 is F; R 12 and R 14 are H 70 8 R 11 is Cl, R 13 is CF 3 ; R 12 and R 14 are H 60 9 R 11 is Br, R 13 is Cl; R 12 and R 14 are H 60 10 R 11 is Cl, R 14 is F; R 12 and R 13 are H 72
  • each target compound is as follows:
  • Test Example 1 Used to determine the inhibitory activity of a control agent and a target compound on succinate dehydrogenase.
  • the enzyme used in this test example is succinate dehydrogenase, which is prepared from pig hearts.
  • the test method is: a total volume of 1.8 mL, the system contains 100 mM Na 2 HPO 4 -NaH 2 PO 4 buffer (pH 7.4), 0.3 mM EDTA, 20 mM sodium succinate, 53 ⁇ M DCIP (2,6- Sodium dichloroindophenolate), 2nM succinate dehydrogenase. 23 °C constant temperature water bath and 600rpm magnetic stirring.
  • the reduction of the DCIP light absorption of the substrate was monitored at a wavelength of 600 nm, and the experimental points in the linear range were collected, that is, the experimental points for controlling the substrate consumption not to exceed 5%.
  • the molar extinction coefficient of DCIP is 21 mM -1 cm -1 . Calculate the reduction yield of DCIP during the reaction time and fit the linear slope, and then subtract the baseline slope to obtain the initial velocity of the reaction.
  • Table 3 lists the compounds obtained in the aforementioned preparation examples and the results of the NNF-0721 enzyme inhibitory activity test of the control agent.
  • Compound Inhibition rate% (10 ⁇ M, SQR) Compound IC 50 ( ⁇ M, SQR) I1 55.33 III1 1.25 ⁇ 0.12 I2 72.41 III2 3.40 ⁇ 0.01 I3 75.22 III3 2.72 ⁇ 0.12 I4 69.26 III4 0.90 ⁇ 0.01 I5 70.56 III5 4.18 ⁇ 0.01 I6 72.36 III6 1.14 ⁇ 0.12 I7 76.64 III7 2.67 ⁇ 0.11 I8 59.83 III8 1.23 ⁇ 0.12 I9 48.78 III9 0.83 ⁇ 0.01 I10 77.93 III10 3.49 ⁇ 0.12
  • Test example 2 screening results of bactericidal activity
  • Test method Each compound in Table 4 was formulated into a 5% by weight emulsifiable concentrate. All experiments used living pots, and the effective concentrations of the compounds were 200 mg / L.
  • a cucumber seedling of true leaf stage and consistent growth was selected, and dried for 24 hours after spray treatment.
  • Fresh spores on cucumber leaves covered with powdery mildew were washed and filtered with a double-layer gauze to prepare a suspension with a spore concentration of about 100,000 / mL and sprayed for inoculation.
  • the inoculated specimens were air-dried naturally, and then moved to the light of a constant temperature room (21-23 ° C). After 8 days, the incidence of the blank control was graded to investigate the incidence of disease.
  • Adopt leaf inoculation method Select two potted strawberry seedlings with consistent growth in the true leaf stage. After the pesticide spray-dried, connect the fungus cake to the leaves. After being kept in the dark at 22-26 °C for 24 hours, the natural light was restored for 4 days. After the onset of the control, the diameter of the spot at each inoculation point was measured with a caliper, and the% control effect was calculated.
  • the grading standard adopts the "Guidelines for Pesticide Field Tests of Pesticides", and the disease control index is used to calculate the prevention and treatment effect%.
  • Disease index ⁇ (number of diseased leaves at each level ⁇ relative value) ⁇ 100 / (total number of leaves ⁇ 9);
  • Control effect (%) (control disease index-treatment disease index) ⁇ 100 / control disease index;
  • the pyrazinamide compounds of the present invention exhibit a certain inhibitory activity against rice sheath blight, cucumber powdery mildew, and cucumber downy mildew at a concentration of 200 mg / L, especially to cucumber Powdery mildew has shown good control effects.
  • Test example 3 rescreening test
  • Test method Some compounds of the present invention (specifically shown in Table 5) are selected for re-screening, and each compound in Table 5 is formulated into a 5% by weight emulsifiable concentrate. All experiments were performed with living pots, and the effective concentrations of the compounds are shown in Table 5.
  • the compound of the present invention exhibits excellent control effects against cucumber powdery mildew or rice sheath blight.
  • Test Example 4 Screening results of bactericidal activity
  • Test method Each compound in Table 6 was formulated into a 5% by weight emulsifiable concentrate. All experiments used living pots, and the effective concentrations of the compounds are shown in Table 6.
  • Two-leaf stage soybean potted seedlings with uniform growth and uniform growth were selected for foliar spray treatment, and a blank control sprayed with clear water was set up. Repeat 3 times. The day after the treatment, the soybean rust spore suspension was inoculated. After the inoculation, it was placed in an artificial climate room (temperature: 20 ° C-25 ° C, relative humidity:> 95%) for moisturizing culture. After 8-16 hours, it was placed in a greenhouse (25 ° C ⁇ 1 ° C) ) Normal management. The control effect was investigated at 7 days after the blank control was fully developed.
  • the grading standard adopts the "Guidelines for Pesticide Field Tests of Pesticides", and the disease control index is used to calculate the prevention and treatment effect%.
  • Disease index ⁇ (number of diseased leaves at each level ⁇ relative value) ⁇ 100 / (total number of leaves ⁇ 9);
  • Control effect (%) (control disease index-treatment disease index) ⁇ 100 / control disease index;

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Abstract

本发明涉及农药杀菌剂领域，公开了吡嗪酰胺类化合物及其制备方法和应用以及杀菌剂，该化合物具有式(I)、式(II)或式(III)所示的结构。本发明通过引入NNF-0721中的吡嗪环片段和具有广泛生物活性的二苯醚片段，设计出了具有全新结构的吡嗪酰胺类化合物，该吡嗪酰胺类化合物能够作为全新的琥珀酸脱氢酶抑制剂或杀菌剂。

Description

吡嗪酰胺类化合物及其制备方法和应用以及杀菌剂 技术领域
本发明涉及农药杀菌剂领域，具体地，涉及一种吡嗪酰胺类化合物、一种制备吡嗪酰胺类化合物的方法以及由该方法制备得到的吡嗪酰胺类化合物、吡嗪酰胺类化合物作为琥珀酸脱氢酶抑制剂的应用和一种杀菌剂。
背景技术
琥珀酸脱氢酶抑制剂(SDHIs,succinate dehydrogenase inhibitors)类杀菌剂是通过作用于病原菌线粒体呼吸电子传递链上的复合体II(也称琥珀酸脱氢酶或琥珀酸泛醌还原酶)干扰呼吸电子传递链上琥珀酸脱氢酶来抑制线粒体功能，阻止其产生能量，抑制病原菌生长，最终导致其死亡，以达到防治病害的目的的。
琥珀酸脱氢酶抑制剂类杀菌剂因其高效、广谱的杀菌活性和环境友好的特点，近年来已经成为最有发展前景的一类杀菌剂，受到世界各大农药公司关注。
2014年新公开的一个杀菌剂为日本农药株式会社开发的琥珀酸脱氢酶抑制剂(SDHI)类杀菌剂Pyraziflumid(试验代号NNF-0721)，主要用于防治水稻、水果和蔬菜上的白粉病、黑星病、灰霉病、菌核病、轮纹病、果斑病及钱斑病等，使用剂量为100-375g/hm 2，预计2018年在日本上市。
发明内容
本发明的目的之一是提供一种具有广谱抑菌和杀菌活性的吡嗪酰胺类化合物。
本发明的目的之二是提供一种能够作为琥珀酸脱氢酶抑制剂的吡嗪酰胺类化合物。
本发明的目的之三是提供一种能够作为杀菌剂的主要活性成分的吡嗪酰胺类化合物。
为了实现上述目的，第一方面，本发明提供一种吡嗪酰胺类化合物，该化合物具有式(I)、式(II)或式(III)所示的结构：
Figure PCTCN2018103826-appb-000001
其中，
在式(I)中，R 11、R 12、R 13和R 14各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素；
在式(II)中，R 11、R 12和R 13各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-4的烷基时，R 11和R 13不为相同的卤素；
在式(III)中，R 11、R 12、R 13和R 14各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同 时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。
第二方面，本发明提供一种制备吡嗪酰胺类化合物的方法，该吡嗪酰胺类化合物具有式(I)、式(II)或式(III)所示的结构，该方法包括：将式(2-1)所示的化合物与式(2-21)、式(2-22)或式(2-23)所示的化合物接触；
Figure PCTCN2018103826-appb-000002
其中，R 11、R 12、R 13、R 14、R 32和R 33的定义如本发明前述所述。
第三方面，本发明提供由本发明前述的方法制备得到的吡嗪酰胺类化合物。
第四方面，本发明提供前述吡嗪酰胺类化合物作为琥珀酸脱氢酶抑制剂的应用。
第五方面，本发明提供一种杀菌剂，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吡嗪酰胺类化合物中的至少一种。
本发明通过引入NNF-0721中的吡嗪环片段和具有广泛生物活性的二苯醚片段，设计出了具有全新结构的吡嗪酰胺类化合物，该吡嗪酰胺类化合物能够作为全新的琥珀酸脱氢酶抑制剂或杀菌剂。
本发明提供的前述吡嗪酰胺类化合物具有明显的琥珀酸脱氢酶抑制活性以及对水稻纹枯病、草莓灰霉病、黄瓜霜霉病、瓜类白粉病、大豆锈病、玉米锈病和小麦白粉病均具有一定的抑制活性，较现有技术中的药剂具有明显的广谱性优势，其中所述瓜类白粉病包括例如黄瓜白粉病等。
同时，本发明提供的制备吡嗪酰胺类化合物的方法所涉及的原料廉价易得，反应条件温和，后处理简单。
并且，本发明通过具体实例中的数据证实了本发明的吡嗪酰胺类化合物可作为良好的琥珀酸脱氢酶抑制剂，且具有良好的杀菌活性。
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。
如前所述，本发明的 第一方面提供了一种吡嗪酰胺类化合物，该化合物具有式(I)、式(II)或式(III)所示的结构：
Figure PCTCN2018103826-appb-000003
其中，
在式(I)中，R 11、R 12、R 13和R 14各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由 1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素；
在式(II)中，R 11、R 12和R 13各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-4的烷基时，R 11和R 13不为相同的卤素；
在式(III)中，R 11、R 12、R 13和R 14各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。
本发明前述卤素表示选自氟元素、氯元素、溴元素和碘元素中的至少一种元素。
“C 1-4的烷基”表示，碳原子数为1-4的烷基，例如可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。针对“C 1-4的烷氧基”也有相似的定义，例如可以为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基。
“由1-4个卤素取代的C 1-4的烷基”表示，碳原子数为1-4的烷基，且该烷基上的1-4个H被卤素取代。针对“由1-4个卤素取代的C 1-4的烷氧基”也有相似的定义。
优选地，在式(I)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、I、C 1-3的烷基、C 1-3的烷氧基、由1-4个卤素取代的C 1-3的烷基和由1-4个卤素取代的C 1-3的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素。更优选地，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、异丙基、三氟甲基、异丙氧基和三氟甲氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素。
优选地，在式(II)中，R 11、R 12和R 13各自独立地选自H、F、Cl、Br、I、C 1-3的烷基、C 1-3的烷氧基、由1-4个卤素取代的C 1-3的烷基和由1-4个卤素取代的C 1-3的烷氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、F、Cl、Br、I、C 1-3的烷基、C 1-3的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-3的烷氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-3的烷基时，R 11和R 13不为相同的卤素。更优选地，R 11、R 12和R 13各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、三氟甲基和三氟甲氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、异丙氧基、三氟甲基和三氟甲氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-3的烷基时，R 11和R 13不为相同的卤素。
优选地，在式(III)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、I、C 1-3的烷基、C 1-3的烷氧基、由1-4个卤素取代的C 1-3的烷基和由1-4个卤素取代的C 1-3的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。更优选地，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、异丙氧基、甲氧基、三氟甲基和三氟甲氧基，且R 11、R 12、R 13和R 14不同时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。
“由1-4个卤素取代的C 1-4的烷基”表示，碳原子数为1-4的烷基，且该烷基上的1-4个H被选自F、Cl、Br和I的卤素取代。
根据一种优选的具体实施方式，在式(I)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素；
在式(II)中，R 11、R 12和R 13各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-4的烷基时，R 11和R 13不为相同的卤素；
在式(III)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。
根据第二种优选的具体实施方式，在式(I)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、异丙基、三氟甲基、异丙氧基和三氟甲氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素；
在式(II)中，R 11、R 12和R 13各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、三氟甲基和三氟甲氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、异丙氧基、三氟甲基和三氟甲氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-3的烷基时，R 11和R 13不为相同的卤素；
在式(III)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、异丙氧基、甲氧基、三氟甲基和三氟甲氧基，且R 11、R 12、R 13和R 14不同时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。
根据另一种优选的具体实施方式，所述吡嗪酰胺类化合物为以下中的至少一种，且化合物I1-化合物I21具有式(I)所示的结构，化合物II1-化合物II13具有式(II)所示的结构，化合物III1-化合物III20具有式(III)所示的结构：
化合物I1：R 12和R 13为F；R 11和R 14为H；
化合物I2：R 12为Cl，R 13为F；R 11和R 14为H；
化合物I3：R 12为F，R 13为Cl；R 11和R 14为H；
化合物I4：R 11为Cl，R 13为OCF 3；R 12和R 14为H；
化合物I5：R 11为Cl，R 14为F；R 12和R 13为H；
化合物I6：R 11为F，R 14为Cl；R 12和R 13为H；
化合物I7：R 11为Br，R 13为Cl；R 12和R 14为H；
化合物I8：R 13为Cl；R 11、R 12和R 14为H；
化合物I9：R 13为OCH(CH 3) 2；R 11、R 12和R 14为H；
化合物I10：R 11和R 14为Cl；R 12和R 13为H；
化合物I11：R 13为OCF 3；R 11、R 12和R 14为H；
化合物I12：R 11为CH 3，R 14为CH(CH 3) 2；R 12和R 13为H；
化合物I13：R 11为Br，R 13为CF 3；R 12和R 14为H；
化合物I14：R 11为OCH 3，R 13为Cl；R 12和R 14为H；
化合物I15：R 11为Cl，R 13为CHCl 2，R 12和R 14为H；
化合物I16：R 11为Cl，R 13为CHF 2，R 12和R 14为H；
化合物I17：R 11为Br，R 13为CH 2CH 3，R 12和R 14为H；
化合物I18：R 11为Br，R 14为CH 3，R 12和R 13为H；
化合物I19：R 11为OCH 2CH 3，R 13为CH 3，R 12和R 14为H；
化合物I20：R 11为F，R 13为CH 2Cl，R 12和R 14为H；
化合物I21：R 11为CH 2CF 3，R 14为CH 3，R 12和R 13为H；
化合物II1：R 11和R 13为Cl，R 12为H；R 33为F，R 32为H；
化合物II2：R 11为Cl，R 13为CF 3；R 12为H；R 33为CH 3，R 32为H；
化合物II3：R 11为Cl，R 13为CF 3；R 12为H；R 33为H，R 32为CH 3；
化合物II4：R 11为Cl，R 13为CF 3；R 12为H；R 33为F，R 32为H；
化合物II5：R 11为Cl，R 13为CF 3；R 12为H；R 33为H，R 32为F；
化合物II6：R 11为CH 3，R 13为CF 3；R 12为H；R 33为CH 2CF 3，R 32为CH 3；
化合物II7：R 11为OCF 3，R 13为Cl；R 12为H；R 33为Cl，R 32为CH(CH 3) 2；
化合物II8：R 11为CH 2CH 3，R 13为F；R 12为H；R 32为CHCl 2，R 33为OCH 3；
化合物II9：R 11为CHCl 2，R 13为Cl；R 12为H；R 33为F，R 32为CH 2CH 3；
化合物II10：R 11为CH(CH 3) 2，R 13为Br，R 12为H；R 33为Br，R 32为CH 3；
化合物II11：R 11为OCH 2CH 3，R 13为F，R 12为H；R 32为H，R 33为CF 3；
化合物II12：R 11为H，R 12为CH 2CF 3，R 13为Cl；R 32为H，R 33为OCH 2CH 3；
化合物II13：R 11为H，R 12为OCH 3，R 13为F；R 32为OCF 3，R 33为H；
化合物III1：R 11为Cl；R 12、R 13和R 14为H；
化合物III2：R 11和R 12为F；R 13和R 14为H；
化合物III3：R 11为Cl，R 12为F；R 13和R 14为H；
化合物III4：R 11和R 12为Cl；R 13和R 14为H；
化合物III5：R 12和R 13为F；R 11和R 14为H；
化合物III6：R 11和R 13为Cl；R 12和R 14为H；
化合物III7：R 11为Cl，R 13为F；R 12和R 14为H；
化合物III8：R 11为Cl，R 13为CF 3；R 12和R 14为H；
化合物III9：R 11为Br，R 13为Cl；R 12和R 14为H；
化合物III10：R 11为Cl，R 14为F；R 12和R 13为H；
化合物III11：R 11为CH 3，R 13为Cl；R 12和R 14为H；
化合物III12：R 11为F，R 12为CH 2CH 3；R 13和R 14为H；
化合物III13：R 11为Cl，R 13为OCF 3；R 12和R 14为H；
化合物III14：R 11为CF 3，R 13为Br；R 12和R 14为H；
化合物III15：R 11为CHCl 2，R 13为Cl；R 12和R 14为H；
化合物III16：R 11为F，R 12为OCH(CH 3) 2；R 13和R 14为H；
化合物III17：R 11和R 12为H，R 13为OCH(CH 3) 2，R 14为Cl；
化合物III18：R 11为Br，R 13为CH 2CF 3，R 12和R 14为H；
化合物III19：R 11为F，R 12为CH 2Cl；R 13和R 14为H；
化合物III20：R 11为F，R 12为CH 3；R 13和R 14为H。
如前所述，本发明的 第二方面提供了一种制备吡嗪酰胺类化合物的方法，该吡嗪酰胺类化合 物具有式(I)、式(II)或式(III)所示的结构，该方法包括：将式(2-1)所示的化合物与式(2-21)、式(2-22)或式(2-23)所示的化合物接触；
Figure PCTCN2018103826-appb-000004
其中，R 11、R 12、R 13、R 14、R 32和R 32的定义如本发明前述所述。
本发明第二方面及以后所涉及的式(I)、式(II)和式(III)所示结构的吡嗪酰胺类化合物中的取代基均与本发明第一方面中所述的吡嗪酰胺类化合物的取代基相同，为了避免重复，本发明不再对吡嗪酰胺类化合物的具体种类进行赘述，本领域技术人员不应理解为对本发明的限制。
并且，本发明式(2-1)所示的化合物和式(2-21)、式(2-22)、式(2-23)所示的化合物中的取代基均与式(I)、式(II)、式(III)所示结构的吡嗪酰胺类化合物中的取代基对应相同。
本发明的方法对所述式(2-1)所示的化合物和所述式(2-21)、式(2-22)、式(2-23)所示的化合物的来源没有特别的限定，例如可以通过商购获得，也可以根据取代基的不同，选择本领域常规的合成方法设计合成。
优选情况下，本发明所述的制备吡嗪酰胺类化合物的方法还包括按照以下步骤制备式(2-1)所示的化合物：
(1)在叠氮钠和钯碳催化剂存在下，将式(2-3)所示的化合物与乙二胺盐酸盐进行第一接触，得到式(2-4)所示的化合物；
(2)将所述式(2-4)所示的化合物与氢氧化锂进行第二接触；
Figure PCTCN2018103826-appb-000005
所述“第一接触”和所述“第二接触”仅是为了区分不同原料的接触过程。
优选情况下，所述第一接触的条件包括：温度为0-120℃，时间为0.5-48h。
优选地，所述第一接触在选自乙酸乙酯和水中的至少一种溶剂存在下进行。
所述式(2-3)所示的化合物与乙二胺盐酸盐、叠氮钠的用量摩尔比可以为1：(0.8-2.4)：(1-10)。
对所述钯碳催化剂的用量没有特别的要求，可以为本领域内常规使用的催化量。
优选情况下，将式(2-3)所示的化合物与乙二胺盐酸盐进行第一接触的步骤包括：将叠氮钠与水和乙二胺盐酸盐混合，然后向其中加入溶有式(2-3)所示的化合物的乙酸乙酯溶液，再加入钯碳催化剂，先在0-50℃下搅拌0.5-4h，然后升温5-50℃反应0.5-4h，最后在回流条件下反应0.2-40h。
优选情况下，由式(2-3)所示的化合物与乙二胺盐酸盐进行第一接触后得到的所述式(2-4)所示的化合物先经过本领域内常规采用的后处理手段进行后处理，然后再引入至下一个步骤中与氢氧化锂反应。
根据一种优选的具体实施方式，所述式(2-1)所示的化合物通过反应式1所示的工艺路线制 得，具体地：将式(2-5)所示的化合物进行取代反应，以得到式(2-3)所示的化合物；进一步地，在叠氮钠和钯碳催化剂存在下，将式(2-3)所示的化合物与乙二胺盐酸盐进行成环反应，得到式(2-4)所示的化合物；进一步地，将式(2-4)所示的化合物进行水解，以得到式(2-1)所示的化合物。
反应式1：
Figure PCTCN2018103826-appb-000006
优选情况下，将所述式(2-4)所示的化合物与氢氧化锂进行第二接触的步骤包括：在四氢呋喃和水存在下，将所述式(2-4)所示的化合物与氢氧化锂进行第二接触，所述第二接触的条件包括：温度为0-50℃，时间为0.1-4h。优选地，所述式(2-4)所示的化合物与氢氧化锂的用量摩尔比为1：(1-8)。由所述式(2-4)所示的化合物与氢氧化锂进行第二接触后得到的产物优选先用盐酸调节pH值至1-6，然后萃取并分离以得到所述式(2-1)所示的化合物。
优选情况下，优选地，将式(2-1)所示的化合物与式(2-21)、式(2-22)或式(2-23)所示的化合物接触的条件包括：温度为0-60℃，时间为1-72h。
更加优选地，将式(2-1)所示的化合物与式(2-21)、式(2-22)或式(2-23)所示的化合物接触的步骤包括：在1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和1-羟基苯并三唑(HOBt)存在下，将式(2-1)所示的化合物置于N,N-二甲基甲酰胺(DMF)中在0-60℃下反应0.5-4h，然后向体系中加入式(2-21)、式(2-22)或式(2-23)所示的化合物并继续反应10-68h。
第三方面，本发明提供了由本发明前述的方法制备得到的吡嗪酰胺类化合物。
第四方面，本发明提供了前述吡嗪酰胺类化合物作为琥珀酸脱氢酶抑制剂的应用。
优选地，在本发明的所述应用中，所述吡嗪酰胺类化合物能够用于抗植物真菌病。
优选地，所述植物真菌病为水稻纹枯病、草莓灰霉病、黄瓜霜霉病、瓜类白粉病、大豆锈病、玉米锈病和小麦白粉病中的至少一种。
第五方面，本发明提供了一种杀菌剂，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吡嗪酰胺类化合物中的至少一种。
优选地，在所述杀菌剂中，所述活性成分的含量为1-99.9重量％；更优选为5-95重量％。
优选地，所述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。
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。
制备例1：根据反应式1制备式(2-3)所示的化合物
在100mL圆底烧瓶中加入三氟乙酰乙酸乙酯(50mmol)，在0℃下，缓慢滴加磺酰氯(55mmol)，25℃搅拌反应12h后停止反应，加入200mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压除去溶剂后得透明液体(收率为90％)，不经进一步纯化，直接投入下一步反应。
制备例2：根据反应式1制备式(2-4)所示的化合物
在100mL圆底烧瓶中加入4mL水和16.5mmol乙二胺盐酸盐，缓慢加入叠氮钠(27.3mmol)，再缓慢滴加8mL溶有制备例1所得中间体(13.7mmol)的乙酸乙酯溶液，再加入0.68g的10重量％ 的钯碳催化剂和2mL乙酸乙酯，25℃搅拌反应2h后，升温至35℃反应1h，然后回流反应2h后停止反应，硅藻土过滤后加入50mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压除去溶剂后得黄色固体(收率为60％)，不经进一步纯化，直接投入下一步反应。
制备例3：根据反应式1制备式(2-1)所示的化合物
在100mL圆底烧瓶中加入制备例2制备得到的中间体(2mmol)，再加入一水合氢氧化锂(4mmol)，再加入10mL四氢呋喃和10mL水，25℃反应0.5h后停止反应，用2M盐酸调节pH至4，加入50mL乙酸乙酯萃取，有机相用饱食盐水洗涤，无水硫酸钠干燥，减压除去溶剂后得黄色固体(收率为84％)，不经进一步纯化，直接投入下一步反应。
制备例4：制备式(II-21)和式(II-22)所示的化合物，其中，取代基分别如表1中所示
Figure PCTCN2018103826-appb-000007
在50mL圆底烧瓶中加入7.1mmol的取代或未取代的2-氟硝基苯，10.6mmol式a所示的取代的苯酚(具体取代基如表1中所示)和10.6mmol的碳酸钾，再加入20mL的DMF后升温至100℃。TLC监测原料反应完全后停止反应，加入50mL乙醚后用30mL的2M的NaOH洗两次后再用50mL饱和食盐水洗1次，减压除去溶剂后得式b所示的2-硝基二苯醚。
分别在100mL圆底烧瓶中加入3.2mmol式b所示的2-硝基二苯醚和氯化铵(3.2mmol)，再加入50mL乙醇和6mL水，加热至回流后加入还原铁粉(9.6mmol)，TLC监测原料反应完毕后停止反应，硅藻土过滤后将滤液减压浓缩，除去大部分溶剂后加入50mL乙酸乙酯萃取，有机相用饱和食盐水洗后加入无水硫酸钠干燥，除去溶剂后得式(II-21)和式(II-22)所示的化合物(表1中命名为中间体，中间体的收率为一步反应的收率)，式(II-21)和式(II-22)所示的化合物的结构表征如下。
表1
序号 取代基情况 中间体收率/％
1 R 12和R 13为F；R 11和R 14为H；R 33和R 32为H； 90
2 R 12为Cl，R 13为F；R 11和R 14为H；R 33和R 32为H； 87
3 R 12为F，R 13为Cl；R 11和R 14为H；R 33和R 32为H； 89
4 R 11为Cl，R 13为OCF 3；R 12和R 14为H；R 33和R 32为H； 90
5 R 11为Cl，R 14为F；R 12和R 13为H；R 33和R 32为H； 91
6 R 11为F，R 14为Cl；R 12和R 13；R 33和R 32为H； 70
7 R 11为Br，R 13为Cl；R 12和R 14为H；R 33和R 32为H； 90
8 R 13为Cl；R 11、R 12和R 14为H；R 33和R 32为H； 82
9 R 13为OCH(CH 3) 2；R 11、R 12和R 14为H；R 33和R 32为H； 91
10 R 11和R 14为Cl；R 12和R 13；R 33和R 32为H； 90
11 R 13为OCF 3；R 11、R 12和R 14为H；R 33和R 32为H； 78
12 R 11为CH 3，R 14为CH(CH 3) 2；R 12和R 13为H；R 33和R 32为H； 80
13 R 11为Br，R 13为CF 3；R 12和R 14为H；R 33和R 32为H； 85
14 R 11和R 13为Cl，R 12和R 14为H；R 33为F，R 32为H； 75
15 R 11为Cl，R 13为CF 3；R 12和R 14为H；R 33为CH 3，R 32为H； 82
16 R 11为Cl，R 13为CF 3；R 12和R 14为H；R 33为H，R 32为CH 3； 65
17 R 11为Cl，R 13为CF 3；R 12和R 14为H；R 33为F，R 32为H； 77
18 R 11为Cl，R 13为CF 3；R 12和R 14为H；R 33为H，R 32为F 81
其中，表1中不同序号表示的不同的式(II-21)和式(II-22)所示的化合物的结构表征如下：
序号1： 1H NMR(600MHz,DMSO)δ7.37(d,J＝9.3Hz,1H),6.95(s,2H),6.82(s,2H),6.67(s,1H),6.55(s,1H),5.01(s,2H).GC-MS:m/z 221[M] +.
Figure PCTCN2018103826-appb-000008
序号2： 1H NMR(600MHz,DMSO)δ7.39(t,J＝9.0Hz,1H),7.07(dd,J＝6.0,2.9Hz,1H),6.99(t,J＝7.6Hz,1H),6.89(ddd,J＝23.8,12.2,5.9Hz,3H),6.60(dd,J＝11.1,4.0Hz,1H),5.05(s,2H).GC-MS:m/z 237[M] +.
Figure PCTCN2018103826-appb-000009
序号3： 1H NMR(600MHz,DMSO)δ7.51(t,J＝8.8Hz,1H),6.98(t,J＝7.5Hz,1H),6.95–6.91(m,1H),6.88(d,J＝7.7Hz,1H),6.83(dd,J＝7.9,1.1Hz,1H),6.69(d,J＝8.9Hz,1H),6.58(t,J＝7.5Hz,1H),5.04(s,2H).GC-MS:m/z 237[M] +.
Figure PCTCN2018103826-appb-000010
序号4： 1H NMR(500MHz,DMSO)δ7.68(d,J＝1.8Hz,1H),7.31(d,J＝9.1Hz,1H),6.97(t,J＝7.6Hz,1H),6.85(d,J＝7.9Hz,1H),6.82–6.76(m,2H),6.57(t,J＝7.6Hz,1H),5.01(s,2H).GC-MS:m/z 303[M] +.
Figure PCTCN2018103826-appb-000011
序号5： 1H NMR(500MHz,DMSO)δ7.59(dd,J＝8.8,6.0Hz,1H),6.97(dt,J＝8.9,5.2Hz,2H),6.86(d,J＝7.9Hz,1H),6.81(d,J＝7.9Hz,1H),6.58(t,J＝7.6Hz,1H),6.50(dd,J＝10.1,2.7Hz,1H),5.00(s,2H).GC-MS:m/z 237[M] +.
Figure PCTCN2018103826-appb-000012
序号6： 1H NMR(500MHz,DMSO)δ7.43–7.36(m,1H),7.16–7.11(m,1H),6.98(t,J＝7.6Hz,1H),6.84(dd,J＝14.4,7.9Hz,2H),6.73(dd,J＝7.2,2.1Hz,1H),6.57(t,J＝7.6Hz,1H),5.08(s,2H).GC-MS:m/z 237[M] +.
Figure PCTCN2018103826-appb-000013
序号7： 1H NMR(500MHz,DMSO)δ7.81(d,J＝2.3Hz,1H),7.38(dd,J＝8.8,2.3Hz,1H),6.96 (t,J＝7.4Hz,1H),6.84(d,J＝7.9Hz,1H),6.73(dd,J＝13.2,8.4Hz,2H),6.56(t,J＝7.5Hz,1H),4.96(s,2H).GC-MS:m/z 298[M] +.
Figure PCTCN2018103826-appb-000014
序号8： 1H NMR(500MHz,DMSO)δ7.36(d,J＝8.9Hz,2H),6.89(d,J＝8.9Hz,2H),6.82(d,J＝7.9Hz,2H),4.94(s,2H).GC-MS:m/z 219[M] +.
Figure PCTCN2018103826-appb-000015
序号9： 1H NMR(500MHz,DMSO)δ6.90–6.83(m,4H),6.78(d,J＝7.8Hz,1H),6.69(dt,J＝19.4,8.9Hz,2H),6.51(t,J＝7.5Hz,1H),4.87(s,2H),1.24(d,J＝6.0Hz,6H),1.21(s,1H).GC-MS:m/z243[M] +.
Figure PCTCN2018103826-appb-000016
序号10： 1H NMR(500MHz,DMSO)δ7.59(d,J＝8.6Hz,1H),7.16(dd,J＝8.5,1.4Hz,1H),7.00(t,J＝7.6Hz,1H),6.86(d,J＝7.9Hz,1H),6.82(d,J＝7.9Hz,1H),6.65(d,J＝1.3Hz,1H),6.59(t,J＝7.6Hz,1H),5.03(s,2H).GC-MS:m/z 253[M] +.
Figure PCTCN2018103826-appb-000017
序号11： 1H NMR(500MHz,DMSO)δ7.32(d,J＝8.7Hz,2H),7.00–6.93(m,3H),6.84(t,J＝8.4Hz,2H),6.57(t,J＝7.6Hz,1H),4.97(s,2H).GC-MS:m/z 269[M] +.
Figure PCTCN2018103826-appb-000018
序号12： 1H NMR(500MHz,DMSO)δ7.18(d,J＝7.7Hz,1H),6.90(d,J＝7.7Hz,1H),6.84(d,J＝7.4Hz,1H),6.79(d,J＝7.5Hz,1H),6.59(s,1H),6.54(d,J＝8.1Hz,1H),6.50(d,J＝7.2Hz,1H),4.90(s,2H),2.18(s,3H),1.14(s,1H),1.11(d,J＝6.9Hz,6H).GC-MS:m/z 241[M] +.
Figure PCTCN2018103826-appb-000019
序号13： 1H NMR(600MHz,DMSO)δ8.07(s,1H),7.67(d,J＝8.5Hz,1H),7.02(t,J＝7.5Hz,1H),6.88(d,J＝7.8Hz,2H),6.76(d,J＝8.6Hz,1H),6.60(t,J＝7.5Hz,1H),5.03(s,2H).GC-MS:m/z331[M] +.
Figure PCTCN2018103826-appb-000020
序号14： 1H NMR(500MHz,DMSO)δ7.68(s,1H),7.32(d,J＝8.7Hz,1H),6.78(d,J＝4.3Hz,1H),6.73(d,J＝8.6Hz,1H),6.60(d,J＝10.8Hz,1H),6.31(t,J＝8.3Hz,1H),5.32(s,2H).GC-MS:m/z271[M +].
Figure PCTCN2018103826-appb-000021
序号15： 11H NMR(600MHz,DMSO)δ7.94(s,1H),7.61(d,J＝8.8Hz,1H),6.76(t,J＝9.3Hz,2H),6.67(s,1H),6.40(d,J＝8.0Hz,1H),4.97(s,2H),2.21(s,3H).GC-MS:m/z 301[M +].
Figure PCTCN2018103826-appb-000022
序号16： 1H NMR(600MHz,DMSO)δ7.95(s,1H),7.63(d,J＝8.2Hz,1H),6.84(d,J＝7.5Hz,1H),6.80–6.76(m,2H),6.72(s,1H),4.85(s,2H),2.15(s,3H).GC-MS:m/z 301[M +].
Figure PCTCN2018103826-appb-000023
序号17： 1H NMR(600MHz,DMSO)δ7.93(s,1H),7.61(d,J＝6.1Hz,1H),6.94–6.86(m,1H),6.76(d,J＝8.3Hz,1H),6.65–6.57(m,1H),6.34(d,J＝2.7Hz,1H),5.42(s,2H).GC-MS:m/z 305[M +].
Figure PCTCN2018103826-appb-000024
序号18： 1H NMR(600MHz,DMSO)δ7.99(s,1H),7.65(d,J＝9.0Hz,1H),6.92–6.83(m,4H),4.97(s,2H).GC-MS:m/z 305[M +].
Figure PCTCN2018103826-appb-000025
制备例5：制备式(II-23)所示的化合物，其中，取代基分别如表2中所示
Figure PCTCN2018103826-appb-000026
在100mL圆底烧瓶中加入4mmol的2-氟苯甲醛，6mmol的式a所示的取代的苯酚(具体取代基参见表2)和8mmol的无水碳酸钾，再加入10mL的DMF后升温至100℃。TLC监测原料反应完 全后停止反应，加入50mL乙醚后用30mL的2M的NaOH洗两次后再用50mL的饱和食盐水洗1次，减压旋去溶剂后得式c所示的化合物。
在100mL圆底烧瓶中加入2mmol的式c化合物和盐酸羟胺(3mmol)，再加入10mL的乙醇，加热至回流，反应0.5h后冷却至25℃，加入锌粉(5mmol)，再缓慢滴加浓盐酸(0.67mL)，TLC监测原料反应完毕后停止反应，硅藻土过滤后将滤液减压浓缩，旋去大部分溶剂后加入50mL乙酸乙酯萃取，有机相用饱和食盐水洗后加入无水硫酸钠干燥，除去溶剂后柱层析得式(II-23)所示的化合物(式(II-23)所示的化合物收率为一步反应的收率)，式(II-23)所示的化合物的结构表征如下。
表2
序号 取代基情况 式(II-23)收率/％
1 R 11为Cl；R 12、R 13和R 14为H 55
2 R 11和R 12为F；R 13和R 14为H 62
3 R 11为Cl，R 12为F；R 13和R 14为H 70
4 R 11和R 12为Cl；R 13和R 14为H 77
5 R 12和R 13为F；R 11和R 14为H 80
6 R 11和R 13为Cl；R 12和R 14为H 71
7 R 11为Cl，R 13为F；R 12和R 14为H 70
8 R 11为Cl，R 13为CF 3；R 12和R 14为H 60
9 R 11为Br，R 13为Cl；R 12和R 14为H 60
10 R 11为Cl，R 14为F；R 12和R 13为H 72
其中，表2中不同序号表示的不同式(II-23)所示的化合物的结构表征如下：
序号1： 1H NMR(500MHz,DMSO)δ7.58(d,J＝7.6Hz,1H),7.55(d,J＝7.1Hz,1H),7.32(t,J＝7.3Hz,1H),7.22(t,J＝7.1Hz,1H),7.17(d,J＝7.1Hz,2H),6.92(d,J＝7.9Hz,1H),6.74(d,J＝7.6Hz,1H),3.73(s,2H).GC-MS:m/z 232[M] +.
Figure PCTCN2018103826-appb-000027
序号2： 1H NMR(500MHz,DMSO)δ7.57(d,J＝6.8Hz,1H),7.52(d,J＝7.1Hz,1H),7.26(d,J＝6.6Hz,1H),6.92(d,J＝7.9Hz,1H),6.88(d,J＝7.8Hz,1H),6.81–6.72(m,2H),3.75(s,2H).GC-MS:m/z 234[M] +.
Figure PCTCN2018103826-appb-000028
序号3： 1H NMR(600MHz,DMSO)δ7.59(d,J＝7.0Hz,1H),7.37–7.30(m,1H),7.30–7.25(m,1H),7.24–7.21(m,1H),7.21–7.15(m,1H),6.87(d,J＝7.7Hz,1H),6.69(d,J＝8.1Hz,1H),3.70(s,2H).GC-MS:m/z 250[M] +.
Figure PCTCN2018103826-appb-000029
序号4： 1H NMR(600MHz,DMSO)δ7.58(d,J＝7.4Hz,1H),7.41(d,J＝8.1Hz,1H),7.32(t,J＝8.2Hz,1H),7.26(t,J＝6.9Hz,1H),7.22(t,J＝7.3Hz,1H),6.84(t,J＝7.5Hz,2H),3.70(s,2H).GC-MS:m/z 266[M] +.
Figure PCTCN2018103826-appb-000030
序号5： 1H NMR(400MHz,DMSO)δ7.53(d,J＝7.4Hz,1H),7.39(dd,J＝19.5,9.4Hz,1H),7.21(ddd,J＝22.9,11.0,6.5Hz,2H),7.06(ddd,J＝11.9,6.7,2.9Hz,1H),6.88(d,J＝7.9Hz,1H),6.74–6.68(m,1H),3.66(s,2H).GC-MS:m/z 239[M] +.
Figure PCTCN2018103826-appb-000031
序号6： 1H NMR(500MHz,DMSO)δ7.75(s,1H),7.56(d,J＝6.5Hz,1H),7.39(d,J＝6.3Hz,1H),7.25(s,1H),7.19(s,1H),6.92(s,1H),6.79(d,J＝7.9Hz,1H),3.72(s,2H).GC-MS:m/z 266[M] +.
Figure PCTCN2018103826-appb-000032
序号7： 1H NMR(500MHz,DMSO)δ7.60(d,J＝8.2Hz,1H),7.54(d,J＝6.9Hz,1H),7.26–7.17(m,2H),7.15(d,J＝6.9Hz,1H),7.08–7.00(m,1H),6.67(d,J＝7.8Hz,1H),3.76(s,2H).GC-MS:m/z250[M] +.
Figure PCTCN2018103826-appb-000033
序号8： 1H NMR(400MHz,DMSO)δ7.53(d,J＝7.4Hz,1H),7.39(dd,J＝19.5,9.4Hz,1H),7.21(ddd,J＝22.9,11.0,6.5Hz,2H),7.06(ddd,J＝11.9,6.7,2.9Hz,1H),6.88(d,J＝7.9Hz,1H),6.74–6.68(m,1H),3.66(s,2H).GC-MS:m/z 300[M] +.
Figure PCTCN2018103826-appb-000034
序号9： 1H NMR(600MHz,DMSO)δ7.87(d,J＝2.2Hz,1H),7.57(d,J＝7.3Hz,1H),7.42(dd,J＝8.8,2.3Hz,1H),7.25(t,J＝7.7Hz,1H),7.20(t,J＝7.4Hz,1H),6.87(d,J＝8.8Hz,1H),6.80(d,J＝7.9Hz,1H),3.70(s,2H).GC-MS:m/z 312[M] +.
Figure PCTCN2018103826-appb-000035
序号10： 1H NMR(400MHz,DMSO)δ7.62(dd,J＝8.8,5.9Hz,1H),7.55(d,J＝6.0Hz,1H),7.22(ddd,J＝16.6,10.5,4.0Hz,2H),7.03(td,J＝8.5,2.9Hz,1H),6.83(d,J＝7.5Hz,1H),6.70(dd,J＝9.8,2.8Hz,1H),3.69(s,2H).
Figure PCTCN2018103826-appb-000036
制备例6：制备式(I)、式(II)和式(III)所示的化合物
在100mL圆底烧瓶中加入式(2-1)所示的化合物(2mmol)，EDCI(2.4mmol)，HOBt(2.4mmol)和10mL的DMF，25℃下反应1h。然后将式(2-21)、式(2-22)或式(2-23)所示的化合物(2.4mmol)加入到上述溶液，25℃下反应24h，除去溶剂后柱层析得目标产物(目标产物的收率为一步反应的收率)。
具体地，各目标化合物的结构和表征数据如下：
化合物I1：收率41％,mp＝101-102℃. 1H NMR(500MHz,DMSO)δ10.52(s,1H),9.02(d,J＝20.9Hz,2H),8.15(d,J＝5.9Hz,1H),7.46(d,J＝8.9Hz,1H),7.24(d,J＝8.3Hz,3H),7.02(d,J＝6.3Hz,1H),6.88(s,1H).HRMS(MALDI)计算值C 17H 10ClF 2N 3O 2[M+H] +:396.07659,实测值396.07433.
Figure PCTCN2018103826-appb-000037
化合物I2：收率47％,mp＝111-112℃. 1H NMR(500MHz,DMSO)δ10.51(s,1H),9.02(d,J＝20.0Hz,2H),8.14(d,J＝7.7Hz,1H),7.44(t,J＝9.0Hz,1H),7.34–7.18(m,3H),7.08–6.95(m,2H).HRMS(MALDI)计算值C 17H 9ClF 3N 3O 2[M+H] +:412.04704,实测值412.04450.
Figure PCTCN2018103826-appb-000038
化合物I3：收率59％,mp＝138.-139℃. 1H NMR(500MHz,DMSO)δ10.51(s,1H),9.15–8.93(m,2H),8.14(d,J＝7.7Hz,1H),7.57(dd,J＝11.4,5.9Hz,1H),7.41–7.22(m,3H),7.21–7.04(m,2H),6.86(d,J＝8.7Hz,1H).HRMS(MALDI)计算值C 18H 12BrF 2N 3O 2[M+H] +:412.04704,实测值412.04612.
Figure PCTCN2018103826-appb-000039
化合物I4：收率48％. 1H NMR(400MHz,DMSO)δ10.58(s,1H),9.04(d,J＝2.0Hz,1H),9.00(d,J＝2.1Hz,1H),8.14(dd,J＝7.8,1.5Hz,1H),7.77(d,J＝2.3Hz,1H),7.42(d,J＝8.7Hz,1H),7.29–7.12(m,3H),6.88(d,J＝7.9Hz,1H).HRMS(MALDI):计算值C 19H 10ClF 6N 3O 3[M+Na] +:500.02071，实测值:500.02099.
Figure PCTCN2018103826-appb-000040
化合物I5：收率49％. 1H NMR(400MHz,DMSO)δ10.59(s,1H),9.04(s,1H),9.00(s,1H),8.15(d,J＝7.7Hz,1H),7.65(dd,J＝8.7,6.1Hz,1H),7.20(ddd,J＝34.7,11.7,4.9Hz,3H),7.00(dd,J＝9.5,2.6Hz,1H),6.87(d,J＝7.9Hz,1H).HRMS(MALDI):计算值C 18H 10ClF 4N 3O 2[M+Na] +：434.02899，实测值：434.02916.
Figure PCTCN2018103826-appb-000041
化合物I6：收率78％. 1H NMR(400MHz,DMSO)δ9.47(s,1H),7.88(d,J＝19.7Hz,2H),7.01(d,J＝7.7Hz,1H),6.31(t,J＝9.5Hz,1H),6.22–5.98(m,5H),5.83(d,J＝7.7Hz,1H).HRMS(MALDI):计算值C 18H 10ClF 4N 3O 2[M+Na] +：434.02899，实测值：434.02911.
Figure PCTCN2018103826-appb-000042
化合物I7：收率62％. 1H NMR(400MHz,DMSO)δ10.58(s,1H),9.05(s,1H),9.00(s,1H),8.18(d,J＝7.6Hz,1H),7.90(t,J＝3.9Hz,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.29–7.07(m,3H),6.78(d,J＝7.8Hz,1H).HRMS(MALDI):计算值C 18H 10F 4N 3O 2[M+Na] +：493.94892，实测值：493.94859.
Figure PCTCN2018103826-appb-000043
化合物I8：收率34％. 1H NMR(600MHz,DMSO)δ10.50(s,1H),9.00(d,J＝25.1Hz,2H),8.15(d,J＝6.5Hz,1H),7.43(d,J＝8.8Hz,2H),7.27–7.17(m,2H),7.00(dd,J＝44.5,7.7Hz,3H).HRMS(MALDI):计算值C 18H 11ClF 3N 3O 2[M+Na] +：416.03841，实测值：416.03829.
Figure PCTCN2018103826-appb-000044
化合物I9：收率44％. 1H NMR(600MHz,DMSO)δ10.49(s,1H),9.03(s,1H),8.98(s,1H),8.18(d,J＝3.4Hz,1H),7.16–7.08(m,2H),6.99(d,J＝8.8Hz,2H),6.94(d,J＝8.7Hz,2H),6.78(d,J＝3.8Hz,1H),1.24(d,J＝5.8Hz,7H).HRMS(MALDI):计算值C 21H 18F 3N 3O 3[M+Na] +：440.11925，实测值：440.11966.
Figure PCTCN2018103826-appb-000045
化合物I10：收率50％.1H NMR(600MHz,DMSO)δ10.58(s,1H),9.02(d,J＝28.7Hz,2H),8.13(s,1H),7.63(s,1H),7.22(dd,J＝58.5,35.8Hz,4H),6.87(s,1H).HRMS(MALDI):计算值C18H10Cl2F3N3O2[M+Na]+：449.99944，实测值：449.99915.
Figure PCTCN2018103826-appb-000046
化合物I11：收率52％. 1H NMR(600MHz,DMSO)δ10.56(s,1H),9.04(s,1H),8.99(s,1H),8.13(s,1H),7.63(d,J＝8.7Hz,1H),7.37–7.17(m,4H),7.14(s,1H),6.87(d,J＝7.4Hz,1H).HRMS(MALDI):计算值C 19H 11F 6N 3O 3[M+Na] +：466.05968，实测值：466.05992.
Figure PCTCN2018103826-appb-000047
化合物I12：收率57％. 1H NMR(600MHz,DMSO)δ10.51(s,1H),9.05(s,1H),8.99(s,1H),8.20(s,1H),7.22(d,J＝7.6Hz,1H),7.10(s,2H),7.02(d,J＝7.3Hz,1H),6.85(s,1H),6.59(s,1H),2.08(s,3H),1.13(d,J＝6.7Hz,7H).HRMS(MALDI):计算值C 22H 20F 3N 3O 2[M+Na] +：438.13998，实测值：438.14075.
Figure PCTCN2018103826-appb-000048
化合物I13：收率70％. 1H NMR(600MHz,DMSO)δ10.55(s,1H),9.01(d,J＝24.6Hz,2H),8.13(s,2H),7.75(d,J＝8.0Hz,1H),7.32(s,1H),7.26(s,1H),7.09(d,J＝7.1Hz,1H),7.01(d,J＝7.9Hz,1H).HRMS(MALDI)计算值C 18H 11F 4N 3O 2[M+H] +:505.99334,实测值505.99058.
Figure PCTCN2018103826-appb-000049
化合物II1：收率50％,mp＝109-112℃. 1H NMR(500MHz,DMSO)δ10.71(s,1H),9.05(s,1H),9.01(s,1H),8.12(d,J＝10.3Hz,1H),7.77(s,1H),7.45(d,J＝8.5Hz,1H),7.13(d,J＝8.4Hz,1H),7.03(t,J＝8.0Hz,1H),6.91(d,J＝4.2Hz,1H).HRMS(MALDI)计算值C 18H 11F 4N 3O 2[M+H] +:446.00807,实测值446.00520.
Figure PCTCN2018103826-appb-000050
化合物II2：收率40％,mp＝107-108℃. 1H NMR(600MHz,DMSO)δ10.49(s,1H),9.03(s,1H),8.99(s,1H),8.01(s,1H),7.94(s,1H),7.68(d,J＝8.5Hz,1H),7.09(d,J＝8.4Hz,1H),7.04(d,J＝8.6Hz,1H),6.97(d,J＝8.3Hz,1H),2.37(s,3H).HRMS(MALDI)计算值C 18H 10Cl 2F 3N 3O 2[M+H] +:476.05950,实测值476.05858.
Figure PCTCN2018103826-appb-000051
化合物II3：收率56％,mp＝137-139℃. 1H NMR(600MHz,DMSO)δ10.48(s,1H),9.03(s,1H),8.99(s,1H),8.02(s,1H),7.96(d,J＝8.2Hz,1H),7.71(d,J＝8.2Hz,1H),7.14(d,J＝8.1Hz,1H),7.09(d,J＝8.6Hz,1H),6.89(s,1H),2.28(s,3H).HRMS(MALDI)计算值C 18H 10ClF 4N 3O 2[M+H] +:476.05950,实测值476.05917.
Figure PCTCN2018103826-appb-000052
化合物II4：收率39％,mp＝103-104℃. 1H NMR(600MHz,DMSO)δ10.74(s,1H),9.05(s,1H),9.01(s,1H),8.09(d,J＝10.3Hz,1H),8.04(s,1H),7.71(d,J＝8.3Hz,1H),7.17–7.10(m,3H).HRMS(MALDI)计算值C 18H 11F 4N 3O 2[M+H] +:480.03443,实测值480.03635.
Figure PCTCN2018103826-appb-000053
化合物II5：收率39％,mp＝133-135℃. 1H NMR(600MHz,DMSO)δ10.59(s,1H),9.04(s,1H),9.00(s,1H),8.08–8.03(m,2H),7.73(d,J＝7.7Hz,1H),7.26–7.17(m,2H),7.05(d,J＝9.4Hz,1H).HRMS(MALDI)计算值C 19H 10ClF 6N 3O 2[M+H] +:480.03443,实测值480.03396.
Figure PCTCN2018103826-appb-000054
化合物III1：收率48％,mp＝93-95℃. 1H NMR(500MHz,DMSO)δ9.30(s,1H),9.04(s,1H),8.98(s,1H),7.61(d,J＝7.4Hz,1H),7.47(d,J＝7.1Hz,1H),7.37(t,J＝7.0Hz,1H),7.28(t,J＝7.1Hz,1H),7.25–7.15(m,2H),7.07(d,J＝7.9Hz,1H),6.73(d,J＝7.8Hz,1H),4.59(s,2H).HRMS(MALDI)计算值C 18H 11ClF 3N 3O 2[M+H] +:408.07212,实测值408.07258.
Figure PCTCN2018103826-appb-000055
化合物III2：收率40％,mp＝94-96℃. 1H NMR(500MHz,DMSO)δ9.31(s,1H),9.03(s,1H),8.97(s,1H),7.49(d,J＝7.1Hz,1H),7.31(d,J＝7.0Hz,1H),7.28–7.17(m,3H),6.90(d,J＝8.0Hz,2H),4.59(s,2H).HRMS(MALDI)计算值C 18H 10Cl 2F 3N 3O 2[M+Na] +:432.07419,实测值432.07553.
Figure PCTCN2018103826-appb-000056
化合物III3：收率39％,mp＝97-99℃. 11H NMR(500MHz,DMSO)δ9.34(t,J＝5.7Hz,1H),9.04(d,J＝1.9Hz,1H),8.98(d,J＝2.0Hz,1H),7.49(t,J＝12.2Hz,1H),7.38(dd,J＝14.8,8.3Hz,1H),7.33(t,J＝7.6Hz,1H),7.23(dd,J＝11.9,5.5Hz,2H),6.86(dd,J＝13.9,8.2Hz,2H),4.57(d,J＝5.9Hz,2H).HRMS(MALDI)计算值C 19H 10ClF 6N 3O 2[M+H] +:426.06269,实测值426.06318.
Figure PCTCN2018103826-appb-000057
化合物III4：收率56％,mp＝123-125℃. 1H NMR(500MHz,DMSO)δ9.33(t,J＝5.8Hz,1H),9.04(d,J＝2.1Hz,1H),8.98(d,J＝2.1Hz,1H),7.50(d,J＝7.4Hz,1H),7.46(dd,J＝8.1,1.2Hz,1H),7.37(dd,J＝10.7,5.7Hz,1H),7.31(dd,J＝11.1,4.3Hz,1H),7.23(dd,J＝13.2,6.2Hz,1H),6.99(dd,J＝8.2,1.1Hz,1H),6.83(t,J＝6.6Hz,1H),4.58(d,J＝5.9Hz,2H).HRMS(MALDI)计算值C 18H 10ClF 4N 3O 2[M+Na] +:464.01509,实测值464.01565.
Figure PCTCN2018103826-appb-000058
化合物III5：收率38％,mp＝84-86℃. 1H NMR(500MHz,DMSO)δ9.30(t,J＝5.6Hz,1H),9.02(t,J＝8.3Hz,1H),8.97(d,J＝1.9Hz,1H),7.49(d,J＝7.4Hz,1H),7.45(dd,J＝19.5,9.5Hz,1H),7.36–7.29(m,1H),7.22(t,J＝7.4Hz,1H),7.14(ddd,J＝11.5,6.7,2.8Hz,1H),6.95(d,J＝8.0Hz,1H),6.88–6.83(m,1H),4.54(d,J＝5.8Hz,2H).HRMS(MALDI)计算值C 18H 10F 5N 3O 2[M+Na] +:432.07419,实测值432.07523.
Figure PCTCN2018103826-appb-000059
化合物III6：收率40％,mp＝107-108℃. 1H NMR(500MHz,CDCl 3)δ9.91(s,1H),8.86(s,1H),8.76(s,1H),8.65(d,J＝7.9Hz,1H),7.27(s,1H),7.17(d,J＝7.4Hz,1H),6.98(d,J＝7.8Hz,1H),6.71(s,2H).HRMS(MALDI)计算值C 18H 9F 6N 3O 2[M+H] +:442.03314,实测值442.03313.
Figure PCTCN2018103826-appb-000060
化合物III7：收率51％,mp＝103-104℃. 1H NMR(500MHz,CDCl 3)δ10.27(s,1H),8.66(d,J＝8.0Hz,1H),8.55(d,J＝10.0Hz,1H),8.52(s,1H),7.17(ddd,J＝15.0,12.8,5.5Hz,5H),7.05(t,J＝7.7Hz,1H),6.80(d,J＝8.0Hz,1H).HRMS(MALDI)计算值C 17H 11ClFN 3O 2[M+Na] +:448.04464,实测值448.04592.
Figure PCTCN2018103826-appb-000061
化合物III8：收率47％,mp＝119-120℃. 1H NMR(500MHz,DMSO)δ9.33(t,J＝5.7Hz,1H),9.03(d,J＝2.0Hz,1H),8.98(d,J＝2.1Hz,1H),8.02(d,J＝1.2Hz,1H),7.69(d,J＝8.6Hz,1H),7.54(d,J＝7.4Hz,1H),7.38(t,J＝7.1Hz,1H),7.33–7.27(m,1H),7.05(d,J＝8.6Hz,1H),7.00(dd,J＝12.9,6.0Hz,1H),4.54(d,J＝5.8Hz,2H).HRMS(MALDI)计算值C 17H 11Cl 2N 3O 2[M+Na] +:498.04144,实测值498.04236.
Figure PCTCN2018103826-appb-000062
化合物III9：收率62％,mp＝78-80℃. 1H NMR(400MHz,dmso)δ9.31(s,1H),9.01(s,1H),8.96(s,1H),7.87(s,1H),7.45(d,J＝8.4Hz,2H),7.28(t,J＝7.3Hz,1H),7.18(t,J＝7.2Hz,1H),7.00(d,J＝8.8Hz,1H),6.77(d,J＝7.9Hz,1H),4.55(d,J＝5.7Hz,2H).HRMS(MALDI)计算值C 17H 11BrClN 3O 2[M+Na] +:507.96457,实测值507.96429.
Figure PCTCN2018103826-appb-000063
化合物III10：收率41％,mp＝93-94℃. 1H NMR(500MHz,DMSO)δ9.33(t,J＝5.7Hz,1H),9.03(d,J＝2.0Hz,1H),8.98(d,J＝2.1Hz,1H),7.66(dd,J＝8.9,5.9Hz,1H),7.50(d,J＝7.1Hz,1H),7.34(dd,J＝11.1,4.3Hz,1H),7.24(t,J＝7.4Hz,1H),7.09(td,J＝8.5,2.9Hz,1H),6.92–6.84(m,2H),4.58(d,J＝5.9Hz,2H).HRMS(MALDI)计算值C 17H 11ClFN 3O 2[M+Na] +:448.04464,实测值448.04573.
Figure PCTCN2018103826-appb-000064
测试例1：用于测定对照药剂、目标化合物对琥珀酸脱氢酶的抑制活性。
本测试例中使用的酶为琥珀酸脱氢酶，从猪心中分离制得。
测试方法为：总体积1.8mL，体系中含100mM的Na 2HPO 4-NaH 2PO 4缓冲液(pH为7.4)、0.3mM的EDTA、20mM的琥珀酸钠、53μM的DCIP(2,6-二氯靛酚钠)，2nM的琥珀酸脱氢酶。23℃恒温水浴及600rpm磁力搅拌。在波长为600nm处监测底物DCIP光吸收的降低，采集线性范围内的实验点，即控制底物消耗不超过5％的实验点。DCIP的摩尔消光系数为21mM -1cm -1。计算在反应时间内DCIP的还原产量并拟合线性斜率，再扣掉基线斜率即为反应的初速度。
表3列出了前述制备例得到的化合物以及对照药剂NNF-0721酶抑制活性测试结果。
表3
化合物 抑制率％(10μM,SQR) 化合物 IC 50(μM,SQR)
I1 55.33 III1 1.25±0.12
I2 72.41 III2 3.40±0.01
I3 75.22 III3 2.72±0.12
I4 69.26 III4 0.90±0.01
I5 70.56 III5 4.18±0.01
I6 72.36 III6 1.14±0.12
I7 76.64 III7 2.67±0.11
I8 59.83 III8 1.23±0.12
I9 48.78 III9 0.83±0.01
I10 77.93 III10 3.49±0.12
I11 60.19    
I12 66.31    
I13 86.98    
II1 64.56    
II2 80.43    
II3 72.64    
II4 63.39    
II5 83.70 NNF-0721 1.52±0.11
从酶抑制活性测试结果中可以看出，本发明中吡嗪酰胺类化合物对猪心来源SQR都表现出了良好的抑制活性，并且多数化合物的效果与对照药剂NNF-0721相当，或者比对照药剂NNF-0721效果更优。
测试例2：杀菌活性筛选结果
测试方法：将表4中的各化合物配制成5重量％的乳油。试验均采用活体盆栽，化合物有效浓度均为200mg/L。
黄瓜霜霉病菌(Pseudoperonospora cubensis)
选择两张真叶期(摘去生长点)长势一致的盆栽黄瓜苗，喷雾处理后自然晾干，处理后24h进行接种，取新鲜黄瓜霜霉病病叶，用毛笔蘸取10℃左右蒸馏水洗下病叶背面孢子囊，配成孢子囊悬浮液(2-3×105个/mL)。用接种喷雾器(压力0.1MPa)在黄瓜苗上均匀喷雾接种，接种后的试材移至人工气候室，保持相对湿度100％，温度为20℃，24h后保持温度20℃，相对湿度90％左右保湿诱发，5d后视空白对照发病情况进行分级调查，按病指计算防效％。
黄瓜白粉病菌(Sphaerotheca uliginea)
选择一片真叶期、长势一致黄瓜苗，喷雾处理后阴干24h。洗取长满白粉菌黄瓜叶片上的新鲜孢子，用双层纱布过滤，制成孢子浓度为10万个/mL左右的悬浮液，喷雾接种。接种后的试材自然风干，然后移至恒温室灯光下(21-23℃)中，8d后视空白对照发病情况进行分级调查，按病指计算防效％。
草莓灰霉病
采用叶片接菌法。选择二张真叶期长势一致盆栽草莓苗，待药剂喷雾晾干后，接菌饼于叶片上。22-26℃暗光保湿24h后，恢复自然光照培养4d。待对照充分发病后用卡尺计量每个接种点病斑直径，计算防效％。
水稻纹枯病(Rhizoctonia solani)
选择二叶一心或三叶一心、长势一致盆栽的稻苗，喷雾处理24小时后，在已喷过药的每盆稻苗基部中央夹接一块纹枯病菌丝块，注意菌块不要与盆土及水层接触。接种后的试材移至保湿箱中(RH100％)培养24h，然后移至温度28℃，湿度90％恢复自然光照培养，7天后视空白对照充分发病时调查防治效果。
调查方法：分级标准采用《农药田间药效试验准则》，以病指数计算防治效果％。
病情指数＝∑(各级病叶数×相对级数值)×100/(总叶数×9)；
防治效果(％)＝(对照病情指数-处理病情指数)×100/对照病情指数；
测试结果如表4中所示。
表4
Figure PCTCN2018103826-appb-000065
Figure PCTCN2018103826-appb-000066
从活性测试结果可以看出，本发明中的吡嗪酰胺类化合物在200mg/L的浓度下对水稻纹枯病菌、黄瓜白粉病菌和黄瓜霜霉病均表现出一定的抑制活性，尤其对黄瓜白粉病表现出良好防效。
测试例3：复筛测试
测试方法：选取本发明的部分化合物(具体如表5所示)进行复筛，将表5中的各化合物配制成5重量％的乳油。试验均采用活体盆栽，化合物有效浓度如表5中所示。
具体地采用如测试例2中的针对黄瓜白粉病菌和水稻纹枯病菌相同的处理进行复筛。其结果如表5中所示。
表5
Figure PCTCN2018103826-appb-000067
Figure PCTCN2018103826-appb-000068
从上述复筛结果可以看出，本发明的化合物对黄瓜白粉病或者以及水稻纹枯病均表现出优异的防治效果。
测试例4：杀菌活性筛选结果
测试方法：将表6中的各化合物配制成5重量％的乳油。试验均采用活体盆栽，化合物有效浓度如表6中所示。
大豆锈病
选择生长整齐一致的2叶期大豆盆栽幼苗进行叶面喷雾处理，另设喷清水的空白对照，3次重复。处理后第二天接种大豆锈病孢子悬浮液，接种后放置人工气候室(温度：20℃-25℃，相对湿度：>95％)保湿培养，8-16小时后放置温室(25℃±1℃)正常管理。7天后视空白对照充分发病时调查防治效果。
玉米锈病
选择生长整齐一致的2-3叶期玉米盆栽幼苗，按照设计浓度进行叶面喷雾处理，另设喷清水的空白对照，3次重复。处理后第二天接种玉米锈病孢子悬浮液，接种后放置人工气候室(温度：昼25℃、夜20℃，相对湿度：95～100％)保湿培养，24小时后放置温室(25℃±1℃)正常管理。7天后视空白对照充分发病时调查防治效果。
小麦白粉病
选择生长整齐一致的2叶期小麦盆栽幼苗，按照设计浓度进行叶面喷雾处理，另设喷清水的 空白对照，3次重复。处理后第二天孢子抖落法接种，接种后的作物放温室(25℃±1℃)正常管理。7天后视空白对照充分发病时调查防治效果。
调查方法：分级标准采用《农药田间药效试验准则》，以病指数计算防治效果％。
病情指数＝∑(各级病叶数×相对级数值)×100/(总叶数×9)；
防治效果(％)＝(对照病情指数-处理病情指数)×100/对照病情指数；
测试结果如表6中所示。
表6
Figure PCTCN2018103826-appb-000069
从表6中的结果可以看出，本发明提供的化合物针对大豆锈病、玉米锈病和小麦白粉病也具有较好的防效。并且，本发明提供的化合物I13对大豆锈病、玉米锈病和小麦白粉病的防效比现有的高效药剂NNF-0721的防效还要好。
另外，从上述结果中还可以看出，本发明提供的化合物在抗菌方面具有明显的广谱性优势。
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. 一种吡嗪酰胺类化合物，该化合物具有式(I)、式(II)或式(III)所示的结构：
    Figure PCTCN2018103826-appb-100001
    其中，
    在式(I)中，R 11、R 12、R 13和R 14各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素；
    在式(II)中，R 11、R 12和R 13各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-4的烷基时，R 11和R 13不为相同的卤素；
    在式(III)中，R 11、R 12、R 13和R 14各自独立地选自H、卤素、C 1-4的烷基、C 1-4的烷氧基、由1-4个卤素取代的C 1-4的烷基和由1-4个卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。
  2. 根据权利要求1所述的化合物，其中，
    在式(I)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 12为卤素时，R 13也为卤素；R 14为卤素时，R 11为卤素以及R 12和R 13为H；R 13为H时，R 14为卤素或C 1-4的烷基；R 13为CF 3时，R 11为Br或F；R 11、R 12和R 14均为H时，R 13不为F；R 11为Cl时，R 13不为卤素；
    在式(II)中，R 11、R 12和R 13各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 11、R 12和R 13不同时为H；R 32和R 33各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 32和R 33不同时为H；R 32或R 33为C 1-4的烷基时，R 11和R 13不为相同的卤素；
    在式(III)中，R 11、R 12、R 13和R 14各自独立地选自H、F、Cl、Br、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、由1-4个选自F和/或Cl的卤素取代的C 1-4的烷基和由1-4个选自F和/或Cl的卤素取代的C 1-4的烷氧基，且R 11、R 12、R 13和R 14不同时为H；R 11为F时，R 12不为H；R 11为Br时，R 13不为H；R 13为F时，R 11和R 12不同时为H。
  3. 根据权利要求1所述的化合物，其中，所述吡嗪酰胺类化合物为以下中的至少一种，且化 合物I1-化合物I21具有式(I)所示的结构，化合物II1-化合物II13具有式(II)所示的结构，化合物III1-化合物III20具有式(III)所示的结构：
    化合物I1：R 12和R 13为F；R 11和R 14为H；
    化合物I2：R 12为Cl，R 13为F；R 11和R 14为H；
    化合物I3：R 12为F，R 13为Cl；R 11和R 14为H；
    化合物I4：R 11为Cl，R 13为OCF 3；R 12和R 14为H；
    化合物I5：R 11为Cl，R 14为F；R 12和R 13为H；
    化合物I6：R 11为F，R 14为Cl；R 12和R 13为H；
    化合物I7：R 11为Br，R 13为Cl；R 12和R 14为H；
    化合物I8：R 13为Cl；R 11、R 12和R 14为H；
    化合物I9：R 13为OCH(CH 3) 2；R 11、R 12和R 14为H；
    化合物I10：R 11和R 14为Cl；R 12和R 13为H；
    化合物I11：R 13为OCF 3；R 11、R 12和R 14为H；
    化合物I12：R 11为CH 3，R 14为CH(CH 3) 2；R 12和R 13为H；
    化合物I13：R 11为Br，R 13为CF 3；R 12和R 14为H；
    化合物I14：R 11为OCH 3，R 13为Cl；R 12和R 14为H；
    化合物I15：R 11为Cl，R 13为CHCl 2，R 12和R 14为H；
    化合物I16：R 11为Cl，R 13为CHF 2，R 12和R 14为H；
    化合物I17：R 11为Br，R 13为CH 2CH 3，R 12和R 14为H；
    化合物I18：R 11为Br，R 14为CH 3，R 12和R 13为H；
    化合物I19：R 11为OCH 2CH 3，R 13为CH 3，R 12和R 14为H；
    化合物I20：R 11为F，R 13为CH 2Cl，R 12和R 14为H；
    化合物I21：R 11为CH 2CF 3，R 14为CH 3，R 12和R 13为H；
    化合物II1：R 11和R 13为Cl，R 12为H；R 33为F，R 32为H；
    化合物II2：R 11为Cl，R 13为CF 3；R 12为H；R 33为CH 3，R 32为H；
    化合物II3：R 11为Cl，R 13为CF 3；R 12为H；R 33为H，R 32为CH 3；
    化合物II4：R 11为Cl，R 13为CF 3；R 12为H；R 33为F，R 32为H；
    化合物II5：R 11为Cl，R 13为CF 3；R 12为H；R 33为H，R 32为F；
    化合物II6：R 11为CH 3，R 13为CF 3；R 12为H；R 33为CH 2CF 3，R 32为CH 3；
    化合物II7：R 11为OCF 3，R 13为Cl；R 12为H；R 33为Cl，R 32为CH(CH 3) 2；
    化合物II8：R 11为CH 2CH 3，R 13为F；R 12为H；R 32为CHCl 2，R 33为OCH 3；
    化合物II9：R 11为CHCl 2，R 13为Cl；R 12为H；R 33为F，R 32为CH 2CH 3；
    化合物II10：R 11为CH(CH 3) 2，R 13为Br，R 12为H；R 33为Br，R 32为CH 3；
    化合物II11：R 11为OCH 2CH 3，R 13为F，R 12为H；R 32为H，R 33为CF 3；
    化合物II12：R 11为H，R 12为CH 2CF 3，R 13为Cl；R 32为H，R 33为OCH 2CH 3；
    化合物II13：R 11为H，R 12为OCH 3，R 13为F；R 32为OCF 3，R 33为H；
    化合物III1：R 11为Cl；R 12、R 13和R 14为H；
    化合物III2：R 11和R 12为F；R 13和R 14为H；
    化合物III3：R 11为Cl，R 12为F；R 13和R 14为H；
    化合物III4：R 11和R 12为Cl；R 13和R 14为H；
    化合物III5：R 12和R 13为F；R 11和R 14为H；
    化合物III6：R 11和R 13为Cl；R 12和R 14为H；
    化合物III7：R 11为Cl，R 13为F；R 12和R 14为H；
    化合物III8：R 11为Cl，R 13为CF 3；R 12和R 14为H；
    化合物III9：R 11为Br，R 13为Cl；R 12和R 14为H；
    化合物III10：R 11为Cl，R 14为F；R 12和R 13为H；
    化合物III11：R 11为CH 3，R 13为Cl；R 12和R 14为H；
    化合物III12：R 11为F，R 12为CH 2CH 3；R 13和R 14为H；
    化合物III13：R 11为Cl，R 13为OCF 3；R 12和R 14为H；
    化合物III14：R 11为CF 3，R 13为Br；R 12和R 14为H；
    化合物III15：R 11为CHCl 2，R 13为Cl；R 12和R 14为H；
    化合物III16：R 11为F，R 12为OCH(CH 3) 2；R 13和R 14为H；
    化合物III17：R 11和R 12为H，R 13为OCH(CH 3) 2，R 14为Cl；
    化合物III18：R 11为Br，R 13为CH 2CF 3，R 12和R 14为H；
    化合物III19：R 11为F，R 12为CH 2Cl；R 13和R 14为H；
    化合物III20：R 11为F，R 12为CH 3；R 13和R 14为H。
  4. 一种制备吡嗪酰胺类化合物的方法，该吡嗪酰胺类化合物具有式(I)、式(II)或式(III)所示的结构，该方法包括：将式(2-1)所示的化合物与式(2-21)、式(2-22)或式(2-23)所示的化合物接触；
    Figure PCTCN2018103826-appb-100002
    其中，R 11、R 12、R 13、R 14、R 32和R 33的定义如权利要求1-3中任意一项所述。
  5. 根据权利要求4所述的方法，其中，所述方法还包括按照以下步骤制备式(2-1)所示的化合物：
    (1)在叠氮钠和钯碳催化剂存在下，将式(2-3)所示的化合物与乙二胺盐酸盐进行第一接触，得到式(2-4)所示的化合物；
    (2)将所述式(2-4)所示的化合物与氢氧化锂进行第二接触；
    Figure PCTCN2018103826-appb-100003
  6. 根据权利要求4或5所述的方法，其中，将式(2-1)所示的化合物与式(2-21)、式(2-22)或式(2-23)所示的化合物接触的条件包括：温度为0-60℃，时间为1-72h。
  7. 由权利要求4-6中任意一项所述的方法制备得到的吡嗪酰胺类化合物。
  8. 权利要求1-3和7中任意一项所述的吡嗪酰胺类化合物作为琥珀酸脱氢酶抑制剂的应用。
  9. 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1-3和7中任 意一项所述的吡嗪酰胺类化合物中的至少一种；优选地，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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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN104557709A (zh) * 2013-10-23 2015-04-29 华中师范大学 含二苯醚的吡唑酰胺类化合物及其应用和农药组合物
CN104872136A (zh) * 2015-05-21 2015-09-02 华中师范大学 一种杀菌剂组合物和制剂及其应用
CN108069915A (zh) * 2016-11-15 2018-05-25 华中师范大学 一种吡嗪酰胺类化合物及其制备方法和应用以及一种杀菌剂

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557709A (zh) * 2013-10-23 2015-04-29 华中师范大学 含二苯醚的吡唑酰胺类化合物及其应用和农药组合物
CN104872136A (zh) * 2015-05-21 2015-09-02 华中师范大学 一种杀菌剂组合物和制剂及其应用
CN108069915A (zh) * 2016-11-15 2018-05-25 华中师范大学 一种吡嗪酰胺类化合物及其制备方法和应用以及一种杀菌剂

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