Hydrazone compounds and preparation methods and applications thereof

Abstract

The present invention relates to the technical field of plant protection, and discloses a hydrazone compound and a preparation method and application thereof. The compound is a compound represented by formula I or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate and pharmaceutically acceptable salt of the compound represented by formula I, wherein R is a single substituent or multiple substituents at any position of the benzene ring, the substituents in the multiple substituents are the same or different, and R is selected from one or more of hydrogen, halogen, alkyl, alkoxy or halogenated alkyl; R 1 is hydrogen, hydroxyl, amino or chlorine; R 2 is hydrogen, hydroxy, methyl, amino or methoxy; R 3 is hydrogen, hydroxy, amino or methyl; R 4 is hydrogen or methyl; and X is carbon or nitrogen. The compound can be used for preparing plant pathogenic bacteria, fungi and blue algae.

Description

Technical Field

[0001] The present invention relates to the technical field of plant protection, and specifically, the present invention relates to hydrazone compounds and preparation methods and applications thereof, and more specifically, the present invention relates to compounds represented by formula I and derivatives thereof and preparation methods, pharmaceutical compositions, and applications of compounds represented by formula I in the preparation of drugs for preventing and controlling plant pathogenic bacteria, fungi and cyanobacteria. Background Art

[0002] Plant diseases caused by pathogenic bacteria and fungi seriously threaten the yield and quality of crops. The long-term repeated use of existing pesticides has led to serious resistance of plant pathogens. In the face of resistant pathogens, the use of pesticides has further increased to maintain the efficacy, resulting in more serious pesticide residues, which not only causes environmental pollution, but also has a great impact on human health. Existing means of controlling plant pathogenic fungi still need to be improved.

[0003] The outbreak of cyanobacteria caused by cyanobacteria will reduce the oxygen content in the water, change the color of the water, produce a large amount of algae toxins, reduce the quality of the water, and pose a huge threat to agriculture and fisheries. The algaecides currently used for cyanobacteria blooms mainly include copper compounds, chemical oxidants and herbicides. Most of these algaecides are non-target inhibitors, which are not selective and may be harmful to the environment or mammals. Therefore, the existing means of controlling cyanobacteria blooms still need to be improved. Summary of the invention

[0004] The purpose of the present invention is to solve one of the technical problems in the related art at least to a certain extent. To this end, the present invention provides a hydrazone compound and a pharmaceutical composition thereof that can be used to prepare plant pathogenic bacteria, fungi and cyanobacteria.

[0005] In order to achieve the above object, the present invention provides a hydrazone compound on one hand, wherein the compound is a compound represented by Formula I or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate and pharmaceutically acceptable salt of the compound represented by Formula I,

[0006]

[0007] Wherein, R is a single substituent or multiple substituents at any position of the benzene ring, the substituents in the multiple substituents are the same or different, and R is selected from one or more of hydrogen, halogen, alkyl, alkoxy or haloalkyl; R 1 is hydrogen, hydroxyl, amino or chlorine; R 2 is hydrogen, hydroxy, methyl, amino or methoxy; R 3 is hydrogen, hydroxy, amino or methyl; R 4 is hydrogen or methyl; X is carbon or nitrogen.

[0008] The second aspect of the present invention provides a method for preparing the above-mentioned compound, which comprises: contacting a compound represented by formula II with a compound represented by formula III to react to obtain a compound represented by formula I;

[0009]

[0010] Among them, R, R 1 , R 2 , R 3 , R 4 and X are as defined above.

[0011] The third aspect of the present invention provides a pharmaceutical composition, which contains the hydrazone compound described above or the hydrazone compound prepared by the method described above.

[0012] The fourth aspect of the present invention provides a use of the hydrazone compound described above, the hydrazone compound prepared by the method described above, or the pharmaceutical composition described above in preventing and controlling plant pathogenic fungi or plant pathogenic bacteria.

[0013] The fifth aspect of the present invention provides a use of the hydrazone compound described above, the hydrazone compound prepared by the method described above, or the pharmaceutical composition described above in inhibiting the growth of algae.

[0014] Compared with the prior art, the hydrazone compounds provided by the present invention have at least the following advantages:

[0015] 1. The compounds of the present invention have not been reported. The inventors used the method of active substructure splicing to combine substituted nitrogen-containing aromatic formaldehyde or aromatic acetone with phenylhydrazine hydrochloride structural units, designed and synthesized new hydrazone compounds, and especially explored and discovered new structural compounds with application value in inhibiting agricultural bacteria, fungi and killing algae. It has important research significance and application value for the development of new high-efficiency fungicides or algaecides.

[0016] 2. The inventors unexpectedly discovered that some of the compounds of the present invention can simultaneously have excellent inhibitory effects on agricultural bacteria, fungi and water bloom cyanobacteria.

[0017] 3. The method for preparing the compound of the present invention proposed by the present invention has cheap and readily available starting materials, and the compound shown in Formula I can be obtained by recrystallization after the reaction, and the post-processing is simple, the synthesis efficiency is high, the product purity is high, the yield is high, the production cost is low, and it is conducive to mass production. In addition, the reaction operation process is simple and easy to control, and no special reaction equipment is involved, which meets the requirements of safe production and green chemistry. The purification and separation of the final product is simple and easy to operate, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0018] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0019] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0020] In a first aspect, the present invention provides a hydrazone compound, wherein the compound is a compound represented by Formula I or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, or pharmaceutically acceptable salt of the compound represented by Formula I.

[0021]

[0022] In the compound shown in formula I of the present invention, R can be a single substituent or multiple substituents at any position of the benzene ring, specifically, for example, R is a single substituent at the ortho, meta or para position on the benzene ring, or a disubstituent at the ortho and meta positions, ortho and para positions, or meta and para positions, or a trisubstituent at the ortho, meta and para positions. In the present invention, R is selected from one or more of hydrogen, halogen, alkyl, alkoxy or haloalkyl. When R is a multiple substituent at any position of the benzene ring, the substituents in the multiple substituents can be the same or different, for example, when R represents that there are 2 substituents on the benzene ring, the 2 substituents can be both halogen, alkyl or alkoxy, or one of the substituents is halogen and the other substituent is alkyl, or one of the substituents is halogen and the other substituent is alkoxy, or one of the substituents is alkyl and the other substituent is alkoxy, or one of the substituents is fluorine and the other substituent is chlorine, or both substituents are chlorine. In the present invention, the haloalkyl group refers to a group in which at least one hydrogen atom in an alkyl group is substituted by a halogen, that is, an alkyl group substituted by a halogen.

[0023] In a specific embodiment, in said R, said halogen is selected from one or more of fluorine, chlorine, bromine and iodine. In a preferred embodiment, said halogen is selected from one or more of fluorine, chlorine and bromine. In a specific embodiment, in said R, said alkyl is selected from C 1-10 Alkyl, the alkyl group herein includes the alkyl group represented by R and the alkyl group in the halogenated alkyl group. In a preferred embodiment, the alkyl group is selected from C 1-4 In a specific embodiment, in said R, said alkoxy group is selected from C 1-6Alkoxy, such as methoxy, ethoxy, etc. In a specific embodiment, in the R, the halogen in the haloalkyl is selected from one or more of fluorine, chlorine, bromine and iodine. In a preferred embodiment, the halogen in the haloalkyl is selected from one or more of fluorine, chlorine and bromine. In a more preferred embodiment, the R is selected from one or more of hydrogen, fluorine, chlorine, bromine, methyl, butyl, methoxy, trifluoromethyl (-CF3) and bromomethyl (-CH2Br).

[0024] In the compound represented by formula I of the present invention, R 1 is hydrogen, hydroxyl, amino or chlorine. In the compound represented by formula I of the present invention, R 2 is hydrogen, hydroxyl, methyl, amino or methoxy. 3 is hydrogen, hydroxyl, amino or methyl. 4 In the compound represented by formula I of the present invention, X is carbon or nitrogen.

[0025] In a preferred embodiment, the compound is the following compound or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate and pharmaceutically acceptable salt of the following compound:

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032] The inventors surprisingly found that the hydrazone compounds provided by the present invention can be used to treat plant diseases and inhibit the growth of water bloom cyanobacteria.

[0033] The second aspect of the present invention provides a method for preparing the above-mentioned compound, which comprises: contacting a compound represented by formula II with a compound represented by formula III to react to obtain a compound represented by formula I;

[0034]

[0035] Among them, R, R 1 , R 2 , R 3 , R 4 and X are as defined above.

[0036] In a specific embodiment, the preparation method of the hydrazone compound specifically comprises: dissolving the compound represented by formula III and a base in a first solvent, stirring for 15-30 minutes, and then adding the compound represented by formula II and a catalyst to the system, and reacting under stirring conditions.

[0037] In a more specific embodiment, the base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, diethylamine, triethylamine, potassium tert-butoxide and butyl lithium. In a more specific embodiment, the first solvent is selected from one or more of acetonitrile, 1,2-dichloroethane, acetone, tert-butanol, water, toluene, benzene, xylene, ethyl acetate, methanol, ethanol, n-hexane, dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide. In a more specific embodiment, the catalyst is selected from one or more of ascorbic acid, acetic acid, tartaric acid, trifluoroacetic acid, formic acid, salicylic acid, malic acid and acetic anhydride.

[0038] In the preparation method of the hydrazone compound, the molar ratio of the compound represented by formula II, the compound represented by formula III, the base and the catalyst can be 1:(1-3):(1-3):(0.1-0.5).

[0039] In the method for preparing the hydrazone compound, in a preferred embodiment, the reaction temperature may be 60-120° C., more preferably 80-110° C., such as 80° C., 85° C., 90° C., 95° C., 100° C., 105° C. or 110° C. In the method for preparing the hydrazone compound, in a preferred embodiment, the reaction time may be 1-12 hours, more preferably 2-6 hours, such as 2 hours, 3 hours, 4 hours, 5 hours or 6 hours.

[0040] The third aspect of the present invention provides a pharmaceutical composition, which contains the hydrazone compound described above or the hydrazone compound prepared by the method described above. Further, the pharmaceutical composition contains an effective amount of the hydrazone compound described above. The effective amount refers to the amount of the compound of the present invention that needs to be added to achieve the expected effect in the application. The pharmaceutical composition may also optionally contain pharmaceutically acceptable excipients, such as carriers, excipients, etc. In a specific embodiment, the excipient may be at least one of a disintegrant, a glidant, a lubricant, a diluent or a filler, a binder and a colorant.

[0041] The fourth aspect of the present invention provides a use of the hydrazone compound described above, the hydrazone compound prepared by the method described above, or the pharmaceutical composition described above in preventing and controlling plant pathogenic fungi or plant pathogenic bacteria.

[0042] In a specific embodiment, the plant pathogenic fungi are selected from one or more of anthracnose of pepper, Fusarium graminearum, Phytophthora capsici, brown rot of peach, Pythium aphanidermatum, rice blast, U.S. smut, early blight of tomato, fusarium head blight of wheat, sclerotinia of rapeseed, sheath blight of rice, apple ring rot, sheath blight of wheat, corn leaf spot, rice seedling blight and gray mold. In a specific embodiment, the plant pathogenic bacteria are selected from one or more of tobacco wilt, rice white leaf blight, watermelon fruit spot, tomato canker, black rot, Xanthomonas campestris and citrus canker.

[0043] The fifth aspect of the present invention provides a use of the hydrazone compound described above, the hydrazone compound prepared by the method described above, or the pharmaceutical composition described above in inhibiting the growth of algae. In a specific embodiment, the algae is Synechocystis or Microcystis aeruginosa.

[0044] Definitions and explanations of terms:

[0045] “C 1-10 "Alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms, preferably C 1-4 Alkyl. Specifically, the "C1-10 alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl and the like and isomers thereof. In particular, the group has 1, 2, 3, 4, 5 or 6 carbon atoms (i.e., "C 1-6 alkyl), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms (i.e., "C 1-3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0046] Unless otherwise specified, when "compounds of the present invention" and similar expressions are used herein, it is intended to cover the compounds of Formula I or stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates and pharmaceutically acceptable salts of the compounds of Formula I.

[0047] The term used in the present invention takes into account all stereoisomers of the compounds of the present invention (whether in a mixture or in a pure or substantially pure form). The term "stereoisomer" used in the present invention includes compounds that are optical isomers by having one or more chiral atoms, and compounds that are optical isomers by limited rotation around one or more bonds. The definition of the compounds of the present invention covers all possible stereoisomers and their mixtures. Racemic forms and separated optical isomers with specific activities are very specifically covered. The racemic form can be split by physical methods, including but not limited to fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by conventional methods, including but not limited to forming salts with optically active acids and then crystallizing.

[0048] Term used in the present invention, compound shown in formula I and salt thereof can exist by their tautomeric form, in which hydrogen atom is transferred to other parts of molecule, and the chemical bond between atoms in molecule is therefore rearranged.It should be understood that all tautomeric forms (as long as they can exist) are just included in the present invention.In addition, compound shown in formula I of the present invention can have trans isomer and cis isomer.

[0049] The term "chemically acceptable salt" used in the present invention refers to a salt formed by the reaction of the compound represented by Formula I with an inorganic acid or an organic acid.

[0050] The term "contact" used herein should be understood in a broad sense, and may be any manner that allows at least two reactants to undergo a chemical reaction, such as mixing the two reactants under appropriate conditions.

[0051] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

[0052] The present invention will be described in detail below by way of examples, but the protection scope of the present invention is not limited thereto. Unless otherwise specified, the raw materials and reagents used in the examples are all commercially available products.

[0053] Example 1

[0054]

[0055] The preparation method of compound 1 comprises the following steps:

[0056] Add ethanol (5 mL), phenylhydrazine hydrochloride (1.5 mmol), triethylamine (1.6 mmol) to a 25 mL single-mouth bottle, stir at room temperature for 15 min, add 2,4-dihydroxypyrimidine-5-carboxaldehyde (1.5 mmol) and glacial acetic acid (0.15 mmol). Heat under reflux at 80 ° C for 6 hours, and monitor the reaction progress by TLC. After the reaction is completed, the system is cooled to room temperature, filtered, and the solid is recrystallized in ethanol to obtain the target compound 1 with a yield of 58% and a melting point of >260 ° C.

[0057] Product structure identification data:

[0058] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.31(s,1H,NH),11.19(s,1H,NH),10.18(s,1H,NH),7.77(s,1H,CH=C),7.72(s,1H,CH=N),7.17(t,J=8.0Hz,2H,Ar H), 6.97 (d, J=8.0Hz, 2H, Ar H), 6.70 (t, J=8.0Hz, 1H, Ar H).

[0059] 13 C NMR (150MHz, DMSO) δ (ppm): 163.55, 151.20, 145.78, 136.46, 130.10, 129.48 (2C), 118.89, 112.24 (2C), 108.82.

[0060] HRMS (ESI):Calculated for C 11 H 10 N4O2[M+H] + :231.0877,found:231.0882.

[0061] Example 2

[0062]

[0063] The preparation method of compound 2 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 62% and a melting point of >260°C.

[0064] Product structure identification data:

[0065] 1 H NMR(400MHz, DMSO-d6)δ(ppm):11.30(s,1H,NH),11.20(s,1H,NH),10.10(s,1H,NH),7.75(d,J=4.0Hz,1H,CH=C),7.68(s,1H,CH=N),6.98(d,J=4.0Hz,2H,Ar H), 6.88 (d, J = 4.0Hz, 2H, Ar H), 2.18 (s, 3H, CH3).

[0066] 13 CNMR (100MHz, DMSO) δ (ppm): 163.53, 151.14, 143.50, 136.13, 129.84 (2C), 129.27, 127.29, 112.20 (2C), 108.88, 20.63.

[0067] HRMS (ESI):Calculated for C 12 H 12 N4O2[M+H] + :245.1033,found:245.1036.

[0068] Example 3

[0069]

[0070] The preparation method of compound 3 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-methoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of >260°C.

[0071] Product structure identification data:

[0072] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.29(s,1H,NH),11.15(s,1H,NH),9.97(s,1H,NH),7.73(s,1H,CH=C),7.65(s,1H,CH=N),6.92(d,J=4.0Hz,2H,Ar H), 6.79 (d, J = 4.0Hz, 2H, Ar H), 3.67 (s, 3H, OCH3).

[0073] 13 CNMR (100MHz, DMSO) δ (ppm): 163.56, 152.87, 151.18, 139.90, 135.93, 128.91, 115.01 (2C), 113.27 (2C), 109.03, 55.70.

[0074] HRMS (ESI):Calculated for C 12 H 12 N4O3[M+H] + :261.0982,found:261.1015.

[0075] Example 4

[0076]

[0077] The preparation method of compound 4 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 55% and a melting point of >260°C.

[0078] Product structure identification data:

[0079] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.31(s,1H,NH),11.20(s,1H,NH),10.17(s,1H,NH),7.78(s,1H,CH=C),7.70(s,1H,CH=N),7.04-6.94(m,4H,Ar H).

[0080] 13 CNMR (100MHz, DMSO) δ (ppm): 163.52, 156.15 (d, J = 232Hz, 1C), 151.20, 142.50, 136.54, 130.19, 115.95 (d, J = 22Hz, 2C), 113.17 (d, J = 7Hz, 2C), 108.75.

[0081] HRMS (ESI):Calculated for C 11 H9FN4O2[M+H] + :249.0782,found:249.0810.

[0082] Example 5

[0083]

[0084] The preparation method of compound 5 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 67% and a melting point of >260°C.

[0085] Product structure identification data:

[0086] 1 H NMR(400MHz, DMSO-d6)δ(ppm):11.33(s,1H,NH),11.23(s,1H,NH),10.33(s,1H,NH),7.80(s,1H,CH=C),7.72(s,1H,CH=N),7.19(d,J=8.0Hz,2H,Ar H), 6.98 (d, J=12.0Hz, 2H, Ar H).

[0087] 13 CNMR (100MHz, DMSO) δ (ppm): 163.49, 151.20, 144.68, 136.90, 130.99, 129.26 (2C), 122.03, 113.63 (2C), 108.55.

[0088] HRMS (ESI):Calculated for C 11 H9ClN4O2[M+H] + :265.0487,found:265.0491.

[0089] Example 6

[0090]

[0091] The preparation method of compound 6 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of >260°C.

[0092] Product structure identification data:

[0093] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.31(s,1H,NH),11.18(s,1H,NH),10.32(s,1H,NH),7.80(s,1H,CH=C),7.73(s,1H,CH=N),7.31(d,J=8.0Hz,2H,Ar H), 6.93 (d, J=8.0Hz, 2H, Ar H).

[0094] 13 C NMR (100MHz, DMSO) δ (ppm): 163.49, 151.21, 145.05, 136.95, 132.09 (2C), 131.12, 114.17 (2C), 109.60, 108.54.

[0095] HRMS (ESI):Calculated for C 11H9BrN4O2[M+H] + :308.9982,found:308.9991.

[0096] Example 7

[0097]

[0098] The preparation method of compound 7 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-nitrophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 66% and a melting point of >260°C.

[0099] Product structure identification data:

[0100] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.50 (s, 1H, NH), 11.41 (s, 1H, NH), 11.16 (s, 1H, NH), 8.08 (d, J=8.0Hz, 2H, Ar H),7.96(s,1H,CH=C),7.90(s,1H,CH=N),7.08(d,J=8.0Hz,2H,Ar H).

[0101] 13 C NMR (100MHz, DMSO) δ (ppm): 163.28, 151.14, 150.86, 138.60, 138.40, 135.73, 126.53 (2C), 111.39, 107.71.

[0102] HRMS (ESI):Calculated for C 11 H9N5O4[M+H] + :276.0727,found:276.0727.

[0103] Example 8

[0104]

[0105] The preparation method of compound 8 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 52% and a melting point of >260°C.

[0106] Product structure identification data:

[0107] 1 H NMR(400MHz, DMSO-d6)δ(ppm):11.36(s,1H,NH),11.28(s,1H,NH),10.65(s,1H,NH),7.86(s,1H,CH=C),7.80(s,1H,CH=N),7.49(d,J=8.0Hz,2H,Ar H),7.10(d,J=8.0Hz,2H,Ar H).

[0108] 13 C NMR (100MHz, DMSO) δ (ppm): 163.45, 151.21, 148.66, 137.54, 132.74, 126.85 (2C), 124.16, 118.50 (t, J = 31.6Hz, 1C), 111.86 (2C), 108.27.

[0109] HRMS (ESI):Calculated for C 12 H9F3N4O2[M+H] + :299.0750,found:299.0754.

[0110] Example 9

[0111]

[0112] The preparation method of compound 9 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 59% and a melting point of >260°C.

[0113] Product structure identification data:

[0114] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.34(s,1H,NH),11.24(s,1H,NH),10.38(s,1H,NH),7.81(s,1H,CH=C),7.74(s,1H,CH=N),7.16(d,J=8.0Hz,2H,Ar H),7.03(d,J=12.0Hz,2H,Ar H).

[0115] 13 C NMR (100MHz, DMSO) δ (ppm): 163.45, 151.17, 144.95, 140.64, 136.92, 131.22, 122.62 (2C), 112.79 (2C), 108.49.

[0116] HRMS(ESI):Calculated for C 12 H9F3N4O3[M+H] + :315.0700,found:315.0702.

[0117] Example 10

[0118]

[0119] The preparation method of compound 10 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 62% and a melting point of >260°C.

[0120] Product structure identification data:

[0121] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.33(s,1H,NH),11.25(s,1H,NH),10.11(s,1H,NH),7.98(s,1H,CH=C),7.84(s,1H,CH=N),7.44(t,J=10.0Hz,1H,Ar H),7.11-7.02(m,2H,Ar H),6.73-6.68(m,1H,Ar H).

[0122] 13 C NMR (100MHz, DMSO) δ (ppm): 163.44, 151.18, 149.27 (d, J = 238Hz, 1C), 137.16, 133.90 (d, J = 1 0Hz, 1C), 133.01, 125.27, 118.63 (d, J = 6Hz, 1C), 115.28 (d, J = 18Hz, 1C), 114.21, 108.60.

[0123] HRMS (ESI):Calculated for C 11 H9FN4O2[M+H] + :249.0782,found:249.0786.

[0124] Embodiment 11

[0125]

[0126] The preparation method of compound 11 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 3-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 64% and a melting point of >260°C.

[0127] Product structure identification data:

[0128] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.34(s,1H,NH),11.25(s,1H,NH),10.41(s,1H,NH),7.87(s,1H,CH=C),7.73(s,1H,CH=N),7.20-7.14(m,1H,Ar H), 6.82 (d, J = 12.0Hz, 1H, Ar H), 6.71 (d, J = 8.0Hz, 1H, Ar H), 6.47 (t, J = 8.0Hz, 1H, Ar H).

[0129] 13 CNMR (100MHz, DMSO) δ (ppm): 163.91 (d, J = 239Hz, 1C), 163.56, 151.28, 147.84 (d, J = 11Hz, 1C), 137.31 ,131.47,131.07(d,J=10Hz,1C),108.49,108.42,104.96(d,J=21Hz,1C),98.81(d,J=27Hz,1C).

[0130] HRMS (ESI):Calculated for C 11 H9FN4O2[M+H] + :249.0782,found:249.0753.

[0131] Example 12

[0132]

[0133] The preparation method of compound 12 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2,4-difluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 55% and a melting point of >260°C.

[0134] Product structure identification data:

[0135] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.33(s,2H,NH),10.05(s,1H,NH),7.96(s,1H,CH=C),7.84(s,1H,CH=N),7.46-7.41(m,1H,Ar H),7.16(t,J=10.0Hz,1H,Ar H), 6.93 (t, J=8.0Hz, 1H, Ar H).

[0136] 13 CNMR(100MHz, DMSO) δ (ppm): 163.43, 154.88 (d, J = 237Hz, 1C), 151.21, 148.55 (d, J = 241. 5Hz, 1C), 137.25, 133.10, 130.96, 114.48, 111.63 (d, J = 21Hz, 1C), 108.55, 104.06.

[0137] HRMS (ESI):Calculated for C 11 H8F2N4O2[M+H] + :267.0688,found:267.0718.

[0138] Example 13

[0139]

[0140] The preparation method of compound 13 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 71% and a melting point of >260°C.

[0141] Product structure identification data:

[0142] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.31(s,1H,NH),11.18(s,1H,NH),9.43(s,1H,NH),8.03(s,1H,CH=C),7.80(s,1H,CH=N),7.34(d,J=8.0Hz,1H,Ar H),7.06(t,J=8.0Hz,1H,Ar H),7.01(d,J=8.0Hz,1H,Ar H),6.66(t,J=8.0Hz,1H,Ar H),2.16(s,3H,CH3).

[0143] 13 CNMR (100MHz, DMSO) δ (ppm): 163.65, 151.28, 143.72, 136.57, 131.80, 130.67, 127.10, 120.87, 118.94, 112.32, 108.96, 17.94; HRMS (ESI): calcd.for C 12 H 12 N4O2[M+H] + 245.1033, found:245.1041.

[0144] HRMS(ESI):Calculated for C 12 H 12 N4O2[M+H] + :245.1033,found:245.1041.

[0145] Embodiment 14

[0146]

[0147] The preparation method of compound 14 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 3-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 74% and a melting point of >260°C.

[0148] Product structure identification data:

[0149] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.29(s,1H,NH),11.15(s,1H,NH),10.10(s,1H,NH),7.77(s,1H,CH=C),7.71(s,1H,CH=N),7.05(t,J=8.0Hz,1H,Ar H),6.81(s,1H,Ar H),6.76(d,J=8.0Hz,1H,Ar H),6.53(d,J=8.0Hz,1H,Ar H),2.23(s,3H,CH3).

[0150] 13 CNMR (100MHz, DMSO) δ (ppm): 163.55, 151.20, 145.70, 138.60, 136.37, 129.83, 129.32, 119.76, 112.67, 109.57, 108.82, 21.77.

[0151] HRMS (ESI):Calculated for C 12 H 12 N4O2[M+H] + :245.1033,found:245.1031.

[0152] Embodiment 15

[0153]

[0154] The preparation method of compound 15 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2,4-dimethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 69% and a melting point of >260°C.

[0155] Product structure identification data:

[0156] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.29(s,1H,NH),11.15(s,1H,NH),9.34(s,1H,NH),7.98(s,1H,CH=C),7.77(s,1H,CH=N),7.22(d,J=12.0Hz,1H,Ar H),6.86(d,J=8.0Hz,1H,Ar H),6.83(s,1H,Ar H),2.17(s,3H,CH3),2.13(s,3H,CH3).

[0157] 13 C NMR (100MHz, DMSO) δ (ppm): 163.61, 151.23, 141.45, 136.24, 131.27, 131.04, 127.44, 127.35, 120.89, 112.50, 109.03, 20.60, 17.81.

[0158] HRMS (ESI):Calculated for C 13 H 14 N4O2[M+H] + :259.1190,found:259.1181.

[0159] Example 16

[0160]

[0161] The preparation method of compound 16 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 66% and a melting point of >260°C.

[0162] Product structure identification data:

[0163] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.33(s,1H,NH),11.26(s,1H,NH),9.81(s,1H,NH),8.15(s,1H,CH=C),7.87(d,J=4.0Hz,1H,CH=N),7.49(d,J=8.0Hz,1H,Ar H),7.28(d,J=8.0Hz,1H,Ar H),7.19(t,J=8.0Hz,1H,Ar H),6.74(t,J=8.0Hz,1H,Ar H).

[0164] 13 C NMR(100MHz, DMSO) δ (ppm): 168.25, 156.02, 146.67, 142.27, 138.90, 134.45, 133.11, 124.47, 121.10, 119.19, 113.36.

[0165] HRMS (ESI):Calculated for C 11 H9ClN4O2[M+H] + :265.0487,found:265.0496.

[0166] Embodiment 17

[0167]

[0168] The preparation method of compound 17 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 72% and a melting point of >260°C.

[0169] Product structure identification data:

[0170] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.34(s,1H,NH),11.23(s,1H,NH),10.38(s,1H,NH),7.86(s,1H,CH=C),7.73(s,1H,CH=N),7.17(t,J=8.0Hz,1H,Ar H),7.03(s,1H,Ar H),6.86(d,J=8.0Hz,1H,Ar H),6.71(d,J=8.0Hz,1H,Ar H).

[0171] 13 C NMR (100MHz, DMSO) δ (ppm): 168.25, 155.98, 151.95, 142.09, 139.05, 136.44, 135.83, 122.99, 116.21, 115.69, 113.15.

[0172] HRMS (ESI):Calculated for C 11 H9ClN4O2[M+H] + :265.0487,found:265.0491.

[0173] Embodiment 18

[0174]

[0175] The preparation method of compound 18 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2,4-dichlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 68% and a melting point of >260°C.

[0176] Product structure identification data:

[0177] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.35(s,2H,NH),9.94(s,1H,NH),8.16(s,1H,CH=C),7.89(s,1H,CH=N),7.50(d,J=8.0Hz,1H,Ar H),7.41(s,1H,Ar H),7.24(d,J=8.0Hz,Ar H).

[0178] 13 C NMR (100MHz, DMSO) δ (ppm): 163.46, 151.27, 141.13, 137.86, 134.97, 128.90, 128.33, 122.21, 116.78, 115.45, 108.40.

[0179] HRMS (ESI):Calculated for C 11 H8Cl2N4O2[M+H] + :299.0097,found:299.0083.

[0180] Embodiment 19

[0181]

[0182] The preparation method of compound 19 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 61% and a melting point of >260°C.

[0183] Product structure identification data:

[0184] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.34(s,1H,NH),11.26(s,1H,NH),9.60(s,1H,NH),8.17(s,1H,CH=C),7.87(s,1H,CH=N),7.47(d,J=8.0Hz,1H,Ar H),7.44(d,J=8.0Hz,1H,Ar H),7.23(t,J=8.0Hz,1H,Ar H),6.69(t,J=8.0Hz,1H,Ar H).

[0185] 13 C NMR (100MHz, DMSO) δ (ppm): 163.50, 151.28, 142.99, 137.58, 134.33, 132.94, 128.90, 120.43, 114.96, 108.61, 106.26.

[0186] HRMS (ESI):Calculated for C 11 H9BrN4O2[M+H] + :308.9982,found:309.0003.

[0187] Embodiment 20

[0188]

[0189] The preparation method of compound 20 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 72% and a melting point of >260°C.

[0190] Product structure identification data: 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.33(s,1H,NH),11.21(s,1H,NH),10.36(s,1H,NH),7.85(s,1H,CH=C),7.73(s,1H,CH=N),7.17(s,1H,Ar H), 7.11 (t, J = 12.0Hz, 1H, Ar H), 6.91 (d, J = 8.0Hz, 1H, Ar H), 6.84 (d, J = 8.0Hz, 1H, Ar H).

[0191] 13 C NMR (100MHz, DMSO) δ (ppm): 163.46, 151.20, 147.28, 137.33, 131.71, 131.38, 122.88, 121.11, 114.28, 111.28, 108.35.

[0192] HRMS (ESI):Calculated for C 11 H9BrN4O2[M+H] + :308.9982,found:308.9970.

[0193] Embodiment 21

[0194]

[0195] The preparation method of compound 21 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 3-fluoro-4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 66% and a melting point of >260°C.

[0196] Product structure identification data:

[0197] 1 H NMR (400MHz, DMSO-d6)δ(ppm):11.30(s,1H,NH),11.20(s,1H,NH),10.24(s,1H,NH),7.83(s,1H,CH=C),7.70(s,1H,CH=N),7.04(t,J=10.0Hz,1H,Ar H), 6.78 (d, J = 12.0Hz, 1H, Ar H), 6.64 (d, J = 8.0Hz, 1H, Ar H), 2.10 (s, 3H, CH3).

[0198] 13 C NMR (100MHz, DMSO) δ (ppm): 163.52, 161.92 (d, J = 238Hz, 1C), 151.24, 145.70 (d, J = 9Hz, 1C), 136.93, 13 2.19(d,J=7Hz,1C),130.65,113.27(d,J=18Hz,1C),108.58,108.13,98.87(d,J=26Hz,1C),13.90.

[0199] HRMS (ESI):Calculated for C 12 H 11 FN4O2[M+H] + :263.0939,found:263.0928.

[0200] Embodiment 22

[0201]

[0202] The preparation method of compound 22 is the same as that of Example 1, except that phenylhydrazine hydrochloride is replaced by 2-methyl-5-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 63% and a melting point of >260°C.

[0203] Product structure identification data:

[0204] 1 H NMR(400MHz, DMSO-d6)δ(ppm):11.32(s,1H,NH),11.24(s,1H,NH),9.60(s,1H,NH),8.07(s,1H,CH=C),7.92(s,1H,CH=N),7.11(d,J=12.0Hz,1H,Ar H),7.00(t,J=8.0Hz,1H,Ar H),6.42(t,J=8.0,1H,Ar H),2.12(s,CH3).

[0205] 13 C NMR (100MHz, DMSO) δ (ppm): 163.61, 162.35 (d, J = 236Hz, 1C), 151.31, 145.31 (d, J = 10Hz, 1C), 137.43, 133.24, 1 31.67(d,J=10Hz,1C),116.59(d,J=2Hz,1C),108.58,104.50(d,J=21Hz,1C),98.98(d,J=27Hz,1C),17.25.

[0206] HRMS (ESI):Calculated for C 12 H 11 FN4O2[M+H] + :263.0939,found:263.0939.

[0207] Embodiment 23

[0208]

[0209] The preparation method of compound 23 comprises the following steps:

[0210] Add ethanol (5 mL), phenylhydrazine hydrochloride (1.5 mmol), and triethylamine (1.6 mmol) to a 25 mL single-mouth bottle, stir at room temperature for 15 min, add 4,6-dihydroxypyrimidine-5-carboxaldehyde (1.5 mmol) and glacial acetic acid (0.15 mmol). Heat to reflux at 80 ° C for 6 hours, and monitor the reaction progress by TLC. After the reaction is completed, the system is cooled to room temperature, filtered, and the solid is recrystallized in ethanol to obtain the target compound 23.

[0211] The obtained pure product is a white solid with a yield of 52% and a melting point of >260°C.

[0212] Product structure identification data:

[0213] 1 H NMR(400MHz, DMSO-d6) δ12.88(s,1H),12.55(s,1H),10.45(s,1H),8.21(s,2H),8. 05(s,1H),7.27(t,J=8.0Hz,2H),6.87(d,J=8.0Hz,2H),6.81(t,J=6.0Hz,1H).

[0214] 13 C NMR (150MHz, DMSO) δ149.94,144.55,136.35,129.85,119.86,112.01,98.96.

[0215] HRMS (ESI):Calculated for C 11 H 10 N4O2[M+H] + :231.0877,found:231.0876.

[0216] Embodiment 24

[0217]

[0218] The preparation method of compound 24 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 62% and a melting point of >260°C.

[0219] Product structure identification data:

[0220] 1 H NMR (400MHz, DMSO-d6) δ12.66(s,2H),10.31(s,1H),8.17(s,1H),8.03(s,1H),7.08(d,J=8.0Hz,2H),6.77(d,J=8.0Hz,2H),2.22(s,3H).

[0221] 13 CNMR (100MHz, DMSO) δ149.85,142.35,130.24,128.62,112.13,98.97,20.61.

[0222] HRMS (ESI):Calculated for C 12 H 12 N4O2[M+H] + :245.1033,found:245.1039.

[0223] Embodiment 25

[0224]

[0225] The preparation method of compound 25 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-methoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 55% and a melting point of >260°C.

[0226] Product structure identification data:

[0227] 1 H NMR (400MHz, DMSO-d6) δ12.92(s,1H),12.49(s,1H),10.18(s,1H),8.17(s,1H),8.03(s,1H),6.90(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H),3.70(s,3H).

[0228] 13 CNMR (100MHz, DMSO) δ153.63,149.84,138.67,115.34,113.49,99.02,55.72.

[0229] HRMS (ESI):Calculated for C 12 H 12 N4O3[M+H] + :261.0982,found:261.1004.

[0230] Embodiment 26

[0231]

[0232] The preparation method of compound 26 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 60% and a melting point of >260°C.

[0233] Product structure identification data:

[0234] 1 H NMR (400MHz, DMSO-d6) δ12.63(s,2H),10.40(s,1H),8.18(s,1H),8.06(s,1H),7.12(t,J=10.0Hz,2H),6.87(dd,J=12.0,4Hz,2H).

[0235] 13 CNMR(100MHz, DMSO) δ157.33,155.78,149.95,141.38,136.72,116.43,116.28,113.24,98.89.

[0236] HRMS (ESI):Calculated for C 11 H9FN4O2[M+H] + :249.0820,found:249.0782.

[0237] Embodiment 27

[0238]

[0239] The preparation method of compound 27 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 68% and a melting point of >260°C.

[0240] Product structure identification data:

[0241] 1 H NMR (400MHz, DMSO-d6) δ12.60(s,2H),10.55(s,1H),8.19(s,1H),8.07(s,1H),7.30(d,J=8.0Hz,2H),6.87(d,J=8.0Hz,2H).

[0242] 13 C NMR (100MHz, DMSO) δ150.07,143.61,129.65,122.99,113.51,98.90.

[0243] HRMS (ESI):Calculated for C 11 H9ClN4O2[M+H] + :265.0487,found:265.0488.

[0244] Embodiment 28

[0245]

[0246] The preparation method of compound 28 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 69% and a melting point of >260°C.

[0247] Product structure identification data:

[0248] 1 H NMR(400MHz, DMSO-d6) δ12.61(s,2H),10.56(s,1H),8.19(s,1H),8.08(s,1H),7.31(d,J=12.0Hz,2H),6.83(d,J=8.0Hz,2H).

[0249] 13 C NMR (100MHz, DMSO) δ150.06,143.99,136.93,132.48,114.01,110.56,98.91.

[0250] HRMS (ESI):Calculated for C 11 H9BrN4O2[M+H] + :308.9982,found:308.9985.

[0251] Embodiment 29

[0252]

[0253] The preparation method of compound 29 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-nitrophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of >260°C.

[0254] Product structure identification data:

[0255] 1 H NMR (400MHz, DMSO-d6) δ12.55(s,2H),11.19(s,1H),8.27(s,1H),8.22(s,1H),8.13(d,J=12.0Hz,2H),6.98(d,J=8.0Hz,2H).

[0256] HRMS (ESI):Calculated for C 11 H9N5O4[M+H] + :276.0727,found:276.0712.

[0257] Embodiment 30

[0258]

[0259] The preparation method of compound 30 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 69% and a melting point of >260°C.

[0260] Product structure identification data:

[0261] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,2H),10.84(s,1H),8.24(s,1H),8.12(s,1H),7.58(d,J=8.0Hz,2H),7.00(d,J=8.0Hz,2H).

[0262] 13 C NMR (100MHz, DMSO) δ164.54,150.15,147.54,137.85,127.08,124.39,119.30,119.06,111.62,98.70.

[0263] HRMS (ESI):Calculated for C 12 H9F3N4O2[M+H] + :299.075,found:299.0743.

[0264] Embodiment 31

[0265]

[0266] The preparation method of compound 31 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 75% and a melting point of >260°C.

[0267] Product structure identification data:

[0268] 1 H NMR (400MHz, DMSO-d6) δ12.53(s,2H),10.59(s,1H),8.20(s,1H),8.07(s,1H),7.27(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,2H).

[0269] 13 C NMR (100MHz, DMSO) δ150.09,143.92,141.18,122.99,119.82,112.79,98.80,71.05.

[0270] HRMS (ESI):Calculated for C 12 H9F3N4O3[M+H] + :315.0700,found:315.0703.

[0271] Embodiment 32

[0272]

[0273] The preparation method of compound 32 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 2-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 72% and a melting point of >260°C.

[0274] Product structure identification data:

[0275] 1 H NMR (400MHz, DMSO-d6) δ12.69(s,2H),10.35(s,1H),8.44(s,1H),8.08(s,1H),7.21-7.08(m,3H),6.83(dd,J=12.0,4Hz,1H).

[0276] 13 C NMR (100MHz, DMSO) δ150.95,150.36,148.57,139.21,133.02,125.68,119.99,115.99,115.81,113.47,98.88.

[0277] HRMS (ESI):Calculated for C 11 H9FN4O2[M+H] + :249.0782,found:249.0785.

[0278] Embodiment 33

[0279]

[0280] The preparation method of compound 33 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 3-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of >260°C.

[0281] Product structure identification data:

[0282] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,2H),10.61(s,1H),8.18(s,1H),8.08(s,1H),7.26(q,J=8.0Hz,1H),6.67(d,J=8.0Hz,1H),6.62-6.55(m,2H).

[0283] 13 C NMR(100MHz, DMSO) δ164.94,162.54,150.12,146.73,137.14,131.57,131.47,108.21,105.92,105.70,98.80,98.53.

[0284] HRMS (ESI):Calculated for C 11 H9FN4O2[M+H] + :249.0782,found:249.0785.

[0285] Embodiment 34

[0286]

[0287] The preparation method of compound 34 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 2,4-difluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 59% and a melting point of >260°C.

[0288] Product structure identification data:

[0289] 1 H NMR (400MHz, DMSO-d6) δ12.60(s,2H),10.24(s,1H),8.39(s,1H),8.07(s,1H),7.29-7.23(m,1H),7.13-7.02(m,2H).

[0290] HRMS (ESI):Calculated for C 11 H8F2N4O2[M+H] + :267.0688,found:267.0694.

[0291] Embodiment 35

[0292]

[0293] The preparation method of compound 35 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 61% and a melting point of >260°C.

[0294] Product structure identification data:

[0295] 1 H NMR(400MHz, DMSO-d6) δ13.04(s,1H),12.51(s,1H),9.64(s,1H),8.51(s,1H),8.06(s,1H),7.18(d ,J=6.0Hz,1H),7.10(d,J=4.0Hz,1H),6.96(d,J=8.0Hz,1H),6.78(t,J=8.0Hz,1H),2.22(s,3H).

[0296] 13 C NMR (100MHz, DMSO) δ150.26,142.67,131.01,127.39,121.98,120.08,111.17,98.87,17.84.

[0297] HRMS (ESI):Calculated for C 12 H 12 N4O2[M+H] + :245.1033,found:245.1030.

[0298] Embodiment 36

[0299]

[0300] The preparation method of compound 36 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 3-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 64% and a melting point of >260°C.

[0301] Product structure identification data:

[0302] 1 H NMR (400MHz, DMSO-d6) δ12.68(s,2H),10.38(s,1H),8.19(s,1H),8.05(s,1H),7.15(t,J=8.0Hz,1H),6.65(t,J=8.0Hz,3H),2.27(s,3H).

[0303] HRMS (ESI):Calculated for C 12 H 12 N4O2[M+H] + :245.1033,found:245.1038.

[0304] Embodiment 37

[0305]

[0306] The preparation method of compound 37 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 2,4-dimethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 66% and a melting point of >260°C.

[0307] Product structure identification data:

[0308] 1 H NMR (400MHz, DMSO-d6)δ13.13(s,1H),12.43(s,1H),9.55(s,1H),8.45(s,1H),8.04(s,1H ),6.96(d,J=8.0Hz,1H),6.93(s,1H),6.84(d,J=8.0Hz,1H),2.20(s,3H),2.18(s,3H).

[0309] 13 CNMR (100MHz, DMSO) δ150.18,131.69,128.89,127.69,122.19,111.54,98.89,20.54,17.75.

[0310] HRMS (ESI):Calculated for C 13 H 14 N4O2[M+H] + :259.1190,found:259.1190.

[0311] Embodiment 38

[0312]

[0313] The preparation method of compound 38 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 60% and a melting point of >260°C.

[0314] Product structure identification data:

[0315] 1 H NMR (400MHz, DMSO-d6) δ12.68(s,2H),10.02(s,1H),8.59(s,1H),8.09(s,1H),7.37(d ,J=4.0Hz,1H),7.30(t,J=8.0Hz,1H),7.13(d,J=8.0Hz,1H),6.84(t,J=6.0Hz,1H).

[0316] 13 C NMR(100MHz, DMSO) δ155.25,145.77,135.34,133.95,133.22,125.94,125.25,121.90,118.52,117.60,103.52.

[0317] HRMS (ESI):Calculated for C 11 H9ClN4O2[M+H] + :265.0487,found:265.0484.

[0318] Embodiment 39

[0319]

[0320] The preparation method of compound 39 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 63% and a melting point of >260°C.

[0321] Product structure identification data:

[0322] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,2H),10.58(s,1H),8.17(s,1H),8.08(s,1H),7.24(t,J=8.0Hz,1H),6.85(s,1H),6.80(d,J=8.0Hz,2H).

[0323] 13 C NMR (100MHz, DMSO) δ150.07,146.16,137.27,134.36,131.41,119.00,111.32,110.72,98.75.

[0324] HRMS (ESI):Calculated for C 11 H9ClN4O2[M+H] + :265.0487,found:265.0487.

[0325] Embodiment 40

[0326]

[0327] The preparation method of compound 40 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 2,4-dichlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 66% and a melting point of >260°C.

[0328] Product structure identification data:

[0329] 1 H NMR (400MHz, DMSO-d6)δ12.51,10.07,8.58,8.12,7.49,7.49,7.36,7.36,7.34,7.34,7.16,7.14.12.51(s,2H),10 .07(s,1H),8.58(s,1H),8.12(s,1H),7.49(d,J=2.0Hz,1H),7.35(dd,J=8.0,2.0Hz,1H),7.15(d,J=8.0Hz,1H).

[0330] 13 C NMR (100MHz, DMSO) δ161.52,150.44,142.43,140.34,134.46,129.23,128.64 ,128.23,122.99,121.70,117.50,117.33,114.81,114.41,98.64,97.31.

[0331] HRMS (ESI):Calculated for C 11 H8Cl2N4O2[M+H] + :299.0097,found:299.0103.

[0332] Embodiment 41

[0333]

[0334] The preparation method of compound 41 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of >260°C.

[0335] Product structure identification data:

[0336] 1 H NMR (400MHz, DMSO-d6)δ12.63(s,2H),9.76(s,1H),8.60(s,1H),8.09(s,1H),7.53(d, J=8.0Hz,1H),7.34(t,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),6.79(t,J=8.0Hz,1H).

[0337] 13 CNMR(100MHz, DMSO) δ150.58,142.21,133.33,129.23,121.38,113.84,107.06,98.71.

[0338] HRMS (ESI):Calculated for C 11 H9BrN4O2[M+H] + :308.9982,found:308.9978.

[0339] Embodiment 42

[0340]

[0341] The preparation method of compound 42 is the same as that of Example 23, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 71% and a melting point of >260°C.

[0342] Product structure identification data:

[0343] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,2H),10.57(s,1H),8.18(s,1H),8.10(s,1H),7. 20(t,J=8.0Hz,1H),7.01(s,1H),6.94(d,J=8.0Hz,1H),6.85(d,J=8.0Hz,1H).

[0344] 13 CNMR (100MHz, DMSO) δ150.08,146.28,137.43,131.70,122.91,121.89,114.20,111.08,98.75.

[0345] HRMS (ESI):Calculated for C 11 H9BrN4O2[M+H] + :308.9982,found:308.9981.

[0346] Embodiment 43

[0347]

[0348] The preparation method of compound 43 comprises the following steps:

[0349] Dissolve 2.4mmol phenylhydrazine hydrochloride and 2.4mmol triethylamine in 10mL methanol solvent and stir for 30min. Add 2mmol 4,6-diaminopyrimidine-5-carboxaldehyde and 0.3mmol glacial acetic acid, heat and stir at 80℃ for 4h, monitor the reaction progress by TLC, add 20mL water after the reaction is completed, stir to precipitate solid, filter, wash with water and ethyl acetate, and dry to obtain a yellow solid. Yield: 62%, melting point: 244-245℃.

[0350] Product structure identification data:

[0351] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.89 (NH, s, 1H), 8.12 (CH = N, s, 1H), 7.80 (pyrimidine-H, s, 1H), 7.21 ( Ar-H,t,J=7.8Hz,2H),7.02((NH2)2,s,4H),6.92(Ar-H,d,J=8.0Hz,2H),6.73(Ar-H,t,J=7.4Hz,1H);

[0352] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 160.87, 156.94, 145.90, 136.15, 129.68, 118.89, 112.02, 90.58;

[0353] HRMS(ESI):calcd.for C 11 H 12 N6[M+H] + 229.11962,found:229.11945.

[0354] Embodiment 44

[0355]

[0356] The preparation method of compound 44 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid, with a yield of 71% and a melting point of 249-250°C;

[0357] Product structure identification data:

[0358] 1H NMR(600MHz,DMSO-d6)δ(ppm):9.88(NH,s,1H),8.12(CH=N,s,1H),7.82(pyrimidin e-H,s,1H),7.08(Ar-H&(NH2)2,d,J=7.8Hz,6H),6.91(Ar-H,dd,J=8.8,4.7Hz,2H);

[0359] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 160.67, 156.62, 156.14 (d, J = 234.3Hz), 142.66, 136.27, 116.17 (d, J = 22.2Hz), 113.00 (d, J = 7.1Hz), 90.41;

[0360] HRMS(ESI):calcd.for C 11 H 11 FN6[M+H] + 247.1102, found:247.11003.

[0361] Embodiment 45

[0362]

[0363] The preparation method of compound 45 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid, with a yield of 83% and a melting point of 242-243°C;

[0364] Product structure identification data:

[0365] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.29 (NH, s, 1H), 8.12 (CH = N, s, 1H), 8.05 (pyrimidine- H,s,1H),7.75((NH2)2,s,4H),7.26(Ar-H,d,J=8.4Hz,2H),6.96(Ar-H,d,J=8.5Hz,2H);

[0366] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 158.37, 152.11, 144.42, 135.12, 129.47, 122.49, 113.68, 89.60;

[0367] HRMS(ESI):calcd.for C 11 H11 ClN6[M+H] + 263.08065,found:263.08029.

[0368] Embodiment 46

[0369]

[0370] The preparation method of compound 46 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 68% and a melting point of 252-253°C.

[0371] Product structure identification data:

[0372] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.19 (NH, s, 1H), 8.17 (CH = N, s, 1H), 7.84 (pyrimidine- H,s,1H),7.35(Ar-H,d,J=8.4Hz,2H),7.14((NH2)2,s,4H),6.88(Ar-H,d,J=8.4Hz,2H);

[0373] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 160.52, 156.31, 145.10, 136.88, 132.22, 113.92, 109.48, 90.23;

[0374] HRMS(ESI):calcd.for C 11 H 11 BrN6[M+H] + 307.03013,found:307.02986.

[0375] Embodiment 47

[0376]

[0377] The preparation method of compound 47 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 66% and a melting point of >260°C.

[0378] Product structure identification data:

[0379] 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.75 (NH, s, 1H), 8.09 (CH = N, s, 1H), 7.80 (pyrimidine-H ,s,1H),7.08–6.95(Ar-H&(NH2)2,m,6H),6.83(Ar-H,d,J=7.9Hz,2H),2.20(CH3,s,3H);

[0380] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 160.73, 156.75, 143.68, 135.50, 130.05, 127.39, 112.04, 90.61, 20.67;

[0381] HRMS(ESI):calcd.for C 12 H 14 N6[M+H] + 243.13527,found:243.13496.

[0382] Embodiment 48

[0383]

[0384] The preparation method of compound 48 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid, with a yield of 65% and a melting point of 234-235°C.

[0385] Product structure identification data:

[0386] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.65 (NH, s, 1H), 8.21 (CH = N, s, 1H), 8.04 (pyrimidine- H,s,1H),7.73((NH2)2,s,4H),7.55(Ar-H,d,J=8.4Hz,2H),7.08(Ar-H,d,J=8.4Hz,2H);

[0387] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 158.93, 153.15, 148.37, 136.97, 127.03, 125.48 (d, J = 271.7Hz), 118.78 (q, J = 32.3Hz), 111.81, 89.49;

[0388] HRMS(ESI):calcd.for C12 H 11 F3N6[M+H] + 297.10701, found:297.10679.

[0389] Embodiment 49

[0390]

[0391] The preparation method of compound 49 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 4-methoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 63% and a melting point of 235-236°C.

[0392] Product structure identification data:

[0393] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.63 (NH, s, 1H), 8.08 (CH = N, s, 1H), 7.80 (pyrimidi ne-H,s,1H),7.00((NH2)2,s,4H),6.86(Ar-H,q,J=8.7Hz,4H),3.68(OCH3,s,3H);

[0394] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 160.70, 156.70, 152.90, 140.14, 135.23, 115.19, 113.16, 90.69, 55.75;

[0395] HRMS(ESI):calcd.for C 12 H 14 N6O[M+H] + 259.13019,found:259.13005.

[0396] Embodiment 50

[0397]

[0398] The preparation method of compound 50 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 68% and a melting point of 218-219°C.

[0399] Product structure identification data:

[0400] 1H NMR (600MHz, DMSO-d6) δ (ppm): 10.45 (NH, s, 1H), 8.16 (CH = N, s, 1H), 8.12 (pyrimidine- H,s,1H),7.98((NH2)2,s,4H),7.24(Ar-H,d,J=8.5Hz,2H),7.04(Ar-H,d,J=9.1Hz,2H);

[0401] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 157.81, 151.03, 144.66, 141.02, 134.98, 122.89, 120.78 (d, J = 52.5Hz), 113.00, 89.34;

[0402] HRMS(ESI):calcd.for C 12 H 11 F3N6O[M+H] + 313.10192, found:313.10196.

[0403] Embodiment 51

[0404]

[0405] The preparation method of compound 51 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 61% and a melting point of 234-235°C.

[0406] Product structure identification data:

[0407] 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.30(NH,s,1H),8.14(CH=N,s,1H),8.00(pyrimidine-H,s,1H),7.62((NH2) 2,s,4H),7.17(Ar-H,t,J=8.0Hz,1H),7.09(Ar-H,t,J=2.0Hz,1H),6.92(Ar-H,ddd,J=12.7,8.0,2.0Hz,2H);

[0408] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 158.97, 153.32, 147.10, 136.17, 131.64, 122.90, 121.45, 114.29, 111.19, 89.63;

[0409] HRMS(ESI):calcd.for C 11 H 11 BrN6[M+H] + 307.03013,found:307.02977.

[0410] Embodiment 52

[0411]

[0412] The preparation method of compound 52 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a grayish yellow solid with a yield of 74% and a melting point of 249-250°C.

[0413] Product structure identification data:

[0414] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.90 (NH, s, 1H), 8.55 (CH = N, s, 1H), 7.84 (pyrimidine-H, s, 1H), 7.51 (Ar-H, d, J = 8.0 Hz,1H),7.31(Ar-H,t,J=7.7Hz,1H),7.20(Ar-H,d,J=8.2Hz,1H),7.04((NH2)2,s,4H),6.73(Ar-H,t,J=7.6Hz,1H);

[0415] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 161.20, 157.60, 142.50, 140.71, 133.10, 129.30, 120.44, 113.53, 106.51, 89.82;

[0416] HRMS(ESI):calcd.for C 11 H 11 BrN6[M+H] + 307.03013,found:307.02987.

[0417] Embodiment 53

[0418]

[0419] The preparation method of compound 53 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 3-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 60% and a melting point of >260°C.

[0420] Product structure identification data:

[0421] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.03(NH,s,1H),8.09(CH=N,s,1H),7.98(pyrimidine-H,s,1H),7.60((NH 2)2,s,4H),7.11(Ar-H,t,J=8.4Hz,1H),6.75(Ar-H,s,2H),6.58(Ar-H,d,J=7.4Hz,1H),2.25(CH3,s,3H);

[0422] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 158.52, 152.54, 145.51, 138.84, 134.22, 129.58, 120.18, 112.70, 109.48, 89.87, 21.86;

[0423] HRMS(ESI):calcd.for C 12 H 14 N6[M+H] + 243.13527,found:243.13485.

[0424] Embodiment 54

[0425]

[0426] The preparation method of compound 54 is the same as that of Example 43, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 64% and a melting point of 235-236°C.

[0427] Product structure identification data:

[0428] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.99 (NH, s, 1H), 8.40 (CH = N, s, 1H), 7.83 (pyrimidine-H ,s,1H),7.16–7.02(Ar-H&(NH2)2,m,7H),6.70(Ar-H,t,J=7.3Hz,1H),2.22(CH3,s,3H);

[0429] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 160.90, 156.90, 143.71, 138.23, 130.87, 127.36, 121.17, 119.04, 111.23, 90.41, 17.84;

[0430] HRMS(ESI):calcd.for C 12 H 14 N6[M+H] + 243.13527, found:243.13503.

[0431] Embodiment 55

[0432]

[0433] The preparation method of compound 55 comprises the following steps:

[0434] Dissolve 2mmol phenylhydrazine hydrochloride and 2mmol triethylamine in 10mL ethanol solvent and stir for 30min; add 2mmol 2-chloropyridine-3-carboxaldehyde and 0.02mmol glacial acetic acid, heat and stir at 80℃ for 4h, monitor the reaction progress by TLC, add 20mL water after the reaction is completed, stir to precipitate solid, filter, wash with water, and dry to obtain a yellow solid. Yield: 85%, melting point: 172-173℃.

[0435] Product structure identification data:

[0436] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.93(NH,s,1H),8.38(Py-H,dd,J=7.8,2.0Hz,1H),8.32(Py-H,dd,J=4.7,2.0Hz,1H),8.12(CH=N ,s,1H),7.45(Py-H,dd,J=7.8,4.5Hz,1H),7.27(Ar-H,t,J=7.7Hz,2H),7.13(Ar-H,d,J=7.8Hz,2H),6.83(Ar-H,t,J=7.2Hz,1H);

[0437] 13 C NMR (151MHz, DMSO-d6) δ (ppm): 148.75, 147.92, 144.90, 134.67, 130.64, 130.37, 129.63, 123.99, 120.16, 112.77;

[0438] HRMS(ESI):calcd.for C 12 H 10 ClN3[M+H] + 232.0636,found:232.06549.

[0439] Embodiment 56

[0440]

[0441] The preparation method of compound 56 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 2-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 88% and a melting point of 132-133°C.

[0442] Product structure identification data:

[0443] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.84 (NH, s, 1H), 8.44 (CH, s, 1H), 8.41 (Py-H, d, J = 7.8Hz, 1H), 8.35 (Py-H, d, J = 4.6Hz, 1H), 7.59 (Py-H, t, J = 8.3Hz,1H),7.47(Ar-H,dd,J=7.8,4.6Hz,1H),7.18(Ar-H,dd,J=12.1,8.2Hz,1H),7.13(Ar-H,t,J=7.7Hz,1H),6.84(Ar-H,t,J=6.7Hz,1H);

[0444] 13 C NMR (151MHz, DMSO-d6) δ (ppm): 149.62 (d, J = 240.1Hz), 149.25, 148.33, 135.02, 133.73,133.15,130.20,125.44,124.01,120.06,155.63(d,J=18.1Hz),114.60;

[0445] HRMS(ESI):calcd.for C 12 H9ClFN3[M+H] + 250.05418,found:250.05297.

[0446] Embodiment 57

[0447]

[0448] The preparation method of compound 57 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 3-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 84% and a melting point of 164-165°C.

[0449] Product structure identification data:

[0450] 1H NMR(600MHz,DMSO-d6)δ(ppm):11.09(NH,s,1H),8.43(Py-H,d,J=7.8Hz,1H),8.34(Py-H,s,1H),8.14(CH,s,1H),7.46(Py-H,dd,J= 7.9, 4.5Hz, 1H), 7.27 (Ar-H, q, J = 7.7Hz, 1H), 6.96 ( Ar-H, d, J = 11.5Hz, 1H), 6.87 ( Ar-H, d, J = 8.2Hz, 1H), 6.60 ( Ar-H, t, J = 7.3Hz, 1H);

[0451] 13 C NMR (151MHz, DMSO-d6) δ (ppm): 163.77 (d, J = 241.6Hz), 149.16, 148.17, 146.96, 135.07 ,132.03,131.27,130.01,124.03,108.93,106.26(d,J=21.1Hz),99.38(d,J=25.7Hz);

[0452] HRMS(ESI):calcd.for C 12 H9ClFN3[M+H] + 250.05418,found:250.05628.

[0453] Embodiment 58

[0454]

[0455] The preparation method of compound 58 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 80% and a melting point of 179-180°C.

[0456] Product structure identification data:

[0457] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.92 (NH, s, 1H), 8.38 (Py-H, d, J = 7.8Hz, 1H), 8.32 (Py -H,s,1H),8.10(CH,s,1H),7.45(Py-H,dd,J=8.1,4.3Hz,1H),7.20–7.03(Ar-H,m,4H);

[0458] 13C NMR (151MHz, DMSO-d6) δ (ppm): 156.83 (d, J = 235.6Hz), 148.76, 147.91, 141.56 ,134.68,130.66,130.31,123.97,116.18(d,J=22.6Hz),113.80(d,J=9.1Hz);

[0459] HRMS(ESI):calcd.for C 12 H9ClFN3[M+H] + 250.05418,found:250.05538.

[0460] Embodiment 59

[0461]

[0462] The preparation method of compound 59 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 2,4-difluorophenylhydrazine hydrochloride. The obtained pure product is an off-white solid with a yield of 87% and a melting point of 149-150°C.

[0463] Product structure identification data:

[0464] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.80 (NH, s, 1H), 8.41 (Py-H, d, J = 5.8Hz, 2H), 8.38–8.32 (CH, m, 1H), 7.57 (Py-H, td, J = 9.2, 5.8Hz,1H),7.47(Ar-H,dd,J=7.8,4.6Hz,1H),7.25(Ar-H,ddd,J=11.7,8.8,2.8Hz,1H),7.03(Ar-H,td,J=8.6,2.8Hz,1H);

[0465] 13 C NMR (101MHz, DMSO-d6) δppm): 150.70 (dd, J=239.4, 11.1Hz), 149.28, 148.96 (dd, J=244.4, 12.1Hz), 148.34, 135.05, 13 3.73,130.18,124.01,114.98(dd,J=9.1,4.0Hz),112.08(d,J=4Hz),111.86(d,J=4.0Hz),104.41(dd,J=28.3,22.2Hz);

[0466] HRMS(ESI):calcd.for C 12H8ClF2N3[M+H] + 268.04476,found:268.04442.

[0467] Embodiment 60

[0468]

[0469] The preparation method of compound 60 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 83% and a melting point of 162-163°C.

[0470] Product structure identification data:

[0471] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.54(NH,s,1H),8.62(CH,s,1H),8.43(Py-H,d,J=7.8Hz,1H),8.37(Py-H,d,J=4.6Hz,1H),7.63(Ar-H,d ,J=8.2Hz,1H),7.48(Py-H,dd,J=7.7,4.6Hz,1H),7.37(Ar-H,d,J=7.9Hz,1H),7.28(Ar-H,t,J=7.7Hz,1H),6.86(Ar-H,t,J=7.6Hz,1H);

[0472] 13 C NMR (151MHz, Methanol-d4) δ (ppm): 150.20, 149.39, 142.06, 135.93, 135.60, 130.98, 130.71, 129.29, 124.82, 121.74, 117.82, 115.66;

[0473] HRMS(ESI):calcd.for C 12 H9Cl2N3[M+H] + 266.02463,found:266.02608.

[0474] Embodiment 61

[0475]

[0476] The preparation method of compound 61 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 89% and a melting point of 198-199°C.

[0477] Product structure identification data:

[0478] 1 H NMR(600MHz,DMSO-d6)δ(ppm):11.07(NH,s,1H),8.42(Py-H,dd,J=7.8,1.9Hz,1H),8.35(Py-H,dd,J=4.5,2.0Hz,1H),8.14(CH,s,1H),7.47(Py-H,d d,J=7.8,4.7Hz,1H),7.26(Ar-H,t,J=8.0Hz,1H),7.18(Ar-H,t,J=2.2Hz,1H),7.01(Ar-H,dd,J=8.2,2.1Hz,1H),6.84(Ar-H,dd,J=7.8,2.1Hz,1H);

[0479] 13 C NMR (151MHz, Methanol-d4) δ (ppm): 149.98, 149.01, 147.19, 135.86, 135.22, 133.09, 132.05, 130.77, 124.86, 120.36, 112.84, 112.33;

[0480] HRMS(ESI):calcd.for C 12 H9Cl2N3[M+H] + 266.02463,found:266.02390.

[0481] Embodiment 62

[0482]

[0483] The preparation method of compound 62 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 75% and a melting point of 203-204°C.

[0484] Product structure identification data:

[0485] 1 H NMR(600MHz,DMSO-d6)δ(ppm):11.03(NH,s,1H),8.38(Py-H,dd,J=7.7,1.9Hz,1H),8.34(Py-H,d,J=3.8Hz,1H ),8.12(CH,s,1H),7.46(Py-H,dd,J=7.8,4.6Hz,1H),7.29(Ar-H,d,J=8.4Hz,2H),7.13(Ar-H,d,J=8.4Hz,2H);

[0486] 13 C NMR (151MHz, Methanol-d4) δ (ppm): 149.79, 148.89, 144.66, 135.62, 132.38, 130.93, 130.25, 124.80, 124.26, 115.02;

[0487] HRMS(ESI):calcd.for C 12 H9Cl2N3[M+H] + 266.02463,found:266.02477.

[0488] Embodiment 63

[0489]

[0490] The preparation method of compound 63 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 2,4-dichlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 88% and a melting point of 157-158°C.

[0491] Product structure identification data:

[0492] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.64(NH,s,1H),8.63(CH,s,1H),8.42(Py-H,d,J=7.8Hz,1H),8.40– 8.28(Py-H,m,1H),7.72–7.56(Py-H,m,1H),7.48(Ar-H,d,J=6.9Hz,2H),7.32(Ar-H,d,J=8.7Hz,1H);

[0493] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 149.68, 148.77, 140.54, 135.65, 135.31, 130.01, 129.18, 128.53, 124.05, 123.62, 117.53, 115.89;

[0494] HRMS(ESI):calcd.for C 12 H8Cl3N3[M+H] + 299.98566,found:299.98316.

[0495] Embodiment 64

[0496]

[0497] The preparation method of compound 64 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 81% and a melting point of 142-143°C.

[0498] Product structure identification data:

[0499] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.34(NH,s,1H),8.65(CH,s,1H),8.42(Py-H,dd,J=7.7,2.0Hz,1H),8.36(Py-H,dd,J=4.6,2.0Hz,1H),7.60(A r-H,d,J=8.2Hz,1H),7.52(Py-H,d,J=7.9Hz,1H),7.48(Ar-H,dd,J=7.8,4.7Hz,1H),7.32(Ar-H,t,J=7.8Hz,1H),6.80(Ar-H,t,J=7.6Hz,1H);

[0500] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 149.52, 148.66, 142.41, 135.25, 134.98, 133.23, 130.23, 129.09, 124.10, 121.67, 115.41, 106.83;

[0501] HRMS(ESI):calcd.for C 12 H9BrClN3[M+H] + 309.97411, found:309.97371.

[0502] Embodiment 65

[0503]

[0504] The preparation method of compound 65 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 95% and a melting point of 203-204°C.

[0505] Product structure identification data:

[0506] 1H NMR(600MHz,DMSO-d6)δ(ppm):11.06(NH,s,1H),8.41(Py-H,dd,J=7.7,1.9Hz,1H),8.34(Py-H,dd,J=4.5,2.0Hz,1H),8.13(CH,s,1H),7.47(P y-H,dd,J=7.8,4.6Hz,1H),7.31(Ar-H,d,J=2.1Hz,1H),7.20(Ar-H,t,J=8.0Hz,1H),7.04(Ar-H,d,J=8.3Hz,1H),6.97(Ar-H,d,J=7.8Hz,1H);

[0507] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 149.30, 148.26, 146.53, 135.17, 132.36, 131.65, 130.01, 124.16, 123.05, 122.53, 114.90, 111.95;

[0508] HRMS(ESI):calcd.for C 12 H9BrClN3[M+H] + 309.97411, found:309.97467.

[0509] Embodiment 66

[0510]

[0511] The preparation method of compound 66 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 76% and a melting point of 195-196°C.

[0512] Product structure identification data:

[0513] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 11.00 (NH, s, 1H), 8.35 (Py-H, dd, J = 7.6, 2.4Hz, 1H), 8.30 (Py-H, dd, J = 4.7, 2.1Hz, 1H),8.08(CH,s,1H),7.43(Py-H,dd,J=7.9,4.3Hz,1H),7.37(Ar-H,d,J=8.8Hz,2H),7.04(Ar-H,d,J=8.9Hz,2H);

[0514] 13C NMR (101MHz, DMSO-d6) δ (ppm): 149.14, 148.13, 144.26, 134.93, 132.35, 131.70, 130.15, 124.11, 114.75, 111.15;

[0515] HRMS(ESI):calcd.for C 12 H9BrClN3[M+H] + 309.97411, found:309.97295.

[0516] Embodiment 67

[0517]

[0518] The preparation method of compound 67 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 73% and a melting point of 191-192°C.

[0519] Product structure identification data:

[0520] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.17(NH,s,1H),8.42(CH,s,1H),8.39(Py-H,dd,J=7.8,1.9Hz,1H),8.32(Py-H,dd,J=4.6,1.9Hz,1 H),7.52–7.41(Ar-H,m,2H),7.13(Py-H,t,J=7.6Hz,1H),7.08(Ar-H,d,J=7.4Hz,1H),6.76(Ar-H,t,J=7.3Hz,1H),2.24(CH3,s,3H);

[0521] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 148.84, 148.17, 142.94, 134.72, 132.24, 130.93, 130.58, 127.22, 124.01, 121.58, 120.15, 112.87, 17.96;

[0522] HRMS(ESI):calcd.for C 13 H 12 ClN3[M+H] + 246.07925,found:246.07918.

[0523] Embodiment 68

[0524]

[0525] The preparation method of compound 68 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 3-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 63% and a melting point of 144-145°C.

[0526] Product structure identification data:

[0527] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.84(NH,s,1H),8.37(Py-H,dd,J=7.9,2.0Hz,1H),8.31(Py-H,dd,J=4.7,2.0Hz,1H),8.09(CH,s,1H),7.45(Ar-H ,dd,J=7.8,4.6Hz,1H),7.13(Py-H,t,J=7.7Hz,1H),6.95(Ar-H,s,1H),6.89(Ar-H,d,J=8.1Hz,1H),6.64(Ar-H,d,J=7.5Hz,1H),2.28(CH3,s,3H);

[0528] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 148.78, 147.91, 144.89, 138.97, 134.72, 130.45, 130.42, 129.56, 124.09, 121.10, 113.23, 110.18, 21.79;

[0529] HRMS(ESI):calcd.for C 13 H 12 ClN3[M+H] + 246.07925,found:246.08182.

[0530] Embodiment 69

[0531]

[0532] The preparation method of compound 69 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 178-179°C.

[0533] Product structure identification data:

[0534] 1H NMR(600MHz,DMSO-d6)δ(ppm):10.81(NH,s,1H),8.35(Py-H,dd,J=7.8,2.0Hz,1H),8.29(Py-H,dd,J=4.8,2.0Hz,1H),8.0 5(CH,s,1H),7.43(Py-H,dd,J=7.9,4.6Hz,1H),7.06(Ar-H,d,J=8.1Hz,2H),7.01(Ar-H,d,J=7.9Hz,2H),2.22(CH3,s,3H);

[0535] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 148.60, 147.81, 142.67, 134.57, 130.54, 130.12, 129.87, 128.86, 124.05, 112.81, 20.73;

[0536] HRMS(ESI):calcd.for C 13 H 12 ClN3[M+H] + 246.07925,found:246.08131.

[0537] Embodiment 70

[0538]

[0539] The preparation method of compound 70 is the same as that of Example 55, except that phenylhydrazine hydrochloride is replaced by 2,4-dimethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 67% and a melting point of 193-194°C.

[0540] Product structure identification data:

[0541] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.12(NH,s,1H),8.40–8.35(Py-H&CH,m,2H),8.30(Py-H,dd,J=4.7,1.9Hz,1H),7.44(Py-H,dd ,J=7.9,4.6Hz,1H),7.35(Ar-H,d,J=8.2Hz,1H),6.94(Ar-H,d,J=8.2Hz,1H),6.90(Ar-H,s,1H),2.20((CH3)2,d,J=2.1Hz,6H);

[0542] 13C NMR (101MHz, DMSO-d6) δ (ppm): 148.70, 148.02, 140.68, 134.63, 131.57, 131.47, 130.71, 128.79, 127.68, 124.07, 121.60, 113.07, 20.66, 17.91;

[0543] HRMS(ESI):calcd.for C 14 H 14 ClN3[M+H] + 260.0949,found:260.09603.

[0544] Embodiment 71

[0545]

[0546] The preparation method of compound 71 comprises the following steps:

[0547] Dissolve 2mmol phenylhydrazine hydrochloride and 2mmol triethylamine in 10mL ethanol solvent and stir for 30min; add 2mmol 2-aminopyridine-3-carboxaldehyde and 0.02mmol glacial acetic acid, heat and stir at 80℃ for 4h, monitor the reaction progress by TLC, add 20mL water after the reaction is completed, stir to precipitate solid, filter, wash with water, and dry to obtain a yellow solid. Yield: 69%, melting point: 209-210℃;

[0548] Product structure identification data:

[0549] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.31(NH,s,1H),7.98(CH,s,1H),7.93(Py-H,dd,J=4.9,2.0Hz,1H),7.51(Py-H,dd,J=7.5,1.9Hz,1H),7 .25(Ar-H,t,J=7.9Hz,2H),7.21(NH2,s,2H),6.95(Ar-H,d,J=8.2Hz,2H),6.77(Ar-H,t,J=7.3Hz,1H),6.62(Py-H,dd,J=7.4,4.9Hz,1H);

[0550] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.30, 147.54, 145.38, 139.45, 138.16, 129.74, 119.27, 112.82, 112.50, 112.09;

[0551] HRMS(ESI):calcd.for C 12 H 12 N4[M+H] + 213.11347,found:213.11251.

[0552] Embodiment 72

[0553]

[0554] The preparation method of compound 72 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 2-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of 173-174°C.

[0555] Product structure identification data:

[0556] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.20 (NH, s, 1H), 8.24 (CH, d, J = 2.7Hz, 1H), 7.96 (Py-H, dd, J = 4.9, 2.0Hz, 1H), 7.49 (P y-H,dd,J=7.5,1.9Hz,1H),7.29–7.09(NH2&3Ar-H,m,5H),6.84–6.74(Ar-H,m,1H),6.63(Py-H,dt,J=8.0,3.9Hz,1H);

[0557] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.48, 149.70 (d, J = 239.2Hz), 148.08, 142.44, 138.68, 133.63 (d, J =9.9Hz), 125.58 (d, J = 3.2Hz), 119.24 (d, J = 7.2Hz), 115.72 (d, J = 17.5Hz), 113.52, 112.57, 112.50;

[0558] HRMS(ESI):calcd.for C 12 H 11 FN4[M+H] + 231.10405,found:231.10274.

[0559] Embodiment 73

[0560]

[0561] The preparation method of compound 73 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 3-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 67% and a melting point of 195-196°C.

[0562] Product structure identification data:

[0563] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.53(NH,s,1H),7.99(CH,s,1H),7.95(Py-H,d d,J=4.9,2.1Hz,1H),7.56(Py-H,dd,J=7.5,1.9Hz,1H),7.26(Ar-H,q,J=8.2Hz ,1H),7.18(NH2,s,2H),6.75(Ar-H,d,J=8.3Hz,1H),6.69(Ar-H,dt,J=11.5,2. 4Hz,1H),6.64(Ar-H,dt,J=7.6,3.9Hz,1H),6.55(Py-H,td,J=8.5,2.6Hz,1H);

[0564] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 163.86 (d, J = 240.8Hz), 156.26, 147.69, 147.33 (d, J = 10.7Hz), 140.61 ,138.73,131.37(d,J=10.3Hz),112.62,112.57,108.34,105.37(d,J=21.5Hz),98.65(d,J=26.2Hz);

[0565] HRMS(ESI):calcd.for C 12 H 11 FN4[M+H] + 231.10405,found:231.10320.

[0566] Embodiment 74

[0567]

[0568] The preparation method of compound 74 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 78% and a melting point of 222-223°C.

[0569] Product structure identification data:

[0570] 1H NMR(600MHz,DMSO-d6)δ(ppm):10.28(NH,s,1H),7.97(CH,s,1H),7.95–7.89(Py-H,m,1H),7.52(Py-H,dd,J=7.5,1.7H z,1H),7.16(NH2,s,2H),7.13–7.07(Ar-H,m,2H),6.94(Ar-H,dd,J=9.1,4.6Hz,2H),6.62(Py-H,dd,J=7.4,4.8Hz,1H);

[0571] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.36 (d, J = 235.3Hz), 156.32, 147.61, 142.17 ,139.64,138.21,116.27(d,J=22.3Hz),113.13(d,J=7.6Hz),112.80,112.54;

[0572] HRMS(ESI):calcd.for C 12 H 11 FN4[M+H] + 231.10405,found:231.10311.

[0573] Embodiment 75

[0574]

[0575] The preparation method of compound 75 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 2,4-difluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 72% and a melting point of 200-201°C.

[0576] Product structure identification data:

[0577] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.15 (NH, s, 1H), 8.23 ​​(CH, s, 1H), 7.96 (Py-H, d, J = 5.3Hz, 1H), 7.51 (Py-H, d, J = 7.5Hz, 1 H),7.25(Ar-H,td,J=9.1,3.1Hz,2H),7.20(NH2,s,2H),7.05(Ar-H,t,J=9.9Hz,1H),6.65(Py-H,dd,J=7.6,4.9Hz,1H);

[0578] 13C NMR (101MHz, DMSO-d6) δ (ppm): 156.38, 152.15 (dd, J = 378.3, 12.3Hz), 152.12 (d, J = 874.7Hz), 147.90, 142.50, 138.76, 130.65 (dd, J = 1 0.3, 4.0Hz), 113.86 (dd, J = 9.9, 5.2Hz), 112.55 (d, J = 4.4Hz), 112.06 (d, J = 4.4Hz), 111.85 (d, J = 4.4Hz), 104.54 (dd, J = 27.4, 22.3Hz);

[0579] HRMS(ESI):calcd.for C 12 H 10 F2N4[M+H] + 249.09463,found:249.09356.

[0580] Embodiment 76

[0581]

[0582] The preparation method of compound 76 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 67% and a melting point of 130-131°C.

[0583] Product structure identification data:

[0584] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.82 (NH, s, 1H), 8.40 (CH, s, 1H), 7.96 (Py-H, dd, J = 4.8, 1.9 Hz, 1H), 7.50 (Py-H, dd, J = 7.4, 2.0 Hz, 1H), 7.3 6(Ar-H,d,J=8.0Hz,1H),7.32–7.24(Ar-H,m,2H),7.19(NH2,s,2H),6.82(Ar-H,td,J=6.3,3.1Hz,1H),6.64(Py-H,dd,J=7.5,4.8Hz,1H);

[0585] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.54, 148.33, 143.58, 141.49, 138.91, 130.05, 128.69, 120.20, 116.88, 113.53, 112.64, 112.38;

[0586] HRMS(ESI):calcd.for C 12 H 11 ClN4[M+H] + 247.0745,found:247.07382.

[0587] Embodiment 77

[0588]

[0589] The preparation method of compound 77 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 88% and a melting point of 189-190°C.

[0590] Product structure identification data:

[0591] 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.51(NH,s,1H),7.99(CH,s,1H),7.95(Py-H, dd,J=4.8,1.9Hz,1H),7.55(Py-H,dd,J=7.4,2.0Hz,1H),7.26(Ar-H,t,J=8.1H z,1H),7.17(NH2,s,2H),6.93(Ar-H,t,J=2.2Hz,1H),6.88(Ar-H,dd,J=8.1,2. 4Hz,1H),6.79(Ar-H,dd,J=7.9,2.2Hz,1H),6.63(Py-H,dd,J=7.4,4.9Hz,1H);

[0592] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.41, 148.07, 146.82, 140.96, 138.65, 134.42, 131.38, 118.66, 112.58, 112.43, 111.36, 110.87;

[0593] HRMS(ESI):calcd.for C 12 H 11 ClN4[M+H] + 247.0745,found:247.07449.

[0594] Embodiment 78

[0595]

[0596] The preparation method of compound 78 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 69% and a melting point of 221-222°C.

[0597] Product structure identification data:

[0598] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.43 (NH, s, 1H), 7.98 (CH, s, 1H), 7.93 (Py-H, dd, J = 4.9, 1.8 Hz, 1H), 7.53 (Py-H, dd, J = 7.5 ,1.9Hz,1H),7.27(Ar-H,d,J=8.7Hz,2H),7.16(NH2,s,2H),6.94(Ar-H,d,J=8.8Hz,2H),6.62(Py-H,dd,J=7.4,4.8Hz,1H);

[0599] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.37, 147.86, 144.32, 140.37, 138.44, 129.54, 122.50, 113.54, 112.60, 112.56;

[0600] HRMS(ESI):calcd.for C 12 H 11 ClN4[M+H] + 247.0745,found:247.07407.

[0601] Embodiment 79

[0602]

[0603] The preparation method of compound 79 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 2,4-dichlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 84% and a melting point of 175-176°C.

[0604] Product structure identification data:

[0605] 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.94 (NH, s, 1H), 8.41 (CH, s, 1H), 7.97 (Py-H, d, J = 5.1Hz, 1H), 7.52 (Py-H, d, J = 7.8Hz, 1H), 7.47(Ar-H,s,1H),7.34(Ar-H,d,J=9.0Hz,1H),7.26(Ar-H,d,J=9.0Hz,1H),7.19(NH2,s,2H),6.65(Py-H,t,J=6.5Hz,1H);

[0606] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.39, 148.14, 144.22, 140.64, 139.28, 129.26, 128.65, 122.75, 117.37, 114.53, 112.67, 112.35;

[0607] HRMS(ESI):calcd.for C 12 H 10 Cl2N4[M+H] + 281.03553,found:281.03522.

[0608] Embodiment 80

[0609]

[0610] The preparation method of compound 80 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow-brown solid with a yield of 68% and a melting point of 132-133°C.

[0611] Product structure identification data:

[0612] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.56 (NH, s, 1H), 8.43 (CH, s, 1H), 7.97 (Py-H, d, J = 5.0Hz, 1H), 7.52 (Py-H, t, J = 7.2Hz, 2H), 7.3 3(Ar-H,t,J=7.7Hz,1H),7.26(Ar-H,d,J=8.2Hz,1H),7.17(NH2,s,2H),6.77(Ar-H,t,J=7.6Hz,1H),6.69–6.62(Py-H,m,1H);

[0613] 13C NMR (101MHz, DMSO-d6) δ (ppm): 156.55, 148.36, 143.74, 142.52, 138.92, 133.28, 129.24, 120.91, 113.99, 112.65, 112.37, 106.79;

[0614] HRMS(ESI):calcd.for C 12 H 11 BrN4[M+H] + 291.02399,found:291.02363.

[0615] Embodiment 81

[0616]

[0617] The preparation method of compound 81 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow-brown solid with a yield of 69% and a melting point of 173-174°C.

[0618] Product structure identification data:

[0619] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.48(NH,s,1H),7.99(CH,s,1H),7.95(Py-H,dd,J=4.8,1.9Hz,1H),7.55(Py-H,dd,J=7.5,2.0Hz,1H) ,7.22–7.13(NH2&Ar-H,m,3H),7.08(Ar-H,t,J=2.1Hz,1H),6.92(Ar-H,td,J=5.8,5.0,2.9Hz,2H),6.63(Py-H,dd,J=7.5,4.8Hz,1H);

[0620] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.38, 148.04, 146.94, 140.99, 138.66, 131.69, 122.98, 121.55, 114.24, 112.58, 112.43, 111.22;

[0621] HRMS(ESI):calcd.for C 12 H 11 BrN4[M+H] + 291.02399,found:291.02375.

[0622] Embodiment 82

[0623]

[0624] The preparation method of compound 82 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 78% and a melting point of 233-234°C.

[0625] Product structure identification data:

[0626] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.44 (NH, s, 1H), 7.99 (CH, s, 1H), 7.94 (Py-H, d, J = 4.8Hz, 1H), 7.54 (Py-H, d, J = 7.5H z,1H),7.40(Ar-H,d,J=8.6Hz,2H),7.15(NH2,s,2H),6.91(Ar-H,d,J=8.7Hz,2H),6.63(Py-H,dd,J=7.7,4.7Hz,1H);

[0627] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.37, 147.89, 144.68, 140.47, 138.49, 132.37, 114.05, 112.57, 110.03;

[0628] HRMS(ESI):calcd.for C 12 H 11 BrN4[M+H] + 291.02399,found:291.02355.

[0629] Embodiment 83

[0630]

[0631] The preparation method of compound 83 is the same as that of Example 71, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 62% and a melting point of 209-210°C.

[0632] Product structure identification data:

[0633] 1H NMR(600MHz,DMSO-d6)δ(ppm):10.18(NH,s,1H),7.94(CH,s,1H),7.91(Py-H,dd,J=4.9,1.9Hz,1H),7.49(Py-H,dd,J=7.5,1.9Hz,1 H),7.19(NH2,s,2H),7.06(Ar-H,d,J=8.3Hz,2H),6.85(Ar-H,d,J=8.3Hz,2H),6.61(Py-H,dd,J=7.5,4.8Hz,1H),2.22(CH3,s,3H);

[0634] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 156.28, 147.35, 143.19, 138.83, 137.95, 130.15, 127.89, 112.98, 112.51, 112.17, 20.69;

[0635] HRMS(ESI):calcd.for C 13 H 14 N4[M+H] + 227.12912, found:227.12837.

[0636] Embodiment 84

[0637]

[0638] The preparation method of compound 84 comprises the following steps:

[0639] Add ethanol (5 mL), phenylhydrazine hydrochloride (2 mmol) and triethylamine (2 mmol) to a 25 mL single-mouth bottle, stir at room temperature for 15 min, add compound 1-(4-amino-2-methylpyrimidin-5-yl)ethan-1-one (1 mmol) and glacial acetic acid (0.2 mmol). Set the heating temperature to 80 ° C, heat under reflux for 6 hours, and monitor the reaction progress by TLC. After the reaction is completed, cool the system to room temperature, filter, and recrystallize the solid in ethanol to obtain the target compound 84. The obtained pure product is a yellow solid with a yield of 68%. The melting point is 241-242 ° C.

[0640] Product structure identification data:

[0641] 1H NMR(400MHz,DMSO-d6)δ(ppm):9.33(s,1H,NH),8.38(m,2H,pyrimidine-H&NH2-H),7.62(s,1H,NH2-H),7.26(t, J=7.7Hz,2H,Ar-H),7.06(d,J=8.0Hz,2H,Ar-H),6.80(t,J=7.3Hz,1H,Ar-H),2.36(s,3H,CH3),2.30(s,3H,CH3);

[0642] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.14, 160.24, 154.24, 146.08, 142.76, 129.66, 119.83, 112.96, 110.78, 25.69, 13.51;

[0643] HRMS(ESI):calcd.for Chemical Formula:C 13 H 15 N5[M+H] + 241.1327, found: 241.1403.

[0644] Embodiment 85

[0645]

[0646] The preparation method of compound 85 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 251-252°C.

[0647] Product structure identification data:

[0648] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.46 (s, 1H, NH), 8.39 (s, 1H, pyrimidine-H), 7.96 (d, J = 238.9Hz, 2H ,NH2),7.41(d,J=8.8Hz,2H,Ar-H),7.01(d,J=8.8Hz,2H,Ar-H),2.36(s,3H,CH3),2.29(s,3H,CH3);

[0649] 13C NMR (100MHz, DMSO-d6) δ (ppm): 165.33, 160.21, 154.49, 145.35, 143.77, 132.26, 114.88, 110.67, 25.68, 13.76;

[0650] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 BrN5[M+H] + 320.0505,found:320.0505.

[0651] Embodiment 86

[0652]

[0653] The preparation method of compound 86 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 53% and a melting point of 259-260°C.

[0654] Product structure identification data:

[0655] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.21 (s, 1H, NH), 8.36 (s, 1H, pyrimidine-H), 7.06 (d, J = 8.2Hz ,2H,Ar-H),6.96(d,J=8.2Hz,2H,Ar-H),2.35(s,3H,CH3),2.27(s,3H,CH3),2.22(s,3H,CH3);

[0656] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.95, 160.21, 153.99, 143.86, 142.06, 130.07, 128.43, 113.02, 110.81, 25.66, 20.71, 13.44;

[0657] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5[M+H] + 256.1557, found:256.1559.

[0658] Embodiment 87

[0659]

[0660] The preparation method of compound 87 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 3-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 48% and a melting point of 241-242°C.

[0661] Product structure identification data:

[0662] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.48 (s, 1H, NH), 8.42 (s, 1H, pyrimidine-H), 7.15 (t, J = 7.7Hz, 1H, Ar-H ),6.93–6.85(m,2H,Ar-H),6.66(d,J=7.4Hz,1H,Ar-H),2.45(s,3H,CH3),2.29(d,J=13.5Hz,6H,CH3);

[0663] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.21, 160.85, 145.70, 140.94, 138.78, 129.54, 121.04, 113.82, 111.19, 110.34, 23.64, 21.89, 13.69;

[0664] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5[M+H] + 256.1557, found:256.1560.

[0665] Embodiment 88

[0666]

[0667] The preparation method of compound 88 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 56% and a melting point of 199-200°C.

[0668] Product structure identification data:

[0669] 1H NMR(400MHz,DMSO-d6)δ(ppm):8.89(s,1H,NH2-H),8.46(s,1H,NH),8.19(s,1H,pyrimidine-H),7.1 5(q,J=7.6Hz,3H,Ar-H),6.83(t,J=7.3Hz,1H,Ar-H),2.39(d,J=20.3Hz,6H,CH3),2.30(s,3H,CH3);

[0670] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 163.77, 160.73, 151.14, 144.45, 143.61, 131.15, 127.35, 123.80, 120.87, 113.06, 110.87, 24.59, 17.68, 13.23;

[0671] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5[M+H] + 256.1557, found:256.1559.

[0672] Embodiment 89

[0673]

[0674] The preparation method of compound 89 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 60% and a melting point of 244-245°C.

[0675] Product structure identification data:

[0676] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.31(s,1H,NH),8.38(m,2H,pyrimidine-H&NH2-H) ,7.62(s,1H,NH2-H),7.22-6.96(m,4H,Ar-H),2.35(s,3H,CH3),2.28(s,3H,CH3);

[0677] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.15, 160.19, 154.27, 142.94, 142.78, 116.28, 116.06, 113.99 (d, J = 8.0Hz), 110.72, 25.67, 13.62.;

[0678] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 FN5[M+H] + 260.1306, found:260.1308.

[0679] Embodiment 90

[0680]

[0681] The preparation method of compound 90 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 58% and a melting point of 246-247°C.

[0682] Product structure identification data:

[0683] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.45(s,1H,NH),8.39(s,1H,pyrimidine-H),7.29(d, J=8.7Hz,2H,Ar-H),7.06(d,J=8.7Hz,2H,Ar-H),2.36(s,3H,CH3),2.29(s,3H,CH3);

[0684] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.21, 160.24, 154.25, 144.95, 143.60, 129.44, 123.06, 114.37, 110.68, 25.61, 13.77;

[0685] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 ClN5[M+H] + 276.1010, found:276.1009.

[0686] Embodiment 91

[0687]

[0688] The preparation method of compound 91 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 59% and a melting point of 235-236°C.

[0689] Product structure identification data:

[0690] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.45 (s, 1H, NH), 8.32 (s, 1H, pyrimidine-H), 8.19 (s, 1H, NH2-H), 7.75 (s, 1H, NH2-H), 7.42 (dd, J=7.9, 1. 4Hz,1H,Ar-H),7.36–7.28(m,1H,Ar-H),7.25(dd,J=8.2,1.6Hz,1H,Ar-H),6.90(td,J=7.6,1.6Hz,1H,Ar-H),2.37(d,J=2.5Hz,6H,CH3);

[0691] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.91, 160.38, 155.16, 147.98, 141.74, 130.11, 128.81, 121.30, 118.60, 114.29, 110.34, 25.76, 13.40;

[0692] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 ClN5[M+H] + 276.1011, found:276.1011.

[0693] Embodiment 92

[0694]

[0695] The preparation method of compound 92 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 57% and a melting point of 246-247°C.

[0696] Product structure identification data:

[0697] 1H NMR(400MHz,DMSO-d6)δ(ppm):9.52(s,1H,NH),8.40(s,1H,pyrimidine-H),8.18(s,1H,NH2-H),7.78(s,1H,NH2-H),7.27(t,J=8.0Hz,1H Ar-H),7.07(s,1H Ar-H),7.01(d,J=8.3Hz,1H Ar-H),6.82(d,J=7.8Hz,1H Ar-H),2.36(s,3H,CH3),2.30(s,3H,CH3);

[0698] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.41, 160.19, 154.59, 147.40, 144.17, 134.18, 131.25, 119.10, 112.33, 111.40, 110.55, 25.64, 13.73;

[0699] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 ClN5[M+H] + 276.1011, found:276.1012.

[0700] Embodiment 93

[0701]

[0702] The preparation method of compound 93 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 4-methoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 55% and a melting point of 221-222°C.

[0703] Product structure identification data:

[0704] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.43(s,1H,NH),9.31(s,1H,NH2-H),8.81(s,1H,NH2-H),8.41(s,1H,pyrimidine-H ),7.05(d,J=8.5Hz,2H,Ar-H),6.89(d,J=8.5Hz,2H,Ar-H),3.71(s,3H,OCH3),2.47(s,3H,CH3),2.29(s,3H,CH3);

[0705] 13C NMR (101MHz, DMSO-d6) δ (ppm): 161.84, 160.85, 153.70, 139.94, 139.71, 115.04, 114.38, 111.28, 55.69, 23.49, 13.60;

[0706] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5O[M+H] + 272.1506,found:272.1506.

[0707] Embodiment 94

[0708]

[0709] The preparation method of compound 94 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of 241-242°C.

[0710] Product structure identification data:

[0711] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.78(s,1H,NH),8.42(s,1H,pyrimidine-H),8.19(s,1H,NH2-H),7.77 (s,1H,NH2-H),7.59(d,J=8.5Hz,2H,Ar-H),7.19(d,J=8.5Hz,2H,Ar-H),2.35(d,J=14.0Hz,6H,CH3);

[0712] 13 C NMR(101MHz,DMSO-d6)δ(ppm):165.53,160.32,154.61,148.95,145.19,127. 02(d,J=4.04Hz),126.78,119.53(J=31.31Hz),112.64,110.62,25.62,13.98;

[0713] HRMS(ESI):calcd.for Chemical Formula:C 14 H 14 F3N5[M+H] + 310.1274, found:310.1274.

[0714] Embodiment 95

[0715]

[0716] The preparation method of compound 95 is the same as that of Example 84, except that phenylhydrazine hydrochloride is replaced by 2,4-dichlorophenylhydrazine hydrochloride. The obtained pure product is a white solid with a yield of 75% and a melting point of 258-259°C.

[0717] Product structure identification data:

[0718] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.43 (d, J = 13.1Hz, 2H, NH & pyrimidine-H), 7.88 (s, 2H, NH2) ,7.57(s,1H,Ar-H),7.38(d,J=8.7Hz,1H,Ar-H),7.24(d,J=8.8Hz,1H,Ar-H),2.37(s,6H,CH 3s );

[0719] HRMS(ESI):calcd.for Chemical Formula:C 13 H 13 Cl2N5[M+H] + 310.0621, found:310.0622.

[0720] Embodiment 96

[0721]

[0722] The preparation method of compound 96 comprises the following steps:

[0723] Add ethanol (5 mL), phenylhydrazine hydrochloride (2 mmol) and triethylamine (2 mmol) to a 25 mL single-mouth bottle, stir at room temperature for 15 min, add compound 2-methoxy-4-aminopyrimidine-5-aldehyde (1 mmol) and glacial acetic acid (0.2 mmol). Heat to reflux at 80 ° C for 6 hours, and monitor the reaction progress by TLC. After the reaction is completed, cool the system to room temperature, filter, and recrystallize the solid in ethanol to obtain the target compound 84. The obtained pure product is a yellow solid with a yield of 68% and a melting point of 219-220 ° C.

[0724] Product structure identification data:

[0725] 1H NMR(400MHz,DMSO-d6)δ(ppm):10.23(s,1H,NH),8.14(s,1H,CH=N),7.93(s,3H,NH2&pyrimidine-H),7 .23(t,J=7.7Hz,2H,Ar-H),6.91(d,J=7.9Hz,2H,Ar-H),6.75(t,J=7.3Hz,1H,Ar-H),3.84(s,3H,OCH3);

[0726] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.11, 161.66, 158.41, 145.45, 136.98, 129.71, 119.14, 112.00, 106.65, 54.42;

[0727] HRMS(ESI):calcd.for Chemical Formula:C 12 H 13 N5O[M+H] + 244.1193, found:244.1190.

[0728] Embodiment 97

[0729]

[0730] The preparation method of compound 97 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 221-222°C.

[0731] Product structure identification data:

[0732] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H, NH), 8.17 (s, 1H, CH = N), 7.94 (s, 2H, NH2), 7.92 (s, 1 H,pyrimidine-H),7.38(d,J=8.3Hz,2H,Ar-H),6.88(d,J=8.4Hz,2H,Ar-H),3.84(s,3H,OCH3);

[0733] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 163.88, 161.72, 158.16, 144.69, 137.82, 132.33, 113.98, 109.89, 106.47, 54.59;

[0734] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 BrN5O[M+H] + 322.0298,found:322.0297.

[0735] Embodiment 98

[0736]

[0737] The preparation method of compound 98 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 53% and a melting point of 225-226°C.

[0738] Product structure identification data:

[0739] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H, NH), 8.14 (s, 1H, CH = N), 7.91 (d, J = 9.4Hz, 3H, NH2&py rimidine-H),7.09(t,J=8.8Hz,2H,Ar-H),6.91(dd,J=8.9,4.6Hz,2H,Ar-H),3.84(s,3H,OCH3);

[0740] 13 C NMR(101MHz,DMSO-d6)δ(ppm):164.15,161.66,158.49,156.27(J=234.32Hz) ,142.22,137.20,116.22(J=22.22Hz),113.04(d,J=7.07Hz),106.60,54.43;

[0741] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 FN5O[M+H] + 262.1099,found:262.1096.

[0742] Embodiment 99

[0743]

[0744] The preparation method of compound 99 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 48% and a melting point of >260°C.

[0745] Product structure identification data:

[0746] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.10(s,1H,NH),8.12(s,1H,CH=N),7.94(s,2H,NH2),7.89(s,1H,pyrim idine-H),7.04(d,J=7.9Hz,2H,Ar-H),6.81(d,J=8.0Hz,2H,Ar-H),3.82(s,3H,OCH3),2.21(s,3H,CH3);

[0747] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.03, 161.65, 158.19, 143.27, 136.36, 130.15, 127.74, 112.06, 106.78, 54.43, 20.69;

[0748] HRMS(ESI):calcd.for Chemical Formula:C 13 H 15 N5O[M+H] + 258.1349,found:258.1346.

[0749] Embodiment 100

[0750]

[0751] The preparation method of compound 100 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 4-methoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 56% and a melting point of 218-219°C.

[0752] Product structure identification data:

[0753] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.31 (s, 1H, NH), 8.59 (d, 2H, J = 60Hz, NH2), 8.24 (s, 1H, CH = N), 7. 91(s,1H,pyrimidine-H),6.88(q,J=9.2,8.7Hz,4H,Ar-H),3.92(s,3H,OCH3),3.69(s,3H,OCH3);

[0754] 13C NMR (101MHz, DMSO-d6) δ (ppm): 161.95, 161.39, 153.25, 153.09, 139.36, 134.57, 115.23, 113.34, 107.14, 55.75, 55.17;

[0755] HRMS(ESI):calcd.for Chemical Formula:C 13 H 15 N5O2[M+H] + 274.1299,found:274.1297.

[0756] Embodiment 101

[0757]

[0758] The preparation method of compound 101 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 60% and a melting point of 222-223°C.

[0759] Product structure identification data:

[0760] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H, NH), 8.16 (s, 1H, CH = N), 7.93 (d, J = 14.9Hz, 3H, NH2 &pyrimidine-H),7.27(d,J=8.4Hz,2H,Ar-H),6.92(d,J=8.4Hz,2H,Ar-H),3.84(s,3H,OCH3);

[0761] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.28, 161.72, 158.84, 144.40, 137.96, 129.54, 122.35, 113.48, 106.48, 54.51;

[0762] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 ClN5O[M+H] + 278.0803,found:278.0800.

[0763] Embodiment 102

[0764]

[0765] The preparation method of compound 102 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 58% and a melting point of 212-213°C.

[0766] Product structure identification data:

[0767] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.42 (s, 1H, NH), 8.17 (s, 1H, CH = N), 7.94 (s, 1H, pyrimidine-H), 7.89 (s, 2H, NH2), 7.24 (t,J=8.1Hz,1H,Ar-H),6.89(s,1H,Ar-H),6.85(d,J=8.3Hz,1H,Ar-H),6.77(d,J=7.8Hz,1H,Ar-H),3.83(s,3H,OCH3);

[0768] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.35, 161.71, 159.07, 146.89, 138.54, 134.37, 131.39, 118.52, 111.27, 110.77, 106.33, 54.51;

[0769] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 ClN5O[M+H] + 278.0803,found:278.0798.

[0770] Embodiment 103

[0771]

[0772] The preparation method of compound 103 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 59% and a melting point of 194-195°C.

[0773] Product structure identification data:

[0774] 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.77 (s, 1H, NH), 8.36 (s, 1H, CH = N), 8.13 (s, 1H, pyrimidine-H), 7.93 (s, 2H, NH2), 7.35 (d, J =7.9Hz,1H,Ar-H),7.28(t,J=7.7Hz,1H,Ar-H),7.23(d,J=8.2Hz,1H,Ar-H),6.80(t,J=7.6Hz,1H,Ar-H),3.85(s,3H,OCH3);

[0775] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.46, 161.82, 159.26, 141.51, 141.15, 130.01, 128.67, 120.05, 116.76, 113.45, 106.30, 54.53;

[0776] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 ClN5O[M+H] + 278.0803,found:278.0799.

[0777] Embodiment 104

[0778]

[0779] The preparation method of compound 104 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 3-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 57% and a melting point of 207-208°C.

[0780] Product structure identification data:

[0781] 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.15(s,1H,NH),8.12(s,1H,CH=N),7.91(s,3H,NH2&pyrimidine-H),7.15–7 .06(m,1H,Ar-H),6.74–6.68(m,2H,Ar-H),6.57(d,J=7.5Hz,1H,Ar-H),3.83(s,3H,OCH3),2.25(s,3H,CH3);

[0782] 13C NMR (101MHz, DMSO-d6) δ (ppm): 163.35, 161.75, 156.94, 145.38, 138.86, 136.39, 129.62, 120.14, 112.61, 109.32, 106.77, 54.66, 21.85;

[0783] HRMS(ESI):calcd.for Chemical Formula:C 13 H 15 N5O[M+H] + 258.1349,found:258.1347.

[0784] Embodiment 105

[0785]

[0786] The preparation method of compound 105 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 55% and a melting point of 213-214°C.

[0787] Product structure identification data:

[0788] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.43 (s, 1H, NH), 8.23 ​​(s, 1H, CH = N), 8.12 (s, 1H, pyrimidine-H), 7.99 (s, 2H, NH2), 7.13 (t,J=7.7Hz,1H,Ar-H),7.07(d,J=7.9Hz,2H,Ar-H),6.72(t,J=7.3Hz,1H,Ar-H),3.84(s,3H,OCH3),2.21(s,3H,CH3);

[0789] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.22, 161.81, 158.58, 143.39, 138.81, 130.97, 127.37, 121.41, 119.33, 111.37, 106.71, 54.50, 18.02;

[0790] HRMS(ESI):calcd.for Chemical Formula:C 13 H 15 N5O[M+H] + 258.1349,found:258.1348.

[0791] Embodiment 106

[0792]

[0793] The preparation method of compound 106 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of 248-249°C.

[0794] Product structure identification data:

[0795] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.69 (s, 1H, NH), 8.19 (s, 1H, CH = N), 8.00 (s, 1H, pyrimidine-H) ,7.92(s,2H,NH2),7.55(d,J=8.3Hz,2H,Ar-H),7.03(d,J=8.4Hz,2H,Ar-H),3.84(s,3H,OCH3);

[0796] 13 C NMR(101MHz,DMSO-d6)δ(ppm):164.46,161.77,159.37,148.30,139.49,127.07( d, J=4.04Hz), 125.47 (J=270.68Hz), 118.76 (J=31.31Hz), 111.67, 106.19, 54.48;

[0797] HRMS(ESI):calcd.for Chemical Formula:C 13 H 12 F3N5O[M+H] + 312.1067, found:312.1063.

[0798] Embodiment 107

[0799]

[0800] The preparation method of compound 107 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 2,4-dichlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 75% and a melting point of >260°C.

[0801] Product structure identification data:

[0802] 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.88 (s, 1H, NH), 8.37 (s, 1H, CH = N), 8.13 (s, 1H, pyrimidine-H), 7.94 (s, 2H,NH2),7.47(s,1H,Ar-H),7.33(d,J=8.7Hz,1H,Ar-H),7.23(d,J=8.8Hz,1H,Ar-H),3.85(s,3H,OCH3);

[0803] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.52, 161.80, 159.51, 141.95, 140.67, 129.19, 128.61, 122.51, 117.21, 114.47, 106.10, 54.53;

[0804] HRMS(ESI):calcd.for Chemical Formula:C 12 H 11 Cl2N5O[M+H] + 312.0413,found:312.0409.

[0805] Embodiment 108

[0806]

[0807] The preparation method of compound 108 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 3-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 71% and a melting point of 206-207°C.

[0808] Product structure identification data:

[0809] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H, NH), 8.17 (s, 1H, CH = N), 7.94 (s, 1H, pyrimidine-H), 7.89 (s, 2H, NH2) ,7.24(td,J=8.2,6.8Hz,1H,Ar-H),6.75–6.62(m,2H,Ar-H),6.53(td,J=8.5,2.5Hz,1H,Ar-H),3.83(s,3H,OCH3);

[0810] 13C NMR (101MHz, DMSO-d6) δ (ppm): 164.33, 163.87 (J = 241.39Hz), 161.70, 159.01, 147.42 (J = 11.11Hz) ,138.28,131.36(d,J=11.11Hz),108.24,106.36,105.21(J=22.22Hz),98.55(J=26.26Hz),54.50.

[0811] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 FN5O[M+H] + 262.1099,found:262.1096.

[0812] Embodiment 109

[0813]

[0814] The preparation method of compound 109 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 2-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 68% and a melting point of 200-201°C.

[0815] Product structure identification data:

[0816] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.12(s,1H,NH),8.18(s,1H,CH=N),8.11(s,1H,pyrimidine-H),7.94(s,2H ,NH2),7.15(ddt,J=29.0,15.5,8.1Hz,3H,Ar-H),6.77(q,J=6.9Hz,1H,Ar-H),3.84(d,J=2.6Hz,3H,OCH3);

[0817] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.33, 161.77, 158.93, 149.60 (J = 240.38Hz), 139.91, 133.66 (J = 9.09Hz ), 125.55 (d, J = 3.03Hz), 119.09 (J = 7.07Hz), 115.68 (J = 18.18Hz), 113.47 (d, J = 4.04Hz), 106.40, 54.48;

[0818] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 FN5O[M+H] + 262.1099,found:262.1096.

[0819] Embodiment 110

[0820]

[0821] The preparation method of compound 110 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 229-230°C.

[0822] Product structure identification data:

[0823] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H, NH), 8.17 (s, 1H, CH = N), 7.94 (s, 1H, pyrimidine-H), 7.89 (s, 2H,NH2),7.18(t,J=8.0Hz,1H,Ar-H),7.04(s,1H,Ar-H),6.89(d,J=8.1Hz,2H,Ar-H),3.83(s,3H,OCH3);

[0824] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.32, 161.69, 159.03, 146.98, 138.55, 131.66, 122.93, 121.39, 114.14, 111.08, 106.31, 54.49;

[0825] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 BrN5O[M+H] + 322.0298,found:322.0292.

[0826] Embodiment 111

[0827]

[0828] The preparation method of compound 111 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 69% and a melting point of 202-203°C.

[0829] Product structure identification data:

[0830] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.51 (s, 1H, NH), 8.38 (s, 1H, CH = N), 8.12 (s, 1H, pyrimidine-H), 7.92 (s, 2H, NH2), 7.51 (d, J =7.9Hz,1H,Ar-H),7.31(t,J=7.8Hz,1H,Ar-H),7.21(d,J=8.2Hz,1H,Ar-H),6.75(t,J=7.6Hz,1H,Ar-H),3.84(s,3H,OCH3);

[0831] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 164.47, 161.82, 159.27, 142.54, 141.34, 133.23, 129.19, 120.74, 113.91, 106.71, 106.29, 54.52;

[0832] HRMS(ESI):calcd.for Chemical Formula:C 12 H 12 BrN5O[M+H] + 322.0298,found:322.0291.

[0833] Embodiment 112

[0834]

[0835] The preparation method of compound 112 is the same as that of Example 96, except that phenylhydrazine hydrochloride is replaced by 2,4-difluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of 214-215°C.

[0836] Product structure identification data:

[0837] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.05 (s, 1H, NH), 8.15 (s, 1H, CH = N), 8.11 (s, 1H, pyrimidine-H), 7.89 (s, 2H,NH2),7.23(t,J=10.8Hz,1H,Ar-H),7.19(s,1H,Ar-H),7.02(t,J=8.9Hz,1H,Ar-H),3.83(s,3H,OCH3);

[0838] 13 C NMR(101MHz,DMSO-d6)δ(ppm):164.36,161.77,159.00,156.34,153.88,150.26,150.14,147. 84,147.72,140.10,130.77,130.69,112.04,111.82,106.35,104.77,104.51,104.28,54.49;

[0839] HRMS(ESI):calcd.for Chemical Formula:C 12 H 11 F2N5O[M+H] + 280.1004,found:280.1002.

[0840] Embodiment 113

[0841]

[0842] The preparation method of compound 113 comprises the following steps:

[0843] Add ethanol (5 mL), phenylhydrazine hydrochloride (2 mmol) and triethylamine (2 mmol) to a 25 mL single-mouth bottle, stir at room temperature for 15 min, add compound 2-methoxy-4-amino-6-methylpyrimidine-5-aldehyde (1 mmol) and glacial acetic acid (0.2 mmol). Heat to reflux at 80 ° C for 6 hours, and monitor the reaction progress by TLC. After the reaction is completed, the system is cooled to room temperature, filtered, and the solid is recrystallized in ethanol to obtain the target compound 113. The obtained pure product is a yellow solid with a yield of 68% and a melting point of 216-217 ° C.

[0844] Product structure identification data:

[0845] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H, NH), 8.26 (s, 1H, CH = N), 7.76 (s, 1H, NH2-H), 7.28–7.19 (m ,2H,Ar-H),6.92–6.86(m,2H,Ar-H),6.75(t,J=7.3Hz,1H,Ar-H),3.81(s,3H,OCH3),2.38(s,3H,CH3);

[0846] 13C NMR (101MHz, DMSO-d6) δ (ppm): 165.43, 163.35, 162.09, 145.46, 136.31, 129.77, 119.10, 111.89, 103.11, 54.22, 21.92;

[0847] HRMS(ESI):calcd.for Chemical Formula:C 13 H 15 N5O[M+H] + 258.1349,found:258.1349.

[0848] Embodiment 114

[0849]

[0850] The preparation method of compound 114 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 236-237°C.

[0851] Product structure identification data:

[0852] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.33 (s, 1H, NH), 8.26 (s, 1H, CH = N), 8.06 (s, 1H, NH2-H), 7.84 (s, 1 H,NH2-H),7.42–7.34(m,2H,Ar-H),6.89–6.81(m,2H,Ar-H),3.82(s,3H,OCH3),2.38(s,3H,CH3);

[0853] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.84, 163.46, 162.09, 144.69, 137.31, 132.36, 113.80, 109.74, 102.90, 54.24, 21.95;

[0854] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 BrN5O[M+H] + 336.0454,found:336.0451.

[0855] Embodiment 115

[0856]

[0857] The preparation method of compound 115 is the same as that of example 113, except that phenylhydrazine hydrochloride is replaced by 4-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 53% and a melting point of 209-210°C.

[0858] Product structure identification data:

[0859] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H, NH), 8.64 (s, 2H, NH2), 8.26 (s, 1H, CH=N), 7. 12(t,J=8.8Hz,2H,Ar-H),6.98–6.90(m,2H,Ar-H),3.94(s,3H,OCH3),2.45(s,3H,CH3).

[0860] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.20, 160.63, 157.58, 155.25, 141.90, 134.85, 116.30 (J = 8.08Hz), 113.10 (d, J = 8.08Hz), 103.39, 55.15, 19.77.

[0861] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 FN5O[M+H] + 276.1255, found:276.1253.

[0862] Embodiment 116

[0863]

[0864] The preparation method of compound 116 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 48% and a melting point of 210-211°C.

[0865] Product structure identification data:

[0866] 1H NMR (600MHz, DMSO-d6) δ (ppm): 10.08 (s, 1H, NH), 8.22 (s, J = 2.8Hz, 1H, CH = N), 7.72 (s, 1H, NH2-H), 7.04 (d, J = 7.8Hz ,2H,Ar-H),6.79(d,J=7.8Hz,2H,Ar-H),3.80(d,J=3.0Hz,3H,OCH3),2.36(d,J=3.0Hz,3H,CH3),2.21(s,3H,CH3);

[0867] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.16, 163.26, 162.04, 143.26, 135.68, 130.18, 127.70, 111.95, 103.20, 54.20, 21.92, 20.69;

[0868] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5O[M+H] + 272.1506, found:272.1504.

[0869] Embodiment 117

[0870]

[0871] The preparation method of compound 117 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 4-methoxyphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 56% and a melting point of 183-184°C.

[0872] Product structure identification data:

[0873] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H, NH), 8.51 (s, 1H, NH2-H), 8.18 (s, 1H, CH=N), 8.0 9(s,1H,NH2-H),6.86(s,4H,Ar-H),3.86(s,3H,OCH3),3.69(s,3H,OCH3),2.39(s,3H,CH3);

[0874] 13C NMR (101MHz, DMSO-d6) δ (ppm): 162.13, 161.55, 153.20, 139.44, 134.27, 115.32, 113.16, 103.51, 55.79, 54.78, 20.63;

[0875] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5O2[M+H] + 288.1455, found:288.1452.

[0876] Embodiment 118

[0877]

[0878] The preparation method of compound 118 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 60% and a melting point of 173-174°C.

[0879] Product structure identification data:

[0880] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H, NH), 8.37 (s, 2H, NH2), 8.27 (s, 1H, CH=N), 7.2 7(d,J=8.5Hz,2H,Ar-H),6.91(d,J=8.5Hz,2H,Ar-H),3.88(s,3H,OCH3),2.41(s,3H,CH3);

[0881] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.74, 162.11, 161.52, 144.09, 136.06, 129.47, 122.42, 113.36, 103.09, 54.81, 20.43;

[0882] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 ClN5O[M+H] + 292.0960,found:292.0955.

[0883] Embodiment 119

[0884]

[0885] The preparation method of compound 119 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 58% and a melting point of 224-225°C.

[0886] Product structure identification data:

[0887] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.42 (s, 1H, NH), 8.27 (s, 1H, CH=N), 8.11 (s, 1H, NH2-H), 7.82 (s, 1H, NH2-H), 7.24 (t, J=8.1Hz, 1H, Ar -H),6.88-6.85(m,1H,Ar-H),6.82(d,J=8.4Hz,1H,Ar-H),6.76(d,J=7.9Hz,1H,Ar-H),3.81(s,3H,OCH3),2.38(d,J=2.4Hz,3H,CH3);

[0888] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.03, 163.51, 162.09, 146.80, 137.76, 134.40, 131.38, 118.41, 111.04, 110.62, 102.78, 54.26, 21.95;

[0889] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 ClN5O[M+H] + 292.0960,found:292.0959.

[0890] Embodiment 120

[0891]

[0892] The preparation method of compound 120 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 59% and a melting point of 244-245°C.

[0893] Product structure identification data:

[0894] 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.76 (s, 1H, NH), 8.76 (s, 1H, CH=N), 8.17 (s, 1H, NH2-H), 7.81 (s, 1H, NH2-H), 7.35 (d, J=8.0Hz, 1H, Ar-H),7.27(t,J=7.5Hz,1H,Ar-H),7.19(d,J=8.2Hz,1H,Ar-H),6.79(t,J=7.6Hz,1H,Ar-H),3.82(s,3H,OCH3),2.39(s,3H,CH3);

[0895] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.69, 163.65, 162.21, 141.46, 140.61, 130.02, 128.70, 119.85, 116.53, 113.09, 102.82, 54.28, 22.01;

[0896] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 ClN5O[M+H] + 292.0960,found:292.0957.

[0897] Embodiment 121

[0898]

[0899] The preparation method of compound 121 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 3-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 57% and a melting point of 239-240°C.

[0900] Product structure identification data:

[0901] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.14 (s, 1H, NH), 8.24 (s, 2H, CH = N & NH2-H), 7.73 (s, 1H, NH2-H), 7.11 (t, J = 7.9Hz, 1H, Ar-H), 6.68 (s, 2H, Ar-H), 6.57 (d, J = 7.3Hz, 1H, Ar-H), 3.80 (s, 3H, OCH3), 2.37 (s, 3H, CH3), 2.25 (s, 3H, CH3);

[0902] 13C NMR (101MHz, DMSO-d6) δ (ppm): 165.32, 163.29, 162.03, 145.41, 138.89, 136.07, 129.64, 119.99, 112.40, 109.15, 103.12, 54.21, 21.93, 21.87.

[0903] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5O[M+H] + 272.1506, found:272.1504.

[0904] Embodiment 122

[0905]

[0906] The preparation method of compound 122 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 55% and a melting point of 229-230°C.

[0907] Product structure identification data:

[0908] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.41 (s, 1H, NH), 8.60 (s, 1H, CH=N), 8.35 (s, 1H, NH2-H), 7.81 (s, 1H, NH2-H), 7.13 (t, J=7.9Hz, 1H ,Ar-H),7.06(dd,J=15.2,7.7Hz,2H,Ar-H),6.71(t,J=7.3Hz,1H,Ar-H),3.82(s,3H,OCH3),2.40(s,3H,CH3),2.22(s,3H,CH3);

[0909] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 165.34, 163.14, 162.17, 143.31, 138.00, 130.93, 127.34, 121.12, 119.15, 111.05, 103.19, 54.30, 21.78, 18.01;

[0910] HRMS(ESI):calcd.for Chemical Formula:C 14 H 17 N5O[M+H] +272.1506, found:272.1502.

[0911] Embodiment 123

[0912]

[0913] The preparation method of compound 123 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of 236-237°C.

[0914] Product structure identification data:

[0915] 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.68(s,1H,NH),8.34(s,1H,CH=N),8.09(s,1H,NH2-H),7.87(s,1H,N H2-H),7.56(d,J=8.2Hz,2H,Ar-H),7.01(d,J=8.3Hz,2H,Ar-H),3.82(s,3H,OCH3),2.40(s,3H,CH3);

[0916] 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.38,163.62,162.15,148.20,138.72,127.11(q,J =4.04Hz), 125.47 (J = 271.69Hz), 118.64 (J = 32.32Hz), 111.48, 102.67, 54.25, 21.94;

[0917] HRMS(ESI):calcd.for Chemical Formula:C 14 H 14 F3N5O[M+H] + 326.1223, found:326.1222.

[0918] Embodiment 124

[0919]

[0920] The preparation method of compound 124 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 2,4-dichlorophenylhydrazine hydrochloride. The obtained pure product is a white solid with a yield of 75% and a melting point of 234-235°C.

[0921] Product structure identification data:

[0922] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.87 (s, 1H, NH), 8.76 (s, 1H, CH=N), 8.06 (s, 1H, NH2-H), 7.81 (s, 1H, NH2-H), 7.49 (d, J= 2.3Hz,1H,Ar-H),7.33(dd,J=8.8,2.5Hz,1H,Ar-H),7.20(d,J=8.8Hz,1H,Ar-H),3.82(s,3H,OCH3),2.39(s,3H,CH3);

[0923] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 167.04, 163.77, 162.23, 141.46, 140.64, 129.27, 128.72, 122.34, 117.01, 114.12, 102.66, 54.33, 22.04.

[0924] HRMS(ESI):calcd.for Chemical Formula:C 13 H 13 Cl2N5O[M+H] + 326.0570,found:326.0568.

[0925] Embodiment 125

[0926]

[0927] The preparation method of compound 125 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 3-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of 231-232°C.

[0928] Product structure identification data:

[0929] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.41 (s, 1H, NH), 8.27 (s, 1H, CH=N), 7.93 (s, 2H, NH2), 7.24 (td, J=8.1, 6.7Hz ,1H,Ar-H),6.73-6.59(m,2H,Ar-H),6.53(td,J=8.6,2.5Hz,1H,Ar-H),3.81(s,3H,OCH3),2.38(s,3H,CH3);

[0930] 13C NMR (101MHz, DMSO-d6) δ (ppm): 165.98, 163.85 (J = 242.4Hz), 163.49, 162.06, 147.28 (J = 11.11Hz), 1 37.51, 131.37 (J = 10.1Hz), 108.07, 105.09 (J = 22.22Hz), 102.78, 98.31 (J = 26.26Hz), 54.24, 21.92;

[0931] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 FN5O[M+H] + 276.1255, found:276.1253.

[0932] Embodiment 126

[0933]

[0934] The preparation method of compound 126 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 2-fluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 67% and a melting point of 229-230°C.

[0935] Product structure identification data:

[0936] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H, NH), 8.59 (s, 1H, CH = N), 8.17 (s, 1H, NH2-H), 7.78 (s, 1 H,NH2-H),7.21-7.07(m,3H,Ar-H),6.81-6.71(m,1H,Ar-H),3.82(s,3H,OCH3),2.37(s,3H,CH3);

[0937] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.22, 163.57, 162.18, 149.55 (J = 239.37Hz), 139.44, 133.67 (J=10.1Hz),125.60,118.90(J=6.06Hz),115.66(J=17.17Hz),113.15,102.89,54.26,21.90;

[0938] HRMS(ESI):calcd.for Chemical Formula:C 13 H14 FN5O[M+H] + 276.1255, found:276.1252.

[0939] Embodiment 127

[0940]

[0941] The preparation method of compound 127 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 66% and a melting point of 228-229°C.

[0942] Product structure identification data:

[0943] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.38 (s, 1H, NH), 8.26 (s, 1H, CH = N), 7.94 (s, 2H, NH2), 7.18 (t, J = 8.0Hz, 1H, Ar- H),7.01(d,J=2.0Hz,1H,Ar-H),6.88(ddd,J=10.6,7.8,2.0Hz,2H,Ar-H),3.81(s,3H,OCH3),2.38(s,3H,CH3);

[0944] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.06, 163.52, 162.10, 146.93, 137.81, 131.70, 123.01, 121.32, 113.93, 110.97, 102.79, 54.27, 21.96;

[0945] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 BrN5O[M+H] + 336.0454,found:336.0451.

[0946] Embodiment 128

[0947]

[0948] The preparation method of compound 128 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 67% and a melting point of 235-236°C.

[0949] Product structure identification data:

[0950] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.53 (s, 1H, NH), 8.78 (s, 1H, CH=N), 8.13 (s, 1H, NH2-H), 7.80 (s, 1H, NH2-H), 7.51 (dd, J=7.9, 1.4Hz, 1H, A r-H),7.36–7.27(m,1H,Ar-H),7.17(dd,J=8.2,1.6Hz,1H,Ar-H),6.74(td,J=7.6,1.6Hz,1H,Ar-H),3.82(s,3H,OCH3),2.40(s,3H,CH3);

[0951] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 166.81, 163.70, 162.27, 142.56, 140.82, 133.30, 129.28, 120.60, 113.58, 106.48, 102.87, 54.32, 22.08;

[0952] HRMS(ESI):calcd.for Chemical Formula:C 13 H 14 BrN5O[M+H] + 336.0454,found:3360451

[0953] Embodiment 129

[0954]

[0955] The preparation method of compound 129 is the same as that of Example 113, except that phenylhydrazine hydrochloride is replaced by 2,4-difluorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 74% and a melting point of 231-232°C.

[0956] Product structure identification data:

[0957] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.97(s,1H,NH),8.56(s,1H,CH=N),8.07(s,1H,NH2-H),7.79(s,1H,NH2-H ),7.28-7.10(m,2H,Ar-H),7.02(ddd,J=11.4,6.4,2.2Hz,1H,Ar-H),3.82(s,3H,OCH3),2.37(s,3H,CH3);

[0958] 13 C NMR(101MHz,DMSO-d6)δ(ppm):166.23,163.57,162.15,153.85,150.14,150.02,147.73,147 .61,139.59,130.77,130.68,112.07,111.86,104.77,104.55,104.28,102.81,54.26,21.91;

[0959] HRMS(ESI):calcd.for Chemical Formula:C 13 H 13 F2N5O[M+H] + 294.1161, found:294.1163.

[0960] Embodiment 130

[0961]

[0962] The preparation method of compound 130 comprises the following steps:

[0963] Add ethanol (5 mL), phenylhydrazine hydrochloride (2 mmol) and triethylamine (2 mmol) to a 25 mL single-mouth bottle, stir at room temperature for 15 min, add compound 4-aminopyrimidine-5-aldehyde (1 mmol) and glacial acetic acid (0.2 mmol). Heat to reflux at 80 ° C for 6 hours, and monitor the reaction progress by TLC. After the reaction is completed, the system is cooled to room temperature, filtered, and the solid is recrystallized in ethanol to obtain the target compound 130. The obtained pure product is a yellow solid with a yield of 80%. The melting point is 156-158 ° C.

[0964] Product structure identification data:

[0965] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.50 (s, 1H, NH), 8.35 (s, 1H, Py-H), 8.30 (s, 1H, C=NH), 7.96 (s, 1H, Py-H) ,7.88(s,2H,NH2),7.27(t,J=7.8Hz,2H,Ar-H),6.96(d,J=7.8Hz,2H,Ar-H),6.80(t,J=7.3Hz,1H,Ar-H).

[0966] 13C NMR (101MHz, DMSO-d6) δ (ppm): 159.40, 156.65, 155.72, 145.05, 136.38, 129.77, 119.60, 112.17, 111.49.

[0967] HRMS(ESI):calcd.for C 11 H 11 N5[M+H] + 214.10872, found:214.10875.

[0968] Embodiment 131

[0969]

[0970] The preparation method of compound 131 is the same as that of Example 130, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 85% and a melting point of 177-179°C.

[0971] Product structure identification data:

[0972] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H, NH), 8.36 (s, 1H, Py-H), 8.28 (s, 1H, C=NH), 8.25 (s, 1H ,Py-H),7.92(s,2H,NH2),7.21-7.04(m,3H,Ar-H),6.75(t,J=7.0Hz,1H,Ar-H),2.23(s,3H,CH3).

[0973] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.53, 156.80, 155.86, 143.01, 138.15, 131.04, 127.38, 121.66, 119.78, 111.61, 111.55, 18.02.

[0974] HRMS(ESI):calcd.for C 12 H 13 N5[M+H] + 228.1244, found:228.1243.

[0975] Embodiment 132

[0976]

[0977] The preparation method of compound 132 is the same as that of example 130, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 82% and a melting point of 201-202°C.

[0978] Product structure identification data:

[0979] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H, NH), 8.34 (s, 1H, Py-H), 8.28 (s, 1H, C=NH), 7.92 (s, 1H, Py-H),7.87(s,2H,NH2),7.07(d,J=8.1Hz,2H,Ar-H),6.86(d,J=8.3Hz,2H,Ar-H),2.22(s,3H,CH3).

[0980] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.35, 156.48, 155.45, 142.83, 135.67, 130.17, 128.22, 112.21, 111.60, 20.68.

[0981] HRMS(ESI):calcd.for C 12 H 13 N5[M+H] + 228.12437, found:228.12467.

[0982] Embodiment 133

[0983]

[0984] The preparation method of compound 133 is the same as that of Example 130, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 72% and a melting point of 172-174°C.

[0985] Product structure identification data:

[0986] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.74 (s, 1H, NH-N), 8.43 (s, 1H, Py-H), 8.39 (s, 1H, CH=N), 8. 05(s,1H,Py-H),7.90(s,2H,NH2),7.34(d,J=8.4Hz,2H,Ar-H),7.09(d,J=8.7Hz,2H,Ar-H).

[0987] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.60, 157.19, 156.43, 141.21, 140.57, 130.10, 128.73, 120.57, 117.01, 113.71, 111.12.

[0988] HRMS(ESI):calcd.for C 11 H 10 ClN5[M+H] + 248.06975,found:248.07012.

[0989] Embodiment 134

[0990]

[0991] The preparation method of compound 134 is the same as that of example 130, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 80% and a melting point of 188-190°C.

[0992] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.57 (s, 1H, NH-N), 8.28 (s, 1H, Py-H), 8.25 (s, 1H, CH=N), 7.89 (s, 1H, Py-H), 7.73 (s ,2H,NH2),7.19(t,J=8.0Hz,1H,Ar-H),6.87(s,1H,Ar-H),6.82(d,J=8.2Hz,1H,Ar-H),6.74(d,J=7.7Hz,1H,Ar-H).

[0993] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.67, 155.97, 154.47, 146.44, 137.42, 134.38, 131.44, 119.12, 111.58, 111.19, 111.05.

[0994] HRMS(ESI):calcd.for C 11 H 10 ClN5[M+H] + 248.06975,found:248.07028.

[0995] Embodiment 135

[0996]

[0997] The preparation method of compound 135 is the same as that of Example 130, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 84% and a melting point of >260°C.

[0998] 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.63(s,1H,NH-N),8.39(s,1H,Py-H),8.35(s,1H,Py-H),8. 00(s,1H,CH=N),7.85(s,2H,NH2),7.33(d,J=8.2Hz,2H,Ar-H),7.00(d,J=8.2Hz,2H,Ar-H);

[0999] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.44, 156.86, 156.06, 144.01, 137.35, 129.58, 122.81, 113.67, 111.27.

[1000] HRMS(ESI):calcd.for C 11 H 10 ClN5[M+H] + 248.06975,found:248.07005.

[1001] Embodiment 136

[1002]

[1003] The preparation method of compound 136 is the same as that of Example 130, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 205-207°C.

[1004] 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.78(s,1H,NH),8.42(s,1H,Py-H),8.38(s,1H,CH=N),8.28(s,1H,Py-H),7.85(s,2H,NH2) ,7.53(d,J=7.8Hz,1H,Ar-H),7.34(t,J=7.6Hz,1H,Ar-H),7.26(d,J=7.4Hz,1H,Ar-H),6.78(dd,J=11.0,4.1Hz,1H,Ar-H).

[1005] 13C NMR (101MHz, DMSO-d6) δ (ppm): 159.58, 157.25, 156.51, 142.26, 140.77, 133.31, 129.25, 121.25, 114.16, 111.09, 106.90.

[1006] HRMS(ESI):calcd.for C 11 H 10 BrN5[M+H] + 292.0192,found:292.0193.

[1007] Embodiment 137

[1008]

[1009] The preparation method of compound 137 is the same as that of Example 130, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 167-169°C.

[1010] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.65 (s, 1H, NH), 8.36 (s, 1H, Py-H), 8.33 (s, 1H, CH=N), 7.97 (s, 1H ,Py-H),7.83(s,2H,NH2),7.21(t,J=8.0Hz,1H,Ar-H),7.09(s,1H,Ar-H),7.01-6.87(m,2H,Ar-H).

[1011] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.45, 157.03, 156.29, 146.63, 138.00, 131.73, 122.95, 121.87, 114.36, 111.30, 111.13.

[1012] HRMS(ESI):calcd.for C 11 H 10 BrN5[M+H] + 292.01923,found:292.01884.

[1013] Embodiment 138

[1014]

[1015] The preparation method of compound 138 is the same as that of Example 130, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of >260°C.

[1016] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.62 (s, 1H, NH), 8.37 (s, 1H, Py-H), 8.32 (s, 1H, CH=N), 7.9 7(s,1H,Py-H),7.83(s,2H,NH2),7.41(d,J=8.7Hz,2H,Ar-H),6.93(d,J=8.8Hz,2H,Ar-H).

[1017] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.42, 156.88, 156.10, 144.35, 137.43, 132.37, 114.15, 111.25, 110.37.

[1018] HRMS(ESI):calcd.for C 11 H 10 BrN5[M+H] + 292.01923,found:292.01993.

[1019] Embodiment 139

[1020]

[1021] The preparation method of compound 139 is the same as that of Example 130, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 78% and a melting point of >260°C.

[1022] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.92 (s, 1H, NH), 8.38 (s, 1H, Py-H), 8.36 (s, 1H, CH=N), 8.0 4(s,1H,Py-H),7.86(s,2H,NH2),7.59(d,J=8.5Hz,2H,Ar-H),7.10(d,J=8.5Hz,2H,Ar-H).

[1023] 13C NMR(101MHz,DMSO-d6)δ(ppm):159.52,157.20,156.61,147.98,139.00,127. 15,127.11,126.73,124.05,119.69,119.37,119.05,118.73,111.93,110.98.

[1024] HRMS(ESI):calcd.for C 12 H 10 F3N5[M+H] + 282.0966,found:282.0974.

[1025] Embodiment 140

[1026]

[1027] The preparation method of compound 140 is the same as that of example 130, except that phenylhydrazine hydrochloride is replaced by 4-nitrophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 75% and a melting point of >260°C.

[1028] 1 H NMR(400MHz,DMSO-d6)δ(ppm):11.44(s,1H,NH-N),8.46(s,1H,Py-H),8.45(s,1H,Py-H),8.23(s ,1H,CH=N),8.20(s,1H,Ar-H),8.17(s,1H,AR-H),7.89(s,2H,NH2),7.14(d,J=9.1Hz,2H,Ar-H).

[1029] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 159.61, 157.72, 157.47, 150.27, 141.79, 139.03, 126.74, 111.61, 110.54.

[1030] HRMS(ESI):calcd.for C 11 H 10 N6O2[M+H] + 259.09435,found:259.09172.

[1031] Embodiment 141

[1032]

[1033] The preparation method of compound 141 comprises the following steps:

[1034] Add ethanol (5 mL), phenylhydrazine hydrochloride (2 mmol) and triethylamine (2 mmol) to a 25 mL single-mouth bottle, stir at room temperature for 15 min, add compound 2,4-diaminopyrimidine-5-aldehyde (1 mmol) and glacial acetic acid (0.2 mmol). Heat to reflux at 80 ° C for 6-8 hours, and monitor the reaction progress by TLC. After the reaction is completed, the system is cooled to room temperature, filtered, and the solid is recrystallized in ethanol to obtain the target compound 141. The obtained pure product is a yellow solid with a yield of 75% and a melting point of 256-258 ° C.

[1035] Product structure identification data:

[1036] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.94 (s, 1H, NH), 7.88 (s, 1H, Py-H), 7.82 (s, 1H, CH=N), 7.49 (s, 2H, NH2), 7.20(t,J=7.8Hz,2H,Ar-H),6.87(d,J=7.9Hz,2H,Ar-H),6.70(t,J=7.3Hz,1H,Ar-H),6.34(s,2H,NH2).

[1037] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.32, 160.76, 158.57, 145.92, 138.81, 129.62, 118.50, 111.75, 102.60.

[1038] HRMS(ESI):calcd.for C 11 H 12 N6[M+H] + 229.1196, found: 229.1208.

[1039] Embodiment 142

[1040]

[1041] The preparation method of compound 142 is the same as that of example 141, except that phenylhydrazine hydrochloride is replaced by 2-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 63% and a melting point of 201-203°C.

[1042] Product structure identification data:

[1043] 1H NMR(600MHz,DMSO-d6)δ(ppm):9.11(s,1H,NH-N),8.08(s,1H,CH=N),7.85(s,1H,Py-H),7.46(s,2H,NH2),7.08(t ,J=7.4Hz,1H,Ar-H),7.03(d,J=6.5Hz,2H,Ar-H),6.65(t,J=7.1Hz,1H,Ar-H),6.34(s,2H,NH2),2.17(s,3H,CH3).

[1044] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.41, 160.87, 158.71, 143.83, 140.65, 130.77, 127.23, 121.01, 118.64, 111.07, 102.62, 18.00.

[1045] HRMS(ESI):calcd.for C 12 H 14 N6[M+H] + 243.1353, found:243.1357.

[1046] Embodiment 143

[1047]

[1048] The preparation method of compound 143 is the same as that of Example 141, except that phenylhydrazine hydrochloride is replaced by 4-methylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 232-234°C.

[1049] Product structure identification data:

[1050] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.79 (s, 1H, NH), 7.86 (s, 1H, Py-H), 7.77 (s, 1H, CH=N), 7.46 (s, 2H, NH2),7.01(d,J=8.2Hz,2H,Ar-H),6.77(d,J=8.3Hz,2H,Ar-H),6.29(s,2H,NH2),2.19(s,3H,CH3).

[1051] 13C NMR (101MHz, DMSO-d6) δ (ppm): 162.13, 160.62, 158.22, 143.63, 138.11, 129.90, 126.91, 111.73, 102.61, 20.53.

[1052] HRMS(ESI):calcd.for C 12 H 14 N6[M+H] + 243.13527, found:243.13440.

[1053] Embodiment 144

[1054]

[1055] The preparation method of compound 144 is the same as that of example 141, except that phenylhydrazine hydrochloride is replaced by 2-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 54% and a melting point of >260°C.

[1056] Product structure identification data:

[1057] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.48 (s, 1H, NH), 8.23 ​​(s, 1H, Py-H), 7.88 (s, 1H, CH = N), 7.49 (s, 2H, NH2), 7.33 (d, J = 7.7 Hz,1H,Ar-H),7.25(t,J=7.5Hz,1H,Ar-H),7.19(d,J=7.9Hz,1H,Ar-H),6.76(t,J=7.3Hz,1H,Ar-H),6.44(s,2H,NH2).

[1058] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.62, 160.92, 159.36, 142.91, 141.89, 129.88, 128.58, 119.36, 116.43, 113.15, 102.24.

[1059] HRMS(ESI):calcd.for C 11 H 12 ClN6[M+H] + 263.08065,found:263.07700.

[1060] Embodiment 145

[1061]

[1062] The preparation method of compound 145 is the same as that of example 141, except that phenylhydrazine hydrochloride is replaced by 3-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 45% and a melting point of 239-241°C.

[1063] Product structure identification data:

[1064] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.76 (s, 1H, NH-N), 8.67 (s, 2H, NH2), 8.11 (s, 1H, Py-H), 7.83 (s, 1H, CH=N), 7.75 (s ,2H,NH2),7.18(t,J=8.1Hz,1H,Ar-H),6.88(s,1H,Ar-H),6.82(d,J=8.2Hz,1H,Ar-H),6.73(d,J=7.9Hz,1H,Ar-H).

[1065] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 161.66, 154.21, 146.51, 144.71, 136.14, 134.36, 131.39, 118.99, 111.54, 111.03, 104.46.

[1066] HRMS(ESI):calcd.for C 11 H 12 ClN6[M+H] + 263.0806, found:263.0818.

[1067] Embodiment 146

[1068]

[1069] The preparation method of compound 146 is the same as that of example 141, except that phenylhydrazine hydrochloride is replaced by 4-chlorophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 76% and a melting point of >260°C.

[1070] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.07 (s, 1H, NH), 7.89 (s, 1H, Py-H), 7.81 (s, 1H, CH=N), 7. 42(s,2H,NH2),7.23(d,J=8.8Hz,2H,Ar-H),6.86(d,J=8.8Hz,2H,Ar-H),6.35(s,2H,NH2).

[1071] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.44, 160.79, 158.93, 144.83, 139.74, 129.41, 121.60, 113.16, 102.40.

[1072] HRMS(ESI):calcd.for C 11 H 11 ClN6[M+H] + 263.08065,found:263.07906.

[1073] Embodiment 147

[1074]

[1075] The preparation method of compound 147 is the same as that of Example 141, except that phenylhydrazine hydrochloride is replaced by 2-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 65% and a melting point of 193-195°C.

[1076] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.21 (s, 1H, NH), 8.23 ​​(s, 1H, Py-H), 7.86 (s, 1H, CH=N), 7.48 (d, J=7.3Hz, 3H, Ar- H,NH2),7.28(t,J=7.6Hz,1H,Ar-H),7.16(d,J=7.6Hz,1H,Ar-H),6.70(t,J=7.1Hz,1H,Ar-H),6.40(s,2H,NH2).

[1077] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.62, 160.92, 159.39, 143.10, 142.90, 133.09, 129.11, 120.09, 113.61, 106.40, 102.21.

[1078] HRMS(ESI):calcd.for C 11 H 11 BrN6[M+H] + 307.0301, found:307.0303.

[1079] Embodiment 148

[1080]

[1081] The preparation method of compound 148 is the same as that of example 141, except that phenylhydrazine hydrochloride is replaced by 3-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 50% and a melting point of 243-245°C.

[1082] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H, NH), 7.90 (s, 1H, Py-H), 7.81 (s, 1H, CH=N), 7.41 (s, 2H, NH2),7.14(t,J=8.0Hz,1H,Ar-H),6.98(s,1H,Ar-H),6.83(d,J=6.7Hz,2H,Ar-H),6.37(s,2H,NH2).

[1083] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 162.45, 160.79, 159.02, 147.41, 140.31, 131.56, 122.92, 120.69, 113.75, 110.87, 102.24.

[1084] HRMS(ESI):calcd.for C 11 H 11 BrN6[M+H] + 307.0301, found:307.0298.

[1085] Embodiment 149

[1086]

[1087] The preparation method of compound 149 is the same as that of example 141, except that phenylhydrazine hydrochloride is replaced by 4-bromophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 75% and a melting point of >260°C.

[1088] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.10 (s, 1H, NH), 7.91 (s, 1H, Py-H), 7.83 (s, 1H, CH=N), 7. 45(s,2H,NH2),7.35(d,J=8.6Hz,2H,Ar-H),6.83(d,J=8.8Hz,2H,Ar-H),6.39(s,2H,NH2).

[1089] 13C NMR (101MHz, DMSO-d6) δ (ppm): 162.44, 160.79, 158.97, 145.16, 139.82, 132.22, 113.68, 109.09, 102.38.

[1090] HRMS(ESI):calcd.for C 11 H 11 BrN6[M+H] + 307.03013, found:307.03114.

[1091] Embodiment 150

[1092]

[1093] The preparation method of compound 150 is the same as that of Example 141, except that phenylhydrazine hydrochloride is replaced by 4-trifluoromethylphenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 78% and a melting point of >260°C.

[1094] 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.79(s,1H,NH),8.13(s,2H,NH2),8.07(s,1H,Py-H),7.9 2(s,1H,CH=N),7.54(d,J=8.6Hz,2H,Ar-H),7.15(s,2H,NH2),7.03(d,J=8.5Hz,2H,Ar-H).

[1095] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 161.24, 158.52, 152.51, 148.32, 139.24, 127.05, 126.81, 124.12, 118.70, 118.39, 111.61, 103.18.

[1096] HRMS(ESI):calcd.for C 12 H 11 F3N6[M+H] + 297.1070, found:297.1071.

[1097] Embodiment 151

[1098]

[1099] The preparation method of compound 151 is the same as that of Example 141, except that phenylhydrazine hydrochloride is replaced by 4-nitrophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 70% and a melting point of >260°C.

[1100] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.99 (s, 1H, NH-N), 8.09 (s, 1H, Py-H), 8.05 (s, 1H, CH=N) ,7.91(d,J=8.7Hz,2H,Ar-H),7.39(s,2H,NH2),6.89(d,J=8.5Hz,3H),6.49(s,2H,NH2).

[1101] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 163.70, 162.78, 160.95, 160.30, 150.68, 144.00, 137.88, 126.84, 110.82, 101.67.

[1102] HRMS(ESI):calcd.for C 11 H 11 N7O2[M+H] + 274.1047, found:274.1048.

[1103] Embodiment 152

[1104]

[1105] The preparation method of compound 152 is the same as that of Example 141, except that phenylhydrazine hydrochloride is replaced by 2,4-dinitrophenylhydrazine hydrochloride. The obtained pure product is a yellow solid with a yield of 75% and a melting point of 188-190°C.

[1106] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.01 (s, 1H, NH-N), 9.44 (s, 1H, Py-H), 8.31 (s, 1H, CH=N), 8.28–8.2 2(m,1H,Ar-H),7.79(s,1H,Ar-H),7.67(d,J=9.7Hz,1H,Ar-H),7.55(s,2H,NH2),7.15(s,2H,NH2).

[1107] 13C NMR (101MHz, DMSO-d6) δ (ppm): 189.49, 167.03, 164.45, 162.76, 149.65, 134.70, 130.06, 127.99, 123.99, 123.99, 116.05, 106.22.

[1108] HRMS(ESI):calcd.for C 11 H 10 N8O4[M+H] + 319.08978,found:319.08700.

[1109] Test Example 1 Test of plant pathogenic bacteria inhibitory activity

[1110] Experimental materials: tobacco bacterial wilt pathogen, rice white leaf blight pathogen, watermelon fruit spot pathogen, tomato canker pathogen, black rot pathogen, wild rapeseed Xanthomonas and citrus canker pathogen.

[1111] Inhibition rate test method:

[1112] (1) Take the bacteria in fresh liquid LB medium at a 1% inoculum and place it in a shaker. The culture conditions are: temperature 28±1°C, speed 180 rpm. The concentration of bacteria is determined by measuring the optical density at 595nm. When the bacterial solution grows to OD595 of 0.7-1.0, it can be used for compound screening experiments.

[1113] (2) Dilute the cultured bacteria to 1×10 6 cells / mL (OD680=0.02), add 198 μL of the diluted algae solution to a 96-well plate using a spray gun, then add 2 μL of the compound to be tested, seal the 96-well plate tightly, and place it in a shaker. The culture conditions are: temperature 28±1°C, speed 180 rpm, culture for about 48 hours, and use an ELISA reader to measure the absorbance of the control group and the experimental group at 595 nm, which are recorded as OD595 control and OD595 experiment, respectively. Each group of experiments is repeated 3 times, and the inhibition rate is calculated according to the following formula:

[1114] Inhibition rate = (OD control group - OD experimental group) × 100% / OD control group.

[1115] (3) Set the concentration gradient of the compound, determine the corresponding inhibition rate, and use the Growth / Sigmoidal module in Origin to fit the EC of the compound. 50 The measurement results are shown in Table 1-11.

[1116] Table 1 Antibacterial activity data of compounds 1-42 (100 μM, in vitro inhibition rate, %)

[1117]

[1118]

[1119] Table 2 Antibacterial activity data of compounds 43-83 (25 μg / mL, in vitro inhibition rate, %)

[1120]

[1121]

[1122] Table 3 Antibacterial activity data of compounds 84-129 (50 ppm, in vitro inhibition rate, %)

[1123]

[1124]

[1125] Table 4 EC of some compounds against tobacco solanacearum 50 (μM)

[1126] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 4 11.44 23 7.62 36 17.67 5 20.90 24 13.92 37 26.46 6 11.73 26 6.55 38 18.30 10 6.04 27 9.58 39 8.17 11 5.60 28 11.05 40 19.09 12 7.93 29 17.10 41 18.47 18 15.42 31 13.12 42 35.29 19 25.18 32 4.60 Chlorphenamine 85.3 20 17.57 33 4.33 21 25.41 34 5.72

[1127] Table 5 EC values ​​of some compounds against Xanthomonas oryzae 50 (μM)

[1128] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 4 19.87 30 12.16 40 20.04 7 13.77 32 9.65 41 11.58 8 14.97 33 25.35 42 25.71 12 33.81 34 8.31 Chlorphenamine 102.2 21 25.87 38 16.86 29 9.11 39 11.65

[1129] Table 6 EC of some compounds against watermelon fruit spot bacteria 50 (μg / mL)

[1130] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 45 7.85 55 15.96 79 13.69 46 6.10 66 5.61 80 14.95 48 6.37 69 14.48 81 8.33 50 4.81 76 10.35 Thiophanate 92.06 51 7.72 77 15.81

[1131] Table 7 EC values ​​of some compounds against tomato canker bacteria 50 (μg / mL)

[1132]

[1133]

[1134] Table 8 EC of some compounds against tobacco solanacearum 50 (μg / mL)

[1135]

[1136]

[1137] Table 9 EC values ​​of some compounds against Xanthomonas campestris 50 (μg / mL)

[1138] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 45 9.42 66 14.88 79 10.09 46 8.19 76 11.89 81 9.87

[1139] Table 10 EC of some compounds against Xanthomonas oryzae 50 (μg / mL)

[1140] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 43 9.16 51 14.42 73 13.94 44 10.99 57 15.01 76 15.76 45 3.89 58 17.95 79 9.95 46 13.84 71 12.66 80 15.09 50 16.83 72 12.10

[1141] Table 11 EC of some compounds against Xanthomonas citri var. 50 (μg / mL)

[1142] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 45 13.61 55 16.93 71 14.08

[1143] The compound of the invention has excellent plant pathogenic bacteria inhibition activity and can be used for preventing and controlling watermelon fruit spot pathogen, tomato canker pathogen, tobacco bacterial wilt pathogen, wild rapeseed Xanthomonas campestris, rice bacterial leaf blight pathogen and citrus canker pathogen.

[1144] Test Example 2 Test of plant pathogenic fungi inhibitory activity

[1145] Experimental materials: pepper anthracnose, graminearum fusarium, pepper blight, peach brown rot, citrus pythium, rice blast, rice false smut, tomato early blight, wheat fusarium, rapeseed sclerotinia, rice sheath blight, apple ring rot, wheat sheath blight, corn leaf blight, rice seedling rust and gray mold.

[1146] Inhibition rate test method: in vitro plate method.

[1147] (1) Preparation of PDA medium: Peel and wash potatoes, weigh 800 g, cut into thin slices, put into a pot with 4 L of distilled water, heat and boil, cook until the potatoes are soft, filter the clear liquid with gauze, add 400 mL of each into a conical flask containing 8 g of glucose and 6 g of agar, shake well, seal, and sterilize by high pressure.

[1148] (2) Preparation and pouring: Weigh a certain amount of target compound using an analytical balance and prepare a 50 mg / mL DMSO solution. Use a pipette to take 400 μL of the target compound solution and add it to the PDA medium heated to liquid in a microwave oven to make the compound concentration 50 μg / mL. Shake the medium and pour it into the culture dish, about 20 mL / dish. After cooling and solidifying, write the compound number.

[1149] (3) Inoculation and culture: The activated fungi were punched into fungus blocks at the edge of the hyphae with a 5 mm diameter puncher, and the fungus blocks were inoculated into the center of the culture medium with an inoculation knife. The culture medium was sealed with a sealing film and then placed in a constant temperature incubator for culture. Three parallel tests were performed for each compound. The results were then observed based on the hyphae growth of the control group.

[1150] (4) Measurement and calculation: Before the mycelium of the control group grows to the edge of the culture dish (about 60-80 mm), take out the culture dish, measure its diameter using the cross method, and record the data. The average value is taken for calculation. Inhibition rate formula:

[1151] Colony growth inhibition rate = (control group diameter - experimental group diameter) × 100% / (control group diameter - 5 mm). The test results are shown in Table 12-28.

[1152] Table 12-1 Preliminary screening of antifungal activity of compound 1-22 (50ppm in vitro inhibition rate, %)

[1153]

[1154]

[1155] Table 12-2 Preliminary screening of antifungal activity of compound 1-22 (50ppm in vitro inhibition rate, %)

[1156]

[1157]

[1158] Table 13-1 Preliminary screening of antifungal activity of compound 23-42 (50ppm in vitro inhibition rate, %)

[1159]

[1160] Table 13-2 Preliminary screening of antifungal activity of compound 23-42 (50ppm in vitro inhibition rate, %)

[1161]

[1162] Table 14-1 Preliminary screening of antifungal activity of compounds 43-63 (50 ppm in vitro inhibition rate, %)

[1163]

[1164]

[1165] Table 14-2 Preliminary screening of antifungal activity of compounds 43-63 (50ppm in vitro inhibition rate, %)

[1166]

[1167]

[1168] Table 15-1 Preliminary screening of antifungal activity of compounds 64-83 (50ppm in vitro inhibition rate, %)

[1169]

[1170] Table 15-2 Preliminary screening of antifungal activity of compounds 64-83 (50ppm in vitro inhibition rate, %)

[1171]

[1172] Table 16-1 Preliminary screening of antifungal activity of compounds 84-106 (50 ppm in vitro inhibition rate, %)

[1173]

[1174]

[1175] Table 16-2 Preliminary screening of antifungal activity of compounds 84-106 (50 ppm in vitro inhibition rate, %)

[1176]

[1177]

[1178] Table 17-1 Preliminary screening of antifungal activity of compounds 107-129 (50 ppm in vitro inhibition rate, %)

[1179]

[1180] Table 17-2 Preliminary screening of antifungal activity of compounds 107-129 (50ppm in vitro inhibition rate, %)

[1181]

[1182]

[1183] Table 18 Preliminary screening of antifungal activity of compounds 130-140 (50 ppm in vitro inhibition rate, %)

[1184] serial number Apple ring pattern Rice sheath blight Botrytis cinerea peach brown rot Phytophthora capsici Pepper Anthrax 130 75.2 79.8 83.9 53.7 81.0 75.3 131 50.4 86.2 52.5 57.3 78.1 62.8 132 70.4 68.9 89.7 19.5 78.5 76.4 133 80.2 66.7 85.9 78.3 45.8 42.7 134 54.0 94.1 64.2 93.7 55.2 90.4 134 73.0 83.5 47.1 6.5 49.8 63.7 136 39.6 71.2 25.8 13.5 28.3 20.3 137 66.8 77.9 94.4 38.4 79.2 84.5 138 64.4 89.1 91.4 38.1 71.0 74.7 139 44.6 91.0 72.1 0 51.7 49.4 140 0 0 44.4 6.8 -6.40 27.0

[1185] Table 19 Preliminary screening of antifungal activity of compounds 141-152 (50 ppm in vitro inhibition rate, %)

[1186]

[1187]

[1188] Table 20 Inhibitory activity of compounds against pepper anthracnose EC 50 (μg / mL)

[1189] Compound No. <![CDATA[EC 50 ]]> Compound No. <![CDATA[EC 50 ]]> Compound No. <![CDATA[EC 50 ]]> 23 5.66 39 5.51 74 7.81 24 14.48 40 4.67 77 5.88 25 23.54 41 5.04 81 12.18 26 4.01 42 4.67 96 31.89 27 5.79 43 7.93 97 17.92 28 7.88 44 6.00 98 5.24 30 13.69 45 14.57 99 50.0 31 8.34 51 12.26 108 2.73 32 3.03 52 26.32 109 3.60 33 2.74 53 20.77 113 22.58 34 1.84 54 25.57 115 12.28 35 16.15 68 11.68 117 43.00 36 6.06 71 11.82 118 9.93 38 2.48 73 8.22 Chlorothalonil 7.51

[1190] Table 21 Inhibitory activity of compounds against peach brown rot pathogen EC 50 (μg / mL)

[1191]

[1192]

[1193] Table 22 Inhibitory activity of compounds against Pythium aphanidermatum EC 50 (μg / mL)

[1194] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 45 20.15 51 18.57 98 47.82 46 16.23 52 19.62 100 47.78 47 20.19 54 21.78 115 17.82 48 18.05 76 5.63 116 34.83 49 21.35 79 5.31 117 20.78 50 12.67 80 5.63

[1195] Table 23 Inhibitory activity of compounds against pepper phytophthora 50 (μg / mL)

[1196] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 43 16.39 52 8.06 96 18.84 44 19.17 53 28.95 98 12.67 45 22.18 54 24.93 99 17.87 46 28.28 76 3.28 100 15.34 47 23.76 79 4.18 115 8.89 48 25.20 80 9.43 51 15.19 81 6.14

[1197] Table 24 Inhibitory activity of compounds against Fusarium graminearum EC 50 (μg / mL)

[1198] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 44 23.11 74 3.35 115 9.08 45 24.88 81 8.09 118 9.82 58 1.63 98 11.81 125 7.56 73 5.00 108 22.51

[1199] Table 25 Inhibitory activity EC of compounds against rice blast fungus 50 (μg / mL)

[1200] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 44 19.20 74 20.13 108 35.03 45 20.63 75 8.93 109 7.76 46 22.58 76 19.27 110 38.40 48 39.64 77 17.96 111 17.55 51 19.44 79 14.21 112 8.42 52 22.95 80 20.19 113 27.92 56 7.97 81 25.04 115 29.77 57 8.79 90 15.57 116 49.38 58 11.23 96 9.76 118 31.54 59 6.32 97 42.20 125 30.00 71 35.74 98 21.25 126 25.33 72 14.29 101 47.63 129 25.95 73 11.56 103 13.67

[1201] Table 26 Inhibitory activity of compounds against Botrytis cinerea EC 50 (μg / mL)

[1202] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 43 30.55 74 3.55 106 9.84 44 12.25 76 4.84 107 16.76 45 7.74 77 7.06 108 9.76 46 8.26 78 1.60 109 2.22 47 3.20 79 4.02 110 4.84 48 0.61 80 8.70 111 8.34 49 18.26 81 1.06 112 0.75 50 0.65 82 1.55 114 18.28 51 1.57 83 5.52 115 13.47 52 33.95 96 33.71 118 17.47 53 15.51 97 2.85 125 19.57 56 10.29 98 2.30 127 40.97 58 1.12 99 17.47 130 19.24 59 0.65 100 50.0 132 26.55 62 1.01 101 1.81 133 11.35 71 8.40 102 20.12 137 16.23 72 5.28 103 14.03 138 7.05 73 3.00 104 20.15 Captan 35.36

[1203] Table 27 Inhibitory activity of compounds against apple ring rot pathogen EC 50 (μg / mL)

[1204] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 143 21.50 149 51.65 Captan 21.19

[1205] Table 28 Inhibitory activity of compounds against rice sheath blight EC 50 (μg / mL)

[1206] Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> Compound <![CDATA[EC 50 ]]> 130 22.50 138 3.36 144 14.58 133 5.35 141 12.30 149 1.98 134 11.38 142 10.58 150 1.22 137 5.56 143 1.67 Captan 107.1

[1207] The compound of the invention has excellent fungicidal activity and can be used for preventing and controlling phytophthora aphanidermatum, phytophthora capsici, anthracnose of pepper, brown rot of peach, rice blast, gray mold, Fusarium graminearum, apple ring rot and rice sheath blight.

[1208] Test Example 3 Test of the inhibitory activity of water bloom cyanobacteria

[1209] Experimental materials: Microcystis aeruginosa FACH905, Synechocystis PCC6803.

[1210] Inhibition rate test method:

[1211] (1) Take the algae solution in fresh BG11 medium at a 1% inoculation rate and place it in an artificial climate incubator. The culture conditions are: temperature 28±1℃, light intensity 6000lx, 12h light: 12h dark cycle, and regular shaking of the algae solution every day to increase the dissolved oxygen content. The concentration of algae cells is determined by measuring the optical density at 680nm. When the algae solution grows to OD680 of 1.0, it can be used for compound screening experiments.

[1212] (2) Dilute the cultured algae to 1×10 6 cells / mL (OD680=0.02), add 98 μL of the diluted algae solution to a 198-well plate using a spray gun, then add 2 μL of the compound to be tested, seal the 96-well plate tightly and carefully mix on a microplate shaker, place it in an artificial climate incubator, take it out and shake it for 30 minutes every day, culture it for 7 days, and use an enzyme marker to measure the absorbance of the algae solution in the control group and the experimental group at 680 nm, which are recorded as OD680 control and OD680 experiment, respectively. Each group of experiments were repeated 3 times in parallel, and the inhibition rate was calculated according to the following formula:

[1213] Inhibition rate = (OD control group - OD experimental group) × 100% / OD control group.

[1214] (3) Set the concentration gradient of the compound, determine the corresponding inhibition rate, and use the Growth / Sigmoidal module in Origin to fit the EC of the compound. 50 The measurement results are shown in Tables 29 to 36.

[1215] Table 29 Preliminary screening data of compound 1-42 on cyanobacteria inhibition activity (100 μM, in vitro inhibition rate, %)

[1216]

[1217]

[1218] Table 30 Preliminary screening data of the inhibitory activity of compounds 43-83 against cyanobacteria (25 μg / mL, in vitro inhibition rate, %)

[1219]

[1220] Table 31 Preliminary screening data of compound 84-129 on cyanobacteria inhibition activity (50 μg / mL, in vitro inhibition rate, %)

[1221]

[1222]

[1223] Table 32 Preliminary screening data of the inhibitory activity of compounds 130-152 against cyanobacteria (100 μM, in vitro inhibition rate, %)

[1224]

[1225] Table 33 Inhibitory activity EC of compounds against cyanobacteria PCC6803 and FACHB905 50 (μM)

[1226]

[1227]

[1228] Table 34 Inhibitory activity EC of compounds against cyanobacteria PCC6803 50 (μg / mL)

[1229] Compound PCC6803 Compound PCC6803 Compound PCC6803 43 2.21 58 7.57 75 0.70 45 2.19 59 0.56 76 3.96 46 3.72 60 1.32 80 2.54 48 4.53 61 2.44 98 11.19 50 13.18 62 1.00 103 11.75 51 0.48 66 1.44 109 6.97 53 8.95 68 13.59 113 16.55 54 3.00 71 1.41 125 12.94 55 6.81 72 0.90 126 7.35 56 0.59 73 1.47 Copper sulfate 0.52 57 0.76 74 0.88

[1230] Table 35 Inhibitory activity EC of compounds against cyanobacteria FACHB905 50 (μg / mL)

[1231]

[1232]

[1233] Table 36 Inhibitory activity EC of compounds against cyanobacteria PCC6803 and FACHB905 50 (μM)

[1234] Compound PCC6803 FACHB905 Compound PCC6803 FACHB905 130 5.18±0.24 1.09±0.16 142 1.21±0.09 29.92±6.8 131 6.22±0.41 3.00±0.36 143 21.68±2.66 ＞100 132 4.57±0.04 1.07±0.14 144 5.71±0.77 3.09±0.5 133 1.39±0.27 0.52±0.03 145 7.51±1.03 4.11±0.49 134 4.34±0.84 2.01±0.14 146 3.24±0.07 3.73±0.9 135 2.47±0.34 1.91±0.22 147 5.51±0.29 7.07±0.76 136 4.12±0.46 3.12±0.61 148 4.81±0.21 0.91±0.24 137 3.75±0.54 1.08±0.05 149 6.40±0.42 2.66±0.33 138 ＞100 0.80±0.03 150 4.95±0.35 5.18±0.26 139 ＞100 1.35±0.28 151 1.25±0.24 1.15±0.07 140 2.97±0.28 ＞100 152 1.14±0.08 8.88±0.39 141 3.47±0.26 11.36±0.5 Copper sulfate 1.85±0.05 2.59±0.06

[1235] The compounds of the invention have excellent cyanobacteria inhibitory activity, and such compounds should have great potential and application prospects in controlling water bloom outbreaks.

[1236] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A hydrazone compound, characterized in that: The compound is the following compound or a pharmaceutically acceptable salt of the following compound: 。 2. A method for preparing the compound according to claim 1, characterized in that: The method comprises: contacting a compound represented by formula II with a compound represented by formula III to react, thereby obtaining a compound represented by formula I; Among them, R, R 1 , R 2 , R 3 , R 4 The definitions of and X correspond to the specific compounds in claim 1.

3. The method according to claim 2, characterized in that The method comprises: dissolving the compound represented by formula III and a base in a first solvent, stirring for 15-30 minutes, then adding the compound represented by formula II and a catalyst to the system, and reacting under stirring; The first solvent is selected from one or more of acetonitrile, 1,2-dichloroethane, acetone, tert-butanol, water, toluene, benzene, xylene, ethyl acetate, methanol, ethanol, n-hexane, dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide; The catalyst is selected from one or more of ascorbic acid, acetic acid, tartaric acid, trifluoroacetic acid, formic acid, salicylic acid, malic acid and acetic anhydride.

4. The method according to claim 3, characterized in that The base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, diethylamine, triethylamine, potassium tert-butoxide and butyl lithium.

5. The method according to claim 3, characterized in that: The molar ratio of the compound represented by formula II, the compound represented by formula III, the base and the catalyst is 1:(1-3):(1-3):(0.1-0.5).

6. The method according to claim 3, characterized in that The reaction conditions include: temperature of 60-120° C.; time of 1-12 hours.

7. The method according to claim 6, characterized in that The reaction temperature is 80-110°C.

8. The method according to claim 6, characterized in that The reaction time is 2-6 hours.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the hydrazone compound according to claim 1 or the hydrazone compound prepared by the method according to any one of claims 2-8.

10. Use of the hydrazone compound according to claim 1, the hydrazone compound prepared by the method according to any one of claims 2 to 8, or the pharmaceutical composition according to claim 9 in preventing and controlling plant pathogenic fungi or plant pathogenic bacteria.

11. The use according to claim 10, characterized in that: The plant pathogenic fungi are selected from one or more of pepper anthracnose, Fusarium graminearum, pepper phytophthora, peach brown rot, citrus pythium, rice blast, rice false smut, tomato early blight, wheat fusarium, rapeseed sclerotinia, rice sheath blight, apple ring rot, wheat sheath blight, corn leaf blight, rice seedling blight and gray mold.

12. The use according to claim 10, characterized in that: The plant pathogenic bacteria are selected from one or more of tobacco bacterial wilt pathogen, rice bacterial blight pathogen, watermelon fruit spot pathogen, tomato canker pathogen, black rot pathogen, wild rapeseed Xanthomonas and citrus canker pathogen.

13. Use of the hydrazone compound according to claim 1, the hydrazone compound prepared by the method according to any one of claims 2 to 8, or the pharmaceutical composition according to claim 9 in inhibiting the growth of algae.

14. The use according to claim 13, characterized in that The algae is Synechocystis or Microcystis aeruginosa.

Images