Heterocycle-containing nicotinamide compound, synthesis method and application of heterocyclic-containing nicotinamide compound in prevention and treatment of plant fungal diseases

Abstract

The invention provides a heterocyclic ring-containing nicotinamide compound, a synthesis method and application of the heterocyclic ring-containing nicotinamide compound in prevention and treatment of plant fungal diseases, and relates to the technical field of pesticides. The heterocyclic ring-containing nicotinamide compound is synthesized by using easily available raw materials and a simple, practical and low-cost synthesis method. The compound has a synergistic effect on rhizoctonia solani, magnaporthe oryzae, mango anthracnose pathogen, rubber anthracnose pathogen, litchi anthracnose pathogen, banana anthracnose pathogen, coffee anthracnose pathogen, fusarium graminearum, wheat powdery mildew pathogen, valsa mali, botrytis cinerea, sclerotinia sclerotiorum, sigatoka musae, banana scab pathogen, apple ring spot pathogen, botrytis cinerea, botrytis cinerea, botrytis cinerea, botrytis cinerea and botrytis cinerea. The compound has an excellent inhibiting effect on plant fungal diseases caused by fungi such as tobacco alternaria alternata, cotton rhizoctonia solani, exserohilum turcicum and hevea brasiliensis, is novel in structure, and has huge potential for creation of novel pesticides.

Description

Technical Field

[0001] This invention relates to the field of pesticide technology, and in particular to a heterocyclic nicotinamide compound, its synthesis method, and its application in the control of plant fungal diseases. Background Technology

[0002] Fungal diseases in crops are significant threats to agricultural production, such as rice blast, sheath blight, wheat scab, and powdery mildew. These diseases cause large-scale yield reductions and seriously threaten crop yield and quality. Currently, chemical control is the most effective and economical method for controlling crop diseases. However, long-term and excessive use of chemical pesticides can easily lead to pesticide resistance in pathogens and poses potential risks to the environment and the safety of agricultural products. Therefore, the development of novel, highly efficient, and low-risk fungicides is imperative.

[0003] In our previous research on the development of small-molecule compounds for the control of important fungal diseases in crops, we used dichloronicotinic acid as a lead compound. Based on the principles of substructure active splicing and bioisosteric electrons, we introduced the heterocyclic thiazole group into nicotinic acid via an amide bond. Activity tests showed that dichloronicotinic acid compounds containing a phenylthiazole amide group at the 3-position exhibited excellent fungicidal activity. Currently, no reports have been made on the agricultural fungicidal activity of this type of compound. Therefore, nicotinamide compounds containing heterocyclic groups have broad application prospects in the development of novel fungicides. Summary of the Invention

[0004] In view of this, the present invention proposes a heterocyclic nicotinamide compound, a synthesis method, and its application in the prevention and control of plant fungal diseases, which can effectively prevent and control plant fungal diseases caused by fungi.

[0005] The technical solution of this invention is implemented as follows: A heterocyclic nicotinamide compound, the structure of which is shown in Formula I:

[0006] In Formula I, R1 is selected from one of hydrogen atom, hydroxyl group, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro, cyano, phenyl or benzyl; R2 is selected from one of hydrogen atom, hydroxyl group, halogen, C1-C5 alkyl group, C1-C5 haloalkyl group, C1-C3 alkoxy group, nitro group, or cyano group.

[0007] Furthermore, the halogen is selected from one of fluorine, chlorine, bromine or iodine; The C1-C5 alkyl group is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or neopentyl; The C1-C2 haloalkyl group is selected from one of trifluoromethane, difluorodichloromethane, trichloromethane, difluoromethane, dichloromethane, monofluoromethane, 1,2-difluoroethane, 1,2-methylfluoroethane, 1,2-dichloroethane, or 1,2-tetrachloroethane. The C1-C3 alkoxy group is selected from one of methoxy, ethoxy, or propoxy. Furthermore, the substituted phenyl group is selected from 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 2,3-difluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl One of the following: 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 2,4-ditrifluoromethylphenyl, 2,6-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2,3-ditrifluoromethylphenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 3,4-dibromophenyl, 2,6-dibromophenyl, 3,5-dibromophenyl, 2,3-dibromophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 3,4-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,3-dihydroxyphenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-trifluoromethylphenyl, 2-bromo-4-chlorophenyl, and 3-chloro-4-fluorophenyl.

[0008] Furthermore, the substituted benzyl group is selected from 4-methylbenzyl, 3-methylbenzyl, 2-methylbenzyl, 3,4-dimethylbenzyl, 2,4-dimethylbenzyl, 2,6-dimethylbenzyl, 3,5-dimethylbenzyl, 2,3-dimethylbenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 3,4-difluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 3,5-difluorobenzyl, 2,3-difluorobenzyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,3-dichloro ...3-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,3-dichlorobenzyl, 4-chlorobenzyl, 3-chlorobenzyl, 3-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 3,4-dichloroben One of the following: chlorobenzyl, 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-trifluoromethylbenzyl, 4-bromobenzyl, 4-hydroxybenzyl, 2-chloro-3-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2-chloro-5-fluorobenzyl, 2-chloro-4-trifluoromethylbenzyl, 2-bromo-4-chlorobenzyl, and 3-chloro-4-fluorobenzyl.

[0009] A method for synthesizing heterocyclic nicotinamide compounds includes the following steps: (1) Using acetophenone with different substituents and N-bromosuccinimide as raw materials, p-toluenesulfonic acid was added to catalyze the reaction and reacted under solvent conditions. The solvent was removed under reduced pressure and extracted to obtain 2-bromoacetophenone with different substituents. (2) Dissolve 2-bromoacetophenone with different substituents in a solvent, add thiourea to react, and after the reaction is completed, desolvate under reduced pressure to obtain 2-amino-4-thiazole with different substituents; (3) Dissolve 3-pyridinecarboxylic acid with different substituents in a solvent, add oxaloyl chloride dropwise and add N,N-dimethylformamide to catalyze the reaction. After the reaction is completed, desolvate under reduced pressure to obtain 3-pyridinecarboxylic chloride with different substituents; (4) Take 3-pyridinecarboxyl chloride with different substituents, 2-amino-4-thiazole with different substituents, and triethylamine, add solvent to react, extract, combine organic layers, dry, desolvent under reduced pressure, and then purify by column chromatography to obtain nicotinamide compounds containing heterocycles.

[0010] Further, in step (1), the solvent is acetonitrile; the molar ratio of the different substituents of acetophenone, N-bromosuccinimide and p-toluenesulfonic acid is 1~2:1~2:1.5~3; the reaction is a reflux reaction for 2.5~3h.

[0011] Furthermore, in step (2), the solvent is anhydrous ethanol; the molar ratio of the different substituents of 2-bromoacetophenone to thiourea is 1:1.1~1.2.

[0012] Furthermore, in step (3), the solvent is dichloromethane; the molar ratio of 3-pyridinecarboxylic acid with different substituents to oxaloyl chloride is 1~2:2~4.

[0013] Furthermore, in step (4), the solvent is dichloromethane; the molar ratio of 3-pyridinecarboxyl chloride with different substituents, 2-amino-4-thiazole with different substituents and triethylamine is 1.5~2:1:3.

[0014] Furthermore, when acetophenone with different substituents is acetophenone, the specific synthesis process of step (1) is as follows: acetophenone and N-bromosuccinimide are dissolved in acetonitrile under the catalysis of p-toluenesulfonic acid, heated under reflux for 2.5~3h, cooled, desolvated under pressure, and extracted with water to obtain 2-bromoacetophenone.

[0015] Furthermore, the molar ratio of acetophenone, N-bromosuccinimide, and p-toluenesulfonic acid is 1:1:1.5.

[0016] Furthermore, when 2-bromoacetophenone with different substituents is 2-bromoacetophenone, the specific synthesis process of step (2) is as follows: 2-bromoacetophenone is dissolved in anhydrous ethanol, placed in a constant temperature stirring reaction bath at room temperature (25℃), thiourea is added, and after the reaction is completed, the solvent is removed under reduced pressure to obtain 2-amino-4-thiazolium.

[0017] Furthermore, the molar ratio of 2-bromoacetophenone to thiourea is 1:1.1~1.2.

[0018] Furthermore, when the 3-pyridinecarboxylic acid with different substituents is 3-pyridinecarboxylic acid, the specific synthesis process of step (3) is as follows: 3-pyridinecarboxylic acid is dissolved in dichloromethane, oxalyl chloride is added, and a trace amount of N,N-dimethylformamide is added for catalysis. After the reaction is completed, the solution is desoluble under reduced pressure to obtain pyridine-3-carboxylic acid.

[0019] Furthermore, the synthesis ratio of 3-pyridinecarboxylic acid and oxaloyl chloride is 1:2.

[0020] Furthermore, when the 3-pyridine carboxyl chloride with different substituents and the 2-amino-4-thiazole with different substituents are 3-pyridine carboxyl chloride and 2-amino-4-thiazole respectively, the specific synthesis process of step (4) is as follows: dissolve the 2-amino-4-thiazole with different substituents in dichloromethane, add the 3-pyridine carboxyl chloride with different substituents for reaction, and add triethylamine as an acid-binding agent. After the reaction is completed, extract, combine the organic layers, dry, desolvate under reduced pressure, separate and purify by column chromatography to obtain the target heterocyclic nicotinamide compound.

[0021] Furthermore, the molar ratio of 2-amino-4-thiazole, 3-pyridinecarboxyl chloride and triethylamine is 1:1.5 to 2:3.

[0022] Application of heterocyclic nicotinamide compounds in the prevention and control of plant diseases caused by fungal pathogens.

[0023] Furthermore, the fungal pathogens are *Rhizoctonia solani*, *Rhizoctonia solani*, *Anthracnose fungus*, *Anthracnose fungus*, *Anthracnose fungus*, *Anthracnose fungus*, *Anthracnose fungus*, *Anthracnose fungus*, *Anthracnose fungus*, *Fusarium graminearum*, *Powdery mildew fungus*, *Ophiopogon japonicus*, *Gray mold fungus*, *Sclerotinia sclerotiorum*, *Leuciscus syriacus*, *Black spot fungus*, *Rhizoctonia solani*, *Red spot fungus*, *Rhizoctonia solani*, *Rhizoctonia solani*, *Leptochloa crus-galli*, *Leptochloa crus-galli*, and *Cyclocarya pallida*.

[0024] Furthermore, the fungal pathogens are rice sheath blight fungus, rice blast fungus, tomato gray mold fungus, mango anthracnose fungus, and wheat scab fungus.

[0025] Compared with the prior art, the beneficial effects of the present invention are: The heterocyclic nicotinamide compounds involved in this invention are made from readily available raw materials, have simple and practical synthesis methods, and are low in cost. They exhibit excellent inhibitory effects on plant fungal diseases and have novel structures. The research results have great potential for the creation of new pesticides. Attached Figure Description

[0026] Appendix Figure 1 This is the general structural formula for the heterocyclic nicotinamide compounds of this invention.

[0027] Appendix Figure 2 This is the proton NMR spectrum of the compound TCP348 of this invention.

[0028] Appendix Figure 3 This is the carbon NMR spectrum of the compound TCP348 of this invention.

[0029] Appendix Figure 4 This is the mass spectrum of the compound TCP348 of this invention.

[0030] Appendix Figure 5 This is the proton NMR spectrum of the compound TCP350 of this invention.

[0031] Appendix Figure 6 This is the carbon NMR spectrum of the compound TCP350 of this invention.

[0032] Appendix Figure 7 This is the mass spectrum of the compound TCP350 of this invention.

[0033] Appendix Figure 8 This is the proton NMR spectrum of the compound TCP362 of this invention.

[0034] Appendix Figure 9 This is the carbon NMR spectrum of the compound TCP362 of this invention.

[0035] Appendix Figure 10 This is the mass spectrum of the compound TCP362 of this invention.

[0036] Appendix Figure 11 This is the proton NMR spectrum of the compound TCP363 of this invention.

[0037] Appendix Figure 12 This is the carbon NMR spectrum of the compound TCP363 of this invention.

[0038] Appendix Figure 13 This is the mass spectrum of the compound TCP363 of this invention. Detailed Implementation

[0039] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0040] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0041] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0042] Example 1 - Synthetic route of heterocyclic nicotinamide compounds Figure 1 The general structural formula of the heterocyclic nicotinamide compound of the present invention is shown below, and the synthetic route of the heterocyclic nicotinamide compound is as follows:

[0043] Specifically, it includes the following steps: (1) Using acetophenone and N-bromosuccinimide with different substituents as raw materials, p-toluenesulfonic acid was added to catalyze the reaction and the reaction was refluxed under acetonitrile solvent conditions for 2.5-3 h. The solvent was removed under reduced pressure and extracted to obtain 2-bromoacetophenone with different substituents; the molar ratio of the acetophenone with different substituents, N-bromosuccinimide and p-toluenesulfonic acid was 1-2:1-2:1.5-3. (2) Dissolve 2-bromoacetophenone with different substituents in anhydrous ethanol solvent, add thiourea to react, and remove the solvent under reduced pressure after the reaction to obtain 2-amino-4-thiazol with different substituents; the molar ratio of the 2-bromoacetophenone with different substituents to thiourea is 1:1.1~1.2. (3) Dissolve 3-pyridinecarboxylic acid with different substituents in dichloromethane solvent, add oxaloyl chloride dropwise and add N,N-dimethylformamide to catalyze the reaction, and remove the solvent under reduced pressure after the reaction is completed to obtain 3-pyridinecarboxylic chloride with different substituents; (4) Take 3-pyridinecarboxyl chloride with different substituents, 2-amino-4-thiazole with different substituents, and triethylamine, add dichloromethane solvent to react, extract, combine organic layers, dry, desolvent under reduced pressure, and then purify by column chromatography to obtain nicotinamide compounds containing heterocycles; the molar ratio of 3-pyridinecarboxyl chloride with different substituents, 2-amino-4-thiazole with different substituents and triethylamine is 1.5~2:1:3.

[0044] R1 is selected from one of hydrogen atom, hydroxyl group, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro, cyano, phenyl or benzyl; R2 is selected from one of hydrogen atom, hydroxyl group, halogen, C1-C5 alkyl, C1-C5 haloalkyl, C1-C3 alkoxy, nitro or cyano; The halogen is selected from one of fluorine, chlorine, bromine or iodine; The C1-C5 alkyl group is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or neopentyl; The C1-C2 haloalkyl group is selected from one of trifluoromethane, difluorodichloromethane, trichloromethane, difluoromethane, dichloromethane, monofluoromethane, 1,2-difluoroethane, 1,2-methylfluoroethane, 1,2-dichloroethane, or 1,2-tetrachloroethane. The C1-C3 alkoxy group is selected from one of methoxy, ethoxy, or propoxy. The substituted phenyl group is selected from 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 2,3-difluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl. One of the following: 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 2,4-ditrifluoromethylphenyl, 2,6-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2,3-ditrifluoromethylphenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl, 2,6-dibromophenyl, 3,5-dibromophenyl, 2,3-dibromophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 3,4-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,3-dihydroxyphenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-trifluoromethylphenyl, 2-bromo-4-chlorophenyl, and 3-chloro-4-fluorophenyl; The substituted benzyl group is selected from 4-methylbenzyl, 3-methylbenzyl, 2-methylbenzyl, 3,4-dimethylbenzyl, 2,4-dimethylbenzyl, 2,6-dimethylbenzyl, 3,5-dimethylbenzyl, 2,3-dimethylbenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 3,4-difluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 3,5-difluorobenzyl, 2,3-difluorobenzyl-4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,3-dichlorobenzyl-4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,3-dichlorobenzyl One of the following: 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-trifluoromethylbenzyl, 4-bromobenzyl, 4-hydroxybenzyl, 2-chloro-3-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2-chloro-5-fluorobenzyl, 2-chloro-4-trifluoromethylbenzyl, 2-bromo-4-chlorobenzyl, and 3-chloro-4-fluorobenzyl.

[0045] Example 2 - Preparation of 2-chloro-N-(4-(4-chlorophenyl)thiazo-2-yl)pyridine amide The preparation process when acetophenone with different substituents is acetophenone and 3-pyridinecarboxylic acid with different substituents is 2-chloro-pyridine-3-carboxylic acid includes the following steps: (1) Preparation of 2-bromo-p-chloroacetophenone intermediate p-Chloroacetophenone (1.0 eq) and N-bromosuccinimide (1 eq) were dissolved in acetonitrile under the catalysis of p-toluenesulfonic acid (1.5 eq) and heated under reflux for 2.5-3 h. After cooling, some of the solvent was removed under reduced pressure, and the mixture was extracted with water and desolventized under reduced pressure to obtain 2-bromo-p-chloroacetophenone.

[0046] (2) Preparation of 2-amino-4-(4-chlorophenyl)thiazole intermediate The intermediate 2-bromo-p-chloroacetophenone (1.0 eq) was added to a round-bottom flask, dissolved in anhydrous ethanol, placed in a constant temperature (25 °C) stirring reaction bath, and thiourea (1.1~1.2 eq) was added. The reaction was monitored by TLC until it was completed, and the intermediate 2-amino-4-(4-chlorophenyl)thiazole was obtained by desolvation under reduced pressure.

[0047] (3) Preparation of intermediates for the preparation of 2-chloro-pyridine-3-carboxyl chloride 2-Chloro-pyridine-3-carboxylic acid (1 eq) was added to a round-bottom flask, dissolved in anhydrous dichloromethane, placed in an ice bath (0-4℃) and stirred. Oxaloyl chloride (2 eq) was added dropwise using a constant pressure titration funnel, and 1%-5% of N,N-dimethylformamide (by volume of oxaloyl chloride) was added to catalyze the reaction. After the reaction was completed, the solution was removed under reduced pressure to obtain the intermediate 2-chloro-pyridine-3-carboxylic acid.

[0048] (4) Preparation of 2-chloro-N-(4-(4-chlorophenyl)thiazolyl)pyridine amide 2-Amino-4-(4-chlorophenyl)thiazole (1 eq) was added to dichloromethane and stirred until dissolved. Then, dichloropyridinyl chloride (1.5~2 eq) and triethylamine (3.0 eq) were added as an acid-binding agent. The reaction was carried out at room temperature (25 ℃) for 6~8 h. The reaction was monitored by TLC until the intermediate was completely reacted. The mixture was extracted, the organic layers were combined, dried, desoluble under reduced pressure, and purified by column chromatography to obtain 2-chloro-N-(4-(4-chlorophenyl)thiazole-2-yl)pyridineamide.

[0049] Example 3 - Structural characterization of heterocyclic nicotinamide compounds The compounds were synthesized and their structures were characterized according to the synthesis procedures of Examples 1-2.

[0050] Compound TCP333: 2-chloro-N-[4-(4-trifluoromethylphenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 65%, white solid, melting point: 163.5 – 164.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.15 (s, 1H), 8.62 (d, J = 4.9 Hz, 1H), 8.23 ​​(d, J = 5.8 Hz, 1H), 8.19 (d, J = 8.1 Hz,2H), 8.05 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.4 Hz, 1H). 13 C NMR (101MHz, DMSO) δ 164.33, 158.34, 151.72, 148.11, 147.13, 139.25, 138.30, 131.23,126.80, 126.22, 123.48, 111.88. HRMS (ESI) m / z for C 16 H9ClF3N3OS [M+H] + calcd:384.0185, found: 384.0186. Compound TCP334: 2-chloro-N-[4-(2,4-dichlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 73%, pale yellow solid, melting point: 191.5 – 192.9 °C. 1 H NMR (600 MHz, DMSO- d 6) δ 13.09 (s, 1H), 8.58 (d, J = 3.0 Hz, 1H), 8.18 (d, J = 9.5 Hz, 1H), 7.88 (d, J = 8.4 Hz,1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 12.4 Hz, 1H), 7.55 (d, J = 6.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 164.28, 157.31, 151.76, 147.08, 145.22, 139.30,133.50, 132.86, HRMS (ESI) m / z for C 16 H9ClF3N3OS [M+H] + calcd: 383.9532, found: 383.9535. Compound TCP335: 2-chloro-N-[4-(2,4-difluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 70%, white solid, melting point: 171.5 – 172.9 °C. 1 H NMR (600 MHz, DMSO- d 6) δ 13.09 (s, 1H), 8.59 (d, J = 6.8 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.12 – 8.04 (m, 1H), 7.64 (s, 1H), 7.60 (d, J = 12.4 Hz, 1H), 7.40 (d, J = 21.0 Hz, 1H), 7.23 (t, J =9.8 Hz, 1H). 13 C NMR (151 MHz, DMSO) δ 163.25, 161.74, 160.18, 159.89, 158.22, 150.70, 141.52, 138.26, 130.19, 129.76, 122.47, 118.11, 112.20, 111.38,104.13. HRMS (ESI) m / z for C 15 H8ClF2N3OS [M+H ]+ calcd: 352.0123, found: 352.0117. Compound TCP336: 2-chloro-N-(4-cyclopropyl-1,3-thiazolyl-2-yl)pyridine-3-carboxamide, yield: 72%, white solid, melting point: 145.3 – 147.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.55 (dd, J = 7.6, 4.8Hz, 1H), 6.92 (s, 1H), 2.17 – 1.88 (m, 1H), 0.87 (d, J = 11.0 Hz, 2H), 0.76 (d, J = 7.4 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 163.86, 157.41, 153.31, 151.50,147.09, 139.12, 131.44, 123.41, 106.47, 12.39, 8.06. HRMS (ESI) m / z forC 12 H 10 ClN3OS [M+H] + calcd: 280.0311, found: 280.0363. Compound TCP337: 2-chloro-N-[4-(p-tolyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 68%, white solid, melting point: 211.1 – 212.3 °C. 1 H NMR (600 MHz, DMSO- d 6) δ 13.02 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.69(s, 1H), 7.63 – 7.56 (m, 1H), 7.25 (d, J = 7.9 Hz, 2H), 2.33 (s, 3H). 13 C NMR(151 MHz, DMSO) δ 174.57, 168.23, 162.11, 160.18, 157.56, 149.71, 148.17,142.35, 141.75, 140.24, 136.59, 133.93, 118.86, 50.39. HRMS (ESI) m / z forC 16 H 12 ClN3OS [M+H] +calcd: 330.0468, found: 330.0467. Compound TCP338: 2-chloro-N-[4-(2-chlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 61%, pale yellow solid, melting point: 181.5 – 182.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.04 (s, 1H), 8.57 (d, J = 6.8 Hz, 1H), 8.17 (d, J = 9.5 Hz, 1H), 7.85 (d, J = 9.5 Hz, 1H), 7.74(s, 1H), 7.58 (t, J = 8.3 Hz, 2H), 7.42 (d, J = 19.3 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 164.26, 157.18, 151.69, 147.11, 146.40, 139.26, 133.46, 131.71,131.52, 131.30, 130.84, 129.94, 127.82, 123.50, 114.09. HRMS (ESI) m / z forC 15 H9Cl2N3OS [M+H] + calcd: 349.9922, found: 349.9916. Compound TCP339: 2-chloro-N-[4-(4-bromophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 78%, white solid, melting point: 198.3 – 199.2 °C. 1 H NMR (600 MHz, DMSO- d 6) δ 13.06 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.85(s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.62 – 7.58 (m, 1H). 13C NMR (151 MHz, DMSO) δ163.17, 157.03, 150.68, 147.41, 146.05, 138.24, 132.70, 131.14, 130.17,127.16, 122.46, 120.44, 113.03, 109.08. HRMS (ESI) m / z for C 15 H9ClBrN3OS [M+3H] + calcd: 395.9396, found: 395.9391. Compound TCP340: 2-chloro-N-[4-(4-hydroxyphenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 56%, white solid, melting point: 174.5 – 175.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s,1H), 8.74 (d, J = 6.9 Hz, 1H), 8.67 – 8.57 (m, 2H), 8.23 ​​(d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.72 (dd, J = 7.7, 4.8 Hz, 1H), 7.64 (dd, J =7.6, 4.9 Hz, 1H), 7.49 (s, 1H). 13 C NMR (101 MHz, DMSO) δ 164.23, 162.36,158.10, 153.38, 151.67, 150.27, 148.79, 147.15, 141.56, 139.24, 132.91,127.50, 123.79, 122.51, 109.65. HRMS (ESI) m / z for C 15 H 10 ClN3O2S [M+H] + calcd:332.0261, found: 332.0266. Compound TCP341: 2-chloro-N-[4-(4-methoxyphenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 58%, white solid, melting point: 220.2 – 221.4 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 12.98 (s,1H), 8.56 (s, 1H), 8.17 (d,J = 9.5 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.64 –7.55 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H). 13 C NMR (151 MHz, DMSO) δ166.99, 163.05, 158.49, 156.70, 150.61, 148.51, 146.07, 138.21, 130.29,126.51, 122.44, 113.54, 106.20, 98.75, 54.91. HRMS (ESI) m / z for C 16 H 12 ClN3O2S[M+H] + calcd: 346.0417, found: 346.0420. Compound TCP342: 2-chloro-N-[4-(trifluoromethyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 63%, white solid, melting point: 171.5 – 172.9 °C. 1 H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 8.59 (s, 1H), 8.19 (d, J = 5.7 Hz, 1H), 8.11 (s, 1H), 7.60 (d, J = 12.3 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 164.68, 160.00, 151.96, 147.13, 139.36, 130.70,123.50, 117.84. HRMS (ESI) m / z for C 10 H5ClF3N3OS [M+H] + calcd: 307.9872, found: 307.9848. Compound TCP343: 2-chloro-N-(4-isopropyl-1,3-thiazolyl-2-yl)pyridine-3-carboxamide, yield: 65%, white solid, melting point: 136.5 – 137.4 °C. 1 H NMR (600 MHz, DMSO- d 6) δ 13.02 (s, 1H), 8.56 (d, J= 12.6 Hz, 1H), 8.13 (d, J = 9.5 Hz, 1H), 7.58 – 7.55 (m, 1H), 6.88(s, 1H), 2.95 (p, J = 6.8 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H). 13 C NMR (151 MHz, DMSO) δ 165.19, 151.16, 150.48, 146.03, 139.49, 138.11, 130.45, 127.53,122.40, 105.41, 29.22, 21.01. HRMS (ESI) m / z for C 12 H 12 ClN3OS [M+H] + calcd:282.0468, found: 282.0481. Compound TCP344: 2-chloro-N-(4-methyl-1,3-thiazolyl-2-yl)pyridine-3-carboxamide, yield: 56%, white solid, melting point: 192.1 – 193.4 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 12.75 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 8.12 (d, J = 9.5 Hz, 1H), 7.70 – 7.33 (m, 1H), 6.89 (s, 1H), 2.29 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 162.92, 156.45, 150.53, 146.06, 138.15,130.48, 122.47, 107.91, 15.42. HRMS (ESI) m / z for C 10 H8ClN3OS [M+H] + calcd:254.0155, found: 254.0160. Compound TCP345: 2-chloro-N-[4-(o-tolyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 77%, white solid, melting point: 224.5 – 225.7 °C. 1 H NMR (600 MHz, DMSO- d6) δ 12.99 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.18 (d, J = 9.5 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.59 –7.57 (m, 1H), 7.41 (s, 1H), 7.30 (d, J = 6.1 Hz, 1H), 7.28 – 7.26 (m, 1H), 2.45(s, 3H). 13 C NMR (151 MHz, DMSO) δ 163.09, 150.60, 146.05, 138.20, 134.86,133.71, 130.23, 128.80, 127.26, 125.27, 122.45, 111.10, 20.40. HRMS (ESI) m / zfor C 16 H 12 ClN3OS [M+H] + calcd: 330.0468, found: 330.0481. Compound TCP346: 2-chloro-N-(4-phenyl-1,3-thiazolyl-2-yl)pyridine-3-carboxamide, yield: 74%, white solid, melting point: 208.6 – 209.5 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.06 (s, 1H), 8.58 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H), 7.58(d, J = 7.6 Hz, 1H), 7.45 (d, J = 13.2 Hz, 2H), 7.34 (d, J = 15.2 Hz, 1H). 13 C NMR(101 MHz, DMSO) δ 164.20, 157.93, 151.65, 149.72, 147.14, 139.23, 134.60,131.34, 129.22, 128.38, 126.23, 123.47, 109.28. HRMS (ESI) m / z for C 15 H10 ClN3OS[M+H] + calcd: 316.0311, found: 316.0367. Compound TCP347: 2-chloro-N-[4-(pyridin-3-yl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 58%, white solid, melting point: 193.2 – 194.8 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.05 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.97 (d, J =1.9 Hz, 2H), 7.63 – 7.58 (m, 1H), 7.60 – 7.49 (m, 2H). 13 C NMR (101 MHz, DMSO)δ 164.34, 158.29, 151.80, 147.11, 146.64, 139.31, 137.81, 135.12, 131.13,127.59, 124.73, 123.52, 112.24.HRMS (ESI) m / z for C 14 H9ClN4OS [M+H] + calcd:317.0264, found: 317.0251. Compound TCP348: 2-chloro-N-[4-(3-trifluoromethylphenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 68%, white solid, melting point: 219.5 – 220.9 °C. ¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.25 (d, J = 12.6 Hz, 2H), 8.19 (d, J = 9.5 Hz, 1H), 8.03 (s, 1H), 7.70 (d, J = 3.3 Hz, 2H), 7.63 – 7.56 (m, 1H). ¹³C NMR (151 MHz, DMSO) δ 163.29, 157.28, 150.76, 146.90, 146.13, 138.32, 134.45,130.14, 129.44, 128.94, 124.57, 123.80, 122.77, 122.49, 121.59, 110.13.. HRMS(ESI) m / z for C 16 H9ClF3N3OS [M+H] + calcd: 384.0185, found: 384.0193. Compound TCP349: 2-chloro-N-[4-(4-fluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 68%, white solid, melting point: 204.5 – 205.3 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.04 (s, 1H),8.58 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.97 (s, 2H), 7.77 (d, J = 5.6 Hz, 1H),7.59 (s, 1H), 7.29 (d, J = 17.7 Hz, 2H). 13 C NMR (151 MHz, DMSO) δ 166.29,164.21, 161.51, 158.01, 152.14, 151.72, 148.63, 147.10, 140.48, 139.29,131.28, 128.21, 123.52, 116.33, 109.11. HRMS (ESI) m / z for C15 H9ClFN3OS [M+H] + calcd: 334.0217, found: 334.0217. Compound TCP350: 2-chloro-N-[4-(3-chlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 63%, pale yellow solid, melting point: 213.5 – 215.5 °C. ¹H NMR (400 MHz): δ 13.18 (s, 1H), 8.63 (s, 1H), 8.23 ​​(d, J = 7.5 Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.57 – 7.49 (m, 1H), 7.45 (d, J = 10.1 Hz, 1H). 13 C NMR (151 MHz, DMSO) δ 164.26, 158.09, 151.77, 147.10, 139.32, 136.56, 134.09, 131.22,128.14, 125.90, 124.75, 123.53, 110.82. HRMS (ESI) m / z for C 15 H9Cl2N3OS [M+H] + calcd: 349.9922, found: 349.9923. Compound TCP351: 2-chloro-N-[4-(3,4-difluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 65%, white solid, melting point: 189.3 – 190.1 °C. 1 H NMR (600 MHz, ) δ 13.06 (s, 1H), 8.58 (d, J = 3.0 Hz, 1H), 8.18 (d, J = 9.5 Hz, 1H), 8.01 – 7.91 (m, 1H), 7.88(s, 1H), 7.78 (s, 1H), 7.60 (dd, J = 7.6, 4.8 Hz, 1H), 7.56 – 7.49 (m, 1H). 13CNMR (151 MHz, DMSO) δ 164.28, 158.16, 151.75, 151.01, 150.41, 150.33, 149.39,149.30, 148.78, 148.70, 147.09, 139.30, 131.20, 123.52, 118.51, 114.98,110.42, 103.10. HRMS (ESI) m / z for C 15 H8ClF2N3OS [M+H] + calcd: 352.0123, found: 352.0127. Compound TCP352: 2-chloro-N-[4-(2-chloro-4-fluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 48%, white solid, melting point: 188.5 – 190.3 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.11 (s,1H), 8.58 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.95 – 7.82 (m, 1H), 7.72 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 7.0 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ164.27, 162.91, 160.44, 157.24, 151.69, 147.10, 145.55, 139.22, 133.22,131.25, 130.26, 123.49, 118.03, 115.26, 113.95. HRMS (ESI) m / z forC 15 H8Cl2FN3OS [M+H] + calcd: 367.9827, found: 367.9830. Compound TCP353: 2-chloro-N-[4-(3,4-dichlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 58%, white solid, melting point: 151.5 – 152.6 °C. 1 H NMR (400 MHz, DMSO- d6) δ 13.08 (s,1H), 8.59 (s, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.99 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H). 13 C NMR (101 MHz, DMSO) δ 164.29,158.26, 151.76, 147.11, 139.27, 135.13, 132.08, 131.52, 131.17, 130.68,127.89, 126.26, 123.50, 111.38. HRMS (ESI) m / z for C 15 H8Cl2N3OS [M+H] + calcd:383.9532, found: 383.9553. Compound TCP354: 2-chloro-N-[4-(2-chloro-4-trifluoromethylphenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 61%, white solid, melting point: 202.2 – 204.5 °C. 1 H NMR (400 MHz, DMSO- d 6) δ13.14 (s, 1H), 8.57 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 13.7 Hz, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.68 – 7.53 (m, 1H). 13 C NMR(101 MHz, DMSO) δ 164.38, 157.55, 151.73, 147.12, 143.73, 139.25, 137.16,133.06, 132.16, 131.19, 127.74, 124.68, 123.48, 115.99. HRMS (ESI) m / z forC 16 H8Cl2F3N3OS [M+H] + calcd: 417.9795, found: 417.9878. Compound TCP355: 2-chloro-N-[4-(2,4-bis(trifluoromethyl)phenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 53%, white solid, melting point: 191.2 – 192.7 °C. 1 H NMR (400 MHz, DMSO- d 6) δ13.09 (s, 1H), 8.58 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.14 (s, 2H), 7.95 (d, J =8.2 Hz, 1H), 7.59 (d, J = 13.1 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 164.40, 157.78,151.71, 147.08, 145.77, 139.27, 138.82, 133.99, 131.22, 129.75, 123.92,123.48, 114.88. HRMS (ESI) m / z for C 17 H8ClF6N3OS [M+H] + calcd: 452.0059, found: 452.0057. Compound TCP356: 2-chloro-N-[4-(4-chlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 75%, white solid, melting point: 213.5 – 214.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.06 (s, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.84(s, 1H), 7.68 – 7.55 (m, 1H), 7.51 (d, J = 8.3 Hz, 2H). 13C NMR (101 MHz, DMSO) δ164.24, 158.11, 151.70, 148.45, 147.12, 139.26, 133.46, 132.88, 131.27,129.27, 127.94, 123.49,110.04. HRMS (ESI) m / z for C 15 H9Cl2N3OS [M+H] + calcd:349.9922, found: 349.9916. Compound TCP357: 2-chloro-N-[4-(2-chloro-3-fluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 68%, white solid, melting point: 205.5 – 206.3 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.11 (s, 1H), 8.57 (d, J = 6.7 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J =8.8 Hz, 1H), 7.59 (t, J = 7.1 Hz, 1H), 7.48 (dd, J = 19.1, 7.5 Hz, 2H). 13 C NMR(101 MHz, DMSO) δ 164.21, 163.56, 161.12, 158.05, 151.66, 148.69, 147.14,139.23, 134.25, 131.32, 128.30, 123.07, 116.18, 109.06.HRMS (ESI) m / z forC 15 H8Cl2FN3OS [M+H] + calcd: 367.9827, found: 367.9850. Compound TCP358: 2-chloro-N-[4-(2-chloro-5-fluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 67%, white solid, melting point: 192.5 – 193.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.10 (s, 1H), 8.58 (d,J = 4.8 Hz, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.89 (s, 1H), 7.69 (d, J =9.9 Hz, 1H), 7.67 – 7.55 (m, 2H), 7.29 (t, J = 8.3 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 164.33, 163.33, 159.71, 157.33, 151.73, 147.09, 145.13, 139.25,132.71, 131.20, 126.73, 123.49, 117.77, 116.77, 115.05. HRMS (ESI) m / z forC 15 H8Cl2FN3OS [M+H] + calcd: 367.9827, found: 367.9897. Compound TCP359: 2-chloro-N-[4-(2-bromo-4-chlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 64%, white solid, melting point: 194.5 – 195.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.09 (s,1H), 8.58 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J = 12.3 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 164.27, 157.36, 151.71,147.09, 146.94, 139.24, 134.74, 133.73, 133.12, 131.23, 128.43, 123.50,122.19, 114.22. HRMS (ESI) m / z for C 15 H8Cl2BrN3OS [M+H] + calcd: 427.9027, found: 427.9054. Compound TCP360: 2-chloro-N-[4-(3,5-dichlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 57%, white solid, melting point: 219.5 – 221.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s,1H), 8.62 (d, J = 3.8 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 8.01(s, 2H), 7.68 – 7.60 (m, 1H), 7.59 (s, 1H). 13 C NMR (101 MHz, DMSO) δ 164.31,158.28, 151.75, 147.13, 146.65, 139.27, 137.81, 135.10, 131.12, 127.55,124.71, 123.48, 112.20. HRMS (ESI) m / z for C 15 H8Cl2N3OS [M+H] + calcd: 383.9532, found: 383.9528. Compound TCP361: 2-chloro-N-[4-(3-fluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 76%, white solid, melting point: 152.5 – 153.5 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.08 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.73 (d, J = 12.9 Hz,1H), 7.63 – 7.57 (m, 1H), 7.50 (q, J = 7.5 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H). 13CNMR (101 MHz, DMSO) δ 164.27, 161.86, 158.05, 151.70, 148.37, 147.11, 139.26,137.10, 131.25, 123.48, 122.26, 115.17, 114.96, 112.88, 112.66, 110.70. HRMS(ESI) m / z for C 15 H9ClFN3OS [M+H] + calcd: 334.0217, found: 334.0213. Compound TCP362: 2-chloro-N-[4-(2,3-dichlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 67%, white solid, melting point: 221.5 – 222.6 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.09 (s, 1H), 8.57 (d, J = 4.1 Hz, 1H), 8.18 (d, J = 9.4 Hz, 1H), 7.75 (d, J = 11.2 Hz, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.61 – 7.54 (m, 1H), 7.46 (t, J = 7.9 Hz, 1H). 13 C NMR(101 MHz, DMSO) δ 164.30, 157.28, 151.70, 147.10, 146.15, 139.24, 136.10,133.17, 131.24, 130.45, 128.67, 123.48, 114.86.HRMS (ESI) m / z for C 15 H8Cl2N3OS[M+H] + calcd: 383.9532, found: 383.9545. Compound TCP363: 2-chloro-N-[4-(2-chloro-3-fluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 59%, white solid, melting point: 198.5 – 199.3 °C. 1 H NMR (400 MHz, DMSO- d6) δ 13.06 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 9.5 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H),7.91 (s, 2H), 7.62 – 7.55 (m, 1H), 7.51 (t, J = 9.0 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 164.26, 158.21, 156.06, 151.72, 147.26, 139.25, 132.52, 131.21,128.12, 126.79, 123.49, 120.53, 117.92, 117.71, 110.41. HRMS (ESI) m / z forC 15 H8Cl2FN3OS [M+H] + calcd: 367.9827, found: 367.9846. Compound TCP364: 2-chloro-N-[4-(3,5-difluorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 61%, white solid, melting point: 203.5 – 205.1 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.06 (s, 1H), 8.58 (d, J = 3.0 Hz, 1H), 8.18 (d, J = 9.5 Hz, 1H), 8.01 (s, 1H), 7.65 –7.60 (m, 2H), 7.60 – 7.56 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 164.37, 162.16,162.02, 158.20, 151.77, 147.11, 139.29, 138.05, 131.17, 123.51, 112.03,109.29, 109.02, 103.61.HRMS (ESI) m / z for C 15 H8ClF2N3OS [M+H ]+ calcd: 352.0123, found: 352.0119 Compound TCP365: 2,6-dichloro-N-[4-(3-chlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 68%, white solid, melting point: 182.5 – 184.7 °C. 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s,1H), 8.32 (d, J = 7.9 Hz, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 7.6Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.4Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 163.34, 157.99, 150.80, 148.10, 146.62, 142.30, 136.54, 134.10, 131.17, 130.36, 128.14, 125.93, 124.74, 124.08,110.88. HRMS (ESI) m / z for C 15 H8Cl3N3OS [M+H] + calcd: 383.9532, found: 383.9538. Compound TCP366: 2,5-dichloro-N-[4-(3-chlorophenyl)-1,3-thiazolyl-2-yl]pyridine-3-carboxamide, yield: 71%, white solid, melting point: 197.5 – 198.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.09 (s, 1H), 8.69 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 7.99 (s, 1H), 7.94 (s,1H), 7.90 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 162.78, 157.95, 150.10, 148.10, 145.58, 138.93,136.53, 134.12, 131.97, 131.20, 130.68, 128.16, 125.92, 124.75, 110.94. HRMS(ESI) m / z for C 15 H8Cl3N3OS [M+H ]+ calcd: 383.9532, found: 383.9536. Example 4: Determination of the antifungal activity of heterocyclic nicotinamide compounds against plant pathogenic fungi. 1. Tested plant pathogenic fungi Rice sheath blight fungus ( Acidovorax citrulli Rice blast fungus ( Xanthomonas oryzae pv. Oryzae ), wheat scab ( Ralstonia solanacearum ), tomato gray mold ( Botrytis cirerea ) and mango anthracnose bacteria ( Colletotrichum gloeosporioides ).

[0051] 2. Antibacterial activity test methods This invention employs the growth rate method to evaluate the inhibitory activity of heterocyclic nicotinamide compounds against the aforementioned plant pathogenic fungi. The specific method is based on the work of Edwards et al. (Edwards S, Seddon B. Mode of antagonism of Brevibacillus brevis against...). Botrytis cinerea in vitro The method described in the Journal of Applied Microbiology, 2001, 91(4): 652-659, was used. First, heterocyclic nicotinamide compounds were dissolved in dimethyl sulfoxide (DMSO) and then mixed with sterile molten PDA to obtain a final concentration of 100 µg / mL. PDA medium (15 mL) was poured into 9 cm diameter petri dishes and inoculated with 5 mm of plant pathogenic fungi. PDA containing the corresponding concentration of acetone was used as a control. Each treatment consisted of three replicates. After the control petri dishes were completely covered by fungal hyphae, the hyphal growth diameter was measured using the method described by Agarwal et al. (Agarwal M., Walia S., Dhingra S., Khambay BPSInsect growth inhibition, antifeedant and antifungal activity of compounds isolated / derived from Zingiber offcinale The inhibition rate was calculated using the formula from Roscoe (ginger) rhizomes. Pest Manag. Sci. 2001, 57: 289-300.

[0052] I(%)=(CT) / (Cd)×100 Where d is the diameter of the cut hyphae (5 mm), I is the inhibition rate (%), and C and T represent the average colony diameter of the control and treated hyphae, respectively.

[0053] 3. Experimental Results The pathogens of wheat scab, rice sheath blight, rice blast fungus, mango anthracnose, and tomato gray mold were selected as test pathogens. The in vitro antibacterial activity of the synthesized heterocyclic nicotinamide compounds was tested, and the results of the antibacterial activity determination are shown in Table 1.

[0054] Table 1. Antibacterial activity of synthesized heterocyclic nicotinamide compounds

[0055] As shown in Table 1, at a test concentration of 100 μg / mL, the synthesized heterocyclic nicotinamide compounds exhibited varying degrees of antibacterial activity. Among them, compound TCP350 showed the highest antibacterial activity, with inhibition rates of 91.36%, 97.96%, 82.44%, and 94.14% against *Rhizoctonia solani*, *Pseudomonas aeruginosa*, *Anthracnose causal agent*, and *Botrytis cinerea*, respectively, which were superior to the control agent, cyazofamid. Compounds TCP351, TCP360, TCP361, TCP362, and TCP363 also showed strong antibacterial activity against the above pathogens. In particular, compounds TCP351 and TCP362 showed inhibition rates of 93.88% and 68.97% against *Pseudomonas aeruginosa* and 87.26% and 67.68% against *Anthracnose causal agent*, respectively, which were superior to the control agent, cyazofamid.

[0056] Example 4 - Activity determination of the compound against tomato gray mold using tissue method Test materials: Tomatoes of commercially available variety, selected from uniform size, healthy and plump tomatoes.

[0057] Test compounds: TCP348, TCP350, TCP362 and TCP363.

[0058] The pot experiment used the tissue method (Ling Zhang, Yu Long, Long-Fei Li, Xiang-WeiXin, Xiao-Di Chen, Xiang Zhou, Li-Wei Liu, Zhi-Bing Wu, Song Yang. Genistein: A promising botanical fungicide candidate for enhancing tomato yield and quality by controlling Alternaria solani (Pesticide Biochemistry and Physiology, 2025, 214, 106588) This study tested the protective and curative effects of an active compound against gray mold in tomatoes. The specific procedure was as follows: Tomato fruits were immersed in a 70% ethanol solution for 1 min for surface disinfection, rinsed with sterile water, and air-dried in a clean bench. A 5 mm × 5 mm cross-shaped wound was aseptically prepared on the fruit surface. A 5 mm diameter mycelial disc was placed on the wound with the mycelial side down. Each treatment was repeated in triplicate, with 10 fruits used in each replicate. The concentration of the tested active compound was 200 μg / mL, and the control agent was 20% boscalid suspension (200 μg / mL). A blank control (CK) was set up, consisting of inoculation without treatment and spraying only with an equal amount of solvent. In the protective effect test, the pesticide was sprayed first, and inoculation was performed 24 hours later (humidity > 85%). In the therapeutic effect test, inoculation was performed first, and then the fruit was kept moist at 25±2℃ and humidity > 85% for 24 hours before pesticide application. All treated fruits were placed in a humidity chamber and cultured in an artificial climate chamber at 25±2℃, humidity 60–80%, and a photoperiod of 16 h light / 8 h darkness. After the blank control group had fully developed the disease, the diameter of the lesions on each treated fruit was measured uniformly. The in vivo control effect of the compound was calculated according to the following formula.

[0059] Control effect (%) = 100 × (diameter of control lesions - diameter of treated lesions) / (diameter of control lesions - 0.5).

[0060] 3. Experimental Results Table 2. Protective and curative effects of compounds against tomato gray mold.

[0061] Note: The data in the table are mean ± standard deviation. Different letters indicate that the difference is significant at the P<0.05 level.

[0062] The results of the tissue method test are shown in Table 2. All four compounds exhibited strong protective and curative effects against tomato gray mold, with compounds TCP350 and TCP363 showing the highest efficacy at a tested concentration of 200 mg / L. At µg / mL, its protective and curative efficacy against tomato gray mold ranged from 74% to 85%, which was superior to the control agent 20% boscalid suspension (73.16% and 68.66%). Meanwhile, compound TCP363 also exhibited strong protective activity against tomato gray mold, with protective and curative efficiencies of 75.05% and 70.34% at the same concentration, respectively, showing a significant difference from the control agent 20% boscalid suspension. Compound TCP348 also showed some protective and curative effects, but its protective efficacy was superior to its curative efficacy. Its protective efficacy at the same concentration was 71.99%, which was not significantly different from the control agent 20% boscalid suspension, but its curative efficacy was 61.63%, lower than the control agent boscalid.

[0063] In summary, heterocyclic nicotinamide compounds exhibit excellent fungicidal activity against plant pathogenic fungi. Furthermore, their novel chemical structures and simple synthetic methods suggest that they are promising candidates for further research and development as a new class of fungicidal agents.

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A heterocyclic nicotinamide compound, characterized in that, The structure of the heterocyclic nicotinamide compound is shown in Formula I: In Formula I, R1 is selected from one of hydrogen atom, hydroxyl group, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro, cyano, phenyl or benzyl; R2 is selected from one of hydrogen atom, hydroxyl group, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano.

2. The heterocyclic nicotinamide compound according to claim 1, characterized in that, The halogen is selected from one of fluorine, chlorine, bromine or iodine; The C1-C5 alkyl group is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or neopentyl; The C1-C2 haloalkyl group is selected from one of trifluoromethane, difluorodichloromethane, trichloromethane, difluoromethane, dichloromethane, monofluoromethane, 1,2-difluoroethane, 1,2-methylfluoroethane, 1,2-dichloroethane, or 1,2-tetrachloroethane. The C1-C3 alkoxy group is selected from one of methoxy, ethoxy, or propoxy. The substituted phenyl group is selected from 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 2,3-difluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl. One of the following: 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 2,4-ditrifluoromethylphenyl, 2,6-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2,3-ditrifluoromethylphenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl, 2,6-dibromophenyl, 3,5-dibromophenyl, 2,3-dibromophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 3,4-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,3-dihydroxyphenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-trifluoromethylphenyl, 2-bromo-4-chlorophenyl, and 3-chloro-4-fluorophenyl; The substituted benzyl group is selected from 4-methylbenzyl, 3-methylbenzyl, 2-methylbenzyl, 3,4-dimethylbenzyl, 2,4-dimethylbenzyl, 2,6-dimethylbenzyl, 3,5-dimethylbenzyl, 2,3-dimethylbenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 3,4-difluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 3,5-difluorobenzyl, 2,3-difluorobenzyl-4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,3-dichlorobenzyl-4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,3-dichlorobenzyl One of the following: 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-methoxybenzyl, 3-methoxybenzyl, 2-methoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-trifluoromethylbenzyl, 4-bromobenzyl, 4-hydroxybenzyl, 2-chloro-3-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2-chloro-5-fluorobenzyl, 2-chloro-4-trifluoromethylbenzyl, 2-bromo-4-chlorobenzyl, and 3-chloro-4-fluorobenzyl.

3. The method for synthesizing the heterocyclic nicotinamide compound according to any one of claims 1-2, characterized in that, Includes the following steps: (1) Using acetophenone with different substituents and N-bromosuccinimide as raw materials, p-toluenesulfonic acid was added to catalyze the reaction and reacted under solvent conditions. The solvent was removed under reduced pressure and extracted to obtain 2-bromoacetophenone with different substituents. (2) Dissolve 2-bromoacetophenone with different substituents in a solvent, add thiourea to react, and after the reaction is completed, desolvate under reduced pressure to obtain 2-amino-4-thiazole with different substituents; (3) Dissolve 3-pyridinecarboxylic acid with different substituents in a solvent, add oxaloyl chloride dropwise and add N,N-dimethylformamide to catalyze the reaction. After the reaction is completed, desolvate under reduced pressure to obtain 3-pyridinecarboxylic chloride with different substituents; (4) Take 3-pyridinecarboxyl chloride with different substituents, 2-amino-4-thiazole with different substituents, and triethylamine, add solvent to react, extract, combine organic layers, dry, desolvent under reduced pressure, and then purify by column chromatography to obtain nicotinamide compounds containing heterocycles.

4. The method for synthesizing heterocyclic nicotinamide compounds according to claim 3, characterized in that, In step (1), the solvent is acetonitrile; the molar ratio of the different substituents of acetophenone, N-bromosuccinimide and p-toluenesulfonic acid is 1~2:1~2:1.5~3; the reaction is a reflux reaction for 2.5~3 hours.

5. The method for synthesizing heterocyclic nicotinamide compounds according to claim 3, characterized in that, In step (2), the solvent is anhydrous ethanol; the molar ratio of 2-bromoacetophenone with different substituents to thiourea is 1:1.1~1.

2.

6. The method for synthesizing heterocyclic nicotinamide compounds according to claim 3, characterized in that, In step (3), the solvent is dichloromethane; the molar ratio of 3-pyridinecarboxylic acid with different substituents to oxaloyl chloride is 1~2:2~4.

7. The method for synthesizing heterocyclic nicotinamide compounds according to claim 3, characterized in that, In step (4), the solvent is dichloromethane; the molar ratio of 3-pyridinecarboxyl chloride with different substituents, 2-amino-4-thiazole with different substituents and triethylamine is 1.5~2:1:

3.

8. The application of heterocyclic nicotinamide compounds according to claims 1-2 or heterocyclic nicotinamide compounds synthesized by any one of the synthetic methods of claims 3-7 in the prevention and control of plant diseases caused by fungal pathogens.

9. The application according to claim 8, characterized in that, The fungal pathogens mentioned are: rice sheath blight fungus, rice blast fungus, mango anthracnose fungus, rubber anthracnose fungus, litchi anthracnose fungus, banana anthracnose fungus, coffee anthracnose fungus, wheat scab fungus, wheat powdery mildew fungus, apple rot fungus, tomato gray mold fungus, rapeseed sclerotium rot fungus, banana leaf spot fungus, banana black spot fungus, apple ring spot fungus, tobacco red spot fungus, cotton damping-off fungus, corn large leaf spot fungus, and rubber tree leaf drop fungus.

10. The application according to claim 9, characterized in that, The fungal pathogens are rice sheath blight fungus, rice blast fungus, tomato gray mold fungus, mango anthracnose fungus, and wheat scab fungus.

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