A phenoxypyridine compound containing acylthiourea and heterocyclic structure, and its preparation method and application

Abstract

The application discloses a phenoxy pyridine compound with an acyl thiourea and a heterocyclic structure, and a preparation method and application thereof. The application belongs to the field of herbicides. The application aims to solve the technical problem that existing herbicides cannot simultaneously consider herbicidal activity and use safety. The phenoxy pyridine compound with the acyl thiourea and the heterocyclic structure has good inhibitory activity on PPO. The phenoxy pyridine compound has particularly excellent herbicidal activity on weeds such as petunia, dogtail grass, chenopodium, and abutilon, and has excellent effects on dicotyledonous weeds, and the control effect is even better than that of some commercial herbicides. The phenoxy pyridine compound can be used as a PPO inhibitor. The phenoxy pyridine compound can also be prepared into a weed control agent and applied to control crop weeds.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of herbicides, and particularly relates to a phenoxy pyridine compound containing acyl thiourea and a heterocyclic structure, and a preparation method and application thereof. BACKGROUND

[0002] The production of food is threatened by natural factors such as diseases, insects and weeds, and the yield of crops can be reduced by nearly 11% due to weeds. Weeds not only compete with crops for resources necessary for plant growth, but also make the breeding and spread of diseases and insects more serious. Therefore, effective control of weeds in crop fields is very important for food production. Using herbicides is a more economical and time-saving method. With the increasing use of herbicides, some negative effects such as environmental pollution, resistant weeds, phytotoxicity and residues have been brought about. In order to solve the problems of phytotoxicity of herbicides and increasingly serious weed resistance, it is necessary to develop new herbicides with ultra-high activity, low residue, low toxicity and selectivity.

[0003] Protoporphyrinogen oxidase (PPO) is an important target for green herbicide research. Currently, PPO herbicides are mainly divided into eight categories. Diphenyl ether is the earliest discovered PPO herbicide. This type of herbicide has a broad weed spectrum, fast weed control, low dosage and is not prone to resistance, and has a broad application prospect. However, due to long-term unreasonable use, problems such as environmental pollution, resistant weeds, phytotoxicity and residues have occurred.

[0004] Currently, there are many problems in commercialized diphenyl ether PPO herbicides. For example, fluorodifen can efficiently control broadleaf weeds in soybean fields, but when the spraying dose is improper or the soil is dry, the control effect is poor and slight phytotoxicity occurs, showing symptoms such as soybean leaf yellowing, wrinkling and browning. Due to the physical and chemical properties of benfluralin, it is easy to stay on the surface of the soil, has a long residual period, and causes phytotoxicity to subsequent crops. In addition, benfluralin residues in the soil are washed away by rainwater, thereby polluting surface water such as rivers, lakes and reservoirs, and underground water. When ethoxyflur is used in rice fields, it needs to be sprayed on sunny days. If heavy rain occurs after spraying and the seedlings are flooded, the seedlings will die due to phytotoxicity. Therefore, it is of great significance to study new diphenyl ether derivative PPO inhibitor herbicides for finding lead compounds with high activity and high safety. SUMMARY

[0005] In order to overcome the above technical defects, the present application provides a phenoxy pyridine compound containing acyl thiourea and a heterocyclic structure, and a preparation method and application thereof.

[0006] The technical scheme of the present application is as follows:

[0007] One of the purposes of the present application is to provide a phenoxy pyridine compound containing acyl thiourea and heterocyclic structure, the structural general formula of the compound is as shown in the following formula (I) or formula (II):

[0008]

[0009] In which R1: is selected from at least one of H, Cl, Br, NO2 or CF3; X: is O or S; R2: is H or Cl.

[0010] The second purpose of the present application is to provide a preparation method of a phenoxy pyridine compound containing acyl thiourea and heterocyclic structure, the method is carried out according to the following steps:

[0011] Step one: 4-aminophenol or 3-aminophenol is dissolved in organic solvent 1 with acid binding agent, then compound a is added, after the reaction is completed, it is cooled to room temperature, distilled water is added, extracted, washed, dried and concentrated to obtain intermediate d or intermediate e; the structural formula of compound a is:

[0012]

[0013] Step two: compound f is dissolved in organic solvent 2 respectively to obtain respective organic solutions, then the organic solutions are mixed, after the reaction is completed, it is cooled, filtered to obtain a solution containing intermediate h; the structural formula of compound f is:

[0014]

[0015] Step three: intermediate d or intermediate e is added to the solution containing intermediate h respectively to carry out reaction, after the reaction is completed, a poor solvent is added to the reaction solution, it is placed, filtered, and the insoluble substance is collected, and recrystallized to obtain a phenoxy pyridine compound (I) or (II) containing acyl thiourea and heterocyclic structure;

[0016] The definitions of R1, X and R2 in compound a and compound f are as described above.

[0017] Further limitation, the organic solvent 1 in step one is N,N-dimethylformamide or dimethyl sulfoxide. Preferably, it is dimethyl sulfoxide.

[0018] Further limitation, the acid binding agent in step one is cesium carbonate or potassium carbonate. Preferably, it is cesium carbonate.

[0019] Further limitation, the molar ratio of compound a to 4-aminophenol or 3-aminophenol and acid binding agent in step one is 1:1:(1-3). Preferably, it is 1:1:2.

[0020] Further limitation, the reaction temperature in step one is 80-100 DEG C. Preferably, it is 90 DEG C.

[0021] Further, the organic solvent 2 in step 2 is acetone or acetonitrile. Preferably, acetonitrile.

[0022] Further, the molar ratio of compound f to potassium thiocyanate in step 2 is <1.

[0023] Further, the reaction temperature in step 2 is 25-70℃. Preferably, 70℃.

[0024] Further, the molar ratio of intermediate d or intermediate e to intermediate h in step 3 is <1.

[0025] Further, the reaction temperature in step 3 is 20-40℃. Preferably, 25-30℃.

[0026] Further, the poor solvent in step 3 is distilled water or NaHCO3 solution with pH = 8-9. Preferably, NaHCO3 solution with pH = 8-9.

[0027] Further, the solvent used for recrystallization in step 3 is acetonitrile-water.

[0028] The third object of the present application is to provide the use of a phenoxy pyridine compound containing acyl thiourea and heterocyclic structure as a protoxidase (PPO) inhibitor.

[0029] The fourth object of the present application is to provide the use of a phenoxy pyridine compound containing acyl thiourea and heterocyclic structure in the control of weeds in crops.

[0030] Further, the weeds are monocotyledonous weeds or dicotyledonous weeds.

[0031] Further, the weeds are at least one of Digitaria sanguinalis, Setaria viridis, Echinochloa crus-galli, Ipomoea indica, Amaranthus retroflexus, and Abutilon theophrasti.

[0032] Further, the crops are wheat, rice, corn, cotton, soybean, or peanut.

[0033] The fifth object of the present application is to provide the use of a phenoxy pyridine compound containing acyl thiourea and heterocyclic structure as an active ingredient in the preparation of a weed control agent.

[0034] Further, the concentration of the active ingredient in the agent is 37.5-300 g ai / ha.

[0035] The present application has the following advantages compared with the prior art:

[0036] The present application provides a phenoxy pyridine compound containing acyl thiourea and heterocyclic structure, a preparation method and use thereof. The compound of the present application has high safety to crops while maintaining high herbicidal activity.

[0037] The phenoxy pyridine compound containing acyl thiourea and heterocyclic structure provided by the present application has good inhibitory activity on PPO. The phenoxy pyridine compound containing acyl thiourea and heterocyclic structure provided by the present application has particularly excellent herbicidal activity on impatiens, setaria, chenopodium, abutilon and the like, especially excellent effect on dicotyledonous weeds, and the control effect is even better than some commercially available commercial herbicides. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 The synthesis route of the phenoxy pyridine compound containing acyl thiourea and heterocyclic structure of the present application is as follows:

[0039] Figure 2 The herbicidal activity effect diagram of I-12 in application example 1 under different application amounts is as follows:

[0040] Figure 3 The crop safety effect diagram of I-12 in application example 3 under the application amount of 300 g ai / ha is as follows. DETAILED DESCRIPTION

[0041] In order to make the purpose, technical scheme and advantages of the present application more clear, the present application will be further described in detail below in combination with examples. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the present application.

[0042] The experimental methods used in the following examples are all conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are all conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained by commercial channels by those skilled in the art.

[0043] The structure of the compound in the following examples is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0044] Example 1, (in combination Figure 1 Preparation of N-[(4-(pyridin-2-yloxy)phenyl)thio carbamoyl]furan-2-carboxamide (I-1)

[0045] Step 1: Preparation of intermediate d

[0046] In a round bottom flask, 20.0 mmol of 4-aminophenol and 40 mmol of cesium carbonate were added, followed by 40 mL of dimethyl sulfoxide, and stirred for 30 minutes at room temperature. 20.05 mmol of 2-chloropyridine was added, followed by heating to 90°C, and the reaction was stirred while monitoring the progress of the reaction using thin layer chromatography (TLC) until the 4-aminophenol was completely reacted. It was cooled to room temperature, filtered under reduced pressure, and the filtrate was collected. 80 mL of distilled water was added to the filtrate, and stirred for 10 minutes. It was extracted with ethyl acetate, and the organic phase was collected and washed with saturated brine. The organic phase was added to anhydrous sodium sulfate, and dried for 24 hours. It was filtered, and the ethyl acetate was removed by rotary evaporation to obtain a viscous liquid, which was the intermediate d.

[0047] Step 2: Preparation of intermediate h

[0048] In a round bottom flask containing 50 mL of acetonitrile, 5 mmol of potassium thiocyanate was added, and stirred until completely dissolved. A solution containing 4 mmol of furan formyl chloride in 40 mL of acetonitrile was added dropwise. It was heated to 70°C, and stirred for 50 minutes. It was cooled to room temperature, and filtered to obtain an acetonitrile solution containing intermediate h.

[0049] Step 3: Preparation of N-[(4-(pyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide (I-1)

[0050] The acetonitrile solution containing intermediate h from Step 2 was all transferred to a round bottom flask, and 3 mmol of intermediate d synthesized in Step 1 was added. It was stirred at room temperature for 2 hours, and the reaction was monitored using TLC until it was completely reacted. The reaction solution was poured into a sodium bicarbonate solution (pH = 8), and the solution became turbid, and was left to stand overnight in a 4°C environment. It was filtered, and the solid was collected to obtain a crude product. The crude product was recrystallized (acetonitrile-water, v / v = 1 / 8) to obtain N-[(4-(pyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide. It was a gray solid, and the yield was 87%.

[0051] The product detection data are as follows: m.p.: 134.2-135.1°C; 1 H NMR (600 MHz, CDC13) δ 12.31 (s, 1H), 9.20 (s, 1H), 8.20 (ddd, J = 5.0, 2.0, 0.8 Hz, 1H), 7.77-7.68 (m, 3H), 7.63 (dd, J = 1.8, 0.9 Hz, 1H), 7.39 (dd, J = 3.6, 0.8 Hz, 1H), 7.21-7.16 (m, 2H), 7.01 (ddd, J = 7.2, 5.0, 1.0 Hz, 1H), 6.94 (dt, J = 8.3, 0.9 Hz, 1H), 6.64 (dd, J = 3.6, 1.7 Hz, 1H); 13C NMR (151 MHz, CDC13) δ 177.94, 163.45, 156.75, 152.47, 147.67, 146.49, 144.93, 139.60, 134.03, 125.45, 121.53, 119.01, 118.74, 113.45, 111.69; HRMS calcd for [M+H+] C 17 H 13 N3O3S, 340.0756, found 340.0754.

[0052] The structure of the product was characterized as:

[0053] Example 2 Preparation of N-[(4-(5-bromopyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (1-2)

[0054] This example differs from Example 1 in that 2-chloropyridine is replaced with 5-bromo-2-chloropyridine in Step 1. Other steps and parameters are the same as Example 1. N-[(4-(5-bromopyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide was obtained. Pink solid, yield 82%.

[0055] Product testing data are as follows: m.p.: 170.0-171.0 °C; 1 H NMR (600 MHz, CDC13) δ 12.32 (s, 1H), 9.20 (s, 1H), 8.22 (dd, J = 2.6, 0.7 Hz, 1H), 7.78 (dd, J = 8.7, 2.6 Hz, 1H), 7.76-7.72 (m, 2H), 7.63 (dd, J = 1.7, 0.8 Hz, 1H), 7.40 (dd, J = 3.6, 0.8 Hz, 1H), 7.20-7.15 (m, 2H), 6.87 (dd, J = 8.7, 0.7 Hz, 1H), 6.64 (dd, J = 3.6, 1.8 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 178.01, 162.31, 156.78, 152.03, 148.36, 146.53, 144.93, 142.08, 134.39, 125.49, 121.56, 119.07, 113.81, 113.48, 113.22; HRMS calcd for [M+H+] C 17 H 12 BrN3O3S, 417.9861, found 417.9859.

[0056] The structure of the product was characterized as:

[0057] Example 3 Preparation of N-[(4-(3-chloropyridin-2-oxy)phenyl)thiocarbamoyl]furan-2-carboxamide (I-3)

[0058] This example differs from Example 1 in that 2-chloropyridine in Step 1 is replaced with 2,3-dichloropyridine. All other steps and parameters are the same as in Example 1. This yields N-[(4-(3-chloropyridin-2-oxy)phenyl)carbamothioyl]furan-2-carboxamide as a purple solid in 93% yield.

[0059] The product test data are as follows: mp: 132.4-133.2°C; 1 H NMR (600MHz, CDCl3) δ12.33(s,1H),9.23(s,1H),8.03(dd,J=4.8,1.7Hz,1H),7.80-7.72(m,3H),7.66-7.60 (m,1H),7.40(d,J=3.6Hz,1H),7.25-7.18(m,2H),6.98(dd,J=7.7,4.8Hz,1H),6.64(dd,J=3.6,1.7Hz,1H); 13 C NMR (151MHz, CDCl3) δ178.03,158.86,156.80,151.87,146.53,145.14,144 .94,139.43,134.44,125.38,121.85,119.52,119.23,119.04,113.45; HRMS calcd for[M+H+]C 17 H 12 ClN3O3S,374.0366, found 374.0367.

[0060] After characterization, the structure of the obtained product is:

[0061] Example 4 Preparation of N-[(4-(5-chloropyridin-2-oxy)phenyl)thiocarbamoyl]furan-2-carboxamide (I-4)

[0062] This example differs from Example 1 in that 2-chloropyridine in Step 1 is replaced with 2,5-dichloropyridine. All other steps and parameters are the same as in Example 1. This yields N-[(4-(5-chloropyridin-2-oxy)phenyl)carbamothioyl]furan-2-carboxamide as a pink solid in 83% yield.

[0063] The product test data are as follows: mp: 165.3-165.5°C; 1H NMR (600 MHz, CDC13) δ 12.32 (s, 1H), 9.21 (s, 1H), 8.19-8.08 (m, 1H), 7.79-7.71 (m, 2H), 7.69-7.60 (m, 2H), 7.39 (dd, J = 3.6, 0.8 Hz, 1H), 7.21-7.13 (m, 2H), 6.95-6.87 (m, 1H), 6.64 (dd, J = 3.6, 1.8 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 178.02, 161.86, 156.79, 152.13, 146.54, 146.06, 144.92, 139.38, 134.35, 126.11, 125.51, 121.54, 119.07, 113.48, 112.63; HRMS calcd for [M + H+] C 18 H 11 ClF3N3O2S2, 374.0366, found 374.0374.

[0064] The structure of the resulting product was characterized as:

[0065] Example 5 Preparation of N-[(4-(3,5-dichloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (1-5)

[0066] This example differs from Example 1 in that 2-chloropyridine is replaced with 2,3,5- trichloropyridine in Step 1. The other steps and parameters are the same as in Example 1. N-[(4-(3,5-dichloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Pink solid, yield 95%.

[0067] Product testing data are as follows: m.p.: 143.4-144.0 °C; 1 H NMR (600 MHz, CDC13) δ 12.32 (s, 1H), 9.21 (s, 1H), 8.19-8.08 (m, 1H), 7.79-7.71 (m, 2H), 7.69-7.60 (m, 2H), 7.39 (dd, J = 3.6, 0.8 Hz, 1H), 7.21-7.13 (m, 2H), 6.95-6.87 (m, 1H), 6.64 (dd, J = 3.6, 1.8 Hz, 1H); 13C NMR (151 MHz, DMSO) δ 179.40, 158.02, 157.53, 151.38, 148.96, 145.18, 144.19, 139.80, 135.51, 126.43, 125.78, 121.94, 119.16, 119.10, 113.16; HRMS calcd for [M+H+] C 17 H 11 Cl2N3O3S, 407.9976, found 407.9970.

[0068] The structure of the product was characterized as:

[0069] Example 6 Preparation of N-[(4-(3-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (1-6)

[0070] This example differs from Example 1 in that 2-chloropyridine is replaced with 2-chloro-3-nitropyridine in Step 1. Other steps and parameters are the same as Example 1. N-[(4-(3-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Orange solid, yield 74%.

[0071] Product testing data are as follows: m.p.: 162.6-163.3 °C; 1 H NMR (600 MHz, CDC13) δ 12.37 (s, 1H), 9.21 (s, 1H), 8.40-8.32 (m, 2H), 7.84-7.77 (m, 2H), 7.64 (dd, J = 1.7, 0.8 Hz, 1H), 7.40 (dd, J = 3.6, 0.8 Hz, 1H), 7.26-7.22 (m, 2H), 7.17 (dd, J = 7.9, 4.8 Hz, 1H), 6.65 (dd, J = 3.6, 1.8 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.99, 156.79, 155.67, 151.72, 150.70, 146.57, 144.91, 135.53, 135.14, 134.57, 125.31, 122.20, 119.09, 118.56, 113.48; HRMS calcd for [M+H+] C 17 H 12 N4O5S, 385.0607, found 385.0601.

[0072] The structure of the product was characterized as: The structure of the product was characterized as:

[0073] Example 7 Preparation of N-[(4-(4-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (I-7)

[0074] This example differs from Example 1 in that 2-chloropyridine is replaced by 2-chloro-4-nitropyridine in Step 1. Other steps and parameters are the same as in Example 1. N-[(4-(4-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Pink solid, yield 93%.

[0075] Product testing data are as follows: m.p.: 166.2-166.9 °C; 1 H NMR (600 MHz, CDC13) δ 12.39 (s, 1H), 9.22 (s, 1H), 8.25 (d, J = 5.7 Hz, 1H), 7.85-7.77 (m, 2H), 7.64 (dd, J = 1.8, 0.8 Hz, 1H), 7.41 (dd, J = 3.6, 0.8 Hz, 1H), 7.15-7.11 (m, 2H), 6.87 (d, J = 2.2 Hz, 1H), 6.83 (dd, J = 5.8, 2.2 Hz, 1H), 6.66 (dd, J = 3.6, 1.7 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 178.15, 166.25, 156.83, 152.79, 151.62, 150.75, 146.64, 144.82, 135.34, 126.03, 121.17, 119.24, 113.54, 112.13, 111.48; HRMS calcd for [M+H+] C 17 H 12 N4O5S, 385.0607, found 385.0605.

[0076] The structure of the product obtained is characterized as:

[0077] Example 8 Preparation of N-[(4-(5-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (I-8)

[0078] This example differs from Example 1 in that 2-chloropyridine is replaced by 2-chloro-5-nitropyridine in Step 1. Other steps and parameters are the same as in Example 1. N-[(4-(5-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Yellow solid, yield 86%.

[0079] Product testing data are as follows: m.p.: 167.7-138.5 °C;1 H NMR (600 MHz, CDC13) δ 12.39 (s, 1H), 9.23 (s, 1H), 9.04 (d, J = 2.7 Hz, 1H), 8.49 (dd, J = 9.0, 2.8 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.64 (s, 1H), 7.41 (d, J = 3.5 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.07 (d, J = 9.1 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 176.19, 164.72, 154.91, 148.92, 144.69, 143.04, 142.94, 138.56, 133.38, 133.09, 123.65, 120.09, 117.26, 111.60, 109.57; HRMS calcd for [M + H+] C 17 H 12 N4O5S, 385.0607, found 385.0607.

[0080] The structure of the product was characterized as:

[0081] Example 9 Preparation of N-[(4-(3-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide (I-9)

[0082] This example differs from Example 1 in that 2-chloropyridine is replaced with 2-chloro-3-(trifluoromethyl)pyridine in Step 1. Other steps and parameters are the same as Example 1. N-[(4-(3-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Pink solid, yield 73%.

[0083] Product testing data are as follows: m.p.: 194.5-195.3 °C; 1 H NMR (600 MHz, CDC13) δ 12.39 (s, 1H), 9.23 (s, 1H), 9.04 (d, J = 2.7 Hz, 1H), 8.49 (dd, J = 9.0, 2.8 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.64 (s, 1H), 7.41 (d, J = 3.5 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.07 (d, J = 9.1 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H); 13C NMR (151 MHz, CDC13) δ 178.00, 160.18, 156.77, 151.33, 150.84, 146.51, 144.95, 137.10 (q, J = 4.5 Hz), 134.71, 125.32, 122.72 (q, J = 271.8 Hz), 122.11, 119.03, 117.99, 114.44 (q, J = 33.2 Hz), 113.45; HRMS calcd for [M+H+] C FC = 4.5 Hz), 134.71, 125.32, 122.72 (q, J FC = 271.8 Hz), 122.11, 119.03, 117.99, 114.44 (q, J FC = 33.2 Hz), 113.45; HRMS calcd for [M+H+] C 18 H 12 F3N3O3S, 408.0630, found 408.0625.

[0084] The structure of the product was characterized as:

[0085] Example 10 Preparation of N-[(4-(4-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide (I-10)

[0086] This example differs from Example 1 in that 2-chloropyridine is replaced by 2-chloro-4-(trifluoromethyl)pyridine in Step 1. Other steps and parameters are the same as in Example 1. N-[(4-(4-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Pink solid, yield 90%.

[0087] Product testing data are as follows: m.p.: 200.1-200.9 °C; 1 H NMR (600 MHz, CDC13) δ 12.35 (s, 1H), 9.21 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.81-7.76 (m, 2H), 7.63 (dd, J = 1.8, 0.8 Hz, 1H), 7.40 (dd, J = 3.6, 0.8 Hz, 1H), 7.23-7.18 (m, 4H), 6.65 (dd, J = 3.6, 1.7 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 178.01, 163.97, 156.79, 151.53, 148.93, 146.53, 144.93, 141.82 (q, J = 37.7 Hz), 134.70, 125.48, 122.47 (q, J = 273.3 Hz), 121.84, 119.06, 114.24 (q, J = 33.2 Hz), 113.45; HRMS calcd for [M+H+] C FC = 4.5 Hz), 134.71, 125.32, 122.72 (q, J FC = 271.8 Hz), 122.11, 119.03, 117.99, 114.44 (q, J FC=3.0Hz),113.47,108.15(q,J FC =4.5Hz); HRMS calcd for[M+H+]C 18 H 12 F3N3O3S,408.0630,found406.0626.

[0088] After characterization, the structure of the obtained product is:

[0089] Example 11 Preparation of N-[(4-(5-trifluoromethylpyridin-2-oxy)phenyl)thiocarbamoyl]furan-2-carboxamide (I-11)

[0090] This example differs from Example 1 in that 2-chloropyridine in Step 1 is replaced with 2-chloro-5-(trifluoromethyl)pyridine. All other steps and parameters are the same as in Example 1. This yields N-[(4-(5-trifluoromethylpyridin-2-oxy)phenyl)carbamothioyl]furan-2-carboxamide as a white solid in 86% yield.

[0091] The product test data are as follows: mp: 111.1-111.3°C; 1 H NMR (600MHz, CDCl3) δ12.36(s,1H),9.22(s,1H),8.44(d,J=2.6Hz,1H),7.91(dd,J=8.7,2.5Hz,1H),7.81-7.73(m,2H ),7.64(d,J=1.7Hz,1H),7.40(d,J=3.6Hz,1H),7.23-7.17(m,2H),7.05(d,J=8.7Hz,1H),6.65(dd,J=3.6,1.7Hz,1H); 13 C NMR (151MHz, CDCl3) δ178.05,165.60,156.80,151.35,146.56,145.46(q,J FC =4.5Hz),144.90,136.82(q,J FC =3.0Hz),134.83,125.53,123.67(q,J FC =271.8Hz),121.96,121.79(q,J FC =33.2Hz),119.11,113.49,111.48; HRMS calcd for[M+H+]C 18 H 12 F3N3O3S,408.0630,found 408.0627.

[0092] The structure of the product was characterized as:

[0093] Example 12 Preparation of N-[(4-(6-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (I-12)

[0094] This example differs from Example 1 in that 2-chloropyridine is replaced with 2-chloro-6- (trifluoromethyl)pyridine in Step 1. Other steps and parameters are the same as Example 1. N-[(4-(6- trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Pink solid, yield 96%.

[0095] Product testing data are as follows: m.p.: 126.7-127.0 °C; 1 H NMR (600 MHz, CDC13) δ 12.35 (s, 1H), 9.20 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.78-7.73 (m, 2H), 7.63 (d, J = 1.7 Hz, 1H), 7.43-7.37 (m, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 3.6, 1.7 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.98, 163.16, 156.76, 151.62, 146.53, 144.92, 146.32 (q, J FC = 36.2 Hz), 140.69, 134.47, 125.37, 121.36, 120.99 (q, J FC = 274.8 Hz), 119.08, 115.22 (q, J FC = 3.0 Hz), 114.60, 113.48; HRMS calcd for [M+H+] C 18 H 12 F3N3O3S, 408.0630, found 408.0630.

[0096] The structure of the product was characterized as:

[0097] Example 13 Preparation of N-[(4-(4-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2- carboxamide (I-13)

[0098] This example differs from example 1 in that in step 1 the 2-chloropyridine is replaced by 2-chloro-4-(trifluoromethyl)pyridine. In step 2 the furanoyl chloride is replaced by thiopheneoyl chloride. The other steps and parameters are the same as in example 1. N-[(4-(4-trifluoromethylpyridine-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. Grey solid, yield 93%.

[0099] Product testing data are as follows: m.p.: 168.1-169.0 °C; 1 H NMR (600 MHz, CDC13) δ 12.43 (s, 1H), 8.95 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 7.76 (dd, J = 22.0, 6.5 Hz, 4H), 7.23-7.16 (m, 5H); 13 CNMR (151 MHz, CDC13) δ 178.06, 163.96, 161.16, 151.57, 148.93, 141.89 (q, J FC = 37.7 Hz), 135.90, 134.66, 134.41, 130.82, 128.59, 125.47, 122.47 (q, J FC = 273.3 Hz), 121.84, 114.25 (q, J FC = 3.0 Hz), 108.18 (q, J FC = 4.5 Hz); HRMS calcd for [M+H+] C 18 H 12 F3N3O2S2, 424.0401, found 424.0400.

[0100] The structure of the product obtained is characterized as:

[0101] Example 14 Preparation of N-[(4-(5-trifluoromethylpyridine-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (1-14)

[0102] This example differs from example 13 in that in step 1 the 2-chloro-4- (trifluoromethyl)pyridine is replaced by 2-chloro-5-(trifluoromethyl)pyridine. The other steps and parameters are the same as in example 13. N-[(4-(5-trifluoromethylpyridine-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. Pink solid, yield 77%.

[0103] Product testing data are as follows: m.p.: 127.6-127.9 °C; 1H NMR (600 MHz, CDC13) δ 12.44 (s, 1H), 8.95 (s, 1H), 8.45 (dt, J = 2.8, 1.0 Hz, 1H), 7.92 (dd, J = 8.7, 2.5 Hz, 1H), 7.81 - 7.71 (m, 4H), 7.24 - 7.18 (m, 3H), 7.05 (d, J = 8.7 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 178.15, 165.58, 161.22, 151.40, 145.46 (q, J FC = 214.2 Hz), 136.81 (q, J FC = 3.0 Hz), 135.90, 134.80, 134.44, 130.86, 128.59, 125.53, 123.66 (q, J FC = 271.8 Hz), 121.95, 121.82 (q, J FC = 33.2 Hz), 111.48; HRMS calcd for [M + H+] C 18 H 12 F3N3O2S2, 424.0401, found 424.0399.

[0104] The structure of the resulting product was characterized as:

[0105] Example 15 Preparation of N-[(4-(6-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (1-15)

[0106] This example differs from Example 13 in that 2-chloro-4- (trifluoromethyl)pyridine is replaced by 2-chloro-6- (trifluoromethyl)pyridine in Step 1. Other steps and parameters are the same as Example 13. N-[(4-(6-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide was obtained. Yellow solid, yield 75%.

[0107] Product testing data are as follows: m.p.: 158.5-159.3 °C; 1 H NMR (600 MHz, CDC13) δ 12.44 (s, 1H), 8.95 (s, 1H), 8.45 (dt, J = 2.8, 1.0 Hz, 1H), 7.92 (dd, J = 8.7, 2.5 Hz, 1H), 7.81 - 7.71 (m, 4H), 7.24 - 7.18 (m, 3H), 7.05 (d, J = 8.7 Hz, 1H); 13C NMR (151 MHz, CDC13) δ 178.02, 163.14, 161.14, 151.66, 146.32 (q, J = 36.0 Hz), 140.69, 135.88, 134.43, 134.40, 130.83, 128.58, 125.35, 121.36, 120.99 (q, J = 273.3 Hz), 115.23 (q, J = 21.8 Hz), 114.62; HRMS calcd for [M+H+] C FC = 34.7 Hz), 140.69, 135.88, 134.43, 134.40, 130.83, 128.58, 125.35, 121.36, 120.99 (q, J = 273.3 Hz), 115.23 (q, J = 21.8 Hz), 114.62; HRMS calcd for [M+H+] C FC = 273.3 Hz), 121.86, 114.28 (q, J = 4.5 Hz), 108.19 (q, J = 4.5 Hz), 107.87; HRMS calcd for [M+H+] C FC = 273.3 Hz), 121.86, 114.28 (q, J = 4.5 Hz), 108.19 (q, J = 4.5 Hz), 107.87; HRMS calcd for [M+H+] C 18 H 12 F3N3O2S2, 424.0401, found 424.0394.

[0108] The structure of the product obtained was characterized as:

[0109] Example 16 Preparation of 5-chloro-N-[(4-((4-trifluoromethylpyridin-2-yloxy)phenyl)thio carbamoyl]thiophene-2-carboxamide (1-16)

[0110] The difference between this example and Example 13 is that in Step 2, thiophenecarbonyl chloride is replaced by 5-chloro-2-carbonyl chloride thiophene. Other steps and parameters are the same as Example 13. 5-chloro-N-[(4-((4-trifluoromethylpyridin-2-yloxy)phenyl)thio carbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 89%.

[0111] The product test data are as follows: m.p.: 199.7-200.4 °C; 1 H NMR (600 MHz, CDC13) δ 12.30 (s, 1H), 8.88 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 7.78-7.72 (m, 2H), 7.53 (d, J = 4.1 Hz, 1H), 7.23-7.19 (m, 4H), 7.03 (d, J = 4.1 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.80, 163.93, 160.04, 151.64, 148.92, 141.88 (q, J = 33.2 Hz), 140.18, 134.54, 134.33, 130.09, 127.93, 125.47, 122.46 (q, J = 273.3 Hz), 121.86, 114.28 (q, J = 4.5 Hz), 108.19 (q, J = 4.5 Hz), 107.87; HRMS calcd for [M+H+] C FC = 273.3 Hz), 121.86, 114.28 (q, J = 4.5 Hz), 108.19 (q, J = 4.5 Hz), 107.87; HRMS calcd for [M+H+] C FC = 273.3 Hz), 121.86, 114.28 (q, J = 4.5 Hz), 108.19 (q, J = 4.5 Hz), 107.87; HRMS calcd for [M+H+] C FC = 273.3 Hz), 121.86, 114.28 (q, J = 4.5 Hz), 108.19 (q, J = 4.5 Hz), 107.87; HRMS calcd for [M+H+] C FC= 4.5 Hz); HRMS calcd for [M + H+] C 18 H 11 ClF3N3O2S2, 458.0012, found 458.0007.

[0112] The structure of the product was characterized as:

[0113] Example 17 Preparation of 5-chloro-N-[(4-((5-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (1-17)

[0114] This example differs from Example 14 in that the thiophenecarbonyl chloride is replaced with 5-chloro-2-carbonyl chloride thiophene in Step 2. The other steps and parameters are the same as Example 14. 5-chloro-N-[(4-((5-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 96%.

[0115] Product testing data are as follows: m.p.: 195.0-195.8 °C; 1 H NMR (600 MHz, CDC13) δ 12.30 (s, 1H), 8.85 (s, 1H), 8.44 (s, 1H), 7.92 (dd, J = 8.6, 2.7 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 4.1 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.08-7.00 (m, 2H); 13 C NMR (151 MHz, CDC13) δ 177.79, 165.55, 160.03, 151.46, 145.46 (q, J FC = 4.5 Hz), 140.20, 136.82 (q, J FC = 3.0 Hz), 134.67, 134.30, 130.09, 127.94, 125.48, 123.66 (q, J FC = 271.8 Hz), 121.96, 121.85 (q, J FC = 34.2 Hz), 111.51; HRMS calcd for [M + H+] C 18 H 11 ClF3N3O2S2, 458.0012, found 458.0008.

[0116] The structure of the product was characterized as:

[0117] Example 18 Preparation of N-[(3-(pyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (II-1)

[0118] This example differs from Example 1 in that 4-aminophenol is replaced by 3- aminophenol in Step 1 to give intermediate e. Other steps and parameters are the same as Example 1. N-[(3-(pyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. White solid, yield 91%.

[0119] Product testing data are as follows: m.p.: 140.2-141.0 °C; 1 H NMR (600 MHz, CDC13) δ 12.37 (s, 1H), 9.17 (s, 1H), 8.21 (dd, J = 5.2, 2.0 Hz, 1H), 7.73-7.68 (m, 1H), 7.67-7.60 (m, 2H), 7.52 (dd, J = 8.1, 2.0 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.38 (d, J = 3.6 Hz, 1H), 7.06 (dd, J = 8.1, 2.3 Hz, 1H), 7.02 (dd, J = 7.2, 5.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.63 (dd, J = 3.6, 1.7 Hz, 1H); 13 CNMR (151 MHz, CDC13) δ 177.73, 163.28, 156.68, 154.36, 147.69, 146.50, 144.87, 139.64, 138.76, 129.81, 120.01, 119.45, 119.06, 118.81, 116.78, 113.45, 111.78; HRMS calcd for [M + H+] C 17 H 13 N3O3S, 340.0756, found 340.0751.

[0120] The structure of the product obtained is characterized as:

[0121] Example 19 Preparation of N-[(3-(3-chloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan- 2-carboxamide (II-2)

[0122] This example differs from Example 3 in that 4-aminophenol is replaced by 3- aminophenol in Step 1 to give intermediate e. Other steps and parameters are the same as Example 3. N-[(3-(3-chloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide is obtained. White solid, yield 80%.

[0123] Product data as follows: m.p.: 146.1-146.9 °C; 1 H NMR (600 MHz, CDC13) δ 12.40 (s, 1H), 9.17 (s, 1H), 8.05 (dd, J = 4.8, 2.3 Hz, 1H), 7.81-7.74 (m, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.57 (dd, J = 8.1, 2.1 Hz, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H), 7.09 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (ddd, J = 7.4, 4.9, 2.3 Hz, 1H), 6.63 (t, J = 2.3 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.64, 158.70, 156.69, 153.78, 146.50, 145.19, 144.87, 139.42, 138.71, 129.68, 120.35, 119.68, 119.56, 119.30, 119.06, 116.93, 113.46; HRMS calcd for [M + H+] C 17 H 12 ClN3O3S, 374.0366, found 374.0362.

[0124] The structure of the resulting product was characterized as:

[0125] Example 20 Preparation of N-[(3-(5-chloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (II-3)

[0126] This example differs from Example 4 in that 4-aminophenol is replaced by 3- aminophenol in Step 1 to give intermediate e. Other steps and parameters are the same as Example 4. N-[(3-(5-chloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. White solid, yield 98%.

[0127] Product data as follows: m.p.: 159.4-159.5 °C; 1H NMR (600 MHz, CDC13) δ 12.39 (s, 1H), 9.17 (s, 1H), 8.14 (t, J = 2.3 Hz, 1H), 7.71-7.64 (m, 2H), 7.62 (dd, J = 1.9, 0.9 Hz, 1H), 7.50 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.40-7.36 (m, 1H), 7.05 (ddd, J = 8.1, 2.4, 1.1 Hz, 1H), 6.92 (dd, J = 8.7, 1.8 Hz, 1H), 6.64 (dt, J = 3.4, 1.7 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.77, 161.70, 156.71, 154.07, 146.53, 146.12, 144.89, 139.40, 138.85, 129.87, 126.19, 120.25, 119.34, 119.09, 116.71, 113.47, 112.69; HRMS calcd for [M + H+] C 17 H 12 ClN3O3S, 374.0366, found 374.0361.

[0128] The structure of the resulting product was characterized as:

[0129] Example 21 Preparation of N-[(3-(3,5-dichloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (II-4)

[0130] This example differs from Example 5 in that 4-aminophenol is replaced by 3- aminophenol in Step 1 to give intermediate e. The other steps and parameters are the same as in Example 5. N-[(3-(3,5-dichloropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide is obtained. White solid, yield 97%.

[0131] The product testing data are as follows: m.p.: 138.2-138.9 °C; 1H NMR (600 MHz, CDC13) δ 12.43 (s, 1H), 9.18 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.72 (t, J = 2.2 Hz, 1H), 7.63 (s, 1H), 7.55 (dd, J = 8.1, 2.1 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 3.4 Hz, 1H), 7.07 (dd, J = 8.2, 2.3 Hz, 1H), 6.64 (dd, J = 3.5, 1.8 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.66, 157.29, 156.71, 153.44, 146.54, 144.84, 143.55, 142.23, 138.92, 138.77, 129.75, 125.92, 120.57, 119.67, 119.55, 119.12, 117.22, 116.85, 113.48; HRMS calcd for [M + H+] C 17 H 11 Cl2N3O3S, 407.9976, found 407.9973.

[0132] The structure of the product obtained was characterized as:

[0133] Example 22 Preparation of N-[(3-(3-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (II-5)

[0134] This example differs from Example 6 in that 4-aminophenol is replaced by 3- aminophenol in Step 1 to give intermediate e. Other steps and parameters are the same as in Example 6. N-[(3-(3-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Yellow solid, yield 93%.

[0135] Product testing data are as follows: m.p.: 171.2-171.5 °C; 1 H NMR (600 MHz, CDC13) δ 12.43 (s, 1H), 9.18 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.72 (t, J = 2.2 Hz, 1H), 7.63 (s, 1H), 7.55 (dd, J = 8.1, 2.1 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 3.4 Hz, 1H), 7.07 (dd, J = 8.2, 2.3 Hz, 1H), 6.64 (dd, J = 3.5, 1.8 Hz, 1H);13 C NMR (151 MHz, CDC13) δ 177.66, 156.73, 155.53, 152.71, 151.77, 146.56, 144.86, 138.86, 135.53, 134.60, 129.79, 120.95, 119.92, 119.13, 118.61, 117.25, 113.48; HRMS calcd for [M+H+] C 17 H 12 N4O5S, 385.0607 found 385.0605.

[0136] The structure of the product was characterized as:

[0137] Example 23 Preparation of N-[(3-(4-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (II-6)

[0138] This example differs from Example 7 in that 4-aminophenol is replaced by 3- aminophenol in Step 1 to give intermediate e. Other steps and parameters are the same as Example 7. N-[(3-(4-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2-carboxamide is obtained. Pink solid, yield 96%.

[0139] Product test data are as follows: m.p.: 142.8-143.2 °C; 1 H NMR (600 MHz, CDC13) δ 12.45 (s, 1H), 9.20 (s, 1H), 8.25 (d, J = 5.8 Hz, 1H), 7.75 (t, J = 2.1 Hz, 1H), 7.63 (dd, J = 1.8, 0.8 Hz, 1H), 7.50-7.43 (m, 2H), 7.40 (dd, J = 3.6, 0.8 Hz, 1H), 7.01 (dt, J = 7.0, 2.2 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.85 (dd, J = 5.8, 2.2 Hz, 1H), 6.65 (dd, J = 3.6, 1.7 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 178.05, 165.99, 156.79, 153.61, 152.82, 150.78, 146.66, 144.77, 139.43, 130.56, 121.06, 119.29, 118.80, 116.54, 113.54, 112.25, 111.53; HRMS calcd for [M+H+] C 17 H 12N4O5S,385.0607,found 385.0616.

[0140] After characterization, the structure of the obtained product is:

[0141] Example 24 Preparation of N-[(3-(3-trifluoromethylpyridin-2-oxy)phenyl)thiocarbamoyl]furan-2-carboxamide (II-7)

[0142] This example differs from Example 9 in that 4-aminophenol is replaced with 3-aminophenol in Step 1 to obtain Intermediate e. All other steps and parameters are the same as in Example 9. This yields N-[(3-(3-trifluoromethylpyridin-2-oxy)phenyl)carbamothioyl]furan-2-carboxamide (II-7) as a white solid in 77% yield.

[0143] The product test data are as follows: mp: 160.9-161.8°C; 1 H NMR (600MHz, CDCl3) δ12.42(s,1H),9.19(s,1H),8.31(dd,J=4.9,1.9Hz,1H),8.00(dd,J=7.7,1.9Hz,1H),7.68(t,J=2.1Hz ,1H),7.65-7.58(m,2H),7.45(t,J=8.1Hz,1H),7.39(dd,J=3.6,0.8Hz,1H),7.15-7.06(m,2H),6.64(dd,J=3.6,1.7Hz,1H); 13 C NMR (151MHz, CDCl3) δ177.69,160.02,156.71,153.23,150.89,146.53,144.83,138.72,137.12(q,J FC =4.5Hz),129.71,122.69(q,J FC =271.8Hz),120.70,119.96,119.11,118.05,117.27,114.44(q,J FC =33.2Hz),113.47; HRMScalcd for[M+H+]C 18 H 12 F3N3O3S,408.0630,found408.0634.

[0144] After characterization, the structure of the obtained product is:

[0145] Example 25 Preparation of N-[(3-(4-trifluoromethylpyridin-2-oxy)phenyl)thiocarbamoyl]furan-2-carboxamide (II-8)

[0146] This example differs from Example 10 in that 4-aminophenol is replaced with 3-aminophenol in Step 1 to obtain Intermediate e. All other steps and parameters are the same as in Example 10. This yields N-[(3-(4-trifluoromethylpyridin-2-oxy)phenyl)carbamothioyl]furan-2-carboxamide (II-8) as a yellow solid in 98% yield.

[0147] The product test data are as follows: mp: 152.7-153.2°C; 1 H NMR (600MHz, CDCl3) δ12.42(s,1H),9.18(s,1H),8.34(d,J=5.2Hz,1H),7.74(t,J=2.2Hz,1H),7.62(dd,J=1.8,0.8Hz,1H),7.53(ddd,J=8.1,2.2, 1.0Hz,1H),7.45(t,J=8.1Hz,1H),7.39(dd,J=3.6,0.8Hz,1H),7.24-7.19(m,2H),7.08(ddd,J=8.1,2.3,1.0Hz,1H),6.64(dd,J=3.6,1.7Hz,1H); 13 C NMR (151MHz, CDCl3) δ177.77,163.81,156.72,153.44,148.97,146.55,144.84,141.86(q,J FC =34.7Hz),138.90,129.93,122.46(q,J FC =273.3Hz),120.61,119.62,119.13,117.02,114.31(q,J FC =3.0Hz),113.49,108.19(q,J FC =4.5Hz); HRMS calcd for[M+H+]C 18 H 12 F3N3O3S,408.0630,found408.0626.

[0148] After characterization, the structure of the obtained product is:

[0149] Example 26 Preparation of N-[(3-(5-trifluoromethylpyridin-2-oxy)phenyl)thiocarbamoyl]furan-2-carboxamide (II-9)

[0150] This example differs from example 11 in that 4-aminophenol is replaced by 3- aminophenol in step 1 to give intermediate e. Other steps and parameters are the same as example 11. N-[(3-(5-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide is obtained. White solid, yield 97%.

[0151] Product testing data are as follows: m.p.: 111.4-112.3 °C; 1 H NMR (600 MHz, CDC13) δ 12.43 (s, 1H), 9.18 (s, 1H), 8.46 (s, 1H), 7.92 (dd, J = 8.7, 2.8 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.39 (t, J = 2.6 Hz, 1H), 7.07 (dd, J = 15.0, 8.4 Hz, 2H), 6.67-6.61 (m, 1H); 13 C NMR (151 MHz, CDC13) δ 177.81, 165.47, 156.74, 153.30, 146.56, 145.52 (q, J FC = 4.5 Hz), 144.86, 138.94, 136.84 (q, J FC = 3.0 Hz), 129.95, 123.68 (q, J FC = 271.8 Hz), 121.85 (q, J FC = 33.2 Hz), 120.75, 119.74, 119.15, 117.16, 113.49, 111.49; HRMS calcd for [M+H+] C 18 H 12 F3N3O3S, 408.0630, found 408.0623.

[0152] The structure of the product obtained is characterized as:

[0153] Example 27 N-[(3-(6-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide (II-10)

[0154] This example differs from example 12 in that 4-aminophenol is replaced by 3- aminophenol in step 1 to give intermediate e. Other steps and parameters are the same as example 12. N-[(3-(6-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]furan-2- carboxamide is obtained. White solid, yield 76%.

[0155] Product testing data as follows: m.p.: 104.0-104.9 °C; 1 H NMR (600 MHz, CDC13) δ 12.41 (s, 1H), 9.19 (s, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.74 (t, J = 2.2 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.0, 2.1 Hz, 1H), 7.47-7.37 (m, 3H), 7.16-7.05 (m, 2H), 6.64 (dt, J = 3.0, 1.5 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.84, 163.09, 156.74, 153.55, 146.56, 146.39 (q, J FC = 34.7 Hz), 144.84, 140.75, 138.87, 129.88, 121.00 (q, J FC = 273.3 Hz), 120.39, 119.31, 119.16, 116.66, 115.31 (q, J FC = 3.0 Hz), 114.56, 113.49; HRMS calcd for [M+H+] C 18 H 12 F3N3O3S, 408.0630, found 408.0628.

[0156] The structure of the resulting product was characterized as:

[0157] Example 28 Preparation of N-[(3-(pyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2- carboxamide (II-11)

[0158] This example differs from Example 18 in that furancarbonyl chloride is replaced by thiophene carbonyl chloride in Step 2 to obtain intermediate e. Other steps and parameters are the same as Example 18. N-[(3-(pyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. Yellow solid, yield 97%.

[0159] Product testing data as follows: m.p.: 170.9-171.5 °C; 1H NMR (600 MHz, CDC13) δ 12.45 (s, 1H), 8.92 (s, 1H), 8.22 (ddd, J = 5.0, 2.1, 0.8 Hz, 1H), 7.74-7.67 (m, 3H), 7.64 (t, J = 2.2 Hz, 1H), 7.52 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.18 (dd, J = 4.9, 3.9 Hz, 1H), 7.07 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.02 (ddd, J = 7.2, 5.0, 1.0 Hz, 1H), 6.95 (dt, J = 8.3, 0.9 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.77, 163.28, 161.07, 154.40, 147.71, 139.64, 138.74, 135.87, 134.37, 130.79, 129.81, 128.55, 119.97, 119.47, 118.83, 116.76, 111.80; HRMS calcd for [M + H+] C 17 H 13 N3O2S2, 356.0527, found 356.0526.

[0160] The structure of the resulting product was characterized as:

[0161] Example 29 Preparation of N-[(3-(5-chloropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (II-12)

[0162] This example differs from Example 20 in that furancarbonyl chloride is replaced by thiophene carbonyl chloride in Step 2 to obtain intermediate e. Other steps and parameters are the same as in Example 20. N-[(3-(5-chloropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 99%.

[0163] Product test data are as follows: m.p.: 199.2-199.8 °C; 1H NMR (600 MHz, DMSO) δ 12.51 (s, 1H), 11.65 (s, 1H), 8.39 (d, J = 3.9 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.06 (dd, J = 4.0, 2.3 Hz, 1H), 7.99 (dp, J = 8.2, 2.2 Hz, 1H), 7.68 (s, 1H), 7.54 - 7.43 (m, 2H), 7.29 - 7.23 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H); 13 C NMR (151 MHz, DMSO) δ 179.08, 162.45, 161.93, 153.99, 146.13, 140.51, 139.69, 137.10, 135.90, 133.25, 130.19, 129.24, 125.95, 121.00, 119.35, 117.16, 113.65; HRMS calcd for [M+H+] C 17 H 12 ClN3O2S2, 390.0138, found 390.0133.

[0164] The structure of the product was characterized as:

[0165] Example 30 Preparation of N-[(3-(3,5-dichloropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (II-13)

[0166] This example differs from Example 21 in that furanoyl chloride is replaced by thiopheneoyl chloride in Step 2 to give intermediate e. Other steps and parameters are the same as in Example 21. N-[(3-(3,5-dichloropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 96%.

[0167] Product testing data are as follows: m.p.: 139.05-140.01 °C; 1 H NMR (600 MHz, CDCl3) δ 12.51 (s, 1H), 8.90 (s, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.72 (dt, J = 8.0, 3.6 Hz, 3H), 7.55 (d, J = 8.2 Hz, 1H), 7.44 (td, J = 8.1, 1.9 Hz, 1H), 7.19 (q, J = 3.2 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H); 13C NMR (151 MHz, CDC13) δ 177.68, 161.09, 157.27, 153.45, 143.55, 138.93, 138.72, 135.79, 134.46, 130.80, 129.76, 128.58, 125.93, 120.55, 119.68, 119.57, 116.84; HRMS calcd for [M+H+] C 17 H 11 Cl2N3O2S2, 423.9748, found 423.9750.

[0168] The structure of the product was characterized as:

[0169] Example 31 Preparation of N-[(3-(3-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2- carboxamide (II-14)

[0170] This example differs from Example 22 in that furancarbonyl chloride is replaced by thiophene carbonyl chloride in Step 2 to give intermediate e. Other steps and parameters are the same as in Example 22. N-[(3-(3-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. Yellow solid, yield 80%.

[0171] Product test data are as follows: m.p.: 169.9-170.9 °C; 1 H NMR (600 MHz, CDC13) δ 12.45 (s, 1H), 9.17 (s, 1H), 8.46-8.26 (m, 2H), 7.78 (t, J = 2.1 Hz, 1H), 7.65-7.57 (m, 2H), 7.47 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.18 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (dd, J = 8.2, 2.3 Hz, 1H), 6.64 (dd, J = 3.6, 1.7 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.66, 156.73, 155.53, 152.71, 151.77, 146.56, 144.86, 138.86, 135.53, 134.60, 129.79, 120.95, 119.92, 119.13, 118.61, 117.25, 113.48; HRMS calcd for [M+H+] C 17 H 12 N4O5S, 385.0607 found 385.0605.

[0172] The structure of the product was characterized as:

[0173] Example 32 Preparation of N-[(3-(4-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (II-15)

[0174] This example differs from Example 23 in that furanoyl chloride is replaced by thiopheneoyl chloride in Step 2 to give intermediate e. Other steps and parameters are the same as Example 23. N-[(3-(4-nitropyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 96%.

[0175] The product was detected as follows: m.p.: 142.8-143.4 °C; 1 H NMR (600 MHz, CDC13) δ 12.54 (s, 1H), 8.95 (s, 1H), 8.26 (d, J = 5.7 Hz, 1H), 7.80-7.71 (m, 3H), 7.50-7.45 (m, 2H), 7.20 (dd, J = 4.9, 3.9 Hz, 1H), 7.01 (dt, J = 6.2, 2.5 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 5.8, 2.2 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 178.11, 166.01, 161.21, 153.60, 152.78, 150.74, 139.40, 135.68, 134.63, 130.96, 130.60, 128.64, 121.07, 118.84, 116.54, 112.27, 111.55; HRMS calcd for [M+H+] C 17 H 12 N4O4S2, 401.0378, found 401.0372.

[0176] The structure of the product was characterized as:

[0177] Example 33 Preparation of N-[(3-(3-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (II-16)

[0178] This example differs from Example 24 in that furanoyl chloride is replaced by thiopheneoyl chloride in Step 2 to give intermediate e. Other steps and parameters are the same as Example 24. N-[(3-(3-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. Yellow solid, yield 75%.

[0179] Product testing data as follows: m.p.: 148.8-150.6 °C; 1 H NMR (600 MHz, CDC13) δ 12.51 (s, 1H), 8.93 (s, 1H), 8.31 (dd, J = 4.9, 2.0 Hz, 1H), 8.00 (dd, J = 7.6, 2.1 Hz, 1H), 7.73 (t, J = 4.6 Hz, 2H), 7.68 (t, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.1, 2.2 Hz, 1H), 7.46 (dd, J = 8.9, 7.5 Hz, 1H), 7.19 (t, J = 4.3 Hz, 1H), 7.14-7.07 (m, 2H); 13 C NMR (151 MHz, CDC13) δ 177.72, 161.11, 160.02, 153.24, 150.89, 138.68, 137.12 (q, J FC = 4.5 Hz), 135.81, 134.46, 130.80, 129.73, 128.58, 122.69 (q, J FC = 271.8 Hz), 120.67, 119.99, 118.06, 117.27, 114.45 (q, J FC = 33.2 Hz); HRMS calcd for [M + H+] C 18 H 12 F3N3O2S2, 424.0401, found 424.0407.

[0180] The structure of the resulting product was characterized as:

[0181] Example 34 Preparation of N-[(3-(4-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (II-17)

[0182] This example differs from Example 25 in that furanoyl chloride is replaced by thiophene carboxyl chloride in Step 2 to obtain intermediate e. Other steps and parameters are the same as in Example 25. N-[(3-(4-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. Yellow solid, yield 76%.

[0183] Product testing data as follows: m.p.: 131.0-131.5 °C; 1H NMR (600 MHz, CDC13) δ 12.50 (s, 1H), 8.90 (s, 1H), 8.35 (dt, J = 5.3, 0.7 Hz, 1H), 7.79-7.68 (m, 3H), 7.54 (ddd, J = 8.2, 2.1, 0.9 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.24-7.18 (m, 3H), 7.08 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H); 13 CNMR (151 MHz, CDC13) δ 177.80, 163.82, 161.10, 153.48, 148.99, 141.88 (q, J FC = 34.7 Hz), 138.87, 135.82, 134.45, 130.82, 129.94, 128.58, 122.47 (q, J FC = 273.3 Hz), 120.58, 119.64, 117.00, 114.33 (q, J FC = 3.0 Hz), 108.20 (q, J FC = 4.5 Hz); HRMS calcd for [M+H+] C 18 H 12 F3N3O2S2, 424.0401, found 424.0404.

[0184] The structure of the resulting product was characterized as:

[0185] Example 35 Preparation of N-[(3-(5-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide (II-18)

[0186] This example differs from Example 26 in that furanoyl chloride is replaced by thiopheneoyl chloride in Step 2 to give intermediate e. The other steps and parameters are the same as in Example 26. N-[(3-(5-trifluoromethylpyridin-2-yloxy)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 98%.

[0187] Product testing data are as follows: m.p.: 136.2-137.2 °C; 1H NMR (600 MHz, CDC13) δ 12.51 (s, 1H), 8.91 (s, 1H), 8.46 (d, J = 2.6 Hz, 1H), 7.92 (dd, J = 8.7, 2.4 Hz, 1H), 7.78 - 7.69 (m, 3H), 7.54 (dd, J = 7.8, 2.1 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.11 - 7.01 (m, 2H); 13 CNMR (151 MHz, CDC13) δ 177.83, 165.45, 161.12, 153.30, 145.52 (q, J FC = 4.5 Hz), 138.90, 136.84 (q, J FC = 3.0 Hz), 135.80, 134.48, 130.84, 129.96, 128.59, 124.67 (q, J FC = 271.8 Hz), 121.86 (q, J FC = 33.2 Hz), 120.72, 119.76, 117.15, 111.50; HRMS calcd for [M+H+] C 18 H 12 F3N3O2S2, 424.0401, found 424.0398.

[0188] The structure of the resulting product was characterized as:

[0189] Example 36 Preparation of N-[(3-(6-trifluoromethylpyridine-2-oxo)phenyl)thiocarbamoyl]thiophene-2-carboxamide (II-19)

[0190] This example differs from Example 27 in that furanoyl chloride is replaced by thiophene carboxyl chloride in Step 2 to obtain intermediate e. Other steps and parameters are the same as Example 27. N-[(3-(6-trifluoromethylpyridine-2-oxo)phenyl)thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 82%.

[0191] Product testing data are as follows: m.p.: 101.2-101.3 °C; 1H NMR (600 MHz, CDC13) δ 12.51 (s, 1H), 8.99 (s, 1H), 7.86 (dt, J = 11.5, 5.3 Hz, 1H), 7.74 (q, J = 4.5 Hz, 3H), 7.49 (d, J = 8.1 Hz, 1H), 7.43 (ddd, J = 18.5, 7.7, 3.5 Hz, 2H), 7.19 (p, J = 4.1 Hz, 1H), 7.15 - 7.07 (m, 2H); 13 C NMR (151 MHz, CDC13) δ 177.92, 163.09, 161.17, 153.57, 146.39 (q, J FC = 34.7 Hz), 140.76, 138.84, 135.82, 134.48, 130.88, 129.90, 128.59, 121.00 (q, J FC = 274.8 Hz), 120.38, 119.34, 116.66, 115.32 (d, J FC = 3.0 Hz), 114.58; HRMS calcd for [M + H+] C 18 H 12 F3N3O2S2, 424.0401, found 424.0407.

[0192] The structure of the resulting product was characterized as:

[0193] Example 37 Preparation of 5-chloro-N-[(3-pyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2-carboxamide (II-20)

[0194] This example differs from Example 28 in that in Step 2 the thiophenecarbonyl chloride is replaced with 5-chloro-2-carbonyl chloride thiophene to give intermediate e. The other steps and parameters are the same as in Example 28. 5-chloro-N-[(3-pyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2-carboxamide is obtained. Yellow solid, yield 82%.

[0195] Product test data are as follows: m.p.: 138.9-139.4 °C; 1H NMR (600 MHz, CDC13) δ 12.32 (s, 1H), 8.82 (s, 1H), 8.28-8.16 (m, 1H), 7.75-7.68 (m, 1H), 7.62 (t, J = 2.1 Hz, 1H), 7.50 (d, J = 4.6 Hz, 2H), 7.42 (t, J = 8.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.2 Hz, 1H), 7.05-6.98 (m, 2H), 6.95 (d, J = 8.3 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.50, 163.26, 159.95, 154.42, 147.72, 140.11, 139.64, 138.63, 134.32, 130.07, 129.83, 127.91, 119.96, 119.55, 118.85, 116.76, 111.83; HRMS calcd for [M + H+] C 17 H 12 ClN3O2S2, 390.0138, found 390.0136.

[0196] The structure of the resulting product was characterized as:

[0197] Example 38 Preparation of 5-chloro-N-[(3,5-dichloropyridin-2-yloxy)phenylthio- carbamoyl]thiophene-2-carboxamide (II-21)

[0198] This example differs from Example 30 in that in Step 2 the thiophenecarbonyl chloride is replaced with 5-chloro-2-carbonyl chloride thiophene to give intermediate e. The other steps and parameters are the same as in Example 30. 5-chloro-N-[(3,5-dichloropyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2- carboxamide is obtained. White solid, yield 98%.

[0199] Product test data are as follows: m.p.: 173.2-173.7 °C; 1 H NMR (600 MHz, CDC13) δ 12.32 (s, 1H), 8.82 (s, 1H), 8.28-8.16 (m, 1H), 7.75-7.68 (m, 1H), 7.62 (t, J = 2.1 Hz, 1H), 7.50 (d, J = 4.6 Hz, 2H), 7.42 (t, J = 8.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.2 Hz, 1H), 7.05-6.98 (m, 2H), 6.95 (d, J = 8.3 Hz, 1H); 13C NMR (151 MHz, DMSO) δ 178.27, 160.63, 156.77, 152.93, 143.69, 139.26, 139.07, 137.15, 135.65, 132.84, 129.60, 128.90, 125.37, 120.85, 118.95, 118.68, 116.67; HRMS calcd for [M+H+] C 17 H 10 Cl3N3O2S2, 457.9358, found 459.9357.

[0200] The structure of the product was characterized as:

[0201] Example 39 Preparation of 5-chloro-N-[(3-nitropyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2-carboxamide (II-22)

[0202] This example differs from Example 31 in that the thiophenecarbonyl chloride is replaced with 5-chloro-2-carbonyl chloride thiophene in Step 2 to give intermediate e. The other steps and parameters are the same as in Example 31. 5-chloro-N-[(3-nitropyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2-carboxamide is obtained. Yellow solid, yield 93%.

[0203] The product test data are as follows: m.p.: 195.2-195.6 °C; 1 H NMR (600 MHz, DMSO) δ 12.36 (s, 1H), 11.75 (s, 1H), 8.60 (dd, J = 8.0, 1.8 Hz, 1H), 8.45 (dd, J = 4.8, 1.8 Hz, 1H), 8.29 (d, J = 4.2 Hz, 1H), 7.73 (t, J = 2.2 Hz, 1H), 7.60-7.53 (m, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.41 (dd, J = 8.0, 4.8 Hz, 1H), 7.32 (d, J = 4.2 Hz, 1H), 7.15 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H); 13 C NMR (151 MHz, CDCl3) δ 177.43, 159.99, 155.50, 152.69, 151.77, 140.24, 138.69, 135.57, 134.57, 134.22, 130.11, 129.84, 127.94, 120.96, 120.05, 118.64, 117.28; HRMS calcd for [M+H+] C 17 H 11CIN4O4S2, 434.9988, found 434.9991.

[0204] The structure of the product was characterized as:

[0205] Example 40 Preparation of 5-chloro-N-[(4-nitropyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2-carboxamide (II-23)

[0206] This example differs from Example 32 in that the thiophenecarbonyl chloride is replaced with 5-chloro-2-carbonyl chloride thiophene in Step 2 to give intermediate e. The other steps and parameters are the same as in Example 32. 5-chloro-N-[(4-nitropyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 97%.

[0207] Product testing data are as follows: m.p.: 174.9-175.3 °C; 1 H NMR (600 MHz, CDC13) δ 12.40 (s, 1H), 8.84 (s, 1H), 8.26 (d, J = 5.8 Hz, 1H), 7.73 (q, J = 1.6 Hz, 1H), 7.52 (d, J = 4.2 Hz, 1H), 7.50-7.44 (m, 2H), 7.05-6.99 (m, 2H), 6.92 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 5.8, 2.2 Hz, 1H); 13 CNMR (151 MHz, CDC13) δ 177.83, 166.01, 160.05, 153.62, 152.77, 150.73, 140.44, 139.29, 134.09, 130.63, 130.19, 127.98, 121.07, 118.93, 116.54, 112.27, 111.56; HRMS calcd for [M + H+] C 17 H 11 CIN4O4S2, 434.9988, found 434.9991.

[0208] The structure of the product was characterized as:

[0209] Example 41 Preparation of 5-chloro-N-[(4-trifluoromethylpyridin-2-yloxy)phenylthiocarbamoyl]thiophene-2-carboxamide (II-24)

[0210] This example differs from example 34 in that in step 2 thiophene carboxylic acid chloride is replaced by 5-chloro-2-carboxylic acid chloride thiophene to give intermediate e. Other steps and parameters are the same as in example 34. 5-Chloro-N-[(4-trifluoromethylpyridin-2-yloxy)phenyl thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 98%.

[0211] Product testing data are as follows: m.p.: 137.4-138.4 °C; 1 H NMR (600 MHz, CDC13) δ 12.38 (s, 1H), 8.88 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.70 (t, J = 2.2 Hz, 1H), 7.51 (dd, J = 7.1, 2.5 Hz, 2H), 7.45 (t, J = 8.1 Hz, 1H), 7.23-7.18 (m, 2H), 7.08 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.01 (d, J = 4.1 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.57, 163.77, 160.02, 153.43, 148.97, 141.86 (q, J FC = 34.7 Hz), 140.24, 138.71, 134.23, 130.12, 129.97, 127.94, 122.44 (q, J FC = 273.3 Hz), 120.62, 119.76, 117.05, 114.34 (q, J FC = 3.0 Hz), 108.2 (q, J FC = 4.5 Hz); HRMS calcd for [M+H+] C 18 H 11 ClF3N3O2S2, 458.0012, found 458.0016.

[0212] The structure of the product obtained was characterized as:

[0213] Example 42 Preparation of 5-chloro-N-[(5-trifluoromethylpyridin-2-yloxy)phenyl thiocarbamoyl]thiophene-2-carboxamide (II-25)

[0214] This example differs from example 35 in that in step 2 thiophene carboxylic acid chloride is replaced by 5-chloro-2-carboxylic acid chloride thiophene to give intermediate e. Other steps and parameters are the same as in example 35. 5-Chloro-N-[(5-trifluoromethylpyridin-2-yloxy)phenyl thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 97%. This example differs from example 35 in that in step 2 thiophene carboxylic acid chloride is replaced by 5-chloro-2-carboxylic acid chloride thiophene to give intermediate e. Other steps and parameters are the same as in example 35. 5-Chloro-N-[(5-trifluoromethylpyridin-2-yloxy)phenyl thiocarbamoyl]thiophene-2-carboxamide is obtained. White solid, yield 97%.

[0215] Product testing data as follows: m.p.: 176.6-177.3 °C; 1 H NMR (600 MHz, CDC13) δ 12.37 (s, 1H), 8.81 (s, 1H), 8.46 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.56-7.43 (m, 3H), 7.07 (dd, J = 18.4, 8.4 Hz, 2H), 7.02 (t, J = 3.2 Hz, 1H); 13 C NMR (151 MHz, CDC13) δ 177.55, 165.43, 159.98, 153.32, 145.52 (q, J FC = 4.5 Hz), 140.27, 138.78, 136.85 (q, J FC = 3.0 Hz), 134.23, 130.09, 129.98, 127.94, 123.66 (q, J FC = 271.8 Hz), 121.89 (q, J FC = 33.2 Hz), 120.71, 119.86, 117.16, 111.52; HRMS calcd for [M+H+] C 18 H 11 ClF3N3O2S2, 458.0012, found 458.0009.

[0216] The structure of the obtained product was characterized as:

[0217] Application Example 1 Determination of the herbicidal activity of the compounds of Examples 1-42

[0218] In order to explore the effect of the compounds on the prevention and control of weeds, common weeds such as barnyard grass, crabgrass, dogtail grass, morningglory, goosegrass and epilobium were selected for testing.

[0219] The planting method of the weeds: fill about 6 cm deep flower soil into a small flower pot (r = 4 cm, h = 8 cm), completely soak with water, put the weed seeds used for testing on the top, cover about 2 cm flower soil on the top, and spray the surface with a watering can, then place it in an artificial incubator and wait for it to grow. Temperature 25-30 °C, humidity 60-70%, light and darkness each for 12 h cycle.

[0220] Preparation of the target compound emulsion: 10 mg of the target compound of Example 1-42 was weighed, dissolved in 1 mL of N,N-dimethylformamide, 1 drop of Tween-80 (T-80) was added as an emulsifier, and distilled water was added to a 10 mL volumetric flask to give an emulsion with a target compound concentration of 1 g / L. Commercial PPO herbicide oxyfluorfen was selected as a control, and an aqueous solution containing only T-80 and DMF without the target compound was used as a blank control.

[0221] When the monocotyledonous weeds grew to the single leaf stage and the dicotyledonous weeds grew to the two leaf stage, the weeds were sprayed with a concentration of 37.5 g ai / ha, 75 g ai / ha, and 150 g ai / ha, respectively, and commercial PPO herbicide oxyfluorfen was used as a control group. Most weed plants showed obvious symptoms of dehydration, leaf curling, burning, and yellowing 12 hours after spraying, and turned white and died 48 hours later.

[0222] As shown in Table 1, most of the target compounds had better inhibition ability on dicotyledonous weeds than on monocotyledonous weeds, and also had high inhibition ability on monocotyledonous weeds such as Setaria viridis. Most of the target compounds showed more than 80% inhibition activity on weeds at a dose of 150 g ai / ha, and even at a low dose of 37.5 g ai / ha, some compounds still had high weed inhibition ability. According to the analysis of the results in Table 1, the compounds containing CF3 on the pyridine ring had strong weed inhibition ability, especially when the CF3 group was located at the 4th and 6th positions of the pyridine. In addition, the herbicidal effect of the compound with a five-membered heterocyclic ring of furan was better than that of thiophene. In addition, when the five-membered heterocyclic ring contains an electron-withdrawing group (Cl), the electron cloud density of the five-membered ring is reduced, resulting in a decrease in herbicidal effect. Compounds I-10, I-12, II-8, and II-10 showed excellent weed inhibition ability, which was comparable to or slightly better than that of oxyfluorfen.

[0223] Example 2 Inhibition activity test of Examples 1-42 on PPO

[0224] Plant tissue sample processing method: The Echinochloa crus-galli leaf was rinsed in 5 mL of ice-cold PBS and wiped dry with filter paper. A 9-fold volume of homogenate medium was added to the homogenizer tube at a ratio of weight (g): volume (mL) = 1:9, the tissue block was cut under ice water bath conditions, and the tissue was thoroughly ground to prepare a 10% homogenate. The prepared 10% homogenate was centrifuged in a high-speed refrigerated centrifuge at 6000 rpm for 15 minutes, and the supernatant was used for determination.

[0225] Homogenate medium: Tris-HCl phosphate buffer (PBS), wherein the concentration of Tris-HCl is 0.05 mol / L, and the pH of the phosphate buffer is 7.4.

[0226] PPO enzyme concentration determination was performed using a Plant protox enzyme ELISA test kit. The results are shown in Table 1. By determining the inhibitory ability of the compounds on PPO enzyme, it was found that the target compound herbicidal activity results were almost consistent with the in vitro PPO inhibitory activity results.

[0227] Table 1 Greenhouse herbicidal activity effect of compounds

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234] Note: The grade scale of herbicidal activity (inhibition percentage): +++, ≥ 90%; ++++, 80-89%; ++, 60-79%; +, 50-59%; -, < 50%.

[0235] Example 3 Crop safety test

[0236] This example is used to illustrate the safety of the phenoxy pyridine compound containing acyl thiourea and heterocyclic structure of the present application to crops. Test target crops: wheat, corn, rice, soybean, cotton and peanut.

[0237] The planting method of the crops: first, the seeds of wheat, corn, rice, soybean and peanut need to be soaked in warm water for 12 h before planting, and then germinated at 25°C for 24 h. Then, 8 uniform and well-germinated crop seeds are selected, and about 6 cm deep flower soil is filled into a small flower pot (r = 4 cm, h = 8 cm), and then completely soaked with water, and then placed into the test seeds, covered with about 2 cm of flower soil on the top, and then sprayed with a spray bottle to keep the surface wet, and then placed in an artificial climate chamber for growth. Humidity 60-70%, light and darkness each for 12 h cycle culture.

[0238] Preparation of target compound emulsion: 10 mg of the target compounds of Example 12 and Example 25 were weighed, respectively dissolved in N,N-dimethylformamide, 1 drop of Tween-80 (T-80) was added as an emulsifying agent, and then distilled water was added to a 10 mL volumetric flask to obtain an emulsion with a concentration of 1 g / L of the target compound.

[0239] When the crops grow to 3-leaf stage, the pesticides are sprayed, the concentration of the pesticides is 150 g ai / ha and 300 g ai / ha respectively, and the commercial PPO herbicide oxyfluorofen is used as crop control. The growth of the crops is observed continuously after the pesticides are sprayed.

[0240] As shown in Table 2, the above compounds can be used as herbicides. When the application dose is 300 g ai / ha, cotton and wheat show high tolerance to compounds I-12 and II-8, and the crop safety is much higher than that of the commercial herbicide oxyfluorofen.

[0241] Table 2 Crop safety of compounds I-12, II-8 and oxyfluorofen

[0242]

[0243] The above description is merely preferred specific embodiments of the present application, which are based on different implementations of the overall concept of the present application. The scope of protection of the present application is not limited to the above specific embodiments, and any changes or substitutions easily conceived by those skilled in the art within the technical scope disclosed by the present application should be encompassed within the scope of protection of the present application. Therefore, the scope of protection of the present application should be determined by the scope of protection of the claims.

Claims

1. A phenoxypyridine compound containing an acylthiourea and a heterocyclic structure, characterized in that: The general structural formula of the compound is shown in the following formula (I) or formula (II): Wherein R1 is at least one selected from H, Cl, Br, NO2 or CF3; X is O or S; R2 is H or Cl.

2. The method for preparing the compound according to claim 1, characterized in that The method: Step 1: Dissolve 4-aminophenol or 3-aminophenol and an acid-binding agent in an organic solvent 1, then add compound a. After the reaction is completed, cool to room temperature, add distilled water, extract, wash, dry and concentrate to obtain intermediate d or intermediate e. The structural formula of compound a is: Step 2: Compound f and potassium thiocyanate are each dissolved in an organic solvent 2 to obtain respective organic solutions, and then the two organic solutions are mixed. After the reaction is completed, the mixture is cooled and filtered to obtain a solution containing intermediate h; the structural formula of compound f is: Step 3: adding intermediate d or intermediate e to a solution containing intermediate h to carry out a reaction. After the reaction is completed, a poor solvent is added to the reaction solution, the solution is allowed to stand, filtered, and the insoluble matter is collected. The solution is recrystallized to obtain a phenoxypyridine compound (I) or (II) containing an acylthiourea and a heterocyclic structure. In compound a and compound f, R1, X and R2 are as defined in claim 1.

3. The method according to claim 2, characterized in that In step 1, the organic solvent 1 is N,N-dimethylformamide or dimethyl sulfoxide, the acid-binding agent is cesium carbonate or potassium carbonate, the molar ratio of compound a to 4-aminophenol or 3-aminophenol and the acid-binding agent is 1:1:(1-3), and the reaction temperature is 80-100°C.

4. The method according to claim 2, characterized in that In step 2, the organic solvent 2 is acetone or acetonitrile, the molar ratio of compound f to potassium thiocyanate is less than 1, and the reaction temperature is 25-70°C.

5. The method according to claim 2, characterized in that In step 3, the molar ratio of intermediate d or intermediate e to intermediate h is less than 1, the reaction temperature is 20-40° C., the poor solvent is distilled water or a NaHCO 3 solution with a pH of 8-9, and the solvent used for recrystallization is acetonitrile-water.

6. Use of the compound according to claim 1 as a PPO inhibitor.

7. Use of the compound according to claim 1 in controlling weeds in crops.

8. The use according to claim 7, characterized in that The weeds are monocotyledonous weeds or dicotyledonous weeds, and the crops are wheat, rice, corn, cotton, soybean or peanut.

9. Use of the compound according to claim 1 as an active ingredient in the preparation of herbicidal agents.

10. The use according to claim 9, characterized in that The active ingredient in the agent is applied at a concentration of 37.5-300 g ai / ha.

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