N-substituted uracil benzamide compounds, and preparation method and application thereof

Abstract

This invention belongs to the field of agricultural herbicide technology, specifically disclosing N-substituted uracil benzamide compounds, their preparation methods, and applications. The general structural formula of the N-substituted uracil benzamide compounds of this invention is shown in Formula I. The preparation method of the compounds provided by this invention is simple, with a high yield, and exhibits good control effects against various broadleaf and gramineous weeds. Some compounds show good safety against crops such as corn and wheat. The compounds of this invention have good application prospects in the field of agricultural weed control. This invention also provides a preparation method for the compounds, their application in weed control, and a herbicide composition.

Description

Technical Field

[0001] This invention relates to the field of agricultural herbicides, and in particular to N-substituted uracil benzamide compounds, their preparation methods, and applications. Background Technology

[0002] Currently, chemical weeding remains an important and effective means of controlling weeds. However, the long-term use of traditional herbicides has led to increasingly prominent problems of weed resistance. At the same time, some varieties have defects such as high environmental residues and poor crop safety.

[0003] Therefore, there is an urgent need to develop novel herbicidal compounds that are highly efficient, low in toxicity, environmentally friendly, and do not exhibit cross-resistance with existing pesticides, in order to meet the needs of sustainable agricultural development. Summary of the Invention

[0004] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention provides a class of N-substituted uracil benzamide compounds, which have the characteristics of high herbicidal activity, low dosage, and good crop safety.

[0005] The present invention also provides a method for preparing the compound.

[0006] This invention also provides applications of the compound.

[0007] In a first aspect, the present invention provides N-substituted uracil benzamide compounds, the general structural formula of which is shown in Formula I:

[0008] Wherein, R is selected from:

[0009] (a) C1-C6 alkyl, C1-C4 alkyl substituted with C1-C4 alkoxy, or C1-C4 alkyl substituted with C1-C4 alkoxycarbonyl;

[0010] (b) C6-C10 aryl, wherein the C6-C10 aryl is directly bonded to the nitrogen atom in Formula I, and the C6-C10 aryl is optionally substituted by 1-2 substituents independently selected from halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0011] (c) C6-C10 aryl-C1-C6 alkyl, wherein the C1-C6 alkyl is straight-chain or branched, the C6-C10 aryl is connected to a nitrogen atom in Formula I through the C1-C6 alkyl, and the C6-C10 aryl is optionally substituted by 1-2 substituents independently selected from halogen, C1-C4 alkyl or C1-C4 alkoxy.

[0012] According to specific embodiments of the present invention, the preparation method of N-substituted uracil benzamide compounds provided by the present invention is simple, has a high yield, and shows good control effects on a variety of broadleaf weeds and grass weeds. Some compounds have good safety for crops such as corn and wheat; they have good application prospects in the field of agricultural weed control.

[0013] According to some embodiments of the present invention, R is a C3-C5 alkyl, a C1-C3 alkyl substituted with C1-C3 alkoxy, a C1-C3 alkyl substituted with C1-C3 alkoxycarbonyl, a phenyl, a substituted phenyl, a benzyl, or a substituted benzyl; the substituent is selected from halogens, C1-C4 alkyl, or C1-C4 alkoxy, and the number of substituents is one or two.

[0014] According to some embodiments of the present invention, the substituent is located at the 2-, 3-, 4-, 2,4-, 2,6-, 3,4-, or 3,5-position of the benzene ring; the substituent is fluorine, chlorine, methyl, ethyl, isopropyl, or methoxy.

[0015] According to some embodiments of the present invention, R is phenyl or substituted phenyl, the substituent is selected from halogen, C1-C4 alkyl or C1-C4 alkoxy, and the number of substituents is 1 or 2; the substituent is located at the 2-, 3-, 4- or 2,6-position of the benzene ring; the substituent is fluorine, chlorine, methyl, ethyl, isopropyl or methoxy.

[0016] According to some embodiments of the present invention, R is benzyl or substituted benzyl, the substituent is selected from halogen or C1-C4 alkyl, and the number of substituents is 1 or 2; the substituent is located at the 2-, 3-, 4-, 2,4-, 2,6-, 3,4-, or 3,5-position of the benzene ring; the substituent is fluorine, chlorine, or methyl.

[0017] According to some preferred embodiments of the present invention, the structural formula of the compound is selected from any one of the following: .

[0018] According to some preferred embodiments of the present invention, R is 2-methoxyethyl, phenyl, 2-methylphenyl, 2-chlorophenyl, 2-ethylphenyl, 2-isopropylphenyl, 2-methoxyphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-fluoro-6-methylphenyl, 2-chloro-6-methylphenyl, 2-chloro-6-fluorophenyl, 2-phenylpropyl-2-yl, 2-methylbenzyl, 2,4-dimethylbenzyl, 2,4-dichlorobenzyl, 4-fluoro-2-methylbenzyl, 2-chloro-4-fluorobenzyl, 4-chloro-2-fluorobenzyl, 3,5-dimethylbenzyl, or 3,5-dichlorobenzyl.

[0019] According to some preferred embodiments of the present invention, R is 2-methylphenyl, 2-chlorophenyl or 2-fluoro-6-methylphenyl.

[0020] A second aspect of the present invention provides a method for preparing an N-substituted uracil benzamide compound as described in any one of claims 1 to 4, characterized in that it comprises the following steps:

[0021] S1. The compound shown in formula A undergoes esterification in an alcohol solvent in the presence of an acid to produce the compound shown in formula B.

[0022] S2, the compound shown in formula B reacts in an alcohol solvent in the presence of a reducing agent to produce the compound shown in formula C;

[0023] S3. The compound shown in formula C and the compound shown in formula D undergo a condensation reaction in an organic solvent in the presence of an acid. The resulting intermediate reacts with iodomethane in the presence of a base to produce the compound shown in formula E.

[0024] Compound S4 and compound E are hydrolyzed in an organic solvent in the presence of acid to produce compound F.

[0025] S5 and the compound shown in formula F react with the amine of formula RNH2 to generate N-substituted uracil benzamide compounds;

[0026] Step S5 is performed using either method A or method B:

[0027] Method A: The compound shown in formula F reacts with an amine of formula RNH2 in the presence of a condensing agent;

[0028] Method B: The compound shown in Formula F first reacts with an acyl chloride reagent to form an acyl chloride, and then reacts with an amine of Formula RNH2;

[0029] The preparation route for steps S1 to S5 is as follows: .

[0030] According to some embodiments of the present invention, in step S1, the alcohol solvent is ethanol, the acid is concentrated sulfuric acid (mass concentration of 95%~98%), and the ratio of compound A to concentrated sulfuric acid is 0.05~0.5 mL of concentrated sulfuric acid per mmol of compound A;

[0031] According to some embodiments of the present invention, in step S1, the esterification reaction is carried out under reflux at 90~110 °C.

[0032] According to some embodiments of the present invention, in step S2, the alcohol solvent is a 65% to 85% aqueous ethanol solution, the reducing agent is iron powder and ammonium chloride, the molar ratio of compound B to iron powder is 1:(3~5), and the molar ratio of compound B to ammonium chloride is 1:(3~5).

[0033] According to some embodiments of the present invention, in step S2, the reaction conditions are a reflux reaction at 100~120°C.

[0034] According to some embodiments of the present invention, in step S3, the acid is acetic acid, the base is selected from sodium carbonate, potassium carbonate or cesium carbonate, the molar ratio of compound C to compound D is 1:(1~1.2), the molar ratio of compound C to base is 1:(1~2), and the molar ratio of compound C to iodomethane is 1:(1~3).

[0035] According to some embodiments of the present invention, in step S3, the condensation reaction is carried out under reflux at 120~140 °C for 6~10 h.

[0036] According to some embodiments of the present invention, in step S4, the acid is selected from hydrochloric acid or sulfuric acid.

[0037] According to some embodiments of the present invention, in step S5, method A, the solvent for the reaction is selected from one or more of dichloromethane, tetrahydrofuran, or N,N-dimethylformamide; the condensing agent includes EDCI and HOBt; an acid-binding agent is also added to the reaction system; the acid-binding agent is selected from triethylamine, pyridine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or cesium carbonate, and the molar ratio of compound F to the acid-binding agent is 1:(1~5); the molar ratio of compound F to the amine of formula RNH2 is 1:(1~1.5); the molar ratio of compound F to EDCI is 1:(1~1.5); and the molar ratio of compound F to HOBt is 1:(1~1.5).

[0038] According to some embodiments of the present invention, in step S5 of method B, the solvent for the reaction is selected from one or more of dichloromethane, tetrahydrofuran or N,N-dimethylformamide, the ratio of compound F to oxalyl chloride is 0.5 to 2.0 mL of oxalyl chloride per mmol of compound F, and the molar ratio of compound F to the amine of formula RNH2 is 1:(1 to 1.5).

[0039] According to some embodiments of the present invention, in step S1, the ratio of compound A to concentrated sulfuric acid is 0.05 to 0.5 mL of concentrated sulfuric acid per mmol of compound A, preferably 0.1 to 0.2 mL.

[0040] According to some embodiments of the present invention, in step S5 of method B, the reaction temperature of compound F with oxalyl chloride is 38~42°C.

[0041] A third aspect of the present invention provides the application of N-substituted uracil benzamide compounds as described in the first aspect of the present invention or compounds prepared by the preparation method described in the second aspect of the present invention in the control of weeds.

[0042] According to some embodiments of the present invention, the weeds are broadleaf weeds and / or grass weeds.

[0043] According to some preferred embodiments of the present invention, the weeds are one or more of the following: Amaranthus retroflexus, Chenopodium album, Abutilon theophrasti, Plantago asiatica, Portulaca oleracea, Barnyardgrass, Crataegus pinnatifida, and Echinochloa crus-galli.

[0044] A fourth aspect of the present invention provides a herbicide composition comprising the N-substituted uracil benzamide compound described in the first aspect of the present invention, and an agriculturally acceptable carrier and / or adjuvant.

[0045] According to some embodiments of the present invention, the dosage form of the composition is a wettable powder, a suspension concentrate, or a water-dispersible granule.

[0046] In this invention, the terms are defined as follows:

[0047] "C1-C6 alkyl" refers to straight-chain or branched alkyl groups with a total number of carbon atoms of 1 to 6, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.

[0048] "C1-C4 alkoxy" refers to straight-chain or branched alkoxy groups with a total number of carbon atoms of 1 to 4, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0049] "C1-C4 alkoxycarbonyl" refers to a group formed by a straight-chain or branched alkoxy group with a total of 1 to 4 carbon atoms attached to a carbonyl group, including but not limited to methoxycarbonyl (-COOCH3), ethoxycarbonyl (-COOCH2CH3), n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.

[0050] "C6-C10 aryl" refers to aromatic hydrocarbon groups with a total number of 6 to 10 carbon atoms, including but not limited to phenyl and naphthyl groups.

[0051] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0052] The beneficial effects of this invention are:

[0053] 1) This invention provides a class of N-substituted uracil benzamide compounds and their preparation method. The preparation method of this class of compounds is simple, has a high yield, and is suitable for industrial production.

[0054] 2) At a low dose of 37.5 g ai / ha, this type of compound showed excellent herbicidal activity (≥90%) against a variety of broadleaf weeds such as Amaranthus retroflexus, Chenopodium album, Abutilon theophrasti, Plantago asiatica, and Portulaca oleracea. It also had good inhibitory effect on grass weeds such as barnyard grass, Crataegus pinnatifida, and Echinochloa crus-galli, and has broad-spectrum herbicidal characteristics.

[0055] 3) Some compounds (such as compounds 7, 13, and 20) still maintain more than 80% control efficacy against Amaranthus retroflexus at ultra-low doses of 2.34–9.38 g ai / ha, demonstrating excellent low-dose activity, which can significantly reduce the amount of pesticides used in the field and reduce environmental residues.

[0056] 4) Crop safety trials showed that at a dose of 75 g ai / ha, these compounds were safe for gramineous crops (especially corn and wheat). Compound 7 caused less than 10% damage to both corn and wheat, which was significantly better than the positive control pyrimisulfuron (40% for corn and 30% for wheat), and has the potential to be developed into a selective herbicide.

[0057] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0058] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein:

[0059] Figure 1 This is a schematic diagram of the preparation route in Example 1 of the present invention. Detailed Implementation

[0060] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0061] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0062] In the following examples, all raw materials and reagents used were commercially available analytical grade products, and the room temperature was 25°C.

[0063] Example 1

[0064] This embodiment provides a method for preparing N-substituted uracil benzamide compounds (compounds 1-53). The specific steps are as follows:

[0065] 1) Preparation of intermediate compound B:

[0066] 2-Chloro-4-fluoro-5-nitrobenzoic acid (CAS No.: 114776-15-7, compound A, 16.47 g, 75 mmol) was dissolved in ethanol (75 mL), and concentrated sulfuric acid (95%~98%, 7.5 mL) was added. The mixture was heated to reflux at 100 °C. After the reaction was completed as monitored by TLC, the reaction solution was poured into ice water (500 mL), and a solid precipitated. The solid was collected by filtration. The solid was dried at 50 °C to obtain crude ethyl 2-chloro-4-fluoro-5-nitrobenzoate (compound B) 17.6 g, which was used directly in the next reaction without purification. The structural formula of compound B is: ;

[0067] 2) Preparation of intermediate compound C:

[0068] Compound B was dissolved in 75% ethanol (80 mL), heated to reflux at 110 °C, and ammonium chloride (16.05 g, 300 mmol) was added, followed by fractional addition of iron powder (16.76 g, 300 mmol). After the reaction was complete, a funnel was lined with diatomaceous earth, and the mixture was filtered while hot. The filtrate was extracted with ethyl acetate, and the organic phases were combined and washed with water. The solvent was removed, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 7:1) to give 9.68 g of pure ethyl 5-amino-2-chloro-4-fluorobenzoate (compound C), with a two-step yield of 59%. The structural formula of compound C is: ;

[0069] 3) Preparation of intermediate compound E:

[0070] Compound C (2.18 g, 10 mmol) and 2-(dimethylamino)-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (CAS No.: 141860-79-9, compound D, 2.08 g, 10 mmol) were dissolved in acetic acid (20 mL) and heated under reflux at 130 °C for 8 hours. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (50 mL × 3). The organic phase was washed successively with water, saturated NaHCO3 solution, and saturated NaCl solution, and dried over anhydrous Na2SO4. After removing the solvent, the residue was dissolved in DMF (20 mL), and potassium carbonate (1.66 g, 12 mmol) and methyl iodide (0.93 mL, 15 mmol) were added. The mixture was stirred overnight at room temperature (mmol); after the reaction was complete, it was quenched with water, extracted with ethyl acetate, washed with water, and dried over anhydrous Na2SO4; purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 12:1) to give 3.05 g of pure ethyl 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]benzoate (compound E), yield 77%; the structural formula of compound E is: ;

[0071] 4) Preparation of intermediate compound F:

[0072] Compound E (0.789 g, 2 mmol) was dissolved in acetic acid (15 mL), and hydrochloric acid (20%, 2 mL) was added. The mixture was heated to reflux at 120 °C. After the reaction was completed by TLC monitoring, the reaction solution was poured into ice water (200 mL), and a solid precipitated. The solid was collected by filtration. The solid was purified by recrystallization to give 0.543 g of pure 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]benzoic acid (compound F), with a yield of 74%. The structural formula of compound F is: ;

[0073] 5) Preparation of the target N-substituted uracil benzamide compound G:

[0074] 5.1) Method A, taking the preparation of compounds 1, 2, and 23 as an example:

[0075] Preparation of compound 1:

[0076] Compound F (550 mg, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt) (243 mg, 1.8 mmol) were dissolved in a mixed solvent of DCM and THF (4:1, 25 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (345 mg, 1.8 mmol) was added, and the mixture was stirred at room temperature for 30 min. Isoamylamine (1.65 mmol) and triethylamine (0.625 mL, 4.5 mmol) were then added, and the reaction continued. After the reaction was complete, the solvent was removed, and the residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, and saturated NaHCO3 solution, and dried over anhydrous Na2SO4. The target compound 1 was obtained by recrystallization purification, with a yield of 93%. The chemical structural formula of compound 1 is as follows: ;

[0077] Preparation of compound 2:

[0078] Compound F (550 mg, 1.5 mmol) and HOBt (243 mg, 1.8 mmol) were dissolved in a mixed solvent of DCM and THF (4:1, 25 mL), and EDCI (345 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 30 min. Subsequently, 2-methoxyethylamine (1.8 mmol) and N,N-diisopropylethylamine (0.784 mL, 4.5 mmol) were added, and the reaction continued. After the reaction was complete, the solvent was removed, and the residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, and saturated NaHCO3 solution, and dried over anhydrous Na2SO4. The target compound 2 was purified by silica gel column chromatography in 79% yield. The structural formula of compound 2 is as follows: ;

[0079] Preparation of compound 23:

[0080] Compound F (550 mg, 1.5 mmol) and HOBt (243 mg, 1.8 mmol) were dissolved in THF (25 mL), and EDCI (345 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 30 min. Then, benzylamine (1.65 mmol) and pyridine (0.364 mL, 4.5 mmol) were added, and the reaction continued. After the reaction was complete, the solvent was removed, and the residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, and saturated NaHCO3 solution, and dried over anhydrous Na2SO4. The target compound 23 was obtained by recrystallization purification. The structural formula of compound 23 is: .

[0081] Target compounds 3-6 and compounds 24-53 can be prepared by replacing isopentylamine, 2-methoxyethylamine, and benzylamine with the corresponding amines as described in Method A above; the solvent, acid-binding agent, and purification method can also be adjusted as needed.

[0082] 5.2) Method B, taking the preparation of compounds 7 and 13 as examples:

[0083] Preparation of compound 7:

[0084] Compound F (550 mg, 1.5 mmol) was dissolved in THF (10 mL), and oxalyl chloride (1 mL) was added. The mixture was stirred overnight at 40 °C. After the reaction was complete, the solvent was removed. The residue was dissolved in a mixed solvent of DCM and THF (4:1, 15 mL). The resulting solution was added dropwise to a mixed solution of DCM and THF containing 2-methylaniline (1.65 mmol) (4:1, 15 mL). The mixture was stirred at room temperature. After the reaction was complete, the solvent was removed, and the residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, and saturated NaHCO3 solution, and dried over anhydrous Na2SO4. The target compound 7 was obtained by recrystallization purification, with a yield of 55%. The structural formula of compound 7 is: ;

[0085] Preparation of compound 13:

[0086] Compound F (550 mg, 1.5 mmol) was dissolved in THF (10 mL), and oxalyl chloride (1 mL) was added. The mixture was stirred overnight at 40 °C. After the reaction was complete, the solvent was removed. The residue was dissolved in THF (15 mL), and the resulting solution was added dropwise to a DCM solution of 1.65 mmol of 2-chloroaniline (1.65 mmol) (15 mL). The mixture was stirred at room temperature. After the reaction was complete, the solvent was removed, and the residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, and saturated NaHCO3 solution, and dried over anhydrous Na2SO4. The target compound 13 was obtained by recrystallization purification, with a yield of 64%. The structural formula of compound 13 is as follows: .

[0087] Target compounds 8-12 and compounds 14-22 can be prepared by replacing 2-methylaniline and 2-chloroaniline with the corresponding amines, as described in method B above; the solvent and purification method can also be adjusted as needed.

[0088] Based on the above method, target compounds 1 to 53 were synthesized, and the structural characterization data of each target compound are as follows:

[0089] Partial intermediate characterization data:

[0090] Ethyl 5-amino-2-chloro-4-fluorobenzoate (Compound C): Orange-yellow solid. 1 H NMR (600 MHz, Chloroform-d) δ 7.29 (d, J = 9.4 Hz, 1H), 7.08 (d, J = 10.5 Hz, 1H), 4.36 (q,J = 7.2 Hz, 2H), 3.83 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0091] 2-Chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]benzoate (Compound E): Yellow gelatinous solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J =7.7 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 6.30 (s, 1H), 4.32 (q, J = 7.1 Hz,2H), 3.49 (q, J = 1.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0092] 2-Chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]benzoic acid (compound F): a yellowish-brown solid. 1 H NMR (600 MHz, DMSO-d6) δ 13.71 (s, 1H), 8.05 (d, J= 7.9 Hz, 1H), 7.84 (d, J = 9.5 Hz, 1H), 6.60 (s, 1H), 3.42 (s, 3H).

[0093] 2-Chloro-4-fluoro-N-isopentyl-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (Compound 1): White solid, 93% yield, melting point 53.8-55.7 °C. 1H NMR (400MHz, Chloroform-d) δ 7.64 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 6.35(s, 1H), 6.30 (t, J = 5.9 Hz, 1H), 3.55 (d, J = 1.3 Hz, 3H), 3.45 (dt, J =8.5, 6.1 Hz, 2H), 1.68 (dp, J = 13.3, 6.7 Hz, 1H), 1.49 (q, J = 7.0 Hz, 2H), 0.95 (s, 3H), 0.94 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 164.3, 159.9,158.0 (d, J = 258.7 Hz), 150.6, 141.9 (q, J = 34.5 Hz), 133.0 (d, J = 10.2Hz), 132.4 (d, J = 4.0 Hz), 131.9 (d, J = 1.8 Hz), 121.2 (d, J = 13.8 Hz),124.5 – 113.4 (m), 118.8 (d, J = 23.3 Hz), 103.0 (q, J = 5.6 Hz), 38.6, 38.2,32.8 (q, J = 3.8 Hz), 25.9, 22.5. HRMS (ESI) calcd for C 18 H 19 ClF4N3O3 ([M + H) + )436.1046, Found 436.1048.

[0094] 2-Chloro-4-fluoro-N-(2-methoxyethyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (Compound 2): Yellow oily liquid, yield 79%. 1 H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 6.71 (s,1H), 6.36 (s, 1H), 3.64 (q, J = 5.1 Hz, 2H), 3.58 – 3.49 (m, 5H), 3.38 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.4, 159.9, 158.1 (d, J = 259.0 Hz), 150.6, 141.9 (q, J = 34.5 Hz), 133.2 (d, J = 9.8 Hz), 132.2 (d, J = 3.6 Hz), 132.0 (d, J = 2.2 Hz), 121.2 (d, J = 13.8 Hz), 119.4 (q, J = 275.4 Hz), 118.9 (d, J = 23.3 Hz), 103.0 (q, J = 5.8 Hz), 70.8, 58.8, 39.9, 32.8 (q, J = 3.7Hz). HRMS (ESI) calcd for C 16 H 15 ClF4N3O4 ([M + H) + ) 424.0682, Found 424.0684.

[0095] 2-Chloro-4-fluoro-N-(methoxycarbonylmethyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 3): white solid, yield 51%, melting point 58.5-68.7 °C. 1 H NMR (400MHz, Chloroform-d) δ 7.73 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 9.1 Hz, 1H), 7.04(t, J = 5.2 Hz, 1H), 6.35 (s, 1H), 4.24 (d, J = 5.0 Hz, 2H), 3.80 (s, 3H), 3.55 (d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.1, 164.6,159.9, 158.4 (d, J = 259.8 Hz), 150.6, 141.9 (q, J = 34.3 Hz), 133.5 (d, J =10.2 Hz), 132.2 (d, J = 2.2 Hz), 131.4 (d, J = 4.0 Hz), 121.3 (d, J = 13.8Hz), 119.4 (q, J = 275.6 Hz), 119.0 (d, J = 23.6 Hz), 103.0 (q, J = 5.4 Hz), 52.5, 41.8, 32.8 (q, J = 3.6 Hz). HRMS (ESI) calcd for C 16 H 13 ClF4N3O5 ([M + H) + )438.0474, Found 438.0477.

[0096] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-phenylbenzamide (compound 4): white solid, yield 34%, melting point 106.7-110.2 °C. 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.86 (d, J = 9.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.73 – 7.66 (m, 2H), 7.44 – 7.29 (m, 2H), 7.22 – 7.05 (m, 1H), 6.62 (s, 1H), 3.43 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.4, 160.0, 157.6 (d, J = 255.4Hz), 150.6, 141.0 (q, J = 33.8 Hz), 138.7, 134.3 (d, J = 4.0 Hz), 132.0 (d, J= HRMS (ESI) calcd forC 19 H 13 ClF4N3O3 ([M + H) + ) 442.0576, Found 442.0577.

[0097] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-(4-methylphenyl)benzamide (compound 5): white solid, yield 56%, melting point 103.5-114.6 °C. 1 H NMR(400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.48 (d, J= 8.5 Hz, 2H), 7.35 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 6.34 (s,1H), 3.55 (s, 3H), 2.34 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.5,160.0, 158.1 (d, J = 259.0 Hz), 150.6, 142.0 (q, J = 34.3 Hz), 135.0, 134.7,133.5 (d, J = 9.8 Hz), 132.7 (d, J = 4.0 Hz), 131.6, 129.6, 121.2 (d, J =13.8 Hz), 120.2, 119.3 (q, J = 275.9 Hz), 118.9 (d, J = 23.6 Hz), 103.1 –102.7 (m), 33.0 – 32.6 (m), 21.0. HRMS (ESI) calcd for C 20 H 15 ClF4N3O3 ([M + H) + 456.0733, Found 456.0734.

[0098] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-(3-methylphenyl)benzamide (compound 6): white solid, yield 45%, melting point 99.5-109.3 °C. 1 H NMR(400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.74 (d, J =7.8 Hz, 1H), 7.55 (s, 1H), 7.50 – 7.42 (m, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.04 – 6.84 (m, 1H), 6.62 (s, 1H), 3.42 (s, 3H), 2.30 (s, 3H). 13C NMR (101MHz, Chloroform-d) δ 162.6, 160.0, 158.1 (d, J = 259.4 Hz), 150.6, 142.0 (q,J = 34.5 Hz), 139.1, 137.5, 133.5 (d, J = 9.8 Hz), 132.8 (d, J = 4.0 Hz), 131.6, 128.9, 125.8, 121.2 (d, J = 13.8 Hz), 120.7, 123.5 – 115.1 (m), 118.9 (d, J = 23.3 Hz), 117.2, 102.9 (q, J = 5.6 Hz), 32.8 (q, J = 3.6 Hz), 21.5.HRMS (ESI) calcd for C 20 H 15 ClF4N3O3 ([M + H) + ) 456.0733, Found 456.0734.

[0099] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-(2-methylphenyl)benzamide (compound 7): white solid, yield 55%, melting point 94.9-102.6 °C. 1 H NMR(400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.79 (d, J =7.8 Hz, 1H), 7.39 (dd, J = 7.8, 1.6 Hz, 1H), 7.27 (dd, J = 7.4, 2.0 Hz, 1H), 7.22 (td, J = 7.6, 2.1 Hz, 1H), 7.17 (td, J = 7.3, 1.6 Hz, 1H), 6.63 (s, 1H), 3.43 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.4, 159.9,158.4 (d, J = 260.1 Hz), 150.6, 142.0 (q, J = 34.3 Hz), 135.3, 133.0 (d, J =9.8 Hz), 132.8, 132.2 (d, J = 3.6 Hz), 130.8, 130.0, 126.9, 126.0, 123.5,121.6 (d, J = 13.8 Hz), 122.7 – 114.9 (m), 119.1 (d, J = 23.6 Hz), 103.1 (d,J = 5.4 Hz), 32.9 (d,J = 4.0 Hz), 18.2. HRMS (ESI) calcd for C 20 H 15 ClF4N3O3([M + H)) + ) 456.0733, Found 456.0733.

[0100] 2-Chloro-4-fluoro-N-(4-fluorophenyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 8): white solid, yield 76%, melting point 110.5-114.8 °C. 1 H NMR (400MHz, Chloroform-d) δ 8.15 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.61 – 7.51 (m,2H), 7.35 (d, J = 9.0 Hz, 1H), 7.06 (dd, J = 9.8, 7.5 Hz, 2H), 6.34 (s, 1H), 3.54 (d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.6, 160.3 (d, J= 143.9 Hz), 160.0, 157.8 (d, J = 159.1 Hz), 150.6, 142.1 (q, J = 34.5 Hz), 133.6 (d, J = 2.9 Hz), 133.5 (d, J = 10.2 Hz), 132.4 (d, J = 4.0 Hz), 131.8(d, J = 2.2 Hz), 122.0 (d, J = 8.0 Hz), 121.3 (d, J = 13.8 Hz), 119.4 (q, J =275.6 Hz), 119.0 (d, J = 23.3 Hz), 115.8 (d, J = 22.5 Hz), 103.0 (t, J = 5.6Hz), 32.8 (t, J = 3.8 Hz). HRMS (ESI) calcd for C 19 H 12 ClF5N3O3 ([M + H) + 460.0482, Found 460.0483.

[0101] 2-Chloro-4-fluoro-N-(3-fluorophenyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 9): white solid, yield 74%, melting point 98.8-112.5 °C. 1 H NMR (400MHz, Chloroform-d) δ 8.24 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.57 (dt, J =10.8, 2.3 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.30 (dd, J = 8.2, 6.2 Hz, 1H), 7.25 – 7.22 (m, 1H), 6.87 (tdd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.34 (s, 1H), 3.55(s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 163.0 (d, J = 245.2 Hz), 162.7,160.1, 158.4 (d, J = 260.1 Hz), 150.6, 142.1 (q, J = 34.5 Hz), 139.1 (d, J =10.5 Hz), 133.5 (d, J = 10.2 Hz), 132.3 (d, J = 4.0 Hz), 131.8 (d, J = 2.2Hz), 130.3 (d, J = 9.4 Hz), 121.4 (d, J = 14.2 Hz), 123.6 – 114.9 (m), 119.1(d, J = 23.6 Hz), 115.5 (d, J = 2.9 Hz), 111.8 (d, J = 21.4 Hz), 107.7 (d, J= 26.5 Hz), 103.0 (t, J = 5.6 Hz), 33.1 – 32.7 (m). HRMS (ESI) calcd forC 19 H 12 ClF5N3O3 ([M + H) + ) 460.0482, Found 460.0485.

[0102] 2-Chloro-4-fluoro-N-(2-fluorophenyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (Compound 10) is a white solid with a yield of 59% and a melting point of 80.6–90.3 °C. 1 H NMR (400MHz, Chloroform-d) δ 8.45 – 8.35 (m, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.40 (d,J = 8.9 Hz, 1H), 7.22 – 7.16 (m, 1H), 7.16 – 7.09 (m, 2H), 6.38 (s, 1H), 3.57(d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.2, 159.9, 158.6 (d,J = 260.1 Hz), 152.9 (d, J = 244.5 Hz), 150.6, 142.0 (q, J = 34.5 Hz), 133.3(d, J = 10.2 Hz), 132.7 (d, J = 1.8 Hz), 131.7 (d, J = 4.0 Hz), 125.9 (d, J =10.2 Hz), 125.3 (d, J = 7.6 Hz), 124.8 (d, J = 3.6 Hz), 122.2, 121.6 (d, J =13.8 Hz), 123.6 – 115.3 (m), 119.3 (d, J = 23.6 Hz), 115.1 (d, J = 19.3 Hz), 103.1 (q, J = 5.6 Hz), 32.9 (q, J = 3.8 Hz). HRMS (ESI) calcd forC 19 H 12 ClF5N3O3 ([M + H) + ) 460.0482, Found 460.0483.

[0103] 2-Chloro-N-(4-Chlorophenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (Compound 11): White solid, 74% yield, melting point 113.5-116.8 °C. 1 H NMR (400MHz, Chloroform-d) δ 8.20 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.59 – 7.47 (m,2H), 7.34 (t, J = 9.2 Hz, 3H), 6.34 (s, 1H), 3.54 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.6, 160.0, 158.4 (d, J = 259.8 Hz), 150.6, 142.1 (q, J =34.5 Hz), 136.1, 133.5, 133.4, 132.2 (d, J = 4.0 Hz), 131.8 (d, J = 2.2 Hz), 130.1, 129.2, 121.4, 119.4 (q, J = 275.6 Hz), 119.1 (d, J = 23.3 Hz), 103.0 (d, J = 5.8 Hz), 32.9 (d, J = 3.6 Hz). HRMS (ESI) calcd for C 19 H 12 Cl2F4N3O3 ([M+ H) + ) 476.0186, Found 476.0187.

[0104] 2-Chloro-N-(3-Chlorophenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 12): white solid, yield 65%, melting point 105.3-108.7 °C. 1 H NMR (400MHz, DMSO-d6) δ 10.91 (s, 1H), 7.98 – 7.85 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.58 (ddd, J = 8.3, 2.1, 1.0 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.20 (ddd, J= 8.0, 2.1, 1.0 Hz, 1H), 6.63 (s, 1H), 3.42 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.7, 160.1, 158.4 (d, J = 259.8 Hz), 150.6, 142.1 (q, J =34.7 Hz), 138.7, 134.8, 133.5 (d, J = 10.2 Hz), 132.2 (d, J = 4.0 Hz), 131.8 (d, J = 1.8 Hz), 130.2, 125.1, 121.4 (d, J = 14.2 Hz), 120.2, 119.4 (q, J =275.6 Hz), 119.1 (d, J = 23.3 Hz), 118.2, 103.0 (d, J = 5.8 Hz), 32.9 (d, J =3.6 Hz). HRMS (ESI) calcd for C 19 H 12 Cl2F4N3O3 ([M + H) + ) 476.0186, Found476.0187.

[0105] 2-Chloro-N-(2-Chlorophenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 13): white solid, yield 64%, melting point 78.8-89.2 °C. 1 H NMR (400MHz, Chloroform-d) δ 8.63 (s, 1H), 8.51 – 8.46 (m, 1H), 7.85 (d, J = 7.6 Hz,1H), 7.44 – 7.42 (m, 1H), 7.42 – 7.39 (m, 1H), 7.33 (ddd, J = 8.6, 7.6, 1.6Hz, 1H), 7.11 (td, J = 7.6, 1.6 Hz, 1H), 6.38 (s, 1H), 3.57 (d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.1, 159.8, 158.7 (d, J = 260.5 Hz), 150.6, 142.0 (q, J = 34.5 Hz), 134.4, 133.2 (d, J = 10.2 Hz), 133.0 (d, J =2.2 Hz), 131.7 (d, J = 4.0 Hz), 129.3, 127.9, 125.5, 123.6, 122.2, 121.7 (d,J = 13.8 Hz), 122.4 – 114.9 (m), 119.3 (d, J = 23.3 Hz), 103.1 (q, J = 5.5Hz), 32.9 (q, J = 3.6 Hz). HRMS (ESI) calcd for C 19 H 12 Cl2F4N3O3 ([M + H) + 476.0186, Found 476.0187.

[0106] 2-Chloro-N-(2-ethylphenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 14): white solid, yield 68%, melting point 79.9-92.6 °C. 1 H NMR(400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.86 (d, J = 9.8 Hz, 1H), 7.77 (d, J =7.8 Hz, 1H), 7.39 – 7.33 (m, 1H), 7.32 – 7.27 (m, 1H), 7.26 – 7.20 (m, 2H), 6.63 (s, 1H), 3.43 (s, 3H), 2.66 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.6, 159.9, 158.4 (d, J = 259.8 Hz), 150.6, 142.0 (q, J = 34.5 Hz), 136.1, 134.5, 132.9 (d, J = 10.2 Hz), 132.8,132.2 (d, J = 4.0 Hz), 128.9, 126.8, 126.4, 124.3, 121.6 (d, J = 13.8 Hz),123.8 – 114.8 (m), 119.0 (d, J = 23.6 Hz), 103.0 (t, J = 5.6 Hz), 32.8 (q, J= 3.6 Hz), 24.5, 14.3. HRMS (ESI) calcd for C 21 H 17 ClF4N3O3 ([M + H) + 470.0889, Found 470.0889.

[0107] 2-Chloro-4-fluoro-N-(2-isopropylphenyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 15): white solid, yield 73%, melting point 92.5-99.8 °C. 1 H NMR(400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.76 (d, J =7.8 Hz, 1H), 7.38 (dd, J = 7.7, 1.8 Hz, 1H), 7.33 – 7.18 (m, 3H), 6.63 (s,1H), 3.43 (s, 3H), 3.28 (p, J = 6.9 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H). 13C NMR(101 MHz, Chloroform-d) δ 162.9, 159.9, 158.5 (d, J = 260.1 Hz), 150.6, 142.0(q, J = 34.7 Hz), 141.6, 133.5, 132.9 (d, J = 9.8 Hz), 132.8 (d, J = 2.2 Hz),132.2 (d, J = 4.0 Hz), 126.9, 126.6, 125.9, 125.3, 121.7 (d, J = 13.4 Hz),123.5 – 115.3 (m), 119.1 (d, J = 23.6 Hz), 103.1 (q, J = 5.5 Hz), 32.9 (q, J= 3.6 Hz), 28.1, 23.3, 23.3. HRMS (ESI) calcd for C 22 H 19 ClF4N3O3 ([M + H) + 484.1046, Found 484.1048.

[0108] 2-Chloro-4-fluoro-N-(2-methoxyphenyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 16): white solid, yield 57%, melting point 88.6-99.5 °C. 1 H NMR(400 MHz, Chloroform-d) δ 8.66 (s, 1H), 8.48 (dd, J = 8.1, 1.7 Hz, 1H), 7.77(d, J = 7.6 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.11 (td, J = 7.8, 1.7 Hz,1H), 7.01 (td, J = 7.8, 1.4 Hz, 1H), 6.92 (dd, J = 8.1, 1.5 Hz, 1H), 6.38 (s,1H), 3.90 (s, 3H), 3.57 (d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ161.9, 159.9, 158.4 (d, J = 259.8 Hz), 150.6, 148.4, 142.0 (q, J = 34.3 Hz), 133.2 (d, J = 10.2 Hz), 132.6 (d, J = 4.0 Hz), 132.5 (d, J = 2.2 Hz), 127.3,124.6, 121.5 (d, J = 13.8 Hz), 121.2, 120.2, 119.4 (q, J = 275.6 Hz), 119.1(d, J = 23.3 Hz), 110.2, 103.1 (q, J = 5.6 Hz), 55.9, 32.9 (q, J = 3.6 Hz).HRMS (ESI) calcd for C 20 H 15 ClF4N3O4 ([M + H) + ) 472.0682, Found 472.0685.

[0109] 2-Chloro-N-(2,6-dimethylphenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 17): yellow solid, 82% yield, melting point 111.2-122.5 °C. 1 H NMR(400 MHz, Chloroform-d) δ 7.81 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.41 (d, J= 9.0 Hz, 1H), 7.18 – 7.15 (m, 1H), 7.15 – 7.10 (m, 2H), 6.37 (s, 1H), 3.57 (d, J = 1.4 Hz, 3H), 2.32 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 162.8,160.0, 158.3 (d, J = 259.4 Hz), 150.6, 143.3 – 140.4 (m), 135.6, 133.3, 133.3(d, J = 10.2 Hz), 132.3 (d, J = 4.0 Hz), 132.2 (d, J = 2.2 Hz), 128.4, 127.8,121.4 (d, J = 13.8 Hz), 119.4 (q, J = 275.6 Hz), 119.0 (d, J = 23.3 Hz), 103.0 (t, J = 5.4 Hz), 32.8 (q, J = 3.6 Hz), 18.8. HRMS (ESI) calcd forC 21 H 17 ClF4N3O3 ([M + H) + ) 470.0889, Found 470.0897.

[0110] 2-Chloro-N-(2,6-difluorophenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 18): white solid, 50% yield, melting point 102.2-112.5 °C. 1 H NMR(400 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.78 (d, J =7.6 Hz, 1H), 7.42 (tt, J = 8.8, 6.3 Hz, 1H), 7.22 (t, J = 8.1 Hz, 2H), 6.62(s, 1H), 3.43 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.6, 160.0, 159.2(d, J = 4.7 Hz), 157.4, 156.7 (d, J = 4.7 Hz), 150.6, 142.1 (q, J = 34.7 Hz), 133.8 (d, J = 10.2 Hz), 132.6, 131.1 (d, J = 3.6 Hz), 128.3 (t, J = 9.6 Hz), 121.5 (d, J = 13.8 Hz), 123.5 – 115.3 (m), 119.2 (d, J = 23.6 Hz), 113.4 (t,J = 16.5 Hz), 112.1 – 112.0 (m), 111.9 (d, J = 5.1 Hz), 103.1 (q, J = 5.6Hz), 32.9 (q, J = 3.6 Hz). HRMS (ESI) calcd for C 19 H 11 ClF6N3O3 ([M + H) + 478.0388, Found 478.0387.

[0111] 2-Chloro-N-(2,6-dichlorophenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 19): white solid, yield 22%, melting point 112.3-123.4 °C. 1 H NMR(400 MHz, Chloroform-d) δ 7.94 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.46 – 7.36(m, 3H), 7.23 (dd, J = 8.6, 7.6 Hz, 1H), 6.37 (s, 1H), 3.56 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.5, 160.0, 158.6 (d, J = 259.8 Hz), 150.6, 142.0 (q, J = 34.3 Hz), 133.9, 133.9 (d, J = 10.2 Hz), 132.3, 131.5,131.3 (d, J = 3.6 Hz), 129.1, 128.6, 121.4 (d, J = 13.8 Hz), 119.4 (q, J =275.4 Hz), 119.2 (d, J = 23.3 Hz), 103.2 – 102.9 (m), 32.8 (q, J = 3.6 Hz).HRMS (ESI) calcd for C 19 H 11 Cl3F4N3O3 ([M + H) + ) 509.9797, Found 509.9791.

[0112] 2-Chloro-4-fluoro-N-(2-fluoro-6-methylphenyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 20): white solid, 50% yield, melting point 106.4-120.3 °C. 1 HNMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.20 (td, J = 8.0, 5.5 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.00 (t, J = 8.9 Hz, 1H), 6.36 (s, 1H), 3.55 (s, 3H), 2.34 (s, 3H). 13CNMR (101 MHz, Chloroform-d) δ 162.9, 160.0, 159.4 (d, J = 78.8 Hz), 156.9 (d,J = 67.2 Hz), 150.6, 142.1 (q, J = 34.7 Hz), 138.0, 133.5 (d, J = 10.2 Hz), 132.4 (d, J = 1.8 Hz), 131.8 (d, J = 3.6 Hz), 128.4 (d, J = 8.7 Hz), 126.1 (d, J = 3.3 Hz), 122.6 (d, J = 13.1 Hz), 121.5 (d, J = 13.8 Hz), 119.4 (q, J= HRMS (ESI) calcd forC 20 H 14 ClF5N3O3 ([M + H) + ) 474.0638, Found 474.0645.

[0113] 2-Chloro-N-(2-Chloro-6-methylphenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 21): white solid, yield 47%, melting point 112.8-127.6 °C. 1 HNMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.41(d, J = 9.0 Hz, 1H), 7.32 (dd, J = 7.2, 2.4 Hz, 1H), 7.24 – 7.14 (m, 2H), 6.37 (s, 1H), 3.56 (d, J = 1.3 Hz, 3H), 2.37 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.7, 160.0, 158.5 (d, J = 259.4 Hz), 150.6, 142.0 (q, J =34.5 Hz), 138.4, 133.6 (d, J = 10.2 Hz), 132.2 (d, J = 2.2 Hz), 132.0, 131.9(d, J = 4.0 Hz), 131.7, 129.4, 128.5, 127.3, 121.5 (d, J = 13.8 Hz), 119.4(q, J = 275.4 Hz), 119.2 (d, J = 23.3 Hz), 103.1 (t, J = 5.4 Hz), 32.9 (q, J= 3.8 Hz), 19.3. HRMS (ESI) calcd for C 20 H 14 Cl2F4N3O3 ([M + H) + ) 490.0343, Found490.0347.

[0114] 2-Chloro-N-(2-Chloro-6-fluorophenyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 22): white solid, yield 21%, melting point 111.3-125.8 °C. 1 H NMR(400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.77 (d, J =7.6 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.37 (ddd, J = 9.8, 7.9, 3.4 Hz, 1H), 6.62(s, 1H), 3.43 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 162.4, 159.9, 159.8(d, J = 37.1 Hz), 157.3 (d, J = 30.5 Hz), 150.6, 142.1 (q, J = 34.9 Hz), 133.8 (d, J = 10.2 Hz), 132.7, 132.3 (d, J = 2.5 Hz), 131.1, 128.8 (d, J =9.1 Hz), 125.4 (d, J = 3.6 Hz), 122.4 (d, J = 15.6 Hz), 121.5 (d, J = 13.8Hz), 123.5 – 115.3 (m), 119.3 (d, J = 23.6 Hz), 115.2 (d, J = 20.7 Hz), 103.1(q, J = 5.6 Hz), 32.9 (t, J = 3.6 Hz). HRMS (ESI) calcd for C 19 H 11 Cl2F5N3O3 ([M+ H) + ) 494.0092, Found 494.0092.

[0115] N-Benzyl-2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 23): white solid, yield 81%, melting point 180.9-182.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (t, J = 6.1 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.64 (d, J =7.8 Hz, 1H), 7.40 – 7.31 (m, 4H), 7.26 (ddt, J = 8.5, 5.5, 2.9 Hz, 1H), 6.60(s, 1H), 4.45 (d, J = 6.0 Hz, 2H), 3.42 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ164.9, 160.1, 157.4 (d, J = 255.0 Hz), 150.6, 141.0 (q, J = 33.8 Hz), 139.0,134.2 (d, J = 4.0 Hz), 131.8 (d, J = 10.5 Hz), 130.8, 128.4, 127.4, 127.0,124.0 – 114.6 (m), 121.8 (d, J = 13.8 Hz), 118.0 (d, J = 23.6 Hz), 102.9 (d,J = 5.8 Hz), 42.7, 32.5 (d, J = 3.6 Hz). HRMS (ESI) calcd for C 20 H 15 ClF4N3O3([M + H)) + ) 456.0733, Found 456.0733.

[0116] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-(2-phenylprop-2-yl)benzamide (compound 24): white solid, 89% yield, melting point 82.6-93.0 °C. 1 H NMR(400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.76 (d, J = 9.6 Hz, 1H), 7.61 (d, J = 7.8Hz, 1H), 7.48 – 7.39 (m, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.24 – 7.16 (m, 1H), 6.61 (s, 1H), 3.42 (s, 3H), 1.62 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ163.1, 159.9, 158.0 (d, J = 258.7 Hz), 150.6, 146.2, 141.9 (q, J = 34.5 Hz), 133.0, 132.9 (d, J = 13.8 Hz), 131.9 (d, J = 1.8 Hz), 128.5, 126.9, 124.9,121.4 (d, J = 13.8 Hz), 119.4 (q, J = 275.6 Hz), 118.8 (d, J = 23.3 Hz),103.0 (q, J = 5.4 Hz), 57.0, 32.8 (q, J = 3.6 Hz), 29.0. HRMS (ESI) calcd for C 22 H 19 ClF4N3O3 ([M + H) + ) 484.1046, Found 484.1049.

[0117] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-(4-methylbenzyl)benzamide (compound 25): white solid, 83% yield, melting point 169.8-171.5 °C. 1 H NMR(400 MHz, DMSO-d6) δ 9.14 (t, J = 6.0 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.61(d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.60(s, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.42 (s, 3H), 2.28 (s, 3H). 13C NMR (101MHz, DMSO-d6) δ 164.8, 160.1, 157.4 (d, J = 254.7 Hz), 150.6, 140.8 (q, J =34.0 Hz), 136.0, 136.0, 134.2 (d, J = 4.0 Hz), 131.8 (d, J = 10.2 Hz), 130.8,128.9, 127.4, 121.8 (d, J = 13.8 Hz), 119.6 (q, J = 275.8 Hz), 118.0 (d, J =23.6 Hz), 102.9 (d, J = 5.5 Hz), 42.5, 32.5 (d, J = 3.3 Hz), 20.8. HRMS (ESI)calcd for C 21 H 17 ClF4N3O3 ([M + H) + ) 470.0889, Found 470.0891.

[0118] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-(3-methylbenzyl)benzamide (compound 26): white solid, yield 69%, melting point 139.5-142.1 °C. 1 H NMR(400 MHz, DMSO-d6) δ 9.16 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.63(d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.18 – 7.12 (m, 2H), 7.07 (d,J = 7.4 Hz, 1H), 6.60 (s, 1H), 4.41 (d, J = 6.0 Hz, 2H), 3.42 (s, 3H), 2.30(s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.9, 160.1, 157.4 (d, J = 254.7 Hz), 150.6, 141.0 (q, J = 34.0 Hz), 138.9, 137.4, 134.2 (d, J = 4.0 Hz), 131.8 (d,J = 10.2 Hz), 130.8, 128.3, 128.1, 127.6, 124.5, 121.8 (d, J = 13.8 Hz), 119.6 (q, J = 275.4 Hz), 118.0 (d, J = 23.6 Hz), 102.9 (d, J = 5.8 Hz), 42.7,32.5 (d, J = 3.6 Hz), 21.1. HRMS (ESI) calcd for C 21 H 17 ClF4N3O3 ([M + H) + 470.0889, Found 470.0889.

[0119] 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)-N-(2-methylbenzyl)benzamide (compound 27): white solid, 85% yield, melting point 72.3-83.6 °C. 1 H NMR(400 MHz, DMSO-d6) δ 9.08 (t, J = 5.8 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.63(d, J = 7.8 Hz, 1H), 7.32 (dh, J = 5.3, 2.9 Hz, 1H), 7.18 (d, J = 3.1 Hz, 3H), 6.60 (s, 1H), 4.43 (d, J = 5.8 Hz, 2H), 3.42 (s, 3H), 2.33 (s, 3H). 13CNMR (101 MHz, DMSO-d6) δ 164.8, 160.1, 157.4 (d, J = 254.7 Hz), 150.6, 141.0(q, J = 33.8 Hz), 136.5, 135.8, 134.3 (d, J = 4.0 Hz), 131.8 (d, J = 10.2Hz), 130.8, 130.0, 127.9, 127.1, 125.8, 121.7 (d, J = 13.8 Hz), 124.0 – 114.7(m), 118.0 (d, J = 23.6 Hz), 102.9 (d, J = 5.4 Hz), 40.9, 32.5, 18.8. HRMS(ESI) calcd for C 21 H 17 ClF4N3O3 ([M + H) + ) 470.0889, Found 470.0888.

[0120] 2-Chloro-4-fluoro-N-(4-fluorobenzyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 28): white solid, 89% yield, melting point 189.1-191.2 °C. 1 H NMR (400MHz, DMSO-d6) δ 9.20 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.63 (d,J = 7.8 Hz, 1H), 7.46 – 7.31 (m, 2H), 7.27 – 7.07 (m, 2H), 6.60 (s, 1H), 4.43(d, J = 6.1 Hz, 2H), 3.42 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.9, 161.3(d, J = 242.3 Hz), 160.1, 157.4 (d, J = 255.0 Hz), 150.6, 141.0 (q, J = 33.6Hz), 135.2 (d, J = 2.9 Hz), 134.1 (d, J = 4.0 Hz), 131.8 (d, J = 10.2 Hz), 130.8, 129.5, 129.4, 121.8 (d, J = 13.8 Hz), 120.9, 118.0 (d, J = 23.6 Hz), 115.2, 115.0, 102.9 (d, J = 5.8 Hz), 42.0, 32.5 (q, J = 3.6 Hz). HRMS (ESI)calcd for C 20 H 14 ClF5N3O3 ([M + H) + ) 474.0638, Found 474.0639.

[0121] 2-Chloro-4-fluoro-N-(3-fluorobenzyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 29): white solid, 87% yield, melting point 185.7-186.8 °C. 1 H NMR (400MHz, DMSO-d6) δ 9.24 (t, J = 6.1 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.66 (d,J = 7.8 Hz, 1H), 7.39 (td, J = 8.0, 6.1 Hz, 1H), 7.25 – 7.14 (m, 2H), 7.12 –7.03 (m, 1H), 6.60 (s, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.42 (s, 3H). 13C NMR(101 MHz, DMSO-d6) δ 165.0, 162.3 (d, J = 243.4 Hz), 160.1, 157.4 (d, J =255.0 Hz), 150.6, 142.0 (d, J = 7.3 Hz), 141.0 (q, J = 33.6 Hz), 134.0 (d, J= 4.0 Hz), 131.8 (d, J = 10.2 Hz), 130.8, 130.4 (d, J = 8.4 Hz), 123.4 (d, J= 2.5 Hz), 121.8 (d, J = 13.8 Hz), 120.9, 118.1 (d, J = 24.0 Hz), 114.1 (d, J = 21.8 Hz), 113.8 (d, J = 21.1 Hz), 102.9 (d, J = 5.1 Hz), 42.2, 32.5 (d, J =3.6 Hz). HRMS (ESI) calcd for C 20 H 14 ClF5N3O3 ([M + H) + ) 474.0638, Found474.0640.

[0122] 2-Chloro-4-fluoro-N-(2-fluorobenzyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 30): white solid, yield 64%, melting point 116.4-123.3 °C. 1 H NMR (400MHz, DMSO-d6) δ 9.20 (t, J = 5.9 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.64 (d,J = 7.8 Hz, 1H), 7.45 (td, J = 7.9, 2.0 Hz, 1H), 7.33 (tdd, J = 7.6, 5.4, 1.8Hz, 1H), 7.26 – 7.14 (m, 2H), 6.60 (s, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.42(s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.0, 160.2 (d, J = 244.9 Hz), 160.1,157.4 (d, J = 255.0 Hz), 150.6, 141.0 (q, J = 34.0 Hz), 134.0 (d, J = 4.0Hz), 131.9 (d, J = 10.2 Hz), 130.8, 129.8 (d, J = 4.4 Hz), 129.2 (d, J = 8.0Hz), 125.5 (d, J = 14.5 Hz), 124.4 (d, J = 3.6 Hz), 121.8 (d, J = 13.8 Hz),120.9, 118.0 HRMS (ESI) calcd for C 20 H 14 ClF5N3O3([M + H)) + ) 474.0638, Found 474.0639.

[0123] 2-Chloro-N-(4-chlorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 31): white solid, 88% yield, melting point 182.9-185.0 °C. 1 H NMR (400MHz, DMSO-d6) δ 9.22 (t, J = 6.1 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.64 (d,J = 7.8 Hz, 1H), 7.44 – 7.34 (m, 4H), 6.60 (s, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.42 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.96, 160.06, 157.43 (d, J =255.0 Hz), 150.62, 140.98 (q, J = 34.2 Hz), 138.08, 134.05 (d, J = 3.6 Hz), 131.83 (d, J = 10.2 Hz), 131.59, 130.81, 129.36, 128.37, 121.79 (d, J = 13.8Hz), 120.92, 118.05 (d, J = 23.6 Hz), 102.92 (d, J = 5.8 Hz), 42.10, 32.54(d, J = 3.3 Hz). HRMS (ESI) calcd for C 20 H 14 Cl2F4N3O3 ([M + H) + ) 490.0343, Found490.0343.

[0124] 2-Chloro-N-(3-Chlorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 32): white solid, 89% yield, melting point 157.7-159.9 °C. 1 H NMR (400MHz, DMSO-d6) δ 9.24 (t, J = 6.1 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.65 (d,J = 7.8 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.41 – 7.35 (m, 1H), 7.33 (dt, J =7.0, 1.8 Hz, 2H), 6.60 (s, 1H), 4.45 (d, J = 6.1 Hz, 2H), 3.42 (s, 3H). 13CNMR (101 MHz, DMSO-d6) δ 165.0, 160.0, 157.4 (d, J = 255.0 Hz), 150.6, 141.6,141.5 – 140.2 (m), 134.0 (d, J = 4.0 Hz), 133.1, 131.8 (d, J = 10.2 Hz), 130.8, 130.3, 127.3, 127.0, 126.1, 122.3 (q, J = 274.7 Hz), 121.8 (d, J =13.8 Hz), 118.1 (d, J = 23.6 Hz), 102.9 (d, J = 5.1 Hz), 42.2, 32.5 (d, J =3.6 Hz). HRMS (ESI) calcd for C 20 H 14 Cl2F4N3O3 ([M + H) + ) 490.0343, Found490.0346.

[0125] 2-Chloro-N-(2-Chlorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 33): white solid, yield 81%, melting point 66.7-78.8 °C. 1 H NMR (400MHz, DMSO-d6) δ 9.23 (t, J = 5.9 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.68 (d,J = 7.8 Hz, 1H), 7.48 (td, J = 7.7, 1.8 Hz, 2H), 7.34 (dtd, J = 17.5, 7.4,1.8 Hz, 2H), 6.61 (s, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.43 (s, 3H). 13C NMR(101 MHz, DMSO-d6) δ 165.1, 160.1, 157.5 (d, J = 255.0 Hz), 150.6, 141.0 (q,J = 34.2, 33.6 Hz), 135.8, 134.0 (d, J = 3.6 Hz), 132.2, 131.9 (d, J = 10.5Hz), 130.8, 129.3, 129.1, 128.9, 127.3, 121.8 (d, J = 13.8 Hz), 120.9, 118.0 (d, J = 24.0 Hz), 102.9 (d, J = 5.8 Hz), 40.7, 32.5 (d, J = 3.6 Hz). HRMS(ESI) calcd for C 20 H 14 Cl2F4N3O3 ([M + H) + ) 490.0343, Found 490.0346.

[0126] 2-Chloro-N-(2,6-dimethylbenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 34): white solid, yield 58%, melting point 94.4-103.2 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.14 (dd, J = 8.4, 6.4 Hz, 1H), 7.06 (d, J = 7.6 Hz, 2H), 6.34 (s, 1H), 6.14(t, J = 4.6 Hz, 1H), 4.65 (d, J = 4.6 Hz, 2H), 3.55 (d, J = 1.4 Hz, 3H), 2.40(s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 164.2, 159.8, 158.2 (d, J = 259.4Hz), 150.6, 142.0 (q, J = 34.5 Hz), 137.6, 133.1 (d, J = 9.8 Hz), 133.1,132.0, 132.0, 128.6, 128.2, 121.4 (d, J = 13.8 Hz), 119.4 (q, J = 275.6 Hz), 118.9 (d, J = 23.3 Hz), 103.0 (q, J = 5.6 Hz), 39.2, 32.8 (q, J = 3.8 Hz), 19.8. HRMS (ESI) calcd for C 22 H 19 ClF4N3O3 ([M + H) + ) 484.1046, Found 484.1046.

[0127] 2-Chloro-N-(2,6-difluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 35): white solid, yield 74%, melting point 70.0-81.2 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (t, J = 5.3 Hz, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.41 (tt, J = 8.5, 6.6 Hz, 1H), 7.10 (dd, J = 8.6, 7.6Hz, 2H), 6.58 (s, 1H), 4.48 (d, J = 5.4 Hz, 2H), 3.40 (d, J = 1.3 Hz, 3H). 13CNMR (101 MHz, Chloroform-d) δ 163.9, 162.8 (d, J = 7.6 Hz), 160.4 (d, J = 7.6Hz), 159.8, 158.3 (d, J = 259.4 Hz), 150.6, 141.9 (q, J = 34.5 Hz), 133.2 (d,J = 10.2 Hz), 132.3 (d, J = 1.8 Hz), 131.7 (d, J = 3.6 Hz), 129.9 (t, J =10.2 Hz), 121.3 (d, J = 13.8 Hz), 119.4 (q, J = 275.6 Hz), 119.0 (d, J = 23.6Hz), HRMS (ESI)calcd for C 20 H 13 ClF6N3O3 ([M + H) + ) 492.0544, Found 492.0547.

[0128] 2-Chloro-N-(2,6-dichlorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 36): white solid, yield 67%, melting point 92.2-105.1 °C. 1 H NMR(400 MHz, Chloroform-d) δ 7.68 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 8.8, 7.4 Hz, 1H), 6.64 (d, J = 5.9Hz, 1H), 6.34 (s, 1H), 4.95 (d, J = 5.4 Hz, 2H), 3.54 (s, 3H). 13C NMR (101MHz, Chloroform-d) δ 163.8, 159.8, 158.3 (d, J = 259.4 Hz), 150.6, 141.9 (q,J = 34.3 Hz), 136.3, 133.3 (d, J = 10.2 Hz), 132.9, 132.3 (d, J = 2.2 Hz), 131.7 (d, J = 3.6 Hz), 130.0, 128.6, 121.3 (d, J = 13.8 Hz), 119.4 (q, J =275.4 Hz), 119.0 (d, J = 23.3 Hz), 103.0 (q, J = 5.6 Hz), 39.9, 32.8 (q, J =3.6 Hz). HRMS (ESI) calcd for C 20 H 13 Cl3F4N3O3 ([M + H) + 523.9953, Found 523.9951.

[0129] 2-Chloro-N-(2-Chloro-6-fluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 37): white solid, yield 60%, melting point 74.4-87.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J = 5.0 Hz, 1H), 7.75 (d, J = 9.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.40 (td, J = 8.1, 5.9 Hz, 1H), 7.36 – 7.32 (m, 1H), 7.24 (ddd, J = 9.5, 8.0, 1.5 Hz, 1H), 6.58 (s, 1H), 4.56 (dd, J = 5.0, 1.9Hz, 2H), 3.40 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 163.8, 161.7 (d, J =250.7 Hz), 159.8, 158.3 (d, J = 259.4 Hz), 150.6, 142.0 (q, J = 34.5 Hz), 135.7 (d, J = 5.5 Hz), 133.3 (d, J = 10.2 Hz), 132.4 (d, J = 2.2 Hz), 131.6 (d, J = 4.0 Hz), 130.1 (d, J = 9.8 Hz), 125.6 (d, J = 3.6 Hz), 123.2 (d, J =17.8 Hz), 121.4 (d, J = 13.8 Hz), HRMS (ESI) calcd for C 20 H 13 Cl2F5N3O3 ([M + H) + ) 508.0249, Found508.0251.

[0130] 2-Chloro-N-(2,4-dimethylbenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 38): grayish-white solid, 85% yield, melting point 83.4-92.6 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.07 – 6.97 (m, 2H), 6.39 (t, J = 5.4 Hz, 1H), 6.35(s, 1H), 4.59 (d, J = 5.3 Hz, 2H), 3.55 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.0, 159.8, 158.2 (d, J = 259.0 Hz), 150.5, 141.9 (q, J = 34.5 Hz), 137.8, 136.4, 133.1 (d, J = 9.8 Hz), 132.1,131.5, 129.0, 127.0, 121.4, 121.2, 124.0 – 114.1 (m), 119.0, 118.8, 103.0 (q,J = 5.5 Hz), 42.3, 32.8 (q, J = 3.6 Hz), 21.1, 19.1. HRMS (ESI) calcd forC 22 H 19 ClF4N3O3 ([M + H) + ) 484.1046, Found 484.1049.

[0131] 2-Chloro-N-(2,4-difluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 39): grayish-white solid, yield 78%, melting point 95.6-104.9 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J = 7.6 Hz, 1H), 7.41 (td, J = 8.5, 6.3Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.85 (dddd, J = 12.6, 11.3, 6.3, 2.6 Hz, 2H), 6.75 (t, J = 5.9 Hz, 1H), 6.35 (s, 1H), 4.63 (d, J = 5.9 Hz, 2H), 3.55 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.4, 163.8 (d, J =12.0 Hz), 161.8 (dd, J = 94.5, 12.0 Hz), 159.9, 158.3 (d, J = 259.4 Hz), 150.6, 142.0 (q, J = 34.3 Hz), 133.2 (d, J = 10.2 Hz), 132.1 (d, J = 1.8 Hz), 131.7 (d, J = 4.0 Hz), 131.4 (dd, J = 9.4, 5.8 Hz), 121.4 (d, J = 13.8 Hz), 121.0 – 120.4 (m), 119.4 (d, J = 277.2 Hz), 119.0 (d, J = 23.6 Hz), 111.5(dd, J = 21.3, 3.8 Hz), 104.0 (t, J = 25.4 Hz), 103.0 (d, J = 5.5 Hz), 37.7(d, J = 3.6 Hz), 32.8 (q, J = 3.8 Hz). HRMS (ESI) calcd for C 20 H 13 ClF6N3O3 ([M+ H) + ) 492.0544, Found 492.0545.

[0132] 2-Chloro-N-(2,4-Dichlorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 40): white solid, yield 79%, melting point 86.5-97.4 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 7.8 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.33 (d, J = 9.0 Hz, 1H), 7.28 – 7.21 (m, 1H), 6.89 (t, J = 5.4 Hz, 1H), 6.35 (s,1H), 4.67 (d, J = 6.1 Hz, 2H), 3.55 (d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.3, 159.9, 158.3 (d, J = 259.4 Hz), 150.6, 142.0 (q, J =34.5 Hz), 134.3 (d, J = 5.1 Hz), 133.7, 133.2, 133.1, 132.2 (d, J = 1.8 Hz), 131.5 (d, J = 4.0 Hz), 131.2, 129.4, 127.5, 121.4 (d, J = 13.8 Hz), 119.4 (q,J = 275.4 Hz), 119.0 (d, J = 23.6 Hz), 103.0 (q, J = 5.6 Hz), 41.6, 32.8 (q,J = 3.6 Hz). HRMS (ESI) calcd for C 20 H 13 Cl3F4N3O3 ([M + H) + 523.9953, Found 523.9951.

[0133] 2-Chloro-4-fluoro-N-(4-fluoro-2-methylbenzyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 41): white solid, 85% yield, melting point 79.2-90.4 °C. 1 H NMR(400 MHz, DMSO-d6) δ 9.08 (t, J = 5.6 Hz, 1H), 7.79 (d, J = 9.8 Hz, 1H), 7.61(dd, J = 7.8, 1.3 Hz, 1H), 7.33 (dd, J = 8.8, 5.8 Hz, 1H), 7.05 (dd, J =10.1, 2.9 Hz, 1H), 6.99 (td, J = 8.6, 2.8 Hz, 1H), 6.60 (s, 1H), 4.39 (d, J =5.8 Hz, 2H), 3.41 (s, 3H), 2.33 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ164.1, 162.3 (d, J = 246.0 Hz), 159.9, 158.2 (d, J = 259.4 Hz), 150.6, 142.0(q, J = 34.5 Hz), 139.0 (d, J = 8.0 Hz), 133.1 (d, J = 9.8 Hz), 132.0 (d, J =2.2 Hz), 131.9 (d, J = 4.0 Hz), 131.0 (d, J = 2.9 Hz), 130.5 (d, J = 8.7 Hz), 121.3 (d, J = 13.8 Hz), 119.4 (q, J = 275.4 Hz), 118.9 (d, J = 23.6 Hz),117.3 (d, J = 21.4 Hz), 112.9 (d, J = 21.1 Hz), 103.0 (q, J = 5.6 Hz), 41.8,32.8 (q, J = 3.8 Hz), 19.3 (d, J = 1.8 Hz). HRMS (ESI) calcd for C 21 H 16 ClF5N3O3([M + H)) + ) 488.0795, Found 488.0794.

[0134] 2-Chloro-N-(2-Chloro-4-fluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 42): pale yellow solid, yield 67%, melting point 76.6-86.9 °C. 1 H NMR(400 MHz, Chloroform-d) δ 7.69 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 8.6, 5.9Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.15 (dd, J = 8.4, 2.6 Hz, 1H), 6.98 (td,J = 8.3, 2.7 Hz, 1H), 6.87 (t, J = 5.9 Hz, 1H), 6.35 (s, 1H), 4.67 (d, J =6.0 Hz, 2H), 3.55 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.3, 162.1 (d,J = 249.6 Hz), 159.9, 158.3 (d, J = 259.4 Hz), 150.6, 142.0 (q, J = 34.7 Hz), 134.4 (d, J = 10.5 Hz), 133.2 (d, J = 10.2 Hz), 132.2 (d, J = 2.2 Hz), 131.6,131.6 (d, J = 4.7 Hz), 131.1 (d, J = 3.6 Hz), 121.4 (d, J = 13.8 Hz), 119.4(q, J = 275.8 Hz), 119.0 (d, J = HRMS (ESI)calcd for C 20 H 13 Cl2F5N3O3 ([M + H) + ) 508.0249, Found 508.0249.

[0135] 2-Chloro-N-(4-Chloro-2-fluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 43): white solid, 87% yield, melting point 123.5-127.0 °C. 1 H NMR(400 MHz, DMSO-d6) δ 9.23 (t, J = 5.8 Hz, 1H), 7.80 (d, J = 9.8 Hz, 1H), 7.62(d, J = 7.8 Hz, 1H), 7.50 – 7.40 (m, 2H), 7.30 (dd, J = 8.3, 2.4 Hz, 1H), 6.61 (s, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.41 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.4, 160.8 (d, J = 242.8 Hz), 159.9, 158.2 (d, J = 252.1Hz), 150.6, 142.0 (q, J = 34.5 Hz), 134.4 (d, J = 10.2 Hz), 133.2 (d, J = 9.8Hz), 132.1 (d, J = 2.2 Hz), 131.6 (d, J = 4.0 Hz), 131.2 (d, J = 5.1 Hz), 124.8 (d, J = 3.6 Hz), 123.4 (d, J = 14.9 Hz), 121.3 (d, J = 13.8 Hz), 119.4(q, J = 275.8 Hz), 119.0 (d, J = 23.3 Hz), 116.3 (d, J = 24.7 Hz), 103.0 (q,J = 5.4 Hz), 37.7 (d, J = 3.6 Hz), 32.8 (q, J = 3.6 Hz). HRMS (ESI) calcd forC 20 H 13 Cl2F5N3O3 ([M + H) + ) 508.0249, Found 508.0247.

[0136] 2-Chloro-N-(3,4-dimethylbenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 44): white solid, 86% yield, melting point 146.9-148.6 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.15 – 7.10 (m, 2H), 7.07 (dd, J = 7.7, 2.1 Hz, 1H), 6.56 (t, J = 7.0 Hz,1H), 6.35 (s, 1H), 4.57 (d, J = 5.6 Hz, 2H), 3.55 (d, J = 1.3 Hz, 3H), 2.26(d, J = 2.9 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 164.1, 159.8, 158.2 (d,J = 259.0 Hz), 150.6, 141.9 (q, J = 34.5 Hz), 137.1, 136.2, 134.8, 133.2 (d,J = 10.2 Hz), 132.2 (d, J = 2.2 Hz), 132.0 (d, J = 4.0 Hz), 130.1, 129.4,125.4, 121.3 (d, J = 13.8 Hz), 123.7 – 114.9 (m), 119.0 (d, J = 23.6 Hz),103.0 (q, J = 5.5 Hz), 44.2, 32.8 (q, J = 3.8 Hz), 19.8, 19.5. HRMS (ESI)calcd for C 22 H 19 ClF4N3O3 ([M + H) + ) 484.1046, Found 484.1048.

[0137] 2-Chloro-N-(3,4-difluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 45): white solid, 83% yield, melting point 177.0-180.0 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.18 (ddt, J = 9.8, 5.3, 2.3 Hz, 1H), 7.13 (dd, J = 10.0, 7.9 Hz, 1H), 7.09 –7.04 (m, 1H), 6.73 (t, J = 6.2 Hz, 1H), 6.35 (s, 1H), 4.58 (d, J = 6.0 Hz,2H), 3.55 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.4, 159.9, 158.4 (d, J= 259.4 Hz), 151.4 (dd, J = 56.5, 12.9 Hz), 150.6, 148.9 (dd, J = 55.4, 12.5Hz), 142.0 (q, J = 34.5 Hz), 134.8 (dd, J = 5.6, 3.8 Hz), 133.2 (d, J = 10.2Hz), 132.2 (d, J = 1.8 Hz), 131.6 (d, J = 4.0 Hz), 123.9 (dd, J = 6.5, 3.6Hz), 121.5 (d, J = 13.8 Hz), 119.4 (q, J = 275.4 Hz), 119.0 (d, J = 23.6 Hz), 117.6 (d, J = 17.4 Hz), 116.9 (d, J = 17.4 Hz), 103.0 (q, J = 5.6 Hz), 43.3(d, J = 1.5 Hz), 32.8 (q, J = 3.6 Hz). HRMS (ESI) calcd for C 20 H 13 ClF6N3O3 ([M+ H) + ) 492.0544, Found 492.0547.

[0138] 2-Chloro-N-(3,4-Dichlorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 46): white solid, 85% yield, melting point 169.5-171.1 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1Hz, 1H), 6.78 (t, J = 5.9 Hz, 1H), 6.35 (s, 1H), 4.58 (dd, J = 6.0, 2.0 Hz, 2H), 3.55 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.5, 159.9, 158.3 (d, J = 259.8 Hz), 150.6, 142.0 (q, J = 34.5 Hz), 138.0, 133.2 (d, J = 9.8 Hz), 132.8, 132.2 (d, J = 1.8 Hz), 131.7, 131.6 (d, J = 3.6 Hz), 130.8, 129.8,127.2, 121.5 (d, J = 13.8 Hz), 119.4 (q, J = 275.6 Hz), 119.0 (d, J = 23.6Hz), 103.0 (d, J = 5.4 Hz), 43.1, 32.8 (q, J = 3.8 Hz). HRMS (ESI) calcd forC 20 H 13 Cl3F4N3O3 ([M + H) + ) 523.9953, Found 523.9951.

[0139] 2-Chloro-4-fluoro-N-(4-fluoro-3-methylbenzyl)-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 47): white solid, 83% yield, melting point 157.0-159.2 °C. 1 HNMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 9.0 Hz,1H), 7.17 (dd, J = 7.4, 2.8 Hz, 1H), 7.13 (ddd, J = 7.6, 4.9, 2.4 Hz, 1H), 7.01 – 6.91 (m, 1H), 6.61 (t, J = 5.6 Hz, 1H), 6.35 (s, 1H), 4.56 (d, J = 5.8Hz, 2H), 3.55 (s, 3H), 2.27 (d, J = 2.1 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.2, 160.9 (d, J = 244.5 Hz), 159.9, 158.3 (d, J = 259.4 Hz), 150.6,142.0 (q, J = 34.5 Hz), 133.2 (d, J = 10.2 Hz), 133.0 (d, J = 3.6 Hz), 132.2(d, J = 2.2 Hz), 131.9 (d, J = 4.0 Hz), 131.2 (d, J = 5.4 Hz), 126.9 (d, J =8.0 Hz), 125.3 (d, J = 17.8 Hz), 121.4 (d, J = 13.8 Hz), 119.4 (q, J = 275.4Hz), 119.0 (d, J = 23.6 Hz), 115.3 (d, J = 22.5 Hz), 103.0 (q, J = 5.6 Hz), 43.7, 32.8 (q, J = 3.6 Hz), 14.6 (d, J = 3.6 Hz). HRMS (ESI) calcd forC 21 H 16 ClF5N3O3 ([M + H) + ) 488.0795, Found 488.0797.

[0140] 2-Chloro-N-(3-Chloro-4-methylbenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 48): white solid, yield 82%, melting point 171.9-174.4 °C. 1 HNMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 7.6 Hz, 1H), 7.33 (dd, J = 5.5,3.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.14 (dd, J = 7.8, 1.9 Hz, 1H), 6.65(t, J = 5.8 Hz, 1H), 6.35 (s, 1H), 4.57 (d, J = 6.3 Hz, 2H), 3.55 (d, J = 1.3Hz, 3H), 2.36 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.3, 159.9, 158.3(d, J = 259.4 Hz), 150.6, 142.0 (q, J = 34.5 Hz), 136.8, 135.5, 134.6, 133.2(d, J = 10.2 Hz), 132.2 (d, J = 1.8 Hz), 131.8 (d, J = 4.0 Hz), 131.3, 128.5,126.2, 121.4 (d, J = 13.8 Hz), 119.0 (d, J = 23.6 Hz), 123.7 – 114.5 (m),103.0 (t, J = 5.6 Hz), 43.5, 32.8 (q, J = 3.8 Hz), 19.8. HRMS (ESI) calcd forC 21 H 16 Cl2F4N3O3 ([M + H) + ) 504.0499, Found 504.0502.

[0141] 2-Chloro-N-(3-Chloro-4-fluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 49): white solid, 87% yield, melting point 179.7-181.0 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 6.9, 2.3Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.23 (ddd, J = 8.5, 4.5, 2.3 Hz, 1H), 7.11(t, J = 8.6 Hz, 1H), 6.75 (t, J = 5.8 Hz, 1H), 6.35 (s, 1H), 4.57 (d, J = 5.1Hz, 2H), 3.55 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.4,159.9, 159.2 (d, J = 79.2 Hz), 156.7 (d, J = 68.3 Hz), 150.6, 142.0 (q, J =34.7 Hz), 134.8 (d, J = 4.0 Hz), 133.2 (d, J = 10.2 Hz), 132.2 (d, J = 2.2Hz), 131.6 (d, J = 4.0 Hz), 130.1, 127.7 (d, J = 7.3 Hz), 121.5 (d, J = 13.8Hz), 121.2 (d, J = 17.8 Hz), 119.4 (q, J = 275.4 HRMS (ESI) calcd for C 20 H 13 Cl2F5N3O3 ([M + H) + ) 508.0249, Found 508.0252.

[0142] 2-Chloro-N-(4-Chloro-3-fluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (Compound 50): White solid, yield 64%, melting point 160.5-164.1 °C. 1 H NMR(400 MHz, Chloroform-d) δ 7.69 (d, J = 7.6 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.16(dd, J = 9.6, 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H), 6.77 (t, J = 5.9Hz, 1H), 6.35 (s, 1H), 4.60 (dd, J = 6.0, 2.1 Hz, 2H), 3.56 (s, 3H). 13C NMR(101 MHz, Chloroform-d) δ 164.6, 159.9, 159.5 (d, J = 18.9 Hz), 157.0 (d, J =8.7 Hz), 150.6, 142.0 (q, J = 34.7 Hz), 138.7 (d, J = 6.5 Hz), 133.2 (d, J =9.8 Hz), 132.1 (d, J = 1.8 Hz), 131.7 (d, J = 4.0 Hz), 130.9, 124.2 (d, J =3.6 Hz), 121.4 (d, J = 13.8 Hz), 120.1 (d, J = 17.8 Hz), 119.4 (q, J = HRMS (ESI) calcd for C 20 H 13 Cl2F5N3O3 ([M+ H) + ) 508.0249, Found 508.0252.

[0143] 2-Chloro-N-(3,5-dimethylbenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (Compound 51): White solid, 83% yield, melting point 168.9-171.1 °C. 1 H NMR(400 MHz, Chloroform-d) δ 7.70 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 6.95 (d, J = 9.4 Hz, 3H), 6.58 (t, J = 5.8 Hz, 1H), 6.35 (s, 1H), 4.56 (d, J= 5.6 Hz, 2H), 3.55 (s, 3H), 2.31 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ164.2, 159.8, 158.1 (d, J = 259.0 Hz), 150.5, 141.9 (q, J = 34.5 Hz), 138.4,137.3, 133.2 (d, J = 10.2 Hz), 132.1 – 132.0 (m), 132.0, 129.3, 125.8, 121.3(d, J = 13.8 Hz), 119.4 (q, J = 275.6 Hz), 118.9 (d, J = 23.3 Hz), 103.0 (q,J = 5.5 Hz), 44.3, 32.8 (q, J = 3.6 Hz), 21.3. HRMS (ESI) calcd for C 22 H 19 ClF4N3O3 ([M + H) + ) 484.1046, Found 484.1047.

[0144] 2-Chloro-N-(3,5-difluorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 52): white solid, yield 86%, melting point 184.2-188.1 °C. 1 H NMR(400 MHz, Chloroform-d) δ 7.69 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.88 (dt, J = 6.4, 2.2 Hz, 2H), 6.81 (t, J = 6.1 Hz, 1H), 6.73 (tt, J = 9.0, 2.4 Hz, 1H), 6.35 (s, 1H), 4.60 (dd, J = 6.0, 2.1 Hz, 2H), 3.55 (s, 3H). 13CNMR (101 MHz, Chloroform-d) δ 164.7, 164.4 (d, J = 12.7 Hz), 161.9 (d, J =12.7 Hz), 159.9, 158.3 (d, J = 259.4 Hz), 150.6, 142.0 – 141.8 (m), 142.6 –141.4 (m), 133.2 (d, J = 10.2 Hz), 131.9 (d, J = 1.8 Hz), 131.7 (d, J = 4.0Hz), 121.4 (d, J = 13.8 Hz), 119.4 (q, J = 275.4 Hz), 119.0 (d, J = 23.6 Hz),110.5 HRMS (ESI) calcd forC 20 H 13 ClF6N3O3 ([M + H) + ) 492.0544, Found 492.0548.

[0145] 2-Chloro-N-(3,5-dichlorobenzyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)benzamide (compound 53): white solid, 85% yield, melting point 175.5-178.8 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.28 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 6.86 (t, J = 6.0 Hz, 1H), 6.34 (s, 1H), 4.56 (dd, J = 6.0, 2.1 Hz, 2H), 3.54 (d, J = 1.3 Hz, 3H). 13CNMR (101 MHz, Chloroform-d) δ 164.6, 159.9, 158.3 (d, J = 259.8 Hz), 150.5,142.0 (q, J = 34.3 Hz), 141.2, 135.2, 133.2 (d, J = 10.2 Hz), 132.0 (d, J =1.8 Hz), 131.6 (d, J = 4.0 Hz), 127.8, 126.2, 121.4 (d, J = 13.8 Hz), 119.4(q, J = 275.6 Hz), 119.0 (d, J = 23.3 Hz), 103.8 – 102.0 (m), 43.1, 32.8 (q,J = 3.6 Hz). HRMS (ESI) calcd for C 20 H 13 Cl3F4N3O3 ([M + H) + 523.9953, Found 523.9951.

[0146] Example 2

[0147] This embodiment tests the herbicidal activity and herbicidal spectrum of the target compound from Example 1.

[0148] The target compounds 1-53 obtained in Example 1 were subjected to indoor herbicidal activity assays using the foliar spray method (NY / T 1155.4-2006).

[0149] The tested weeds included: broadleaf weeds—Amaranthus retroflexus (Amaranthaceae), Oxybasis glauca (Amaranthaceae), Abutilon theophrasti (Malvaaceae), Plantago asiatica (Plantagoasiatica, Plantaginaceae), and Portulaca oleracea (Portulacaceae); and grass weeds—Echinochloa crus-galli, Digitaria sanguinalis, and Leptochloachinensis.

[0150] Among them, Amaranthus retroflexus, Chenopodium album, barnyard grass, and Digitaria sanguinalis were used for initial screening and herbicidal activity determination; the remaining four were used for herbicidal spectrum determination.

[0151] Test method:

[0152] The potted foliar spraying method was used. Seeds of the tested weeds were sown in 8.5 cm diameter plastic pots, covered with 0.5–1.0 cm of soil, and cultivated in a greenhouse. Foliar spraying was applied when broadleaf weeds reached the 2–4 leaf stage and grass weeds reached the 1–3 leaf stage.

[0153] The test compound was dissolved in a small amount of DMF and diluted with an aqueous solution containing 0.5% Tween-80. For the initial screening test, a solution with a concentration of 37.5 g ai / ha was prepared. For the concentration gradient test, 37.5 g ai / ha was used as the highest concentration, and six concentration gradients were set up using the 2:5 dilution method: 37.5, 18.75, 9.38, 4.69, 2.34, and 1.17 g ai / ha. An aqueous solution with equal volumes of solvent and emulsifier served as a blank control, and the commercially available herbicide pyrimethanil served as a positive control. Each treatment was replicated four times.

[0154] Handheld sprayers were used for spraying, with a dosage calculated at 37.5 g ai / ha. After treatment, the plants were placed in a greenhouse for continued cultivation, and the growth status of weeds was observed and recorded regularly. Seven days after application, the herbicidal activity was assessed visually, and recorded according to the degree of weed damage. The corresponding control efficacy ranges for each value are as follows: 95% indicates herbicidal activity of 90%–100%, 85% indicates herbicidal activity of 80%–89%, 75% indicates herbicidal activity of 70%–79%, 65% indicates herbicidal activity of 60%–69%, 55% indicates herbicidal activity of 50%–59%, and 25% indicates herbicidal activity of less than 50%.

[0155] Herbicidal activity test results:

[0156] The herbicidal activity results of the 53 target compounds are shown in Table 1.

[0157] Note: Bold data indicates herbicidal activity ≥80%.

[0158] Based on the initial screening and considering the type of substituent, compounds 7 (2-methylphenyl), 13 (2-chlorophenyl), and 20 (2-fluoro-6-methylphenyl) were selected for herbicidal spectrum determination. The tested weeds were expanded to eight species (Amaranthus retroflexus, Abutilon theophrasti, Portulaca oleracea, Chenopodium album, Plantago asiatica, Barnyardgrass, Crataegus pinnatifida, and Echinochloa crus-galli), which were classified into broadleaf weeds and grass weeds. The results are shown in Table 2.

[0159] Note: Bold data indicates herbicidal activity ≥80%.

[0160] In addition, using Amaranthus retroflexus and Barnyardgrass as test weeds, the herbicidal activity of compounds 7, 13, and 20 was determined at six concentration gradients, and the results are shown in Table 3.

[0161] Note: Bold data indicates herbicidal activity ≥80%.

[0162] As shown in Table 1, the preliminary screening results revealed that the 53 target compounds exhibited varying degrees of herbicidal activity against the tested weeds at a dosage of 37.5 g ai / ha, demonstrating a clear structure-activity relationship. Overall, the activity was superior against broadleaf weeds (Amaranthus retroflexus and Chenopodium album) and grass weeds (Barnyardgrass and Digitaria sanguinalis). Phenyl compounds showed better activity than benzyl compounds. The position of the substituent on the benzene ring significantly affected the activity; 4-position substitution resulted in poor activity, 3-position substitution in moderate activity, and 2-position substitution in the best activity. The activity differences between 2,6-disubstituted phenyl compounds and 2-monosubstituted phenyl compounds were small, both exhibiting excellent activity.

[0163] As shown in Table 2, at a dose of 37.5 g ai / ha, compounds 7, 13, and 20 all exhibited herbicidal activity exceeding 90% against five broadleaf weeds (Amaranthus retroflexus, Chenopodium album, Abutilon theophrasti, Plantago asiatica, and Portulaca oleracea). Their activity against grass weeds was weaker than that against broadleaf weeds, but their efficacy against Echinochloa crus-galli was still over 50%.

[0164] As shown in Table 3, the three compounds still exhibited more than 80% herbicidal activity against Amaranthus retroflexus at a dose of 9.38 g ai / ha; compounds 13 and 20 still exhibited more than 80% activity against Amaranthus retroflexus at a dose of 2.34 g ai / ha, demonstrating excellent low-dose activity.

[0165] In summary, compounds 7, 13, and 20 exhibit excellent broad-spectrum herbicidal activity against broadleaf weeds, and also demonstrate excellent low-dose activity, showing promising prospects for development and application.

[0166] Example 3

[0167] This embodiment conducts crop safety tests on target compounds 7, 13, and 20.

[0168] The tested crops included: soybean, cotton, wheat, rice, and corn.

[0169] Test method:

[0170] The foliar spraying method was used for potted plants. Seeds of the tested crops were sown in 8.5 cm diameter plastic pots, covered with 0.5–1.0 cm of soil, and cultivated in a greenhouse. Once the tested crops reached their appropriate leaf age, foliar spraying was applied.

[0171] The test compound was dissolved in a small amount of DMF and diluted with an aqueous solution containing 0.5% Tween-80 to prepare a solution with a concentration of 75 g a.i. / ha. An aqueous solution of equal volume of solvent and emulsifier was used as a blank control, and the commercially available herbicide pyrimethanil was used as a positive control. Each treatment was replicated four times.

[0172] Handheld sprayers were used for foliar spraying, with an application rate of 75 g ai / ha. After treatment, the crops were placed in a greenhouse for continued cultivation, and their growth status was observed and recorded regularly. Seven days after application, crop safety was assessed visually, and the severity of damage was graded and recorded.

[0173] The results of the crop safety test are shown in Table 4.

[0174] As shown in Table 4, at a dose of 75 g ai / ha, compounds 7, 13, and 20 caused relatively high damage (85%–95%) to broadleaf crops soybean and cotton, comparable to the positive control pyrimisulfuron (95%–100%). The damage to gramineous crops wheat and maize was significantly reduced (10%–30%), but the damage to rice was 35%–60%, higher than that to wheat and maize. Overall, the three target compounds showed better safety in gramineous crops than in broadleaf crops, with compound 7 showing the lowest damage (10%) to maize and wheat, demonstrating excellent safety.

[0175] In summary, this invention provides a class of N-substituted uracil benzamide compounds, their preparation methods, and their weeding applications. The preparation method for these compounds is simple and yields high amounts. Weeding activity tests show that most target compounds exhibit excellent control effects against tested broadleaf weeds (Amaranthus retroflexus and Chenopodium album) at a dose of 37.5 g ai / ha, and some compounds also show good inhibitory activity against gramineous weeds (barnyardgrass and crabgrass). Further weeding spectrum and concentration gradient tests show that compounds 7, 13, and 20 exhibit broad-spectrum and highly efficient weeding activity against broadleaf weeds, maintaining excellent control efficacy even at low doses. Crop safety tests show that these compounds are safe for gramineous crops (especially corn and wheat). In conclusion, the compounds of this invention have good application prospects and development value in the field of agricultural weed control.

[0176] The embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. N-substituted uracil benzamide compounds, characterized in that, The general structural formula of the compound is shown in Formula I: Wherein, R is selected from: (a) C1-C6 alkyl, C1-C4 alkyl substituted with C1-C4 alkoxy, or C1-C4 alkyl substituted with C1-C4 alkoxycarbonyl; (b) C6-C10 aryl, wherein the C6-C10 aryl is directly bonded to the nitrogen atom in Formula I, and the C6-C10 aryl is optionally substituted by 1-2 substituents independently selected from halogen, C1-C4 alkyl or C1-C4 alkoxy; (c) C6-C10 aryl-C1-C6 alkyl, wherein the C1-C6 alkyl is straight-chain or branched, the C6-C10 aryl is connected to a nitrogen atom in Formula I through the C1-C6 alkyl, and the C6-C10 aryl is optionally substituted by 1-2 substituents independently selected from halogen, C1-C4 alkyl or C1-C4 alkoxy.

2. The N-substituted uracil benzamide compound according to claim 1, characterized in that, Wherein R is a C3-C5 alkyl, a C1-C3 alkyl substituted with C1-C3 alkoxy, a C1-C3 alkyl substituted with C1-C3 alkoxycarbonyl, a phenyl, a substituted phenyl, a benzyl, or a substituted benzyl; the substituent is selected from halogens, C1-C4 alkyl, or C1-C4 alkoxy, and the number of substituents is one or two.

3. The N-substituted uracil benzamide compound according to claim 2, characterized in that, The substituent is located at the 2-, 3-, 4-, 2,4-, 2,6-, 3,4-, or 3,5-position of the benzene ring; the substituent is fluorine, chlorine, methyl, ethyl, isopropyl, or methoxy.

4. The N-substituted uracil benzamide compound according to claim 1, characterized in that, The structural formula of the compound is selected from any of the following: 。 5. A method for preparing an N-substituted uracil benzamide compound as described in any one of claims 1 to 4, characterized in that, Includes the following steps: S1. The compound shown in formula A undergoes esterification in an alcohol solvent in the presence of an acid to produce the compound shown in formula B. S2, the compound shown in formula B reacts in an alcohol solvent in the presence of a reducing agent to produce the compound shown in formula C; S3. The compound shown in formula C and the compound shown in formula D undergo a condensation reaction in an organic solvent in the presence of an acid. The resulting intermediate reacts with iodomethane in the presence of a base to produce the compound shown in formula E. Compound S4 and compound E are hydrolyzed in an organic solvent in the presence of acid to produce compound F. S5 and the compound shown in formula F react with the amine of formula RNH2 to generate N-substituted uracil benzamide compounds; Step S5 is performed using either method A or method B: Method A: The compound shown in formula F reacts with an amine of formula RNH2 in the presence of a condensing agent; Method B: The compound shown in Formula F is first reacted with oxalyl chloride, and then with an amine of Formula RNH2; The preparation route for steps S1 to S5 is as follows: 。 6. The preparation method according to claim 5, characterized in that, In step S1, the alcohol solvent is ethanol, the acid is concentrated sulfuric acid, and the ratio of compound A to concentrated sulfuric acid is 0.05 to 0.5 mL of concentrated sulfuric acid per mmol of compound A. In step S2, the alcohol solvent is a 65% to 85% aqueous ethanol solution, the reducing agent is iron powder and ammonium chloride, the molar ratio of compound B to iron powder is 1:(3~5), and the molar ratio of compound B to ammonium chloride is 1:(3~5). In step S3, the acid is acetic acid, the base is selected from sodium carbonate, potassium carbonate or cesium carbonate, the molar ratio of compound C to compound D is 1:(1~1.2), the molar ratio of compound C to base is 1:(1~2), and the molar ratio of compound C to iodomethane is 1:(1~3). In step S4, the acid is selected from hydrochloric acid or sulfuric acid; In step S5, method A, the solvent for the reaction is selected from one or more of dichloromethane, tetrahydrofuran, or N,N-dimethylformamide; the condensing agent includes EDCI and HOBt; an acid-binding agent is also added to the reaction system; the acid-binding agent is selected from triethylamine, pyridine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or cesium carbonate, and the molar ratio of compound F to the acid-binding agent is 1:(1~5); the molar ratio of compound F to the amine of formula RNH2 is 1:(1~1.5); the molar ratio of compound F to EDCI is 1:(1~1.5); and the molar ratio of compound F to HOBt is 1:(1~1.5). In step S5, method B, the solvent for the reaction is selected from one or more of dichloromethane, tetrahydrofuran, or N,N-dimethylformamide. The ratio of compound F to oxaloyl chloride is 0.5 to 2.0 mL of oxaloyl chloride per mmol of compound F. The molar ratio of compound F to the amine of formula RNH2 is 1:(1 to 1.5).

7. The use of the N-substituted uracil benzamide compound as described in any one of claims 1 to 4, or the compound prepared by the method described in claim 5 or 6, in the control of weeds.

8. The application according to claim 7, characterized in that, The weeds are broadleaf weeds and / or grass weeds.

9. A herbicide composition comprising an N-substituted uracil benzamide compound as described in any one of claims 1 to 4, and an agriculturally acceptable carrier and / or adjuvant.

10. The herbicide composition according to claim 9, characterized in that, The composition is in the form of a wettable powder, a suspension, or a water-dispersible granule.

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