Pyridine and pyrimidine derivatives as herbicides

Abstract

The present invention relates to compounds of formula (I), wherein A 1 , A 2 , A 3 , R 1 , R 3 , Q and X are as defined herein. The present invention further relates to herbicidal compositions comprising compounds of formula (I), and to the use of compounds of formula (I) for controlling weeds, in particular in crops of useful plants.(I).

Description

[0001] This invention relates to novel herbicidal compounds, methods for their preparation, herbicidal compositions comprising these novel compounds, and their use for controlling weeds—particularly in useful plant crops—or for inhibiting plant growth.

[0002] WO 2010 / 064688 discloses the use of pyrimidine derivatives as herbicides. WO 2016 / 149315 discloses substituted pyrimidineoxypyridine derivatives as herbicides. WO 2020 / 002089 discloses substituted 2-heteroaryloxypyridines. WO 2021 / 204706 discloses 5-haloalkoxy-pyrimidine herbicidal compounds. GB 2594931 discloses phenoxypyridine compounds. WO 2022 / 002838 discloses substituted heteroaryloxypyridines. WO 2023 / 186691 discloses substituted 2-C-acrazine. This invention relates to novel herbicidal compounds.

[0003] Therefore, according to the present invention, a compound having formula (I) is provided:

[0004]

[0005] in

[0006] X is O or CHR 8 ,

[0007] Q is a phenyl or C-linked 6-membered heteroaryl group, wherein the phenyl or 6-membered heteroaryl group is optionally linked by one or more R groups. 4 replace;

[0008] A 1 Is it CH or N?

[0009] A 2 It is CR 2 Or N,

[0010] Where A 1 and A 2 At least one of them is N,

[0011] A 3 It is CR 5 Or N;

[0012] Where X is O, then when A 2 It is CR 2 And A 3 When it is N, A 1 Not N;

[0013] R 1Choose from the following groups: hydrogen, halogen, -CN, nitro, C1-C4 alkyl-, C2-C4 alkenyl-, C2-C4 alkynyl-, C1-C4 haloalkyl-, C1-C4 alkoxy-, C1-C4 haloalkoxy-, -S(O) p C1-C4 alkyl and C3-C6 cycloalkyl-;

[0014] R 2 Choose from the group consisting of: hydrogen, halogens, and C1-C6 alkyl groups;

[0015] R 3 Choose from the group consisting of: halogens, C1-C4 haloalkyl- and C1-C2 haloalkoxy-;

[0016] R 4 Choose from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxy-C1-C3 alkyl-, C1-C4 alkoxy-C1-C3 alkoxy-, C1-C4 alkoxy-C1-C3 alkoxy-C1-C3 alkyl-, -CN, NO2, C2-C4 alkenyl, C2-C4 alkynyl, -S(O) p C1-C4 alkyl groups, -S(O) p C1-C4 haloalkyl, -C(O)OC1-C4 alkyl and -C(O)NR 6 R 7 ;

[0017] R 5 It is hydrogen or halogen;

[0018] R 6 Selected from the group consisting of: hydrogen, C3-C4 cycloalkyl, C1-C4 alkyl, and C1-C4 haloalkyl;

[0019] R 7 Selected from the group consisting of: hydrogen, C3-C4 cycloalkyl, C1-C4 alkyl, and C1-C4 haloalkyl;

[0020] R 8 It is hydrogen or hydroxyl; and

[0021] p is 0, 1, or 2;

[0022] Or agriculturally acceptable salt.

[0023] Alkyl groups (e.g., C1-C6 alkyl groups) include, for example, methyl (Me, CH3), ethyl (Et, C2H5), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl (s-Bu), and tert-butyl (t-Bu).

[0024] The alkenyl and alkynyl moieties can be straight-chain or branched, and these alkenyl moieties can have (E)- or (Z)-configurations, where appropriate. Examples are vinyl, allyl, and propargyl. The alkenyl and alkynyl moieties can contain one or more double and / or triple bonds in any combination.

[0025] Halogens (or halogen groups) encompass fluorine, chlorine, bromine, or iodine. The above applies correspondingly to halogens in other definitional contexts, such as alkyl halogens.

[0026] Haloalkyl groups (e.g., C1-C6 haloalkyl groups) are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl, heptafluoropropyl and perfluorohexyl.

[0027] Alkoxy groups (e.g., C1-C4 alkoxy-) are, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, preferably methoxy and ethoxy.

[0028] Alkoxyalkyl (e.g., C1-C4 alkoxy-C1-C3 alkyl-) includes, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl, isopropoxymethyl, or isopropoxyethyl.

[0029] Cycloalkyl (e.g., C3-C6 cycloalkyl-) includes, for example, cyclopropyl (c-propyl, c-Pr), cyclobutyl (c-butyl, c-Bu), cyclopentyl (c-pentyl), and cyclohexyl (c-hexyl) and may be substituted or unsubstituted as indicated.

[0030] C1-C6 alkyl-S-(alkylthio) is, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, or tert-butylthio, preferably methylthio or ethylthio.

[0031] C1-C6 alkyl-S(O)- (alkyl sulfinyl) is, for example, methyl sulfinyl, ethyl sulfinyl, propyl sulfinyl, isopropyl sulfinyl, n-butyl sulfinyl, isobutyl sulfinyl, sec-butyl sulfinyl or tert-butyl sulfinyl, preferably methyl sulfinyl or ethyl sulfinyl.

[0032] C1-C6 alkyl-S(O)2- (alkylsulfonyl) is, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl or ethylsulfonyl.

[0033] In a preferred embodiment of the invention, in a compound having formula (I), X is CH2.

[0034] In one embodiment of the invention, a compound having formula (I) is provided, wherein A 1 It is N and A 2 It is CR 2 (where R) 2 (e.g., H or a halogen group). In another embodiment of the invention, a compound having formula (I) is provided, wherein A 1 It is CH and A 2 It is N. In another embodiment of the invention, a compound having formula (I) is provided, wherein A 1 It is N and A 2 It is N.

[0035] In another embodiment of the invention, a compound having formula (I) is provided, wherein A 3 It is N. In another embodiment of the invention, A 3 It is CR 5 In this embodiment, preferably, R 5 It is hydrogen or halogen, such as chlorine or fluorine, with fluorine being the most preferred.

[0036] Therefore, in one embodiment of the invention, a compound having formula (I) is provided, wherein A 1 It is N, A 2 It is CH and A 3 It is N (where X is CHR) 8 In another embodiment of the invention, A 1 It is CH, A 2 It is N and A 3 It is N. In another embodiment of the invention, A 1 It is N, A 2 It is N and A 3 It is N.

[0037] In another embodiment of the invention, a compound having formula (I) is provided, wherein A 1 It is N, A 2 It is CH and A 3 It is CR 5 Preferably CH or CF. In another embodiment of the invention, A 1 It is CH, A 2 It is N and A 3 It is CR 5 Preferably CH or CF. In another embodiment of the invention, A 1 It is N, A 2It is N and A 3 It is CR 5 Preferably CH or CF.

[0038] In one embodiment of the invention, a compound having formula (I) is provided, wherein R 1 The group selected is from the group consisting of: hydrogen, halogen, C1-C4 alkyl-, and C1-C4 haloalkyl-. In a more preferred embodiment of the invention, R 1 It is hydrogen, methyl, or -CF3.

[0039] In one embodiment of the invention, a compound having formula (I) is provided, wherein R 3 It is a halogen (e.g., bromine or chlorine, most preferably chlorine), a C1-C4 haloalkyl- (e.g., -CF3), or a C1-C4 haloalkoxy- (e.g., -OCF3). In a more preferred embodiment, R 3 It is a halogen (e.g., bromine or chlorine, preferably chlorine).

[0040] In another embodiment of the invention, a compound having formula (I) is provided, wherein Q is selected from the group consisting of:

[0041]

[0042] Where n is 0, 1, or 2.

[0043] In a more preferred embodiment of the invention, a compound having formula (I) is provided, wherein Q is selected from the group consisting of: optionally being formed by one or two R 4 The substitutes Q-1, Q-3, and Q-4. In one embodiment of the invention, a compound having formula (I) is provided, wherein Q is optionally replaced by one or two R. 4 Replaces Q-1 or Q-4. In another embodiment of the invention, Q is optionally replaced by one or both R. 4 Replaces Q-1.

[0044] In a more preferred embodiment, Q is Q-1, R 3 It is a halogen or a C1-C4 haloalkyl group and n is 1 (wherein, in a preferred embodiment, Q is 4-CF3-phenyl-). In another preferred embodiment of the invention, Q is Q-1, R 3 It is a halogen and n is 2 (wherein, in a preferred embodiment, Q is 3,4-dihalophenyl- (e.g., 3-F,4-Cl-phenyl-, 3-Cl,4-F-phenyl-, 3,4-dichlorophenyl- or 3,4-difluorophenyl-)).

[0045] In another embodiment of the invention, Q is optionally represented by one or two R. 4Replaced by Q-3. In one embodiment of the invention, Q is optionally replaced by one or two R. 4 Replaced by Q-4. In another preferred embodiment of the invention, Q is Q-3, R 3 It is a halogen and n is 2 (wherein, in a preferred embodiment, Q is 6,5-dihalo-3-pyridinyl- (e.g., 6-chloro-5-fluoro-3-pyridinyl or 6-fluoro-5-chloro-3-pyridinyl)).

[0046] In one embodiment of the invention, n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2. In embodiments of the invention where n is 1 or 2, each R 4 Preferably selected from the group consisting of halogens (e.g., fluorine or chlorine) and C1-C4 haloalkyl groups (e.g., -CF3).

[0047] The compounds of formula (I) according to the present invention can be used as herbicides on their own, but they are typically formulated into herbicidal compositions using formulation adjuvants such as carriers, solvents, and surfactants (SAAs). Therefore, the present invention further provides a herbicidal composition comprising the herbicidal compound according to the present invention and an agriculturally acceptable formulation adjuvant. The composition may be in the form of a concentrate, which is diluted prior to use, although it may also be formulated as a ready-to-use composition. Final dilution is typically carried out with water, but may be performed using, in addition to water, liquid fertilizers, micronutrients, biological organisms, oils, or solvents.

[0048] As described above, the compounds of the present invention may contain an asymmetric center. Therefore, the compounds of the present invention may exist in a composition as a racemic mixture of two enantiomers. Alternatively, the compounds of the present invention may exist in an enantiomer-rich form.

[0049] The herbicidal composition typically contains 0.1% to 99%, particularly 0.1% to 95% by weight of a compound having Formula I and 1% to 99.9% by weight of a formulation adjuvant, which preferably contains 0% to 25% by weight of a surfactant.

[0050] The composition can be selected from many formulation types. These include emulsion concentrates (EC), suspension concentrates (SC), suspension emulsions (SE), capsule suspensions (CS), water-dispersible granules (WG), emulsifiable granules (EG), water-in-oil emulsions (EO), oil-in-water emulsions (EW), microemulsions (ME), oil dispersants (OD), oil-miscible flow agents (OF), oil-miscible liquids (OL), soluble concentrates (SL), ultra-low volume suspensions (SU), ultra-low volume liquids (UL), parent drug (TK), dispersible concentrates (DC), soluble powders (SP), wettable powders (WP), and soluble granules (SG). In any case, the type of formulation chosen will depend on the specific intended purpose and the physical, chemical, and biological properties of the compound having formula (I).

[0051] Soluble powders (SPs) can be prepared by mixing a compound having formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate, or magnesium sulfate) or one or more water-soluble organic solids (such as polysaccharides) and optionally one or more wetting agents, one or more dispersants, or a mixture of said reagents to improve water dispersibility / water solubility. The mixture is then ground into a fine powder. Similar compositions can also be granulated to form water-soluble granules (SGs).

[0052] Wettable powders (WPs) can be prepared by mixing a compound having formula (I) with one or more solid diluents or carriers, one or more wetting agents, and preferably one or more dispersants, and optionally one or more suspending agents to promote dispersion in a liquid. The mixture is then ground into a fine powder. Similar compositions can also be granulated to form water-dispersible granules (WGs).

[0053] Granules (GR) can be formed by granulating a mixture of a compound having formula (I) with one or more powdered solid diluents or carriers, or by absorbing a compound having formula (I) (or a solution thereof in a suitable reagent) into a porous particulate material (such as pumice, attapulgite clay, bleaching clay, kieselguhr, diatomaceous earth, or corn cob powder), or by adsorbing a compound having formula (I) (or a solution thereof in a suitable reagent) onto a hard core material (such as sand, silicates, mineral carbonates, sulfates, or phosphates) and drying it if necessary, from pre-formed blanks. Reagents typically used to aid absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones, and esters) and binders (such as polyvinyl acetate, polyvinyl alcohol, dextrin, sugars, and vegetable oils). One or more other additives (such as emulsifiers, wetting agents, or dispersants) may also be included in the granules.

[0054] Dispersible concentrates (DCs) can be prepared by dissolving a compound having formula (I) in water or an organic solvent such as a ketone, alcohol, or glycol ether. These solutions may contain surfactants (e.g., to improve water dilution or prevent crystallization in a spray can).

[0055] Emulsifiable concentrates (ECs) or oil-in-water emulsions (EWs) can be prepared by dissolving a compound having formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifiers, or a mixture of said reagents). Suitable organic solvents used in ECs include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150, and SOLVESSO 200; SOLVESSO is a registered trademark), ketones (such as cyclohexanone or methylcyclohexanone), and alcohols (such as benzyl alcohol, furfuryl alcohol, or butanol), N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone), and dimethylamides of fatty acids (such as C8-C...). 10 (Fatty acid dimethylamide) and chlorinated hydrocarbons. EC products can spontaneously emulsify when added to water, producing an emulsion with sufficient stability to allow for spray application using appropriate equipment.

[0056] The preparation of an emulsion (EW) involves obtaining a compound of formula (I) as a liquid (or, if not a liquid at room temperature, which can melt at a suitable temperature typically below 70°C) or in solution (by dissolving it in a suitable solvent), and then emulsifying the resulting liquid or solution into water containing one or more SAAs under high shear to produce an emulsion. Suitable solvents used in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzene), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes), and other suitable organic solvents with low solubility in water.

[0057] Microemulsions (MEs) can be prepared by mixing water with a blend of one or more solvents and one or more SAAs to spontaneously produce a thermodynamically stable, isotropic liquid formulation. The compound having formula (I) is initially present in water or in a solvent / SAA blend. Suitable solvents used in MEs include those described above used in ECs or EWs. MEs can be oil-in-water or water-in-oil systems (whichever system is present can be determined by conductivity measurements) and can be adapted to mix water-soluble and oil-soluble biocides in the same formulation. MEs are suitable for dilution in water, maintaining as a microemulsion or forming a conventional oil-in-water emulsion.

[0058] Suspension concentrates (SCs) may comprise aqueous or non-aqueous suspensions of finely fragmented, insoluble solid particles of a compound having formula (I). SCs can be prepared by ball milling or bead milling of a solid compound having formula (I) with one or more dispersants in a suitable medium to produce a fine-particle suspension of the compound. One or more wetting agents may be included in the composition, and a suspending agent may be included to reduce the rate of particle settling. Alternatively, the compound having formula (I) may be dry-milled and added to water containing the reagents described above to produce the desired final product.

[0059] Aerosol formulations comprise compounds having formula (I) and suitable propellants (e.g., n-butane). Compounds having formula (I) can also be dissolved or dispersed in a suitable medium (e.g., water or a water-miscible liquid, such as n-propanol) to provide compositions for use in unpressurized, manually operated spray pumps.

[0060] Capsule suspensions (CS) can be prepared in a manner similar to that used in the preparation of EW formulations, but with an additional polymerization stage, resulting in an aqueous dispersion of oil droplets, each droplet encapsulated in a polymer shell and containing a compound of formula (I) and optionally a carrier or diluent for that droplet. The polymer shell can be produced via interfacial polycondensation or via a coagulation process. These compositions can provide controlled release of compounds of formula (I) and can be used for seed treatment. Compounds of formula (I) can also be formulated in a biodegradable polymer matrix to provide slow, controlled release of the compound.

[0061] The composition may contain one or more additives to improve the biological properties of the composition, such as by improving wettability, retention, or distribution on a surface; rain resistance on the treated surface; or absorption or migration of compounds having formula (I). Such additives include surfactants (SAAs), oil-based spray additives such as certain mineral oils or natural vegetable oils (such as soybean and rapeseed oils), modified vegetable oils (such as methylated rapeseed oil (MRSO)), and blends of these with other bio-enhancing adjuvants (components that may assist or modify the effects of compounds having formula (I)).

[0062] The wetting agent, dispersant, and emulsifier can be cationic, anionic, amphoteric, or nonionic SAA.

[0063] Suitable cationic types of SAAs include quaternary ammonium compounds (such as cetyltrimethylammonium bromide), imidazolines, and amine salts.

[0064] Suitable anionic SAAs include alkali metal salts of fatty acids, salts of aliphatic monoesters of sulfuric acid (e.g., sodium lauryl sulfate), salts of sulfonated aromatic compounds (e.g., sodium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, butyl naphthalene sulfonate, and mixtures of sodium di-isopropyl-naphthalene sulfonate and sodium tri-isopropyl-naphthalene sulfonate), ether sulfates, alcohol ether sulfates (e.g., sodium laureth-3-sulfate), ether carboxylates (e.g., sodium laureth-3-carboxylate), phosphate esters (products of reactions between one or more fatty alcohols and phosphoric acid (mainly monoesters) or with phosphorus pentoxide (mainly diesters), such as the reaction between lauryl alcohol and tetraphosphate; additionally, these products may be ethoxylated), sulfosuccinates, paraffin or olefin sulfonates, taurine, lignin sulfonates, and phosphate / sulfate salts of tristyrylphenol.

[0065] Suitable amphoteric types of SAAs include betaine, propionate, and glycine salt.

[0066] Suitable nonionic types of SAAs include condensation products of alkyl oxidases (such as ethylene oxide, propylene oxide, butane oxide, or mixtures thereof) with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol, or octylcresol); partial esters derived from long-chain fatty acids or hexyl anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; monoesters (e.g., fatty acid polyethylene glycol esters); amine oxides (e.g., lauryl dimethylamine oxide); lecithin and sorbitol and their esters, alkyl polyglycosides, and tristyrylphenols.

[0067] Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone, or sodium carboxymethyl cellulose) and expansive clays (such as bentonite or attapulgite).

[0068] The compounds of the present invention can also be used in mixtures with one or more other herbicides and / or plant growth regulators. Examples of such other herbicides or plant growth regulators include acetochlor, trifluralin (including trifluralin-sodium), bensulfuron, atrazine, azoxystrobin, chlorpyrifos, chlorpyrifos, atrazine, flubutyroxyfen-M, benquitrione, bensulfuron-methyl (including bensulfuron-methyl), bentazon, dicyclopyranone, bispyribac-sodium, bispyribac-sodium, bixlozone, chlorpyrifos, bromobenzonitrile, butachlor, flupropyrin, chlorpyrifos (including chlorpyrifos-ethyl), chlorpyrifos-methyl (including chlorpyrifos-methyl), chlorpyrifos-methyl (including chlorpyrifos-ethyl), chlorpyrifos-methyl, ... Clacyfos, clethodim, clodinafopyridine (including clodinafopyr), isoxaflutole, dichloropyridinic acid, cyclopyranil, cyclopyrimorate, cycloprosulfuron, cyhalofop-butyl (including cyhalofop-butyl), 2,4-D (including its choline salt and 2-ethylhexyl ester), 2,4-DB, betaine, dicamba (including its aluminum, aminopropyl, bis-aminopropylmethyl, choline, dichloropropane, diethylene glycolamine, dimethylamine, dimethylammonium, potassium salt and sodium salt), dichlorvos, pyrfluthrin, flupyrazole, metolachlor, fenfluridine, dioxopyritrione, dibromodiphenyl ether Fast, diuron, flupyrifenacil, ethylbutyrazole, ethoxysulfuron, quizalofop-p-ethyl (including quizalofop-p-ethyl), fenoxasulfone, fenquinotrione, tetrazolium, pyrimisulfuron, diflubenzuron, florpyrauxifen (including florpyrauxifen benzyl ester), quizalofop-p-butyl (including quizalofop-p-butyl), flumetsulam (including flumetsulam-sodium), fluthiamethoxam, pyrimisulfuron, propyzoxystrobin, fluroxypyr, flupyrsulfuron (including flupyrsulfuron-methyl-sodium), clopyralid (including flupyroxypyr-) Fluroxypyr-meptyl, flufenoxuron, formamide-sulfuron, glufosinate (including L-glufosinate and its ammonium salts), glyphosate (including its hydrazine, isopropylammonium, and potassium salts), halauxifen (including methyl halauxifen), flupyridine (including flupyridine-methyl), cycloazinone, hydantocidin, methoxyfenozide (including R-methoxyfenozide), imidacloprid, metolachlor, imidacloprid, indazon, iofensulfuron (including iofensulfuron-methyl-sodium), iofensulfuron (including iofensulfuron-sodium), iofensulfuron, isoproturon,Isoxadixyl, lancotrione, MCPA, MCPB, mecoprop-P, mesosulfuron (including mesosulfuron-methyl), mesosulfuron, benzimidone, pyrazosulfuron, methiozolin, metolachlor, sulfadiazine, cyprodinil, mesosulfuron-methyl, dichlorvos, nicosulfuron, dapoxuron, oxadiazon, cyclosulfuron, ethoxysulfuron, paraquat dichlorvos, pendimethalin, penflusulfuron-methyl, benzimidone, chlorpyrifos, clodinafop-methyl, propargite, propargite, oxychlorpyrifos, propyrisulfuron, pendimethalin, benzimidone, flusulfuron-methyl, cyprodinil Pyraflufen (including pyraflufen-ethyl), sulfonylurea, pyrazosulfuron, cyclopyrazosulfuron, pyrimisulfan, pyroxasulfone, pyrazosulfuron, quinclorac, chlorpyrifos, quizalofop-P-tefuryl (including quizalofop-ethyl and quizalofop-P-tefuryl), rimisoxafen, sulfonylurea, pyrimisulfuron, pyrimisulfuron, silazine, simazine, metolachlor, mesosulfuron, sulfonylurea, butyrazosulfuron, terbufos, cyclosulfuron, terbufos, terbufos, tetflupyrolimet, thiamethoxam. (thiencarbazone), thifensulfuron, tiafenacil, tolpyralate, bensulfuron-methyl, triafamone, fensulfuron-methyl, bensulfuron-methyl, chlorpyrifos, trifludimoxazin (including trifludimoxazin-sodium), triflurazole, fluroxypyr, trisulfuron-methyl, triazolesulfuron, 3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid ethyl ester, 4 -hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2-one, 4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2-one, 5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2-one, 4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2-one, 4-hydroxy-1,5-dimethyl-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]imidazolidine-2-one, (4R)1-(5-tert-butylisoxazol-3-yl)-4-ethoxy-5-hydroxy-3-methyl-imidazolidine-2-one4-Amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylic acid (including its agrochemically acceptable esters, such as methyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylic acid, prop-2-ynyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylic acid, and cyanomethyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylic acid), 3-ethylthioalkyl-N-(1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[ 4,3-a]pyridine-8-carboxamide, 3-(isopropylthioalkylmethyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide, 3-(isopropylsulfonylmethyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide, 3-(ethylsulfonylmethyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide, 2- Ethyl [[3-[[3-chloro-5-fluoro-6-[3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]-2-pyridinyl]oxy]ethyl acetate, 6-chloro-4-(2,7-dimethyl-1-naphthyl)-5-hydroxy-2-methylpyridazin-3-one, (2R)-2-[(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]tetrahydrofuran-2-methyl propionate, (2R)-2-[(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]tetrahydrofuran-2-methyl propionate, 2-[(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]tetrahydrofuran-2-methyl propionate 2-Fl-2-ylmethyl ester, 2-[(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]propionic acid, 2-fluoro-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-[(R)-propylsulfinyl]-4-(trifluoromethyl)benzamide, 2-fluoro-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-propylsulfinyl-4-(trifluoromethyl)benzamide, 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid (2-fluorophenyl)methyl ester, and 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid.

[0069] Mixtures of compounds having formula (I) may also be in the form of esters or salts, as mentioned, for example, in The Pesticide Manual, 16th edition, British Crop Protection Council, 2012.

[0070] Compounds having formula (I) can also be used in combination with other agrochemicals, such as fungicides, nematicides or insecticides, examples of which are given in The Pesticide Manual.

[0071] The mixing ratio of the compound having formula (I) to the mixed compatibility is preferably 1:100 to 1000:1.

[0072] These mixtures can be advantageously used in the formulations mentioned above (in which case, "active ingredient" refers to the corresponding mixture of a compound having formula (I) with a mixed formulation).

[0073] The compounds or mixtures of the present invention can also be used in combination with one or more herbicide safeners. Examples of such safeners include cloquintocet, cloquintocet (including cloquinoline), cyclopropanesulfonamide, dichloropropeneamine, cloquinoxal (including cloquinoxalyl ethyl ester), cloquinoxaline, flufenoxam, cloquinoxalic acid (including cloquinoxalic acid-ethyl), mefenpyr (including cloquinoxalyl ester), metcamifen, and cloquinoxalic acid nitrate.

[0074] Particularly preferred are mixtures of compounds having formula (I) with cyclopropanesulfonamide, ethyl bis(benzoxazolyl) ester, oxadiazolyl ester and / or N-(2-methoxybenzoyl)-4-[(methyl-aminocarbonyl)amino]benzenesulfonamide.

[0075] Safeguards of compounds having formula (I) may also be in the form of esters or salts, as mentioned, for example, in The Pesticide Manual, 16th edition (BCPC), 2012. References to antidotes also apply to their lithium, sodium, potassium, calcium, magnesium, aluminum, iron, ammonium, quaternary ammonium, sulfonium, or phosphonium salts, as disclosed in WO 02 / 34048.

[0076] Preferably, the mixing ratio of the compound having formula (I) to the safener is 100:1 to 1:10, especially 20:1 to 1:1.

[0077] The present invention further provides a method for controlling weeds in a site, the method comprising applying to the site a composition comprising a compound having formula (I) to control the amount of weeds. Furthermore, the present invention can further provide a method for selectively controlling weeds in a site comprising crop plants and weeds, wherein the method comprises applying to the site a composition according to the present invention to control the amount of weeds. 'Control' means killing, reducing, or delaying growth or preventing or reducing germination. It should be noted that the compounds of the present invention exhibit significantly improved selectivity compared to known structurally similar compounds. Typically, the plant to be controlled is an unwanted plant (weed). 'Site' means an area in which the plant is growing or will grow. Application can be made to the site before and / or after the emergence of the crop plants. Some crop plants can inherently tolerate the herbicidal effects of compounds having formula (I). Preferred crop plants include corn, wheat, barley, and rice.

[0078] The application rate of compounds having formula I can vary within a wide range and depends on soil properties, application method (pre- or post-emergence; seed dressing; application in seed furrows; no-till application, etc.), crop plant, one or more weeds to be controlled, major climatic conditions, and other factors governed by the application method, application time, and target crop. Compounds having formula I according to the invention are typically applied at a rate of 10 to 2500 g / ha, particularly 25 to 1000 g / ha, and even more particularly 25 to 250 g / ha.

[0079] The composition is usually applied by spraying, typically using a tractor-mounted sprayer for large areas, but other methods such as dusting (for powders), dripping, or immersion can also be used.

[0080] Crop plants should be understood to also include those crop plants that have been conferred tolerance to other herbicides or multiple classes of herbicides (e.g., ALS-inhibitors, GS-inhibitors, EPSPS-inhibitors, PPO-inhibitors, HPPD-inhibitors, inhibitor-PDS, and ACC enzyme-inhibitors) through conventional breeding methods or through genetic engineering. An example of a crop conferred tolerance to imidazolinones (e.g., methoxyfenozide) through conventional breeding methods is Clearfield® Summer Canola (Canola). Examples of crops conferred herbicide tolerance through genetic engineering include, for example, maize varieties resistant to glyphosate and glufosinate, which are commercially available under the brand names RoundupReady® and LibertyLink®.

[0081] Crop plants should also be understood as those conferred resistance to harmful insects through genetic engineering, such as Bt maize (resistant to the European corn borer), Bt cotton (resistant to the boll weevil), and Bt potato (resistant to the Colorado beetle). An example of Bt maize is NK®'s Bt 176 maize hybrid (SyngentaSeeds). Bt toxins are proteins naturally formed by the soil bacteria Bacillus thuringiensis. Examples of toxins or transgenic plants capable of synthesizing such toxins are described in EP-A-451 878, EP-A-374753, WO 93 / 07278, WO 95 / 34656, WO 03 / 052073, and EP-A-427 529. Examples of transgenic plants containing one or more genes encoding insecticidal resistance and expressing one or more toxins are KnockOut® (maize), YieldGard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potato), NatureGard®, and Proteincta®. Plant crops or their seed material can be both herbicide resistant and insect-resistant (“superimposed” transgenic events). For example, seeds can express the insecticidal protein Cry3 while simultaneously being resistant to glyphosate.

[0082] Crop plants should also be understood to include those obtained through conventional breeding or genetic engineering methods and containing so-called output traits (e.g., improved storage stability, higher nutritional value, and improved flavor).

[0083] These compositions can be used to control unwanted plants (collectively referred to as 'weeds'). Weeds to be controlled can be monocotyledonous species, such as *Agrostis*, *Alopecurus*, *Avena*, *Brachiaria*, *Bromus*, *Cenchrus*, *Cyperus*, *Digitaria*, *Echinochloa*, *Eleusine*, *Lolium*, *Monochoria*, *Rottboellia*, *Sagittaria*, *Scirpus*, and *Setaria*. a) and the genus *Sorghum*, which can also be dicotyledonous species, such as *Abutilon*, *Amaranthus*, *Ambrosia*, *Chenopodium*, *Chrysanthemum*, *Conyza*, *Galium*, *Ipomoea*, *Nasturtium*, *Sida*, *Sinapis*, *Solanum*, *Stellaria*, *Veronica*, *Viola*, and *Xanthium*.

[0084] In another aspect of the invention, the use of compounds having formula (I) as defined herein is provided as herbicides.

[0085] The compounds of the present invention can be prepared according to the following scheme.

[0086] Method for preparing compounds having formula (I)

[0087] Methods for preparing compounds (e.g., compounds having formula (I) (which may optionally be salts of which are chemically acceptable for agricultural use)) are now described and form another aspect of the invention.

[0088] Option 1:

[0089]

[0090] A compound having formula I1 is a compound having formula I, where X is O and R is... 1 A 1 A 2 Q, A 3 and R 3It is as defined in Formula I above. As shown in Scheme 1, a compound having Formula I1 can be prepared by a known procedure via an alkoxylation reaction, which involves reacting a compound having Formula III with a compound having Formula II (where LG... 1 The halogen, preferably iodine, bromine, or chlorine (or a pseudohalogen leaving group, such as (halo)alkyl or phenyl sulfonates, e.g., trifluoromethanesulfonate), is reacted in an inert solvent (such as tetrahydrofuran, dioxane, water, N,N-dimethylformamide DMF, N,N-dimethylacetamide, sulfolane, or acetonitrile, etc.) in the presence of a base (such as sodium hydride or alkaline earth metal hydrides, carbonates (e.g., sodium carbonate, potassium carbonate, or cesium carbonate) or hydroxide), optionally in the presence of potassium iodide, at a temperature between 0°C and 120°C. Compounds having formula III can be prepared by deprotection of compounds having formula IV, where PG is an alcohol protecting group, such as methyl, tert-butyl, etc. Such reactions are well known in the literature and are known to those skilled in the art. Compounds having formula IV can be prepared by the Suzuki cross-coupling reaction, which involves reacting a compound having formula V (where X...) with... 1 The reaction is carried out with a halogen (preferably bromine or iodine) and a compound having the formula Q-Yb3 (where Yb3 can be a boron-derived functional group, such as B(OH)2 or B(ORb3)2, where Rb3 can be a C1-C4 alkyl group or both ORb3 can form a five-membered ring with the boron atom, such as pinacol boronic acid ester). The reaction can be catalyzed by a palladium-based catalyst (e.g., tetrakis(triphenylphosphine)palladium(O), (1,1'-bis(diphenylphosphine)ferrocene)dichloro-palladium-dichloromethane (1:1 complex), or chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos cyclic palladium complex)) in the presence of a base (such as sodium carbonate, tripotassium phosphate, or cesium fluoride), in a solvent or solvent mixture (such as, for example, a mixture of dioxane, acetonitrile, N,N-dimethylformamide, 1,2-dimethoxyethane, and water, or a dioxane / water mixture, or a toluene / water mixture), preferably under an inert atmosphere. The reaction temperature can preferably be in the range from room temperature to the boiling point of the reaction mixture, or the reaction can be carried out under microwave irradiation. Such Suzuki reactions are well known to those skilled in the art.

[0091] Option 2:

[0092]

[0093] Compounds having formula I2 are compounds having formula I, wherein X is CH2 and R1, A1, A2, A3, Q, and R3 are as defined in formula I above (Scheme 2). Compounds having formula I2 can be prepared by decarboxylation of compounds having formula VI, wherein R... 11 It is a C1-C6 alkyl or phenyl (Scheme 2). Such decarboxylation reactions can be carried out under thermal conditions (e.g., heating at 100°C to 180°C) in a solvent (such as isopropanol / water) or under alkaline conditions (such as using sodium hydroxide or potassium hydroxide).

[0094] Compounds having formula VI can be prepared by reacting a compound having formula VII with a compound having formula VIII (where LG) 2 It is a halogen, preferably iodine, bromine or chlorine (or a pseudohalogen leaving group, such as (halo)alkyl or phenyl sulfonate, for example trifluoromethanesulfonate)) reacted in the presence of a base (such as sodium hydride or alkaline earth metal hydride, carbonate (such as sodium carbonate, potassium carbonate or cesium carbonate) or hydroxide), optionally in the presence of potassium iodide, in an inert solvent (such as tetrahydrofuran, dioxane, water, N,N-dimethylformamide DMF, N,N-dimethylacetamide, sulfolane or acetonitrile, etc.) at a temperature between 0°C and 120°C.

[0095] Option 3:

[0096]

[0097] Alternatively, compounds having formula I2 can be prepared from compounds having formula IX via deoxygenation or reduction of alcohols. The reduction of such alcohols is described in detail in the literature and can be carried out using reducing agents (such as LiAlH4, DIBAL-H) ​​or triphenylphosphine in the presence of iodine and imidazole, or triethylsilane in the presence of trifluoroacetic acid. Compounds having formula IX can be prepared by: reacting a compound having formula XI (where X...) with... 11 It is a halogen (preferably bromine or iodine) that reacts with an organometallic reagent (such as a metallizing reagent like BuLi or isopropyl magnesium chloride / LiCl complex) to form intermediate XIa (where M(Ln) is a halogen). p It is the corresponding metal (such as lithium or magnesium) derived from the organometallic reagent and (Ln) p It is a group that can be optionally substituted (like chlorine), and then it reacts with a compound having the formula X.

[0098]

[0099] Option 4:

[0100]

[0101] Alternatively, compounds having formula I2 can be prepared according to scheme 4. In scheme 4, compounds having formula I2 can be prepared by: making a compound having formula IXab (where X...) 22 The halogen, preferably iodine, bromine, or chlorine (or a pseudohalogen leaving group, such as (halo)alkyl or phenyl sulfonate, for example trifluoromethanesulfonate), reacts with a compound having formula Va under Suzuki cross-coupling conditions similar to the procedure described in Scheme 1 for converting a compound having formula V to a compound having formula IV. A compound having formula IXab can be prepared from a compound having formula Xab via a procedure similar to the procedure described in Scheme 3 for converting a compound having formula X to a compound having formula I2.

[0102] Alternatively, compounds having formula I (where A) 1 and A 2 (It is a nitrogen atom) can be prepared according to scheme 5. A compound having formula I3 is a compound having formula I, wherein A 1 and A 2 It is a nitrogen atom.

[0103] Option 5:

[0104]

[0105] Compounds having formula I3 can be prepared by a nucleophilic substitution reaction involving reacting a compound having formula XVII with a compound having formula XVIIa or a compound having formula XVIIb (where M is a metal such as sodium, lithium, or potassium). Compounds having formula XVII can be prepared from compounds having formula XVI via oxidation using an oxidizing agent (such as hydrogen peroxide or m-chloroperoxybenzoic acid). Compounds having formula XVI can be prepared from compounds having formula XV by decarboxylation, similar to the procedure described in Scheme 2 for synthesizing compounds having formula I2 from compounds having formula VI. Compounds having formula XV can be prepared by reacting a compound having formula XIII (where R...) with a compound having formula XIII... 15 (is C1-C6 alkyl or phenyl) and compounds having formula XIV (where LG) 3 (The leaving group, such as Cl, Br, SO2CH3, or SO2Ph) is reacted according to the procedure described in Scheme 2 for synthesizing compounds of formula VI by reacting compounds of formulas VII and VIII. Compounds of formula XIII can be prepared by reacting a compound of formula XII (where X is a leaving group, such as Cl, Br, SO2CH3, or SO2Ph) with a leaving group. 15The reaction is carried out with a halogen (such as Cl or Br) and a compound having formula XIIa (where Yb4 can be a boron-derived functional group, such as B(OH)2 or B(ORb4)2, where Rb4 can be a C1-C4 alkyl group or both ORb4 can form a five-membered ring with the boron atom, such as pinacol boronic acid ester) according to the procedure for synthesizing a compound having formula IV from a compound having formula V and a compound having formula Va as described in Scheme 1.

[0106] Alternatively, compounds having formula I3 can be prepared according to scheme 6.

[0107] Option 6:

[0108]

[0109] In scheme 6, a compound having formula I3 can be prepared by: making a compound having formula XVIII (where X...) 12 The reaction involves a halogen (such as Cl, Br) or a toluenesulfonyl or methanesulfonyl functional group) reacting with a compound having formula XIIa according to the procedure described in Scheme 5 for synthesizing a compound having formula XIII from a compound having formula XIIa and a compound having formula XIIa. The compound having formula XVIII (where X...) 12 Halogens can be prepared from compounds having formula XIX by halogenation using reagents such as POCl3 or POBr3. Alternatively, compounds having formula XVIII (where X is a halogen) can be prepared from compounds having formula XIX by halogenation. 12 (The compound having formula XIX) can be prepared by reacting a compound having formula XIX with a reagent (such as p-toluenesulfonyl chloride or methanesulfonyl chloride) in the presence of a base (such as triethylamine or pyridine), and optionally the reaction can be carried out in the presence of 4-dimethylaminopyridine. Such reactions are well known in the literature and are known to those skilled in the art. Compounds having formula XIX can be prepared by the condensation reaction of amidine XII with a compound having formula XX. Such reactions are known in the literature and are described, for example, in Tetrahedron [Tetrahedron] 2017, 73, 27–28, 3939-3948. Compounds having formula XX can be prepared by reacting a compound having formula XXII with a compound having formula XXIII (where R... 41 It is prepared by reacting C1-C4 alkyl groups in the presence of a base (such as sodium hydride, potassium hydride, etc.). Such reactions are known in the literature and described, for example, in Tetrahedron [Tetrahedron] 2017, 73, 27–28, 3939-3948.

[0110] Alternatively, compounds having formula I2 can also be prepared according to scheme 7.

[0111] Option 7:

[0112]

[0113] In Scheme 7, a compound having formula I2 can be prepared by reacting a compound having formula XXIV with a compound having formula Va (where Yb3 can be a boron-derived functional group, such as B(OH)2 or B(ORb3)2, where Rb3 can be a C1-C4 alkyl group or both ORb3 groups can form a five-membered ring with boron atoms, such as pinacol boronic acid ester) according to the procedure described in Scheme 1 for synthesizing a compound having formula IV from a compound having formula V and a compound having formula Va. A compound having formula XXIV can be prepared from a compound having formula XXVI via a two-step procedure involving base-mediated arylation and decarboxylation reactions, as described in Scheme 2 for converting a compound having formula VII into a compound having formula I2.

[0114] The following non-limiting examples provide specific methods for synthesizing representative compounds used in this invention (as mentioned in the table below).

[0115] Example 1: 5-(5-chloropyrimidin-2-yl)oxy-2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]-pyrimidine (1.007)

[0116] (1.007)

[0117] Step 1: Preparation of 5-methoxy-2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]-pyrimidine (I-1)

[0118] (I-1)

[0119] A mixture of 4-chloro-5-methoxy-2-(trifluoromethyl)pyrimidine (155 mg, 0.72 mmol), 4-(trifluoromethyl)phenylboronic acid (253 mg, 1.27 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (30 mg, 0.034 mmol) in a 50 mL round-bottom flask was placed under a nitrogen atmosphere and treated with acetonitrile (2.8 mL) and degassed tripotassium phosphate (1.0 M in water) (1.4 mL). The reaction mixture was stirred at room temperature for another 15 min. The reaction mixture was heated to 40°C and stirred for an additional 1 h. The reaction mixture was cooled to room temperature, diluted with brine (20 mL), and extracted with ethyl acetate (2 × 15 mL). The combined organics were concentrated under vacuum. The residue was loaded onto diatomaceous earth and subjected to silica gel column chromatography using 0-40% ethyl acetate in cyclohexane. Fractions forming the target main peak were combined and concentrated under vacuum to produce 5-methoxy-2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]-pyrimidine I-1 (237 mg, 95%) as a beige solid. 1 H NMR (400 MHz, CDCl3) δ = 8.59 (s, 1H), 8.29 (d, 2H), 7.76 (d, 2H), 4.11 (s, 3H)

[0120] Step 2: Preparation of 2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]pyrimidin-5-ol (I-2)

[0121] (I-2)

[0122] A solution of 5-methoxy-2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine I-1 (61 mg, 0.18 mmol) in N-methyl-2-pyrrolidone (0.5 mL) in a 50 mL round-bottom flask was treated with 1-dodecanethiol (110 µL, 0.450 mmol) and sodium hydroxide in water (50% by mass) (25 µL, 0.485 mmol). A precipitate was observed upon addition of the base. The reaction mixture was heated to 100°C and stirred for 30 min. The reaction mixture was cooled to room temperature. The mixture was quenched with an aqueous solution of ammonium chloride (10 mL), diluted with water (10 mL), and extracted with ethyl acetate (2 × 10 mL). The combined organics were washed with brine (10 mL) and concentrated under vacuum. The residue was loaded onto diatomaceous earth and subjected to column chromatography using 0–100% ethyl acetate in cyclohexane as the eluent. The fractions that form the target main peak are combined and concentrated in a vacuum to produce 2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]pyrimidin-5-ol I-2 (54 mg, 87%), which is a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1H), 8.29 (d, 2H), 7.80 (d, 2H), 6.49 (br s, 1H).

[0123] Step 3: Preparation of 5-(5-chloropyrimidin-2-yl)oxy-2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]-pyrimidine (1.007)

[0124] (1.007)

[0125] A mixture of 2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]pyrimidin-5-ol I-2 (54 mg, 0.157 mmol), 2,5-dichloropyrimidine (41 mg, 0.27 mmol), and potassium carbonate (44 mg, 0.31 mmol) in a 50 mL round-bottom flask was treated with acetonitrile (1.0 mL). The reaction mixture was heated to 90°C and stirred for 30 min. The reaction mixture was treated with sulfolane (1.0 mL) and stirred for another 4 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and brine (10 mL), and extracted with tert-butyl methyl ether (2 × 15 mL). The combined organic compounds were concentrated. The residue was loaded onto diatomaceous earth and subjected to silica gel column chromatography using 0–40% ethyl acetate in cyclohexane as the eluent. The fractions that form the target main peak are combined and concentrated in a vacuum to produce 5-(5-chloropyrimidin-2-yl)oxy-2-(trifluoromethyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (1.007). 1 H NMR (400 MHz, CDCl3) δ = 8.85 (s, 1H), 8.44 (s, 2H), 8.23 ​​(d, 2H), 7.72 (d, 2H).

[0126] Example 2: 5-Chloro-2-[[2-(3,4-difluorophenyl)-5-fluoro-3-pyridyl]methyl]pyrimidine (1.015)

[0127] (1.015)

[0128] Step 1: Preparation of (2-chloro-5-fluoro-3-pyridyl)-(5-chloropyrimidin-2-yl)methanol (I-3)

[0129] (I-3)

[0130] A solution of 5-chloro-2-iodopyrimidine (2.525 g, 10.50 mmol) in toluene (35 mL) in a 250 mL round-bottom flask was placed under a nitrogen atmosphere, cooled to -78°C, and treated with n-butyllithium (2.5 M in hexane, 4.5 mL, 11 mmol). The resulting mixture was stirred for 10 min and then treated with a solution of 2-chloro-5-fluoronicotinaldehyde (1.126 g, 7.058 mmol) in toluene (23 mL). The resulting mixture was further stirred for 30 min, quenched with 0.5 M hydrochloric acid, and extracted with ethyl acetate. The combined organic compounds were concentrated and subjected to silica gel column chromatography using 0-100% ethyl acetate in cyclohexane. The fractions forming the desired main peak were combined and concentrated under vacuum to yield (2-chloro-5-fluoro-3-pyridyl)-(5-chloropyrimidin-2-yl)methanol I-3 (1.062 g, 52%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.71 (s, 2H), 8.22(d, 1H), 7.56 (dd, 1H), 6.20 (d, 1H), 4.52 (d, 1H).

[0131] Step 2: Preparation of 5-chloro-2-[(2-chloro-5-fluoro-3-pyridyl)methyl]pyrimidine (I-4)

[0132] (I-4)

[0133] A solution of (2-chloro-5-fluoro-3-pyridyl)-(5-chloropyrimidin-2-yl)methanol I-3 (1.062 g, 3.68 mmol), imidazole (389 mg, 5.71 mmol), and triphenylphosphine (1.968 g, 7.35 mmol) in tetrahydrofuran (21 mL) was placed under a nitrogen atmosphere and treated dropwise with a solution of iodine (1.217 g, 4.80 mmol) in tetrahydrofuran (5.5 mL). The resulting mixture was stirred for 5 minutes, quenched with an aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The combined organic compounds were concentrated and subjected to silica gel column chromatography using 0–40% ethyl acetate in cyclohexane. The fractions that form the target main peak are combined and concentrated in a vacuum to produce 5-chloro-2-[(2-chloro-5-fluoro-3-pyridyl)methyl]pyrimidine I-4 (918 mg, 87%), which is a light brown oil. 1 H NMR (400 MHz, CDCl3) δ = 8.64 (s, 2H), 8.20 (d,1H), 7.44 (dd, 1H), 4.41 (s, 2H).

[0134] Step 3: Preparation of 5-chloro-2-[[2-(3,4-difluorophenyl)-5-fluoro-3-pyridyl]methyl]pyrimidine (1.015)

[0135] (1.015)

[0136] A mixture of 5-chloro-2-[(2-chloro-5-fluoro-3-pyridyl)methyl]pyrimidine I-4 (154 mg, 0.537 mmol), 3,4-difluorophenylboronic acid (185 mg, 1.11 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (47 mg, 0.056 mmol) in 2–5 mL microwave-safe vials was placed under a nitrogen atmosphere and treated with 2-methyltetrahydrofuran (2.0 mL) and tripotassium phosphate (1.0 M in water, 1.3 mL, 1.3 mmol). The resulting mixture was irradiated with microwaves at 100°C for 30 min, diluted with water, and extracted with ethyl acetate. The combined organic compounds were concentrated and subjected to silica gel column chromatography using 0–30% ethyl acetate in cyclohexane. The fractions that form the target main peak are combined and concentrated in a vacuum to produce 1.015 chloro-2-[[2-(3,4-difluorophenyl)-5-fluoro-3-pyridyl]methyl]pyrimidine. 1 HNMR (400 MHz, CDCl3) δ = 8.63 (s, 2H), 8.44 (d, 1H), 7.50 - 7.40 (m, 2H), 7.32 - 7.27 (m, 1H), 7.25 - 7.17 (m, 1H), 4.31 (s, 2H).

[0137] Example 3: 5-[(5-chloropyrimidin-2-yl)methyl]-2-(difluoromethoxy)-4-(3,4-difluorophenyl)pyrimidine (1.021)

[0138] (1.021)

[0139] Step 1: Preparation of ethyl 2-[4-(3,4-difluorophenyl)-2-methylthioalkyl-pyrimidin-5-yl]acetate (I-5)

[0140] (I-5)

[0141] A mixture of ethyl 2-(4-chloro-2-methylthioalkyl-pyrimidin-5-yl)acetate (4.012 g, 16.26 mmol), 3,4-difluorophenylboronic acid (3.810 g, 24.13 mmol), and XPhos Pd G3 (422 mg, 0.499 mmol) was treated with a solution of 2-methyltetrahydrofuran (32 mL) and potassium phosphate in water (1.0 M, 24 mL, 24.0 mmol). The resulting mixture was stirred at 80°C for 2.5 h, then another portion of XPhos Pd G3 (423 mg, 0.500 mmol) was added and stirred for another hour. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic compounds were concentrated and subjected to silica gel column chromatography using 0–30% ethyl acetate in cyclohexane. The fractions that form the target main peak are combined and concentrated in a vacuum to produce ethyl acetate 2-[4-(3,4-difluorophenyl)-2-methylthioalkyl-pyrimidin-5-yl] ethyl acetate I-5 (3.617 g, 69%), which is a light yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.51 (s, 1H), 7.50 - 7.43 (m, 1H), 7.36 -7.30 (m, 1H), 7.30 - 7.22 (m, 1H), 4.15 (q, 2H), 3.60 (s, 2H), 2.59 (s, 3H),1.24 (t, 3H).

[0142] Step 2: Preparation of ethyl 2-(5-chloropyrimidin-2-yl)-2-[4-(3,4-difluorophenyl)-2-methylthioalkyl-pyrimidin-5-yl]acetate (I-6)

[0143] (I-6)

[0144] A solution of ethyl acetate I-5 (3.617 g, 11.15 mmol) of 2,5-dichloropyrimidine (5.034 g, 33.79 mmol) in DMSO (20 mL) was treated with potassium phosphate (9.533 g, 44.91 mmol), and the resulting mixture was stirred at 70°C for one hour. The mixture was cooled, treated with 1.0 M hydrochloric acid, and extracted with tert-butyl methyl ether. The combined organics were concentrated and subjected to silica gel column chromatography using 0-40% ethyl acetate in cyclohexane. The fractions forming the desired main peak were combined and concentrated under vacuum to produce ethyl acetate I-6 (4.682 g, 87%) of 2-(5-chloropyrimidine-2-yl)-2-[4-(3,4-difluorophenyl)-2-methylthioalkylpyrimidine-5-yl] as an orange oil. 1 H NMR (400 MHz, CDCl3) δ = 8.86 (s, 1H), 8.67 (s, 2H), 7.58 - 7.52 (m,1H), 7.43 - 7.38 (m, 1H), 7.32 - 7.23 (m, 1H), 5.47 (s, 1H), 4.26 - 4.18 (m,2H), 2.58 (s, 3H), 1.23 (t, 3H).

[0145] Step 3: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylthioalkyl-pyrimidine (1.029)

[0146] (1.029)

[0147] A solution of ethyl acetate I-6 (4.682 g, 9.65 mmol) of 2-(5-chloropyrimidin-2-yl)-2-[4-(3,4-difluorophenyl)-2-methylthioalkyl-pyrimidin-5-yl] in methanol (48 mL) was treated with an aqueous sodium hydroxide solution (2.0 M, 35 mL, 70 mmol) and stirred at room temperature for 1.5 h. The mixture was acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The combined organic matter was dried and concentrated under vacuum to yield 1.029 g (3.453 g, 93%) of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylthioalkyl-pyrimidin, a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ =8.61 (s, 2H), 8.56 (s, 1H), 7.60 - 7.54 (m, 1H), 7.44 - 7.39 (m, 1H), 7.26 -7.18 (m, 1H), 4.28 (s, 2H), 2.59 (s, 3H).

[0148] Step 4: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylsulfonyl-pyrimidine (1.028)

[0149] (1.028)

[0150] A solution of 1.029 g (3.453 g, 9.47 mmol) of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylthioalkyl-pyrimidine in ethyl acetate (28 mL) was ice-cooled and treated with 3-chloroperoxybenzoic acid (77%, 4.667 g, 20.82 mmol). The resulting reaction mixture was stirred at 0°C for 2 hours. The mixture was diluted with ethyl acetate and quenched with an aqueous sodium thiosulfate solution. The organic matter was washed with an aqueous sodium bicarbonate solution and water, then concentrated under vacuum and subjected to silica gel column chromatography using 30%–100% ethyl acetate in cyclohexane. The fractions forming the desired main peak were combined and concentrated under vacuum to yield 1.028 g (3.295 g, 83%) of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylsulfonyl-pyrimidine as a creamy solid. 1 H NMR (400 MHz, CDCl3) δ = 8.96 (s,1H), 8.64 (s, 2H), 7.68 - 7.61 (m, 1H), 7.52 - 7.45 (m, 1H), 7.32 - 7.24 (m,1H), 4.47 (s, 2H), 3.39 (s, 3H).

[0151] Step 5: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-6-(3,4-difluorophenyl)-1H-pyrimidin-2-one (I-7)

[0152] (I-7)

[0153] A solution of 1.028 g (760 mg, 1.82 mmol) of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylsulfonyl-pyrimidine in THF (9 mL) was treated with an aqueous sodium hydroxide solution (2.0 M, 35 mL, 70 mmol) and stirred at room temperature for 2.5 h. The mixture was acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The combined organic matter was dried and concentrated under vacuum. The resulting solid was milled with tert-butyl methyl ether to yield 5-[(5-chloropyrimidin-2-yl)methyl]-6-(3,4-difluorophenyl)-1H-pyrimidin-2-one I-7 (560 g, 89%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6)δ = 12.10 (br s, 1H), 8.77 (s, 2H), 8.17 (br s, 1H), 7.58 - 7.49 (m, 1H),7.48 - 7.38 (m, 1H), 7.29 - 7.21 (m, 1H), 4.12 (s, 2H).

[0154] Step 6: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-2-(difluoromethoxy)-4-(3,4-difluorophenyl)pyrimidine (1.021)

[0155] (1.021)

[0156] A solution of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-ol I-7 (159 mg, 0.475 mmol) in DMF (2.4 mL) was treated with potassium carbonate (149 mg, 1.08 mmol) and sodium dichlorofluoroacetate (121 mg, 0.794 mmol). The resulting mixture was stirred at 70°C for 45 min, then a further amount of sodium dichlorofluoroacetate (114 mg, 0.748 mmol) was added and stirred for another 90 min. The mixture was cooled, diluted with water, and extracted with tert-butyl methyl ether. The combined organics were concentrated and subjected to silica gel column chromatography using 0-100% ethyl acetate in cyclohexane. The product-rich fraction was concentrated and subjected to reversed-phase chromatography (MeCN in water, both MeCN and water containing 0.1% formic acid). The fractions forming the target main peak were combined and concentrated in vacuum to produce 5-[(5-chloropyrimidin-2-yl)methyl]-2-(difluoromethoxy)-4-(3,4-difluorophenyl)pyrimidine 1.021. ¹H NMR (400 MHz, chloroform) δ = 8.61 (s, 2H), 7.93 (s, 1H), 7.59 (t, 1H), 7.56 - 7.49 (m, 1H), 7.42 - 7.36 (m, 1H), 7.25 - 7.17 (m, 1H), 4.18 (s, 2H).

[0157] Example 4: 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-carboxynitrile (1.025)

[0158] (1.025)

[0159] Step 1: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-carboxynitrile (1.025)

[0160] (1.025)

[0161] A solution of 1.028 mg (53 mg, 0.127 mmol) of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylsulfonyl-pyrimidine in MeCN (0.6 mL) and DMSO (10 µL) was stirred at room temperature for 90 hours. The mixture was diluted with an aqueous sodium solution and extracted with ethyl acetate. The combined organic compounds were concentrated and subjected to silica gel column chromatography using 0–80% ethyl acetate in cyclohexane. The fractions forming the desired main peak were combined and concentrated under vacuum to yield 1.025 mg of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-carboxynitrile. 1 H NMR (400 MHz, CDCl3) δ = 8.88 (s, 1H), 8.64 (s, 2H), 7.66 - 7.59 (m, 1H), 7.49 - 7.43 (m, 1H), 7.33 - 7.27 (m, 1H), 4.44 (s, 2H).

[0162] Example 5: 5-[(5-chloropyrimidin-2-yl)methyl]-2-cyclopropyl-4-(3,4-difluorophenyl)pyrimidine (1.030)

[0163] (1.030)

[0164] Step 1: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-2-cyclopropyl-4-(3,4-difluorophenyl)pyrimidine (1.030)

[0165] (1.030)

[0166] A solution of 1.028 mg (47 mg, 0.113 mmol) of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-methylsulfonyl-pyrimidine in THF (1.1 mL) was cooled to 0°C and treated dropwise with a solution of cyclopropylmagnesium bromide in THF (0.5 M, 0.3 mL, 0.15 mmol). The mixture was stirred for 5 min, treated with another solution of cyclopropylmagnesium bromide in THF (0.5 M, 0.08 mL, 0.04 mmol), and stirred for an additional 45 min. The mixture was quenched with water and extracted with ethyl acetate. The combined organics were concentrated and subjected to reversed-phase column chromatography using MeCN in water (both water and MeCN contained 0.1% formic acid). The fractions that form the target main peak are combined and concentrated in a vacuum to produce 1.030 5-[(5-chloropyrimidin-2-yl)methyl]-2-cyclopropyl-4-(3,4-difluorophenyl)pyrimidine.1 H NMR (400 MHz, CDCl3) δ = 8.61 (s,2H), 8.58 (s, 1H), 7.57 - 7.50 (m, 1H), 7.41 - 7.35 (m, 1H), 7.25 - 7.17 (m,1H), 4.28 (s, 2H), 2.32 - 2.24 (m, 1H), 1.20 - 1.04 (m, 4H).

[0167] Example 6: 5-Chloro-2-[[2-(6-chloro-5-fluoro-3-pyridyl)-6-(trifluoromethyl)-3-pyridyl]methyl]pyrimidine (1.016)

[0168] (1.016)

[0169] Step 1: Preparation of diethyl 2-(5-chloropyrimidin-2-yl)malonate (I-8)

[0170] (I-8)

[0171] A mixture of 2,5-dichloropyrimidine (3.0 g, 20.20 mmol) and tripotassium phosphate (9.59 g, 44.3 mmol) in a 250 mL round-bottom flask was placed under a nitrogen atmosphere, and 33 mL of dimethyl sulfoxide (DMSO) was added, followed by diethyl malonate (5.1 g, 31.0 mmol). The resulting mixture was heated to 80°C and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic matter was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with 0–15% ethyl acetate in cyclohexane. After fractional concentration, diethyl 2-(5-chloropyrimidin-2-yl)malonate I-8 (5.2 g, 90%) was obtained as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 8.71 (s, 2 H), 5.09 (s, 1 H), 4.29 (q, 4 H), 1.29 (t, 6 H).

[0172] Step 2: Preparation of ethyl 2-(5-chloropyrimidin-2-yl)acetate (I-9)

[0173] (I-9)

[0174] Sodium chloride (1.4 g, 58.44 mmol) and water (1.0 mL) were added to a solution of diethyl 2-(5-chloropyrimidin-2-yl)malonate (I-8, 5.2 g) in DMSO (52 mL), and the reaction mixture was heated at 150°C for 3 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic compounds were concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0–15% ethyl acetate in cyclohexane as the eluent. After concentration, ethyl 2-(5-chloropyrimidin-2-yl)acetate I-9 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ = 8.68 (s, 2 H), 4.22 (q, 2 H), 4.02 (s, 2 H), 1.28 (t, 3 H).

[0175] Step 3: Preparation of ethyl 2-(5-chloropyrimidin-2-yl)-2-[2-chloro-6-(trifluoromethyl)-3-pyridyl]acetate (I-10)

[0176] (I-10)

[0177] 2-chloro-3-fluoro-6-(trifluoromethyl)pyridyl]ethyl acetate (I-9, 2.1 g, 10.5 mmol) in DMSO (17.5 mL) was added to a solution of 2-(5-chloropyrimidin-2-yl)ethyl acetate (I-9, 2.1 g, 10.5 mmol), followed by the addition of tripotassium phosphate (3.76 g, 17.54 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding 5 mL of saturated ammonium chloride solution and diluted with 100 mL of water. The aqueous phase was extracted with ethyl acetate (3 × 100 mL), and the combined organic layers were washed with brine and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0–20% ethyl acetate in cyclohexane as the eluent. After concentration, ethyl acetate I-10 (1.6 g, 43%) of 2-(5-chloropyrimidin-2-yl)-2-[2-chloro-6-(trifluoromethyl)-3-pyridyl]ethyl acetate was obtained as a pale yellow gel. 1 H NMR (400 MHz, CDCl3) δ = 8.70(s, 2 H), 8.04 (d, 1 H), 7.64 (d, 1 H), 5.90 (s, 1 H), 4.28 (q, 2 H), 1.27(t, 3 H)

[0178] Step 4: Preparation of 5-chloro-2-[[2-chloro-6-(trifluoromethyl)-3-pyridyl]methyl]pyrimidine (I-11)

[0179] (I-11)

[0180] Ethyl 2-(5-chloropyrimidin-2-yl)-2-[2-chloro-6-(trifluoromethyl)-3-pyridyl]ethyl pyrimidine I-10 (310 mg, 0.81 mmol) was dissolved in 3.1 mL of propionitrile in a Teflon-coated vial. 0.31 mL of water was added, and the vial was placed in a pressure reactor and heated at 175°C for 8 h. After this time, the reaction mixture was cooled to room temperature and diluted with 5 mL of water. The aqueous layer was extracted with ethyl acetate (3 × 15 mL), and the combined organic layers were evaporated under vacuum to give 5-chloro-2-[[2-chloro-6-(trifluoromethyl)-3-pyridyl]methyl]pyrimidine I-11 (200 mg, 72%) as a pale brown liquid. 1H NMR (400 MHz, CDCl3) δ = 8.64 (s, 2 H), 7.86 (d, 1 H), 7.63 (d, 1 H), 4.50 (s, 2 H).

[0181] Step 5: Preparation of 5-chloro-2-[[2-(6-chloro-5-fluoro-3-pyridyl)-6-(trifluoromethyl)-3-pyridyl]methyl]pyrimidine (1.016)

[0182] (1.016)

[0183] In a 25 mL two-necked flask, 5-chloro-2-[[2-chloro-6-(trifluoromethyl)-3-pyridyl]methyl]pyrimidine I-11 (240 mg, 0.78 mmol), (6-chloro-5-fluoro-3-pyridyl)boronic acid (137 mg, 0.78 mmol), and tripotassium phosphate (334 mg, 1.55 mmol) were dissolved in 4.8 mL of cyclopentylmethyl ether, and the reaction mixture was degassed by bubbling with nitrogen for 5 min. 0.5 mL of water was added, followed by dichloro-[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) (60.0 mg, 0.078 mmol), and the reaction mixture was heated at 75°C for 3 h. The reaction mixture was cooled to room temperature and quenched by adding 25 mL of water. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), and the combined organic layers were concentrated under vacuum. The crude product was purified by reversed-phase chromatography using water / acetonitrile as the eluent. After fractional concentration, 1.016 g of 5-chloro-2-[[2-(6-chloro-5-fluoro-3-pyridinyl)-6-(trifluoromethyl)-3-pyridinyl]methyl]pyrimidine was obtained as a grayish-white solid. ¹H NMR (400 MHz, CDCl₃) δ = 8.65 (s, 2 H), 8.57 (br s, 1 H), 8.00 (br d, 1 H), 7.94 (br d, 1 H), 7.71 (br d, 1 H), 4.40 (s, 2 H).

[0184] Example 7: 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine (1.033)

[0185] (1.033)

[0186] Step 1: Preparation of ethyl 4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine-5-carboxylate (I-12)

[0187] (I-12)

[0188] Ethyl 4-chloro-2-(trifluoromethyl)pyrimidin-5-carboxylate (3.6 g, 14 mmol), (3,4-difluorophenyl)boronic acid (3.3 g, 21 mmol), and tetrahydrofuran (36 mL) were added to a 250 mL two-necked flask, followed by potassium fluoride (2.6 g, 42 mmol). The reaction mixture was degassed by bubbling with nitrogen for 15 min. Bis(tri-tert-butylphosphine)palladium(O) (0.38 g, 0.71 mmol) was added to the solution, and the reaction was heated to 45°C for 12 h. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography using 0–15% ethyl acetate in cyclohexane as the eluent. After fractionation and concentration, ethyl 4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine-5-carboxylate I-12 (4 g, 85%) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 9.20 (s, 1 H), 7.60 (m, 1 H), 7.42 - 7.47 (m, 1 H), 7.26 - 7.33 (m, 1 H), 4.35 (q, 2 H), 1.26 (t, 3 H).

[0189] Step 2: Preparation of [4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]methanol (I-13)

[0190] (I-13)

[0191] Ethyl 4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidin-5-carboxylate I-12 (4 g, 12.04 mmol) and tetrahydrofuran (120 mL) were added to a three-necked round-bottom flask. The mixture was cooled to 0°C using an ice bath, and diisobutylaluminum hydride (1.0 mol / L) was slowly added in toluene (25.2 mL, 25.2 mmol) over a 5-minute period, with stirring at 0°C for 30 min. The reaction mixture was quenched with an aqueous solution of ammonium chloride (25 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude compound. The crude compound was purified by silica gel column chromatography using 15%–20% ethyl acetate in cyclohexane. After concentration, [4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]methanol I-13 (1.8 g, 52%) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ = 9.09 (s,1 H), 7.70 - 7.76 (m, 1 H), 7.56 - 7.61 (m, 1 H), 7.28 - 7.37 (m, 1 H), 4.86 (s, 2 H).

[0192] Step 3: Preparation of 4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine-5-carboxaldehyde (I-14)

[0193] (I-14)

[0194] [4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]methanol I-13 (1.8 g, 6.2 mmol) in acetonitrile (18 mL) was added to a 2-necked round-bottom flask equipped with a nitrogen inlet, and the mixture was cooled to 0°C. 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzyl-3-(1H)-one (3.2 g, 7.4 mmol) was added to this solution in portions, and the reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was quenched with 10% sodium thiosulfate solution (6 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude material was purified by silica gel column chromatography by elution with 15% to 20% ethyl acetate in cyclohexane to obtain 4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine-5-carboxaldehyde I-14 (1.5 g, 80%), which is a brown colloidal substance. 1 H NMR (400 MHz, CDCl3) δ = 10.22 (s, 1 H), 9.37 (s, 1 H), 7.69 - 7.76 (m, 1 H), 7.41 - 7.48 (m, 2 H).

[0195] Step 4: Preparation of (5-chloropyrimidin-2-yl)-[4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]methanol (1.034)

[0196] (1.034)

[0197] A solution of 5-chloro-2-iodopyrimidine (0.41 g, 1.71 mmol) in toluene (5 mL) in a 250 mL round-bottom flask was placed under a nitrogen atmosphere, cooled to -78°C, and treated with n-butyllithium (2.5 M in hexane) (0.94 mL, 2.34 mmol). The mixture turned red and became gel-like. The mixture was stirred for 10 minutes and then treated with a solution of 4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine-5-carboxaldehyde I-14 (500 mg, 1.56 mmol) in toluene (5 mL). The mixture was stirred for 30 minutes and then slowly heated to 0°C. The reaction mixture was quenched by slowly adding 20 mL of saturated ammonium chloride solution at 0°C. The reaction mixture was then extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude material. The crude product was purified by silica gel column chromatography using 40%-50% ethyl acetate in cyclohexane. After fractional concentration, 1.034 g (0.19 g, %) of (5-chloropyrimidin-2-yl)-[4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]methanol, a yellow gelatinous substance, was obtained. ¹H NMR (400 MHz, CDCl₃) δ = 8.78 (s, 2H), 8.75 (s, 1H), 7.94 (m, 1H), 7.78 (m, 1H), 7.31–7.38 (m, 1H), 6.14 (s, 1H).

[0198] Step 5: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine (1.033)

[0199] (1.033)

[0200] In a vial, 1.034 g (70 mg, 0.17 mmol) of (5-chloropyrimidin-2-yl)-[4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]methanol and 2,4,6-trimethylpyridine (21 mg, 0.17 mmol) were dissolved in 1.7 mL of acetonitrile. The solution was degassed by bubbling with nitrogen for 10 min. Triphenylphosphine (230 mg, 0.86 mmol) was added, followed by [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1]bis-[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]-phenyl-C]iridium(III) hexafluorophosphate (3.9 mg, 0.0034 mmol), and the reaction was stirred and irradiated with blue light (Penn photoreactor, 450 nm) for 24 h. The reactants were quenched with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain the crude product. This crude product was purified by reversed-phase chromatography using 60%–65% acetonitrile in water to give 1.033 g of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-(trifluoromethyl)pyrimidine, which appeared as a brown gel. ¹H NMR (400 MHz, CDCl₃) δ = 8.94 (s, 1H), 8.64 (s, 2H), 7.68–7.60 (m, 1H), 7.51–7.45 (m, 1H), 7.32–7.23 (m, 1H), 4.45 (s, 2H)

[0201] Example 8: 5-[(5-chloropyrimidin-2-yl)methyl]-2-(difluoromethyl)-4-(3,4-difluorophenyl)pyrimidine (1.038)

[0202] (1.038)

[0203] Step 1: Preparation of diethyl 2-[(5-chloropyrimidin-2-yl)methyl]malonate (I-15)

[0204] (I-15)

[0205] In a 500 mL two-necked flask under a nitrogen atmosphere, diethyl malonate (11.79 g, 73.62 mmol) was dissolved in 100 mL of dimethyl sulfoxide. Potassium phosphate (39.47 g, 184.1 mmol) was added, followed by 5-chloro-2-(chloromethyl)pyrimidine (10.00 g, 61.35 mmol), and the reaction mixture was stirred at room temperature for 12 h. 400 mL of water was added, and the aqueous layer was extracted with ethyl acetate (3 × 150 mL). The combined organic matter was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude compound. The crude material was further purified by silica gel column chromatography using 30% ethyl acetate in cyclohexane to give diethyl 2-[(5-chloropyrimidin-2-yl)methyl]malonate I-15 (13.0 g, 66%) as a pale yellow liquid. 1 ¹H NMR (400 MHz, CDCl₃): (a mixture of ketoenol tautomers) δ = 8.62 (s, 2H), 4.13–4.27 (m, 4H), 3.60 (d, 2H), 3.39 (s, 1H), 1.25–1.33 (m, 6H).

[0206] Step 2: Preparation of ethyl 3-(5-chloropyrimidin-2-yl)propionate (I-16)

[0207] (I-16)

[0208] Diethyl 2-[(5-chloropyrimidin-2-yl)methyl]malonate I-15 (3.0 g, 10.0 mmol), dimethyl sulfoxide (30 mL), water (2 mL), and sodium chloride (0.6 g, 10 mmol) were added to a 150 mL Teflon vial, and the vial was placed in a pressure reactor and heated at 160°C for 16 h. After cooling the reaction mixture to room temperature, 200 mL of water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were concentrated under vacuum, and the resulting crude product was purified by silica gel column chromatography using 20%–25% ethyl acetate in cyclohexane. After concentration, ethyl 3-(5-chloropyrimidin-2-yl)propionate I-16 (1.5 g, 60.1%) was obtained. 1 H NMR (400 MHz, CDCl3) δ = 8.61 (s,2 H), 4.13 (q, 2 H), 3.29 (t, 2 H), 2.86 (t, 2 H), 1.23 (t, 3 H).

[0209] Step 3: Preparation of ethyl 2-[(5-chloropyrimidin-2-yl)methyl]-3-oxo-propionate (I-17)

[0210] (I-17)

[0211] A mixture of ethyl 3-(5-chloropyrimidin-2-yl)propionate I-16 (3.5 g, 16.0 mmol) and ethyl formate (4.7 g, 64 mmol) was treated with 70 mL of tetrahydrofuran, and the mixture was cooled to 0°C by an ice / water bath. Sodium hydride (2.6 g, 64 mmol, 60 wt%) was added to the solution in portions. After the addition was complete, the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was cooled to 0°C and quenched by the slow addition of an aqueous solution of ammonium chloride (100 mL). The aqueous layer was extracted with ethyl acetate (3 × 75 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound. The crude material was then purified by silica gel column chromatography using 40% ethyl acetate in cyclohexane to obtain a pale yellow liquid of 2-[(5-chloropyrimidin-2-yl)methyl]-3-oxopropionic acid ethyl ester I-17 (2.1 g, 55%) as a mixture of ketoenol tautomers (1.6:1). 1 ¹H NMR (400 MHz, CDCl₃) ketone form δ = 10.04 (s, 1H), 8.58 (s, 2H), 4.25 (q, 2H), 4.01–404 (m, 1H), 3.60–3.63 (m, 2H), 1.26 (t, 3H); enol form δ = 11.58 (d, 1H), 8.62–8.65 (m, 2H), 7.21 (d, 1H), 4.12–4.17 (q, 2H), 3.74 (s, 2H), 1.24 (q, 3H).

[0212] Step 4: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-2-(methoxymethyl)pyrimidin-4-ol (I-18)

[0213] (I-18)

[0214] In a Teflon-coated vial, ethyl 2-[(5-chloropyrimidin-2-yl)methyl]-3-oxo-propionate I-17 (2.1 g, 7.7 mmol) was dissolved in 63 mL of methanol, and (2-methoxyethyleneimine)ammonium chloride (2.46 g, 19.47 mmol) and potassium carbonate (6.5 g, 46.7 mmol) were added. The vial was placed in a pressure reactor and heated at 80°C for 5 h. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was evaporated, and the obtained solid was washed with tert-butyl dimethyl ether (30 mL) and cyclohexane (70 mL). The crude solid was then purified by reversed-phase chromatography using water / acetonitrile as the eluent. After fractional concentration, 5-[(5-chloropyrimidin-2-yl)methyl]-2-(methoxymethyl)pyrimidin-4-ol I-18 (1.25 g, 50%) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.75 (s, 2H), 7.44(s, 1H), 7.26 (br s, 1H), 4.02 (s, 2H), 3.79 (s, 2H), 3.72 (s, 3H).

[0215] Step 5: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-2-(methoxymethyl)pyrimidin-4-ol (I-19)

[0216] (I-19)

[0217] A mixture of 5-[(5-chloropyrimidin-2-yl)methyl]-2-(methoxymethyl)pyrimidin-4-ol I-18 (2.0 g, 3.0 mmol) in 40 mL of dichloromethane was cooled to 0°C, and N,N-dimethylaminopyridine (74 mg, 0.6 mmol) followed by triethylamine (1.51 g, 15.0 mmol) was added to the mixture. The reaction mixture was stirred at 0°C for 5 min, and p-toluenesulfonyl chloride (1.71 g, 9.0 mmol) was added, followed by stirring at room temperature for 12 h. After this time, the reaction mixture was diluted with 100 mL of water, and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude compound. The crude material was purified by silica gel column chromatography using 40% ethyl acetate in cyclohexane to obtain 5-[(5-chloropyrimidin-2-yl)methyl]-2-(methoxymethyl)pyrimidin-4-ol I-19 (0.57 g, 21%), which was a pale yellow gelatinous material. 1H-NMR (400 MHz, CDCl3) δ = 8.66 (s, 1H), 8.60 (s,2H), 8.00 (d, 2H), 7.37 (d, 2H), 4.61 (s, 2H), 4.31 (s, 2H), 3.53 (s, 3H), 2.49 (s, 3H).

[0218] Step 6: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-(methoxymethyl)pyrimidine (I-20)

[0219] (I-20)

[0220] In a microwave-safe vial, 4-methylbenzenesulfonic acid [5-[(5-chloropyrimidin-2-yl)methyl]-2-(methoxymethyl)pyrimidin-4-yl] ester I-19 (250 mg, 0.59 mmol) was dissolved in 15 mL of dioxane. To this solution, (3,4-difluorophenyl)boronic acid (93.80 mg, 0.59 mmol), tetrakis(triphenylphosphine)palladium(O) (69.33 mg, 0.059 mmol), potassium carbonate (331.70 mg, 2.37 mmol), and water (1 mL) were added. The reaction mixture was degassed by bubbling with nitrogen for 10 min and then heated at 100°C for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and 20 mL of water was added. The aqueous layer was extracted with ethyl acetate (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated crude product was purified by silica gel column chromatography using 25%-30% ethyl acetate in cyclohexane to obtain 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-(methoxymethyl)pyrimidine I-20 (180 mg, 50%), a pale yellow gelatinous material. ¹H-NMR (400 MHz, CDCl₃) δ = 8.80 (s, 1H), 8.62 (s, 2H), 7.54–7.56 (m, 1H), 7.39–7.43 (m, 1H), 7.21–7.27 (m, 1H), 4.74 (s, 2H), 4.35 (s, 2H), 3.58 (s, 3H).

[0221] Step 7: Preparation of [5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-pyrimidin-2-yl]methanol (I-21)

[0222] (I-21)

[0223] A solution of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-2-(methoxymethyl)-pyrimidine I-20 (300 mg, 0.49 mmol) in dichloromethane (2 mL) was cooled to 0°C, and a solution of boron tribromide (1 M) in dichloromethane (2.48 mL, 2.48 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 12 h. After this time, the reaction mixture was cooled to 0°C and slowly quenched by adding 20 mL of saturated sodium bicarbonate aqueous solution. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound. The crude product was further purified by silica gel column chromatography using 50%-60% ethyl acetate in cyclohexane to obtain [5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-yl]methanol I-21 (65 mg, 38%) as a yellow liquid. 1 H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1H), 8.64 (s, 2H), 7.55-7.58 (m, 1H), 7.41-7.45(m, 1H), 7.23-7.28 (m, 1H), 4.89 (s, 2H), 4.38 (s, 2H).

[0224] Step 8: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)-pyrimidin-2-carboxaldehyde (I-22)

[0225] (I-22)

[0226] A solution of [5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-yl]methanol I-21 (100 mg, 0.14 mmol) in acetonitrile (6 mL) was cooled to 0°C, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyliodo-3(1H)-one (Dies Martin periodide) (121.62 mg, 0.28 mmol) was added in portions. The reaction mixture was then stirred at room temperature for 12 h, and quenched by adding 10 mL of aqueous sodium bicarbonate followed by 10 mL of aqueous sodium thiosulfate. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude compound. The crude product was purified by silica gel column chromatography using 40% ethyl acetate in cyclohexane to obtain 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-carboxaldehyde I-22 (35 mg, 39%), a pale yellow gel-like material. ¹H NMR (400 MHz, CDCl₃): δ = 10.16 (s, 1H), 9.02 (s, 1H), 8.64 (s, 2H), 7.45–7.68 (m, 3H), 4.47 (s, 2H).

[0227] Step 9: Preparation of 5-[(5-chloropyrimidin-2-yl)methyl]-2-(difluoromethyl)-4-(3,4-difluorophenyl)pyrimidine (1.038)

[0228] (1.038)

[0229] A solution of 5-[(5-chloropyrimidin-2-yl)methyl]-4-(3,4-difluorophenyl)pyrimidin-2-carboxaldehyde I-22 (30 mg, 0.05 mmol) in dichloromethane (1.5 mL) was cooled to 0°C, and diethylaminosulfur trifluoride (33.46 mg, 0.027 mL) was added dropwise. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was then slowly poured into 20 mL of an aqueous sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude compound. The crude product was then purified by silica gel column chromatography using 25% ethyl acetate in cyclohexane to give 1.038g of 5-[(5-chloropyrimidin-2-yl)methyl]-2-(difluoromethyl)-4-(3,4-difluorophenyl)pyrimidin as a pale yellow gel. 1H NMR (400 MHz, CDCl3) δ = 8.92 (s, 1H), 8.64 (s, 2H), 7.62 (br d, 1H), 7.46 (br dd, 1H), 7.22-7.32 (m, 1H), 6.70 (t, 1H), 4.43 (s, 2H).

[0230] Example 9: 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-(trifluoromethyl)pyrimidine (1.017)

[0231] (1.017)

[0232] Step 1: Preparation of ethyl 2-[4-(6-chloro-5-fluoro-3-pyridyl)-2-methylthioalkyl-pyrimidin-5-yl]acetate (I-23)

[0233] (I-23)

[0234] A mixture of ethyl 2-(4-chloro-2-methylthio-pyrimidin-5-yl)acetate (703 mg, 2.85 mmol), (6-chloro-5-fluoro-3-pyridyl)boronic acid (322 mg, 1.84 mmol), and XPhos Pd G3 (79 mg, 0.093 mmol) was treated with a solution of 2-methyltetrahydrofuran (3.7 mL) and potassium phosphate in water (1.0 M, 2.7 mL, 2.7 mmol). The resulting mixture was stirred at 80°C for 1.5 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic compounds were concentrated and subjected to silica gel column chromatography using 0–50% ethyl acetate in cyclohexane. The product-rich fractions were concentrated and subjected to reversed-phase chromatography (acetonitrile in water, both acetonitrile and water containing 0.1% formic acid). The fractions that form the target main peak are combined and concentrated in a vacuum to produce ethyl acetate 2-[4-(6-chloro-5-fluoro-3-pyridyl)-2-methylthioalkyl-pyrimidin-5-yl] I-23 (57 mg, 9%), which is a colorless oil. 1 H NMR (400 MHz, CDCl3) δ = 8.56 (s, 1H), 8.45 (d, 1H), 7.83 (dd, 1H), 4.17 (q, 2H), 3.62 (s, 2H), 2.59 (s, 3H), 1.25 (t, 3H).

[0235] Step 2: Preparation of ethyl 2-[4-(6-chloro-5-fluoro-3-pyridyl)-2-methylthioalkyl-pyrimidin-5-yl]-2-(5-chloropyrimidin-2-yl)ethyl acetate (I-24)

[0236] (I-24)

[0237] A solution of 2-[4-(6-chloro-5-fluoro-3-pyridinyl)-2-methylthioalkyl-pyrimidin-5-yl]ethyl acetate I-23 (57 mg, 0.167 mmol) and 2,5-dichloropyrimidine (78 mg, 0.524 mmol) in DMSO (0.8 mL) was treated with potassium phosphate (148 mg, 0.697 mmol), and the resulting mixture was stirred at 70°C for 30 min. The mixture was cooled, treated with 0.5 M hydrochloric acid, and extracted with tert-butyl methyl ether. The combined organic compounds were concentrated and subjected to silica gel column chromatography using 0-30% ethyl acetate in cyclohexane. The fractions that form the target main peak are combined and concentrated in a vacuum to produce ethyl acetate 2-[4-(6-chloro-5-fluoro-3-pyridyl)-2-methylthioalkyl-pyrimidin-5-yl]-2-(5-chloropyrimidin-2-yl)acetate I-24 (42 mg, 51%), which is a yellow gel. 1 H NMR (400 MHz, CDCl3) δ = 8.94 (s, 1H), 8.68 (s, 2H),8.59 (d, 1H), 7.94 (dd, 1H), 5.40 (s, 1H), 4.28 - 4.18 (m, 2H), 2.58 (s, 3H),1.23 (t, 3H).

[0238] Step 3: Preparation of 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-methylthioalkyl-pyrimidine (1.036)

[0239] (1.036)

[0240] A solution of ethyl acetate I-24 (42 mg, 0.0878 mmol) in acetonitrile (1 mL) and water (0.1 mL) was heated to 180°C for 30 minutes under microwave irradiation. After completion, the mixture was concentrated under vacuum to yield 1.036 (33 mg, 93%) of 4-(6-chloro-5-fluoro-3-pyridinyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-methylthioalkyl-pyrimidine as a beige solid. 1H NMR (400 MHz, CDCl3) δ = 8.64 (s, 1H), 8.63 (s, 2H), 8.60 (d, 1H), 7.99 (dd, 1H), 4.27 (s, 2H), 2.58 (s, 3H).

[0241] Step 4: Preparation of 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-methylsulfonyl-pyrimidine (1.037)

[0242] (1.037)

[0243] A solution of 1.036 (42 mg, 0.0820 mmol) of 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-methylthioalkyl-pyrimidine in ethyl acetate (1 mL) was treated with 3-chloroperoxybenzoic acid (77%, 42 mg, 0.187 mmol). The resulting mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate and quenched with an aqueous sodium thiosulfate solution. The organic matter was washed with an aqueous sodium bicarbonate solution and water, then concentrated under vacuum and subjected to silica gel column chromatography using 40%–100% ethyl acetate in cyclohexane. The fractions forming the desired main peak were combined and concentrated under vacuum to yield 1.037 (25 mg, 70%) of 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-methylsulfonyl-pyrimidine as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 9.05 (s, 1H), 8.65 (s,2H), 8.63 (d, 1H), 8.04 (dd, 1H), 4.47 (s, 2H), 3.40 (s, 3H).

[0244] Step 5: Preparation of 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-(trifluoromethyl)pyrimidine (1.017)

[0245] (1.017)

[0246] A solution of 1.037 g (25 mg, 0.573 mmol) of 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-methylsulfonyl-pyrimidine in THF (0.5 mL) was treated with potassium fluoride (19 mg, 0.327 mmol) and trimethyl(trifluoromethyl)silane (50 µL, 0.338 mmol). The reaction mixture was stirred for 5 h, treated with another 50 µL of trimethyl(trifluoromethyl)silane, and stirred for an additional 16 h. The reaction mixture was treated with another 50 µL of trimethyl(trifluoromethyl)silane, and stirred for an additional 2.5 h. The mixture was treated with an aqueous sodium bicarbonate solution and extracted with ethyl acetate, then concentrated under vacuum and subjected to silica gel column chromatography using 0–50% ethyl acetate in cyclohexane. The fractions that form the target main peak are combined and concentrated in a vacuum to produce 1.017 4-(6-chloro-5-fluoro-3-pyridyl)-5-[(5-chloropyrimidin-2-yl)methyl]-2-(trifluoromethyl)pyrimidine. 1 H NMR (400 MHz, CDCl3) δ = 9.03 (s, 1H), 8.67 - 8.64 (m, 3H), 8.04 (dd, 1H), 4.46 (s, 2H).

[0247] Table 1. Compounds of the present invention

[0248]

[0249] Biological examples

[0250] Seeds of several test species were sown in standard soil in pots: Amaranthus retoflexus (AMARE), Amaranthus palmeri (AMAPA), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), and Ipomoea hederacea (IPOHE). After one day (pre-emergence) or eight days (post-emergence) of cultivation in a greenhouse under controlled conditions (24°C / 16°C, day / night; 14-hour light; 65% humidity), the plants were sprayed with an aqueous solution derived from an industrial-grade formulation of the active ingredient in an acetone / water (50:50) solution containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). Unless otherwise specified, the compound was applied at 250 g / ha. Test plants were then grown in a greenhouse under controlled conditions (24°C / 16°C, day / night; 14-hour light; 65% humidity) and watered twice daily. The percentage of damage to the plants was evaluated before emergence and 13 days after emergence. Bioactivity (% phytotoxicity) is shown in Tables B1 and B2 below using a five-point scale (5 = 81% to 100%; 4 = 61% to 80%; 3 = 41% to 60%; 2 = 21% to 40%; 1 = 0% to 20%). NT = Not tested.

[0251] Table B1. Application after emergence.

[0252]

[0253] Table B2. Apply before emergence.

[0254] .

Claims

1. A compound having formula (I): in X is O or CHR 8 , Q is a phenyl or C-linked 6-membered heteroaryl group, wherein the phenyl or 6-membered heteroaryl group is optionally linked by one or more R groups. 4 replace; A 1 Is it CH or N? A 2 It is CR 2 Or N, Where A 1 and A 2 At least one of them is N, A 3 It is CR 5 Or N; Where X is O, then when A 2 It is CR 2 And A 3 When it is N, A 1 Not N; R 1 Choose from the following groups: hydrogen, halogen, -CN, nitro, C1-C4 alkyl-, C2-C4 alkenyl-, C2-C4 alkynyl-, C1-C4 haloalkyl-, C1-C4 alkoxy-, C1-C4 haloalkoxy-, -S(O) p C1-C4 alkyl and C3-C6 cycloalkyl-; R 2 Choose from the group consisting of: hydrogen, halogens, and C1-C6 alkyl groups; R 3 Choose from the group consisting of: halogens, C1-C4 haloalkyl- and C1-C2 haloalkoxy-; R 4 Choose from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxy-C1-C3 alkyl-, C1-C4 alkoxy-C1-C3 alkoxy-, C1-C4 alkoxy-C1-C3 alkoxy-C1-C3 alkyl-, -CN, NO2, C2-C4 alkenyl, C2-C4 alkynyl, -S(O) p C1-C4 alkyl groups, -S(O) p C1-C4 haloalkyl, -C(O)OC1-C4 alkyl and -C(O)NR 6 R 7 ; R 5 It is hydrogen or halogen; R 6 Selected from the group consisting of: hydrogen, C3-C4 cycloalkyl, C1-C4 alkyl, and C1-C4 haloalkyl; R 7 Selected from the group consisting of: hydrogen, C3-C4 cycloalkyl, C1-C4 alkyl, and C1-C4 haloalkyl; R 8 It is hydrogen or hydroxyl; and p is 0, 1, or 2; Or agriculturally acceptable salt.

2. The compound according to claim 1, wherein, A 1 It is N and A 2 It is CH.

3. The compound according to claim 1, wherein, A 1 It is CH and A 2 It is N.

4. The compound according to claim 1, wherein, A 1 It is N and A 2 It is N.

5. The compound according to any one of the preceding claims, wherein, A 3 Is it N or CR? 5 , where R 5 It's fluorine.

6. The compound according to any one of the preceding claims, wherein, R 1 Choose from the group consisting of: halogens, C1-C4 alkyl- and C1-C4 haloalkyl-.

7. The compound according to any one of the preceding claims, wherein, R 3 It is a halogen or a C1-C4 haloalkyl group.

8. The compound according to any one of the preceding claims, wherein, Q selects a group from the following: Where n is 0, 1, or 2.

9. The compound according to claim 8, wherein, Q can be freely grouped from the following: Q-1, Q-3, and Q-4.

10. The compound according to claim 9, wherein, n is 1 or 2, and R 4 The group consisting of halogens and C1-C4 haloalkyl groups is selected independently.

11. A herbicidal composition comprising a compound according to any one of the preceding claims and an agriculturally acceptable formulation adjuvant.

12. The herbicidal composition of claim 11, further comprising at least one additional pest control agent.

13. The herbicidal composition according to claim 12, wherein, The other pest control agent mentioned is a herbicide or a herbicide safener.

14. A method for controlling weeds at a site, the method comprising applying to the site a composition for controlling the amount of weeds according to any one of claims 11 to 13.

15. Use of the compound having formula (I) according to claim 1 as a herbicide.

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