Herbicidal compounds

Abstract

The present application relates to compounds of Formula (I) or to an agronomically acceptable salt of said compounds, wherein X 1 , Y 1 , Y 2 , Z 1 , Z 2 , R 1 , R 2 , R 5 , R 6 , R 9 and n are as defined herein. The present application further relates to herbicidal compositions comprising a compound of Formula (I) and to the use of a compound of Formula (I) for controlling weeds, in particular in crops of useful plants.

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

[0003]

[0004] Or its agronomically acceptable salt.

[0005] Y 1 Is it N or CR? 3 ;

[0006] Y 2 Is it N or CR? 4 ;

[0007] The premise is Y 1 and Y 2 Not all of them are N;

[0008] R 1 Choose from the group consisting of: hydrogen, halogens, C1-C3 alkyl groups and C1-C3 haloalkyl groups;

[0009] R 2 Selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy-, C1-C3 haloalkoxy- and C1-C3 haloalkyl;

[0010] R 3 Choose from the group consisting of: hydrogen, halogen, -CN, nitro, C1-C4 alkyl, C2-C4 alkenyl-, C2-C4 alkynyl-, C1-C4 haloalkyl-, C1-C4 alkoxy-, C1-C4 haloalkoxy-, and -S(O). n C1-C4 alkyl;

[0011] R 4 Choose from the group consisting of: hydrogen, halogen, -CN, nitro, C1-C4 alkyl, C2-C4 alkenyl-, C2-C4 alkynyl-, C1-C4 haloalkyl-, C1-C4 alkoxy-, C1-C4 haloalkoxy-, and -S(O). n C1-C4 alkyl;

[0012] Each R 5 Independently selected from the group consisting of: halogen, -CN, nitro, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy-, C1-C4 haloalkoxy-, –S(O) pC1-C4 alkyl groups and –S(O) p C1-C4 haloalkyl;

[0013] R 6 Independently selected from the group consisting of: hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl-, C1-C6 alkoxy-, C1-C6 haloalkoxy- and C3-C6 cycloalkyl-;

[0014] X 1 It is CH2 or O;

[0015] Z 1 Is it N or CR? 7 ;

[0016] Z 2 Is it N or CR? 8 ;

[0017] R 7 Choose from the group consisting of: hydrogen, C1-C4 alkyl, halogen, -CN, nitro, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy-, C1-C4 haloalkoxy-, -S(O). p C1-C4 alkyl groups and -S(O) p C1-C4 haloalkyl;

[0018] R 8 Choose from the group consisting of: hydrogen, C1-C4 alkyl, halogen, -CN, nitro, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy-, C1-C4 haloalkoxy-, -S(O). p C1-C4 alkyl groups and -S(O) p C1-C4 haloalkyl;

[0019] R 9 The group selected from the following: C1-C6 alkyl, C1-C6 haloalkyl- and pyrimidin-2-yl, wherein the pyrimidin-2-yl is optionally substituted by one or two substituents independently selected from the following: halogen, CN, C1-C2 alkyl, C1-C2 alkoxy- and C1-C2 haloalkoxy-;

[0020] n = 0, 1, or 2; and

[0021] p = 0, 1, or 2.

[0022] C1-C4 alkyl- and C1-C6 alkyl- 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, and tert-butyl (t-Bu). C1-C2 alkyl- are methyl (Me, CH3) or ethyl (Et, C2H5).

[0023] Halogens (or halogenated) include, for example, fluorine, chlorine, bromine, or iodine. The above applies correspondingly to halogens in other definitions, such as alkyl halogens.

[0024] C1-C6 halogenated alkyl groups include, 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-tetrafluoropropyl and 2,2,2-trichloroethyl, heptafluoropropyl and perfluorohexyl. C1-C4 and C1-C2 halogenated alkyl groups include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, or 1,1-difluoro-2,2,2-trichloroethyl.

[0025] C1-C4 alkoxy and C1-C2 alkoxy include, for example, methoxy and ethoxy.

[0026] C1-C6 and C1-C4 haloalkoxy groups include, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, or 2,2,2-trichloroethoxy, preferably difluoromethoxy, 2-chloroethoxy, or trifluoromethoxy.

[0027] C2-C4 alkenyl groups include, for example, -CH=CH2 (vinyl) and -CH2-CH=CH2 (allyl).

[0028] C2-C4 ynyl group refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond, having two to four carbon atoms, and attached to the rest of the molecule by single bonds. Examples of C2-C4 ynyl groups include, but are not limited to, propynyl-1-ynyl, propynyl (propynyl-2-ynyl), and butynyl-1-ynyl.

[0029] C1-C4 alkyl-S-(alkylthio) includes, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, or tert-butylthio, preferably methylthio or ethylthio.

[0030] C1-C4 alkyl-S(O)-(alkylsulfinyl) includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl or tert-butylsulfinyl, preferably methylsulfinyl or ethylsulfinyl.

[0031] C1-C4 alkyl-S(O)2-(alkylsulfonyl) includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl or ethylsulfonyl.

[0032] In one embodiment of the invention, a compound having formula (I) is provided, wherein Y 1 It is CR 3 And Y 2 It is N (in this embodiment, R) 1 and R 2 Preferably hydrogen); or Y 1 It is CR 3 And R 2 It is CR 4 (In this embodiment, R) 1 and R 2 Preferably hydrogen); or Y 1 It is N and Y 2 It is CR 4 (In this embodiment, R) 1 and R 2 Preferably, it is hydrogen. In a more preferred embodiment of the invention, a compound having formula (I) is provided, wherein Y 1 It is CR 3 And Y 2 It is N, where R 3 It is a C1-C4 alkyl (preferably methyl) or halogen (preferably chlorine), more preferably halogen (preferably chlorine).

[0033] In another embodiment of the invention, a compound having formula (I) is provided, wherein Z 1 It is CR 7 (preferably CH) and Z 2 It is CR 8 (preferably CH); or Z 1 It is CR 7 (preferably CH) and Z 2 It is N; or Z 1 It is N and Z 2 It is N; or Z 1 It is N and Z 2 It is CR 8 In a more preferred embodiment, Z 1It is N and Z 2 It is N.

[0034] In another embodiment of the invention, a compound having formula (I) is provided, wherein n = 0. In another embodiment of the invention, a compound having formula (I) is provided, wherein n = 1, wherein R 5 Choose from the following groups: fluorine, chlorine, bromine, and CN.

[0035] In another embodiment of the invention, a compound having formula (I) is provided, wherein R 6 The group selected is from the group consisting of: hydrogen, C1-C6 alkyl (preferably methyl), C1-C6 alkoxy- (preferably methoxy), and C1-C6 haloalkyl- (preferably CF3). In another embodiment of the invention, a compound having formula (I) is provided, wherein R 6 The group consisting of hydrogen, C1-C6 alkyl (preferably methyl) and C1-C6 haloalkyl (preferably CF3) is selected.

[0036] In another embodiment of the invention, X 1 It is CH2.

[0037] In another embodiment of the invention, a compound having formula (I) is provided, wherein R 9 It is a pyrimidin-2-yl group, which is optionally substituted by one or two substituents independently selected from the group consisting of: halogen, CN, C1-C2 alkyl, C1-C2 alkoxy- and C1-C2 haloalkoxy-, preferably chlorine.

[0038] In another embodiment of the invention, a compound having formula (I) is provided, wherein R 9 It is a C1-C6 alkyl or a C1-C6 haloalkyl-.

[0039] In a preferred embodiment of the present invention, X 1 It is CH2 and R 9 It is a C1-C6 alkyl or a C1-C6 haloalkyl-.

[0040] In a particularly preferred embodiment of the invention, R 1 and R 2 It's hydrogen, Y 1 It is CR 3 And Y 2 It is N, where R 3 It is a C1-C4 alkyl (preferably methyl) or halogen (preferably chlorine), n is 0, R 6 Selected from the group consisting of: hydrogen, C1-C6 alkyl (preferably methyl), C1-C6 alkoxy- (preferably methoxy), and C1-C6 haloalkyl- (preferably CF3), Z1 It is N, Z 2 It is N, X 1 It is CH2 and R 9 It is a C1-C6 alkyl or a C1-C6 haloalkyl-.

[0041] Compounds having formula (I) may contain an asymmetric center and may exist as a single enantiomer, in any ratio of enantiomer pairs, or, in the presence of more than one asymmetric center, contain diastereomers in all possible ratios. Typically, one of these enantiomers has enhanced biological activity compared to the other possibilities.

[0042] The present invention also provides agronomically acceptable salts of compounds having formula (I). Preferably, compounds having formula (I) can form salts with: amines, including primary, secondary and tertiary amines (e.g., ammonia, dimethylamine and triethylamine), alkali metal bases and alkaline earth metal bases, transition metal bases or quaternary ammonium bases.

[0043] The compounds of formula (I) according to the present invention can be used as herbicides on their own, but 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 a herbicidal compound according to any one of the preceding claims 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 carried out using, in addition to water, liquid fertilizers, micronutrients, biological organisms, oils, or solvents.

[0044] The herbicidal composition generally comprises, by weight, from 0.1% to 99%, particularly from 0.1% to 95% of a compound having Formula I and by weight, from 1% to 99.9% of a formulation adjuvant, which preferably comprises, by weight, from 0 to 25% of a surfactant.

[0045] 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 suspensions (OF), oil-soluble 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).

[0046] 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).

[0047] 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).

[0048] 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 earths, 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, if necessary, drying it to form pre-formed blank granules. Reagents commonly 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 (e.g., emulsifiers, wetting agents, or dispersants) may also be included in the granules.

[0049] 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 spray cans).

[0050] 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.

[0051] The preparation of an emulsion (EW) involves obtaining a compound of formula (I) as a liquid (if it is not liquid at room temperature, it can be melted at a reasonable temperature typically below 70°C) or a 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.

[0052] 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 the 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 used 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.

[0053] Suspension concentrates (SCs) may comprise aqueous or non-aqueous suspensions of finely dispersed 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, a compound having formula (I) may be dry-milled and added to water containing the reagents described above to produce the desired final product.

[0054] 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.

[0055] 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.

[0056] The composition may contain one or more additives to improve the biocompatibility of the composition, for example by improving wettability, retention, or distribution on a surface; rain resistance on the treated surface; or absorption or flow 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 bioenhancing adjuvants (components that can help or modify the effects of compounds having formula (I)).

[0057] The wetting agent, dispersant, and emulsifier can be cationic, anionic, amphoteric, or nonionic SAA.

[0058] Suitable cationic types of SAAs include quaternary ammonium compounds (e.g., cetyltrimethylammonium bromide), imidazolines, and amine salts.

[0059] 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 the reaction between one or more fatty alcohols and phosphoric acid (mainly monoesters) or phosphorus pentoxide (mainly diesters), such as the reaction between lauryl alcohol and tetraphosphate; these products may also be ethoxylated), sulfosuccinates, paraffin or olefin sulfonates, taurines, lignosulfonates, and phosphate / sulfate salts of tristyrylphenols.

[0060] Suitable amphoteric types of SAAs include betaine, propionate, and glycine salt.

[0061] 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.

[0062] Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone, or sodium carboxymethyl cellulose) and expansive clays (such as bentonite or attapulgite).

[0063] The compounds of this invention can also be used in combination 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, flubutyrazole-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, ... Cyfos, clethodim, clodinafop-propargyl (including clodinafop-propargyl), isoxaflutole, dichloropyridinic acid, cyclopyranil, cyclopyrimorate, cyprosulfuron-methyl, cyhalofop-propargyl (including cyhalofop-propargyl-butyl), 2,4-D (including its choline salt and 2-ethylhexyl ester), 2,4-DB, betaine, dicamba (including its aluminum, aminopropyl, bis-aminopropylmethyl, choline, dichloropropargyl, diethylene glycolamine, dimethylamine, dimethylammonium, potassium salt and sodium salt), dichlorvos, pyrfluthrin, flupyrazole, metolachlor, fenfluridine, dioxopyritrione, dibromodiphenyl ether, dichlorvos Epyrifenacil, ethylbutyrate, ethoxysulfuron, quizalofop-p-ethyl, fenoxasulfone, fenquinotrione, tetrazolium, pyrimisulfuron, florpyrauxifen (including florpyrauxifen-benzyl), quizalofop-p-ethyl (including quizalofop-p-butyl), flumetsulam (including flumetsulam-sodium), fluthiamethoxam, pyrimisulfuron, propyzoxystrobin, fluroxypyr, flumetsulam, flupyrsulfuron-methyl-sodium, flumetsulam (including chlorpyrifos) Fluroxypyr-meptyl), flufenoxuron, formamide-sulfuron, glufosinate (including L-glufosinate and its ammonium salts), glyphosate (including its hydrazine, isopropylammonium, and potassium salts), halauxifen (including halauxifen-methyl), flupyridine (including flupyridine-methyl), cycloazinone, hydantocidin, methoxyfenozide (including R-methoxyfenozide), imidacloprid, metolachlor, imidacloprid, imidacloprid, indazon-flufenozide, iofensulfuron (including iofensulfuron-methyl-sodium), iofensulfuron (including iofensulfuron-sodium), iofensulfuron, isoproturon,Isoxazolidinone, lancotrione, MCPA, MCPB, mecoprop-P, mesosulfuron-methyl (including mesosulfuron-methyl), mesosulfuron-methyl, benzimidone, pyrazosulfuron, isoxazolin, metolachlor, sulfadiazine, cyprodinil, mesosulfuron-methyl, dichlorvos, nicosulfuron, dapoxuron, oxadiazon, cyclosulfuron-methyl, 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, sulfadiazine, pyrimisulfuron, oxadiazine, simazine, metolachlor, mesosulfuron, sulfonylurea, butyrazosulfuron, terbufos, terbufos, tetflupyrolimet, thiamethoxam (t... hiencarbazone), thifensulfuron, tiafenacil, tolpyralate, bensulfuron-methyl, triafamone, fensulfuron-methyl, chlorpyrifos, trifludimoxazin (including trifludimoxazin-sodium), triflurazole, flufensulfuron-methyl, trisulfuron-methyl, 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-one,4-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.

[0064] 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.

[0065] 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.

[0066] The mixing ratio of the compound having formula (I) to the mixed formulation is preferably from 1:100 to 1000:1.

[0067] 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).

[0068] 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 (including cloquinoline), cyclopropanesulfonamide, dichloropropeneamine, cloquinoxal (including cloquinoxal-ethyl), cloquinoxaline, flufenoxam, cloquinoxalic acid (including cloquinoxalic acid-ethyl), mefenpyr (including mefenpyr-diethyl), metcamifen, and cloquinoxalic acid nitrate.

[0069] Particularly preferred are compounds having formula (I) and mixtures of cyclopropanesulfonamide, ethyl bis(oxazolyl) ester, antidote quinone and / or metcamifen.

[0070] 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 antitoxin quinine also apply to its lithium, sodium, potassium, calcium, magnesium, aluminum, iron, ammonium, quaternary ammonium, sulfonium, or phosphonium salts (as disclosed in WO 02 / 34048).

[0071] Preferably, the mixing ratio of the compound having formula (I) to the safener is from 100:1 to 1:10, especially from 20:1 to 1:1.

[0072] The present invention further provides a method for controlling weeds at 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 at 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 maize, wheat, barley, and rice.

[0073] 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 species, one or more weeds to be controlled, prevailing 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 rates from 10 g / ha to 2500 g / ha, particularly from 25 g / ha to 1000 g / ha, and even more particularly from 25 g / ha to 250 g / ha.

[0074] 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.

[0075] 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. Examples of crops conferred tolerance to imidazolinones (e.g., methoxyfenozide) through conventional breeding methods are... Summer rapeseed (canola). Examples of crops that have been conferred herbicide tolerance through genetic engineering include, for example, maize varieties resistant to glyphosate and glufosinate. and The trademarked products are commercially available. The compounds of this invention can also be used in combination with the plants disclosed in WO 2020 / 236790.

[0076] Crop plants should also be understood as those that have been genetically engineered to resist harmful insects, such as Bt corn (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 corn is... The Bt 176 maize hybrid (Syngenta Seeds). Bt toxin is a protein naturally formed by the soil bacterium 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... (Corn), Yield (corn), (cotton), (cotton), (potato), as well as Plant crops or their seed material can be both herbicide-resistant and insect-resistant (“cumulative” transgenic events). For example, seeds can express the insecticidal Cry3 protein while simultaneously being resistant to glyphosate.

[0077] Crop plants should also be understood to include those obtained through conventional breeding or genetic engineering methods and that contain so-called exported traits (such as improved storage stability, higher nutritional value, and improved flavor).

[0078] 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*. ) 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.

[0079] In another aspect of the invention, the use of compounds having formula (I) as defined herein as herbicides is provided.

[0080] Methods for preparing compounds (e.g., compounds having formula (I) (which may optionally be agriculturally chemically acceptable salts)) are now described and form another aspect of the invention.

[0081]

[0082] Methods for preparing compounds (e.g., compounds having formula (I) (which may optionally be agriculturally chemically acceptable salts)) are now described and form another aspect of the invention.

[0083]

[0084] Compounds having Formula I can be prepared from compounds having Formula A by reacting a compound having Formula II (where LG represents a suitable leaving group, such as F, Cl, Br, or SO2Me) in the presence of a suitable base and in a suitable solvent. Suitable bases may include NaH, K2CO3, or Cs2CO3. Suitable solvents may include THF, CH3CN, or DMF. Compounds having Formula II are commercially available or can be prepared by known methods.

[0085]

[0086] Compounds having formula A can be prepared from compounds having formula B (where PG represents a suitable protecting group such as Me or Tf) by a deprotection reaction in a suitable solvent. Suitable deprotection conditions may include BBr3 or dodecylthiol / LiO t Bu (for PG=Me) or K2CO3 (for PG=Tf). Suitable solvents may include DCM, DCE, or CH3CN.

[0087]

[0088] In an alternative method, a compound having formula A can be prepared from a compound having formula Ba (where X2 is a leaving group such as Cl, Br, or F). This involves contacting the compound having formula Ba with a nucleophilic substitute for a hydroxide (such as acetylhydroxamic acid) in the presence of a suitable base (such as potassium carbonate) and a suitable solvent (such as dimethyl sulfoxide), as described in the literature *Orgletter* [Organic Chemistry Communications] 2016, 18, 2244-2247.

[0089]

[0090] In alternative methods, compounds having formula Ia (compounds having formula I, where X) 1 =O,Z 1 =CR 7 Z 3 =CR 8 And R 9 =Pyrimidine-2-yl) can be generated from a compound having formula C by reacting with a compound having formula IIa (a compound having formula II, wherein R 1 =R 2 =H,Y 1 =CR 3 Y 2=N and LG represent suitable leaving groups such as F, Cl, Br, or SO2Me) are prepared by reaction in the presence of a suitable base and in a suitable solvent. Suitable bases may include K2CO3 or Cs2CO3. Suitable solvents may include CH3CN or DMF. Compounds having formula C and formula IIa are commercially available or can be prepared by known methods.

[0091]

[0092] Compounds having the formula Ba (compounds having the formula B, where X) 1 =O and Z 1 =N) can be prepared from a compound having formula D by reacting it with a compound having formula III in the presence of a suitable phosphine and a suitable azodicarbonate reagent in a suitable solvent. A suitable phosphine may include triphenylphosphine. A suitable azodicarbonate reagent may include diisopropyl azodicarbonate. A suitable solvent may include chloroform. The compound having formula III is commercially available or can be prepared by known methods.

[0093]

[0094] Compounds having the formula Da (compounds having the formula D, where Z) 2 =N) can be prepared from a compound having formula E by reacting it with a compound having formula IV and an ammonia source in the presence of a suitable base and optionally in the presence of a suitable catalyst and in a suitable solvent. A suitable ammonia source may include ammonium acetate. A suitable base may include triethylamine. A suitable catalyst may include 4-dimethylaminopyridine. A suitable solvent may include toluene.

[0095]

[0096] Compounds having the formula Bb (compounds having the formula B, where X) 1 =CH2,Z 1 and Z 2 =N) can be prepared from a compound having formula F by a two-step process. The first step involves reacting with a compound having formula V (where M is a suitable organometallic such as Li or MgHal) optionally in the presence of a suitable catalyst and in a suitable solvent. A suitable catalyst may include a lanthanum(III) bis(lithium chloride) complex. A suitable solvent may include THF. The second step involves reacting with a suitable oxidant in a suitable solvent. A suitable oxidant may include 3-dichloro-5,6-dicyano-1,4-benzoquinone or potassium ferricyanide. A suitable solvent may include THF or Et₂O / water.

[0097]

[0098] Alternatively, compounds having the formula Bb can also be derived from X. 2 It is the preparation of compounds of the formula Db or Dc, such as Cl, Br, or F. It involves reacting with compounds of the formula V or Va and compounds of the formula Db or Dc (where M is a suitable organometallic such as Li or MgHal) optionally in the presence of a suitable catalyst and in a suitable solvent. Suitable catalysts may include copper chloride, ferric acetylacetonate (III), and suitable solvents may include tetrahydrofuran.

[0099]

[0100] Compounds having formula F can be prepared from compounds having formula G by reacting them with compounds having formula IV and an ammonia source in the presence of a suitable base and optionally in the presence of a suitable catalyst and in a suitable solvent. Suitable ammonia sources may include ammonium acetate. Suitable bases may include triethylamine. Suitable catalysts may include 4-dimethylaminopyridine. Suitable solvents may include toluene. Compounds having formulas G and IV are commercially available or can be prepared by known methods.

[0101]

[0102] Compounds having the formula Bc (compounds having the formula B, where X) 1 =CH2,Z 1 =CR 7 Z 2 =CR 8 This compound can be prepared by reacting a compound having the formula H with a suitable reducing agent in a suitable solvent. Suitable reducing agents may include triethylsilane / trifluoroacetic acid. Suitable solvents may include dimethyl silane (DCM).

[0103]

[0104] Compounds having formula H can be prepared from compounds having formula J by metallization with a suitable organometallic reagent and reaction with compounds having formula VI in a suitable solvent. Suitable organometallic reagents may include n-butyllithium. Suitable solvents may include THF. Compounds having formulas VI and J are commercially available or can be prepared by known methods.

[0105]

[0106] Compounds having formula K can be prepared from compounds having formula L by reacting them with compounds having formula VII in the presence of a suitable catalyst (e.g., p-toluenesulfonic acid) and a suitable solvent (e.g., dimethylformamide). Compounds having formula L can be prepared by known methods.

[0107]

[0108] Compounds having formula M can be prepared from compounds having formula N by reacting them with an acyl chloride and a cyanide reagent, followed by reacting them with compounds having formula VIII in the presence of a suitable base (such as sodium hydride). A suitable cyanide reagent may be trimethylsilyl cyanide. Compounds having formula N are commercially available or can be prepared by known methods.

[0109] The following non-limiting examples provide specific methods for synthesizing representative compounds used in this invention (as mentioned in the table below).

[0110] LCMS spectra were recorded on an ACQUITY mass spectrometer (SQD or SQDII single quadrupole mass spectrometer) from Waters Corporations, equipped with an electroejector source (polarity: positive or negative ion), capillary: 3.0 kV, cone: 30 V, extractor: 3.00 V, source temperature: 150 °C, desolvation temperature: 400 °C, cone gas flow rate: 60 L / hr, desolvation gas flow rate: 700 L / hr, mass range: 140 to 800 Da) and an ACQUITY UPLC from Waters Corporations, which features a solvent degassing device, a binary pump, a heated column chamber, and a diode array detector. Column: Waters UPLC HSST3, 1.8 μm, 30 × 2.1 mm, temperature: 60 °C, DAD wavelength range (nm): 210 to 400, solvent gradient: A = water / methanol 9:1 + 0.1% formic acid, B = acetonitrile + 0.1% formic acid, gradient: 0%-100% B, over 2.5 min; flow rate (ml / min): 0.75.

[0111] Example 1: Synthesis of 5-chloro-2-[[8-(5-chloropyrimidin-2-yl)oxy-1-naphthyl]oxy]pyrimidine (compound 1.001)

[0112]

[0113] 2,5-Dichloropyrimidine (0.558 g, 3.75 mmol) was added to a stirred solution of naphthalene-1,8-diol (0.200 g, 1.25 mmol) and K₂CO₃ (0.88 g, 6.25 mmol) in N,N-dimethylformamide (6.2 mL), and the resulting mixture was heated to 80 °C for 1 h. The reaction was cooled to room temperature, diluted with H₂O, and extracted with DCM. The combined organic extracts were dried over MgSO₄ and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–30% gradient of EtOAc in cyclohexane as eluent to give the desired product (0.204 g, 42%) as a white solid.

[0114] 1 H NMR(400MHz, CDCl3)δ8.41(s,4H),7.89(dd,2H),7.55(t,2H),7.21(dd,2H)

[0115] Example 2: Synthesis of 5-chloro-2-[[8-(4,4,4-trifluorobutyl)-1-naphthyl]oxy]pyrimidine (compound 1.002)

[0116] Step 1: Synthesis of 4,4,4-trifluoro-1-(8-methoxy-1-naphthyl)but-1-ol

[0117]

[0118] At -78 °C under a nitrogen atmosphere, n-butyllithium (0.47 mL of 2.5 M solution in hexane, 1.2 mmol) was added dropwise to a solution of 1-bromo-8-methoxy-naphthalene (0.23 g, 0.97 mmol) in tetrahydrofuran (9.7 mL). The mixture was stirred at -78 °C for 30 min, then 4,4,4-trifluorobutanal (0.13 g, 1.1 mmol) in THF was added, and the reaction was stirred at -78 °C for 1 h. The reaction was heated to room temperature and quenched by adding saturated ammonium chloride aqueous solution, extracted to ethyl acetate, dried over MgSO4, and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–30% gradient of EtOAc / cyclohexane to give the desired product (92 mg, 33%).

[0119] 1H NMR(400MHz, CDCl3)δ7.75-7.70(m,2H),7.48-7.35(m,3H),6.90(d,1H),5.80(br,1H) ,3.97(s,3H),2.75(br,1H),2.50-2.25(m,2H),2.22-2.15(m,1H),2.00-1.92(m,1H).

[0120] Step 2: Synthesis of 1-methoxy-8-(4,4,4-trifluorobutyl)naphthalene

[0121]

[0122] Triethylsilane (0.18 mL, 1.1 mmol) was added to a stirred solution of 0.080 g (0.28 mmol) of 4,4,4-trifluoro-1-(8-methoxy-1-naphthyl)but-1-ol in dichloromethane (0.95 mL). After stirring for 15 min, trifluoroacetic acid (0.13 mL, 1.7 mmol) was added and the reaction was heated to 40 °C overnight. The reaction was cooled to room temperature and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography using a 0%–20% gradient of EtOAc / cyclohexane as eluent to give the desired product (19 mg, 25%).

[0123] 1 H NMR(400MHz, CDCl3)δ7.67(dd,1H),7.45-7.40(m,1H),7.40-7.32(m,2H),7.19(d,1H), 6.88-6.82(m,1H),3.96(s,3H),3.36-3.28(m,2H),2.23-2.10(m,2H),2.00-1.90(m,2H)

[0124] Step 3: Synthesis of 8-(4,4,4-trifluorobutyl)naphthalene-1-ol

[0125]

[0126] At 0 °C and under a N2 atmosphere, boron tribromide (0.28 mL of 1 M solution in DCM, 0.28 mmol) was added dropwise to a stirred solution of 1-methoxy-8-(4,4,4-trifluorobutyl)naphthalene (0.03 g, 0.112 mmol) in DCM (1.12 mL). The reaction was stirred at room temperature for 6 h and then quenched by adding a saturated aqueous solution of NaHCO3. The organic phase was separated and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–30% gradient of EtOAc / cyclohexane as eluent to give the desired product (12 mg, 42%).

[0127] 1 H NMR (400MHz, CDCl3) δ7.72-7.61(m,1H),7.43(dd,1H),7.38-7.31(m,1H),7.29-7.22(m,1H),7.22-7.14 (m,1H),6.74-6.68(m,1H),5.33-5.23(m,1H),3.37-3.26(m,2H),2.23-2.08(m,2H),2.06-1.94(m,2H).

[0128] Step 4: Synthesis of 5-chloro-2-[[8-(4,4,4-trifluorobutyl)-1-naphthyl]oxy]pyrimidine (compound 1.002)

[0129]

[0130] 2,5-Dichloropyrimidine (8.5 mg, 0.057 mmol) was added to a stirred solution of 8-(4,4,4-trifluorobutyl)naphthyl-1-ol (12 mg, 0.047 mmol) and potassium carbonate (13 mg, 0.094 mmol) in DMF (0.12 mL). The reaction mixture was heated at 80 °C for 3.5 h and then cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (×2). The combined organic extracts were dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–20% gradient of EtOAc / cyclohexane as eluent to give the desired product (16 mg, 94%).

[0131] 1 H NMR(400MHz, CDCl3)δ8.50(s,2H),7.85-7.78(m,2H),7.48(t,1H),7.40(t,1H) ),7.30(d,1H),7.20(d,1H),3.10(t,2H),2.20-2.07(m,2H),1.92-1.83(m,2H)

[0132] Example 3: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)quinazoline (compound 1.003).

[0133] Step 1: Synthesis of 5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline

[0134]

[0135] Iodine crystals were added to magnesium shavings (0.155 g, 6.24 mmol) stirred in THF (60 mL). The reaction was stirred for 10 minutes and a small amount of 1-bromo-4,4,4-trifluorobutane was added. The reaction was heated with a hot air gun until the solution changed from yellow to colorless. The remaining 1-bromo-4,4,4-trifluorobutane (1.20 g, 6.24 mmol) was added dropwise, and the reaction was then heated at 75 °C until no solid remained (about 30 minutes), and then allowed to cool to room temperature.

[0136] A solution of 5-methoxyquinazoline (0.500 g, 3.12 mmol) in 30 mL of THF was added to the magnesium bromine (4,4,4-trifluorobutyl) formed above, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic matter was washed with brine, dried over MgSO4, and evaporated under reduced pressure to dryness to give 5-methoxy-4-(4,4,4-trifluorobutyl)-3,4-dihydroquinazoline as a pale orange gel.

[0137] The crude intermediate was dissolved in diethyl ether (15 mL), and KOH (2.5 mL of 20% aqueous solution) and potassium ferricyanide (2.08 g, 6.24 mmol) were added. The mixture was stirred vigorously at room temperature for 44 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–50% gradient of EtOAc / cyclohexane as eluent to give the desired product (0.548 g, 65%) as a white solid.

[0138] 1 H NMR(400MHz, CDCl3)δ9.12(s,1H),7.82-7.75(m,1H),7.62(dd,1H),6.98(d ,1H),4.03(s,3H),3.58-3.49(m,2H),2.37-2.20(m,2H)2.16-2.05(m,2H).

[0139] Step 2: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)quinazoline (compound 1.003).

[0140]

[0141] LiO was added to a stirred solution of 5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (0.050 g, 0.19 mmol) and 1-dodecylthiol (0.076 g, 0.37 mmol) in DMF (0.5 mL). t Bu (0.37 mL of 1 M solution in THF, 0.37 mmol). The reaction was heated at 100 °C for 1.5 h, and then allowed to cool to room temperature.

[0142] Cs₂CO₃ (0.15 g, 0.46 mmol) and 2,5-dichloropyrimidine (0.073 g, 0.46 mmol) were added to the cooled reaction mixture, and the reaction was heated to 80 °C for 18 hours. The reaction was then cooled to room temperature and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–50% gradient of EtOAc / cyclohexane as eluent to give the desired product (0.032 g, 47%) as a pale yellow solid.

[0143] 1 H NMR(400MHz, CDCl3)δ9.22(s,1H),8.53(s,2H),8.02(dd,1H),7.90(t,1H),7.37(dd,1H),3.38(t,2H),2.27-2.18(m,2H),2.08-2.04(m,2H)

[0144] Example 4: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.004)

[0145] Step 1: Synthesis of 5-methoxy-2-(trifluoromethyl)quinazoline

[0146]

[0147] At 0 °C, triethylamine (2.04 mL, 14.6 mmol) was added to a stirred solution of 2-amino-6-methoxy-benzaldehyde (1.00 g, 6.62 mmol) and 4-dimethylaminopyridine (0.082 g, 0.662 mmol) in toluene (20 mL), followed by the slow addition of trifluoroacetic anhydride (1.43 mL, 9.92 mmol). The reaction was heated to room temperature and stirred for 18 hours. Ammonium acetate (1.16 g, 14.6 mmol) was added to the reaction, and the reaction was heated at 90 °C for 24 hours, then cooled to room temperature. The reaction mixture was diluted with water, stirred vigorously for 30 minutes, and then the phases were separated. The aqueous phase was extracted with EtOAc (×2). The combined organic phases were dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–50% gradient of EtOAc / cyclohexane as eluent to obtain the desired product (0.69 g, 46%) as a pale yellow solid.

[0148] 1 H NMR(400MHz, CDCl3)δ9.87(s,1H),7.95(t,1H),7.75(d,1H),7.08(d,1H),4.09(s,3H)

[0149] Step 2: Synthesis of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline

[0150]

[0151] Iodine crystals were added to stirred magnesium shavings (0.170 g, 6.84 mmol) in THF (10 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred for 10 minutes and a small amount of 1-bromo-4,4,4-trifluorobutane was added. The reaction was heated with a hot air gun until the solution changed from yellow to colorless. The remaining 1-bromo-4,4,4-trifluorobutane (0.848 mL, 6.84 mmol) was added dropwise, and the mixture was then heated at 75 °C for 30 minutes until no solid remained.

[0152] Add 5-methoxy-2-(trifluoromethyl)quinazoline (0.52 g, 2.28 mmol) and a lanthanum(III) chloride bis(lithium chloride) complex (11.4 mL of 0.6 M solution in THF, 6.84 mmol) to the Grignard reagent formed above, and stir the reaction at room temperature for 18 hours. Quench the reaction with a saturated aqueous ammonium chloride solution and extract with EtOAc (×2). Wash the combined organic extracts with brine, dry to MgSO4 and evaporate to dryness under reduced pressure to give 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)-3,4-dihydroquinazoline as a pale orange gel.

[0153] At 0 °C, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.581 g, 2.51 mmol) was added to a solution of crude 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)-3,4-dihydroquinazoline in THF (10 mL). The reaction was heated to room temperature and stirred for 2 h. The reaction was cooled to 0 °C, quenched with 2 M NaOH and stirred for 5 min, and then extracted with EtOAc (×2). The combined organic extracts were washed with water and brine, dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–10% gradient of EtOAc / cyclohexane as eluent to give the desired product (0.377 g, 49%) as a pale yellow solid.

[0154] 1 H NMR (400MHz, CDCl3) δ7.93-7.84(m,1H),7.76(dd,1H),7.10(d,1H),4.06(s,3H),3.66-3.55(m,2H),2.39-2.24(m,2H),2.29-2.08(m,2H).

[0155] Step 3: Synthesis of 4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazolin-5-ol

[0156]

[0157] Lithium tert-butoxide (2.13 mL of 1M solution in THF, 2.13 mmol) was added to a solution of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (0.360 g, 1.06 mmol) and 1-dodecylthiol (0.52 mL, 2.13 mmol) in DMF (3.6 mL). The reaction was heated at 100 °C for 1.5 h, then cooled to room temperature, quenched with 1M HCl, and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–20% gradient of EtOAc / cyclohexane as eluent to give the desired product (0.250 g, 72%) as a pale yellow solid.

[0158] 1 H NMR (400MHz, CDCl3) δ7.83-7.71(m,2H),7.05(dd,1H),6.54(br s,1H),3.66(t,2H),2.39-2.24(m,2H),2.24-2.14(m,2H).

[0159] Step 4: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.004)

[0160]

[0161] At 0 °C under a N2 atmosphere, a solution of 4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline-5-ol (0.100 g, 0.308 mmol) in THF (2 mL) was added dropwise to a stirred suspension of sodium hydride (0.019 g in a 60% suspension in mineral oil, 0.463 mmol) in THF (2 mL). The reaction was stirred at 0 °C for 30 min, and then 2,5-dichloropyrimidine (0.073 g, 0.463 mmol) in THF (2 mL) was added dropwise. The reaction was heated under reflux for 96 h, then cooled to room temperature and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–10% gradient of EtOAc / cyclohexane as eluent to give the desired product (0.057 g, 42%) as a pale yellow solid.

[0162] 1H NMR (400MHz, CDCl3) δ8.54(s,2H),8.16(d,1H),8.02(t,1H),7.51(d,1H),3.47(t,2H),2.28-2.21(m,2H),2.12-2.09(m,2H)

[0163] Example 5: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)quinazoline (1.006)

[0164] Step 1: Synthesis of 5-methoxy-2-(trifluoromethyl)-3H-quinazolin-4-one

[0165]

[0166] At 0 °C, triethylamine (7.39 mL, 52.6 mmol) was added to a stirred mixture of 2-amino-6-methoxybenzoic acid (2.00 g, 12.0 mmol) and 4-dimethylaminopyridine (0.148 g, 1.20 mmol) in toluene (36 mL), followed by dropwise addition of trifluoroacetic anhydride (5.35 mL, 37.1 mmol). The reaction mixture was heated to room temperature and stirred overnight, then ammonium acetate (4.18 g, 52.6 mmol) was added and the reaction was heated at 90 °C overnight. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and stirred vigorously. The resulting solid was filtered, washed with water and Et₂O, and dried under vacuum to give the desired product (1.57 g, 54%) as a paste.

[0167] 1 H NMR (400MHz, d6-DMSO) δ13,29(br s,1H),7.80(t,1H),7.31(d,1H),7.20(d,1H),3.90(s,3H).

[0168] Step 2: Synthesis of 5-hydroxy-2-(trifluoromethyl)-3H-quinazolin-4-one

[0169]

[0170] At 0 °C, boron tribromide (5.12 mL of 1 M solution in DCM, 5.12 mmol) was added dropwise to a solution of 5-methoxy-2-(trifluoromethyl)-3H-quinazolin-4-one (0.500 g, 2.05 mmol) in DCE (41.0 mL). The reaction was heated to room temperature and then under reflux overnight. The reaction was cooled to room temperature, quenched with water, made alkaline with a saturated aqueous solution of NaHCO3, and extracted with EtOAc (×3). The combined organic extracts were washed with water and brine, dried over MgSO4, and evaporated under reduced pressure to dryness to give the desired product (0.445 g, 94%) as a brown solid.

[0171] 1 H NMR(400MHz,d6-DMSO)δ11.74(br,1H),7.77(t,1H),7.27(d,1H),7.02(d,1H)

[0172] Step 3: Synthesis of [4-oxo-2-(trifluoromethyl)-3H-quinazolin-5-yl]trifluoromethane sulfonate

[0173]

[0174] At 0 °C, Cs₂CO₃ (0.616 g, 1.89 mmol) was added to a suspension of 5-hydroxy-2-(trifluoromethyl)-3H-quinazolin-4-one (0.435 g, 1.89 mmol) in THF (8.70 mL), followed by 1,1,1-trifluoro-N-(2-pyridyl)-N-(trifluoromethanesulfonyl)methanesulfonamide (0.677 g, 1.89 mmol). After 1 hour, the reaction was heated to room temperature and stirred for 72 hours. The reaction was cooled to 0 °C and additional Cs₂CO₃ (300 mg) and 1,1,1-trifluoro-N-(2-pyridyl)-N-(trifluoromethanesulfonyl)methanesulfonamide (330 mg) were added, and the mixture was stirred overnight at room temperature. The reaction was then heated at 40 °C for 1 hour and then at 50 °C overnight. The reaction was cooled to room temperature, then quenched with water and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–100% gradient of EtOAc / cyclohexane as eluent to give the desired product (0.109 g) as a beige solid in a mixture inseparable from the starting material.

[0175] Step 4: Synthesis of [2-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)quinazolin-5-yl]trifluoromethane sulfonate

[0176]

[0177] At room temperature and under a nitrogen atmosphere, 3,3,3-trifluoroprop-1-ol (0.037 mL, 0.41 mmol) was added to a suspension of [4-oxo-2-(trifluoromethyl)-3H-quinazolin-5-yl]trifluoromethanesulfonate (0.060 g, 0.17 mmol) and triphenylphosphine (0.11 g, 0.41 mmol) in chloroform (1.2 mL). The solution was cooled to 0 °C and DIAD (0.82 mL, 0.41 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 10 min and then allowed to warm to room temperature. The reaction was quenched with water and extracted with EtOAc (×3). The combined organic extracts were washed with 2 M HCl, then with brine, dried over MgSO4, and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–40% gradient of EtOAc / cyclohexane as eluent to obtain the desired product (0.068 g, 90%) as a colorless gel.

[0178] 1 H NMR(400MHz, CDCl3)δ8.19(d,1H),7.99(t,1H),7.59(d,1H),4.87(t,2H),2.89(m,2H)

[0179] Step 5: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)quinazoline (1.006)

[0180]

[0181] Cs₂CO₃ (0.21 g, 1.1 mmol) and 2,5-dichloropyrimidine (0.033 g, 0.22 mmol) were added to a solution of [2-(trifluoromethyl)-4-(3,3,3-trifluoropropoxy)quinazolin-5-yl]trifluoromethanesulfonate (0.068 g, 0.15 mmol) in acetonitrile (1.1 mL), and the reaction was heated overnight at 80 °C. The reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over MgSO₄, and evaporated to dryness under reduced pressure. The crude product was purified by rapid chromatography on silica gel using a 0%–40% gradient of EtOAc / cyclohexane as eluent to give the desired product (24 mg, 37%) as a white solid.

[0182] 1H NMR(400MHz, CDCl3)δ8.47(s,2H),8.08(d.1H),8.00(t,1H),7.48(d,1H),4.67(t,2H),2.48(m,2H)

[0183] Example 6: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1.013)

[0184]

[0185] Step 1: Synthesis of 1-(2,6-difluorophenyl)-5,5,5-trifluoro-pentan-1-ol

[0186]

[0187] Iodine crystals were added to a mixture of stirred magnesium shavings (3.42 g, 140.74 mmol) in tetrahydrofuran (40 mL). The reaction was stirred for 10 minutes and heated to reflux. Then a small amount of 1-bromo-4,4,4-trifluorobutane in tetrahydrofuran was added. Heating continued until the color of the solution changed from yellow to gray. The remaining 1-bromo-4,4,4-trifluorobutane (20.16 g, 105.55 mmol) in tetrahydrofuran (70 mL) was added dropwise under heating, and the reaction was then heated at 75 °C for 1 h, followed by cooling to room temperature. At 0 °C, the above solution of bromo(4,4,4-trifluorobutyl)magnesium in tetrahydrofuran was added dropwise to a cooled solution of 2,6-difluorobenzaldehyde (10 g, 70.37 mmol) in tetrahydrofuran (80 mL), and the reaction was stirred at room temperature for 16 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (3 × 500 mL). The combined organic compounds were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to dryness to give 1-(2,6-difluorophenyl)-5,5,5-trifluoro-pentan-1-ol (17.8 g, 99.5%) as a yellow oil.

[0188] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.15–7.23 (m, 1H), 6.80–6.90 (m, 2H), 5.01 (br s, 1H), 2.11–2.30 (m, 2H), 1.97–2.15 (m, 2H), 1.69–1.90 (m, 2H)

[0189] Step 2: Synthesis of 1-(2,6-difluorophenyl)-5,5,5-trifluoro-pentan-1-one

[0190]

[0191] At 0 °C, (1,1-diacetoxy-3-oxo-1λ5,2-benzyl-1-yl)acetate (30.70 g, 70.220 mmol) was added in portions to a solution of 1-(2,6-difluorophenyl)-5,5,5-trifluoro-pentane-1-ol (17 g, 66.87 mmol) in acetonitrile (340 mL), and the reaction mixture was heated to room temperature and stirred at room temperature for 2 h. The reaction was quenched with a saturated solution of sodium thiosulfate (32.04 g, 200.63 mmol) in water (1000 mL), followed by quenching with sodium bicarbonate solution and extraction with ethyl acetate (3 × 500 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica with ethyl acetate and cyclohexane (10:90) to give 1-(2,6-difluorophenyl)-5,5,5-trifluoro-pentan-1-one (14.8 g, 87.8%) as a yellow oil.

[0192] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.40 (tt, 1H) 6.91-7.00 (m, 2H) 2.98 (t, 2H) 2.13-2.26 (m, 2H) 1.96-2.05 (m, 2H)

[0193] Step 3: Synthesis of 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one

[0194]

[0195] A solution of 1-(2,6-difluorophenyl)-5,5,5-trifluoro-pentan-1-one (8 g, 31.72 mmol) in acetonitrile (26 mL) was added to a solution of 30% ammonia (210 mL, 1546.5 mmol). The mixture was heated in a miniclave at 120 °C for 10 h. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (3 × 500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (0.5:95) to give 1-(2-amino-6-fluorophenyl)-5,5,5-trifluoro-pentan-1-one (4.5 g, 33%) as a yellow oil.

[0196] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.40 (tt, 1H), 6.91–7.00 (m, 2H), 2.98 (t, 2H), 2.13–2.26 (m, 2H), 1.96–2.05 (m, 2H)

[0197] Step 4: Synthesis of 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline

[0198]

[0199] Ammonium acetate (1.7 g, 22 mmol) was added to a solution of 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentane-1-one (2.3 g, 7.4 mmol) in 2,4-pentanedione (0.91 mL, 8.9 mmol), and the mixture was then heated to 120 °C for 18 h. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (3 × 200 mL), washed with a saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (10:90) to give 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1 g, 49%) as a yellow solid.

[0200] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.71-7.79 (m, 2H), 7.17-7.25 (m, 1H), 3.39 (td, 2H), 2.83 (s, 3H) 2.19-2.36 (m, 2H) 2.07-2.19 (m, 2H).

[0201] Step 5: Synthesis of 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline

[0202]

[0203] A solution of 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1 g, 3.67 mmol) in methanol (11.02 mL) and N,N-dimethylformamide (11.02 mL) was added to a solution of 25% sodium methoxide (1.26 mL, 5.51 mmol). The reaction mixture was heated to 55 °C for 8 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 100 mL). The mixture was washed with a saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (10:90) to give 0.7 g, 67.02%, a pale yellow solid of 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline.

[0204] 1¹H NMR (400MHz, chloroform-d) δppm 7.74(t, 1H), 7.53(dd, 1H), 6.91(d, 1H), 4.02(s, 3H) 3.44–3.51(m, 2H) 2.82(s, 3H), 2.22–2.31(m, 2H), 2.04–2.12(m, 2H).

[0205] Step 5: Synthesis of 2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol

[0206]

[0207] Add pyridine-1-onium hydrochloride (1.046 g, 8.794 mmol) to 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (0.1 g, 0.35 mmol). Heat at 180 °C for 90 min. Cool the reaction mixture to room temperature, quench with ice-cold water, and extract in ethyl acetate (3 × 50 mL). Wash with brine (50 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by passing it through (200–400) silica using ethyl acetate and cyclohexane (25:75) to give 2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (0.03 g, 30.3%) as a white solid.

[0208] 1 ¹H NMR (400MHz, methanol-d⁴) δppm 7.70(t, ¹H), 7.35(dd, ¹H), 6.96(dd, ¹H), 3.49–3.57(m, 2H), 2.73(s, 3H), 2.24–2.40(m, 2H), 2.00–2.11(m, 2H).

[0209] Step 6: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1.013)

[0210]

[0211] Potassium carbonate (0.038 g, 0.2776 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.022 g, 0.111 mmol) were added to a solution of 2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (25 mg, 0.092 mmol) in DMF (0.5 mL). The mixture was heated to 50 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 20 mL). The extract was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200–400) silica using ethyl acetate and cyclohexane (10:90) to give 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (24.5 mg, 69.2%) as a white solid.

[0212] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.53 (s, 2H), 7.91 (dd, 1H), 7.85 (t, 1H), 7.29 (s, 1H), 3.32 (t, 2H), 2.85 (s, 3H), 2.14–2.26 (m, 2H), 1.97–2.07 (m, 2H).

[0213] Example 7: Synthesis of 8-chloro-5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1.019)

[0214]

[0215] Step 1: Synthesis of 8-bromo-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline

[0216]

[0217] N-bromosuccinimide (0.313 g, 1.76 mmol) was added to a solution of 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (0.5 g, 1.759 mmol) in acetonitrile (5.3 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 × 50 mL), washed with a saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (10:90) to give 8-bromo-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (0.56 g, 87.67%) as a yellow solid.

[0218] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.04 (d, 1H), 6.81 (d, 1H), 4.01 (s, 3H), 3.45–3.52 (m, 2H), 2.88 (s, 3H), 2.20–2.33 (m, 2H), 2.02–2.11 (m, 2H)

[0219] Step 2: Synthesis of 8-chloro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol

[0220]

[0221] Add pyridine-1-onium hydrochloride (1.64 g, 13.77 mmol) to 8-bromo-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (0.2 g, 0.55 mmol). Heat at 180 °C for 90 min. Cool the reaction mixture to room temperature, quench with ice-cold water, and extract in ethyl acetate (3 × 50 mL). Wash with brine (50 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue through (200–400) silica using ethyl acetate and cyclohexane (15:85) to give 8-chloro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (0.04 g, 23.84%) as a grayish-white solid.

[0222] 1 ¹H NMR (400MHz, methanol-d⁴) δppm 7.80 (d, 1H), 6.92 (d, Hz, 1H), 3.50–3.58 (m, 2H), 2.79 (s, 3H), 2.24–2.38 (m, 2H), 2.01–2.11 (m, 2H).

[0223] Step 3: Synthesis of 8-chloro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (1.019)

[0224]

[0225] Potassium carbonate (0.031 g, 0.22 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.013 g, 0.067 mmol) were added to a solution of 8-chloro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (23 mg, 0.074 mmol) in DMF (0.5 mL). The mixture was heated to 40 °C for 3 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 20 mL). The mixture was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200–400) silica using ethyl acetate and cyclohexane (10:90) to give 8-chloro-5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (15 mg, 48.6%) as a yellow solid.

[0226] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.53 (s, 2H), 7.96 (d, 1H), 7.22–7.25 (d, 1H), 3.33 (t, 2H), 2.92 (s, 3H), 2.14–2.26 (m, 2H), 1.97–2.08 (m, 2H)

[0227] Example 8: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (1.017)

[0228]

[0229] Step 1: Synthesis of 5-methoxy-2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline

[0230]

[0231] Methylboronic acid (0.111 g, 1.85 mmol) and cesium carbonate (0.61 g, 1.85 mmol) were added to 8-bromo-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (0.21 g, 0.58 mmol) and (0.2 g, 0.55 mmol) in 1,4-dioxane (12.6 mL). After degassing for 15 min, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.051 g, 0.069 mmol) was added. The mixture was heated in a microwave at 100 °C for 60 min. The reaction mixture was cooled to room temperature, quenched with water, and extracted in ethyl acetate (3 × 50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica through ethyl acetate and cyclohexane (15:85) to give 5-methoxy-2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (0.14 g, 81.17%) as a grayish-white solid.

[0232] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.57 (dd, ¹H), 6.80 (d, ¹H), 3.98 (s, ³H), 3.42–3.49 (m, ²H), 2.83 (s, ³H), 2.63 (s, ³H), 2.20–2.32 (m, ²H), 2.00–2.11 (m, ²H)

[0233] Step 2: Synthesis of 2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazolin-5-ol

[0234]

[0235] Add pyridine-1-onium hydrochloride (1.36 g, 11.73 mmol) to 5-methoxy-2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (0.14 g, 0.47 mmol). Heat at 180 °C for 90 min. Cool the reaction mixture to room temperature, quench with ice-cold water, and extract in ethyl acetate (3 × 50 mL). Wash with a saline solution (50 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by reversed-phase column chromatography (C18 column) using acetonitrile and water (10:90) to give 2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (0.06 g, 45%) as a grayish-white solid.

[0236] 1¹H NMR (400MHz, methanol-d⁴) δppm 7.45 (dd, ¹H), 6.78 (d, ¹H), 3.41–3.46 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H), 2.19–2.36 (m, 2H) 1.92–2.06 (m, 2H)

[0237] Step 3: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (1.017)

[0238]

[0239] Potassium carbonate (0.061 g, 0.44 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.026 g, 0.148 mmol) were added to a solution of 2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazolin-5-ol (42 mg, 0.148 mmol) in dimethylformamide (0.8 mL). The mixture was heated to 40 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 30 mL). The mixture was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica through ethyl acetate and cyclohexane (10:90) to give 5-(5-chloropyrimidin-2-yl)oxy-2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (0.041 g, 69.94%) as a grayish-white solid.

[0240] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.51(s, 2H), 7.68(d, 1H), 7.16(d, 1H), 3.29(t, 2H), 2.85(s, 3H), 2.75(s, 3H), 2.12–2.25(m, 2H), 1.95–2.04(m, 2H).

[0241] Example 9: Synthesis of 8-bromo-5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.048)

[0242]

[0243] Step 1: Synthesis of 5-methoxy-2-(trifluoromethyl)-3H-quinazolin-4-one

[0244]

[0245] At 0 °C, trifluoroacetic anhydride (66.82 mL, 463.62 mmol) was added to a stirred mixture of 2-amino-6-methoxybenzoic acid (25.00 g, 149.55 mmol) and 4-dimethylaminopyridine (1.85 g, 14.95 mmol) in toluene (450 mL), followed by dropwise addition of triethylamine (92.4 mL, 658.04 mmol). The reaction mixture was heated to room temperature and stirred overnight. Ammonium acetate (20.92 g, 263.22 mmol) was then added and the reaction was heated at 110 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with ice-cold water (1000 mL), and stirred vigorously. The resulting solid was filtered, washed with water and methyl tert-butyl ether, and dried under vacuum to give 5-methoxy-2-(trifluoromethyl)-3H-quinazolin-4-one (30.4 g, 82%) as a paste-like solid.

[0246] 1 H NMR (400MHz, DMSO-d6) δppm 7.80 (t, 1H), 7.32 (d, 1H), 7.20 (d, 1H), 3.90 (s, 3H).

[0247] Step 2: Synthesis of 4-bromo-5-methoxy-2-(trifluoromethyl)quinazoline

[0248]

[0249] Phosphorus tribromooxy (14 g, 49 mmol) was added to a stirred mixture of 5-methoxy-2-(trifluoromethyl)quinazoline-4-ol (8.0 g, 33 mmol) in toluene (30 mL). The mixture was heated to 140 °C for 3 h. The reaction mixture was cooled to room temperature and poured into a saturated sodium bicarbonate solution. Extraction was performed in ethyl acetate (3 × 500 mL), washed with a saline solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (5:95) to give 4-bromo-5-methoxy-2-(trifluoromethyl)quinazoline (5.5 g, 55%) as a pale yellow solid.

[0250] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.95(t, 1H), 7.76(d, 1H), 7.16(d, 1H), 4.06(s, 3H).

[0251] Step 3: Synthesis of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline

[0252]

[0253] Iodine crystals were added to a mixture of stirred magnesium shavings (1.018 g, 41.88 mmol) in tetrahydrofuran (25 mL). The reaction was stirred for 10 minutes and heated to reflux. Then a small amount of 1-bromo-4,4,4-trifluorobutane in tetrahydrofuran was added. Heating continued until the color of the solution changed from yellow to gray. The remaining 1-bromo-4,4,4-trifluorobutane (4.0 g, 20.94 mmol) solution in tetrahydrofuran (25 mL) was added dropwise under heating, and the reaction was then heated at 75 °C for 1 h, followed by cooling to room temperature. At 0 °C, the above solution of bromo(4,4,4-trifluorobutyl)magnesium in tetrahydrofuran was added dropwise to an ice-cooled solution of 4-bromo-5-methoxy-2-(trifluoromethyl)quinazoline (2.0 g, 6.51 mmol) and cuprous iodide (I) (0.027 g, 0.105 mmol) in tetrahydrofuran (16 mL), and the reaction was stirred at room temperature for 16 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (3 × 500 mL). The combined organic matter was washed with brine (200 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to dryness to give 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (2.1 g, 95%).

[0254] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.88(t, 1H), 7.74(dd, 1H), 7.09(d, 1H), 4.06(s, 3H), 3.59(t, 2H), 2.23–2.36(m, 2H), 2.07–2.21(m, 2H).

[0255] Step 4: Synthesis of 8-bromo-5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline

[0256]

[0257] N-bromosuccinimide (0.921 g, 5.17 mmol) was added to a solution of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.75 g, 5.17 mmol) in acetonitrile (15.5 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 × 200 mL), washed with a saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (10:90) to give 8-bromo-5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.51 g, 53.3%) as a yellow solid.

[0258] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.15 (d, 1H), 6.99 (d, 1H), 4.07 (s, 3H), 3.57–3.64 (m, 2H), 2.31 (dt, 2H), 2.11–2.18 (m, 2H)

[0259] Step 5: Synthesis of 8-bromo-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazolin-5-ol

[0260]

[0261] Lithium tert-butoxide (0.235 g, 2.877 mmol) was added to a stirred solution of 1-dodecanethiol (2.877 mmol) in N,N-dimethylformamide (3 mL). After stirring for 5 minutes, a solution of 8-bromo-5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (600 mg, 1.439 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was heated at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, quenched with ice-cold water, acidified with 2N hydrochloric acid solution, extracted with ethyl acetate (3 × 50 mL), washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica with ethyl acetate and cyclohexane (20:80) to give 8-bromo-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazolin-5-ol (0.30 g, 51.74%) as a brown solid.

[0262] 1¹H NMR (400MHz, methanol-d⁴) δppm 8.11(d, 1H), 7.06(d, 1H), 3.68(t, 2H), 2.28–2.41(m, 2H), 2.08–2.17(m, 2H).

[0263] Step 6: Synthesis of 8-bromo-5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.048)

[0264]

[0265] Potassium carbonate (0.309 g, 2.23 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.302 g, 1.49 mmol) were added to a solution of 8-bromo-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline-5-ol (0.30 g, 0.744 mmol) in isopropanol (3 mL). The mixture was heated to 55 °C for 18 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 50 mL). The mixture was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (10:90) to give 8-bromo-5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (0.178 g, 46.39%) as a grayish-white solid.

[0266] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.54 (s, 2H), 8.32 (m, 1H), 7.41 (m, 1H), 3.48 (t, 2H), 2.20–2.32 (m, 2H), 2.07–2.20 (m, 2H)

[0267] Example 10: Synthesis of 8-bromo-5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.047)

[0268]

[0269] Step 1: Synthesis of 8-bromo-5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.047)

[0270]

[0271] To a solution of 8-bromo-5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.048; 0.09 g, 0.175 mmol) in N,N-dimethylformamide (1.75 mL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.028 g, 0.0349 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0165 g, 0.0175 mmol) were added, followed by zinc cyanide (0.0307 mg, 0.26 mmol). The reaction mixture was heated at 90 °C for 4 h. The reaction mixture was then quenched in water (20 mL), extracted in ethyl acetate (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (10:90) to give 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazolin-8-carboxynitrile (0.023 g, 28.53%) as a grayish-white solid.

[0272] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.59(s, 2H), 8.39(d, 1H), 7.61(d, 1H), 3.55(t, 2H), 2.20–2.32(m, 2H), 2.08–2.20(m, 2H)

[0273] Example 11: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.046)

[0274]

[0275] Step 1: Synthesis of 5-methoxy-8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline

[0276]

[0277] Methylboronic acid (0.147 g, 2.45 mmol) and cesium carbonate (0.80 g, 2.45 mmol) were added to 8-bromo-5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (0.32 g, 0.767 mmol) in 1,4-dioxane (5 mL). After degassing for 15 min, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.067 g, 0.092 mmol) was added. The mixture was heated at 100 °C for 90 min. The reaction mixture was cooled to room temperature, quenched with water, and extracted in ethyl acetate (3 × 50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (15:85) to give 5-methoxy-8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (0.232 g, 85.84%) as a grayish-white solid.

[0278] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.72 (d, 1H), 7.00 (d, 1H), 4.03 (s, 3H) 3.57–3.63 (m, 2H), 2.69 (s, 3H), 2.30 (m, 2H), 2.09–2.18 (m, 2H)

[0279] Step 2: Synthesis of 8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazolin-5-ol

[0280]

[0281] Add pyridine-1-onium hydrochloride (1.60 g, 13.48 mmol) to 5-methoxy-8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (0.19 g, 0.54 mmol). Heat at 190 °C for 2 h. Cool the reaction mixture to room temperature, quench with ice-cold water, and extract in ethyl acetate (3 × 50 mL). Wash with brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by passing it through (200–400) silica using ethyl acetate and cyclohexane (15:85) to give 8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline-5-ol (0.11 g, 57.9%) as a grayish-white solid.

[0282] 1¹H NMR (400MHz, methanol-d⁴) δppm 7.52 (d, 1H), 6.92 (d, 1H), 3.55 (t, 2H), 2.52 (s, 3H), 2.22–2.37 (m, 2H), 1.99–2.12 (m, 2H).

[0283] Step 3: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (1.046)

[0284]

[0285] Potassium carbonate (0.0858 g, 0.62 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.063 g, 0.31 mmol) were added to a solution of 8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline-5-ol (0.07 mg, 0.207 mmol) in N,N-dimethylformamide (0.8 mL). The mixture was heated to 50 °C for 18 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 30 mL). The mixture was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (10:90) to give 5-(5-chloropyrimidin-2-yl)oxy-8-methyl-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (66 mg, 70.74%) as a grayish-white solid.

[0286] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.53 (s, 2H), 7.86 (dd, 1H), 7.40 (d, 1H), 3.44 (t, 2H), 2.83 (s, 3H), 2.17–2.30 (m, 2H), 2.05–2.14 (m, 2H)

[0287] Example 12: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2,7-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (1.016)

[0288]

[0289] Step 1: Synthesis of 5-methoxy-2,7-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline

[0290]

[0291] Methylboronic acid (0.24 g, 3.96 mmol) and cesium carbonate (1.29 g, 3.96 mmol) were added to 7-bromo-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (0.45 g, 1.24 mmol) in 1,4-dioxane (27 mL). After degassing for 15 min, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.109 g, 0.149 mmol) was added. The mixture was heated at 100 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted in ethyl acetate (3 × 100 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica with ethyl acetate and cyclohexane (15:85) to give 5-methoxy-2,7-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (0.28 g, 75.76%) as a grayish-white solid.

[0292] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.34(s, 1H), 6.73(s, 1H), 4.01(s, 3H), 3.41-3.48(m, 2H), 2.80(s, 3H), 2.54(s, 3H), 2.27(br s, 2H), 2.07(br d, 2H)

[0293] Step 2: Synthesis of 2,7-dimethyl-4-(4,4,4-trifluorobutyl)quinazolin-5-ol

[0294]

[0295] Add pyridine-1-onium hydrochloride (2.39 g, 20.11 mmol) to 5-methoxy-2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (0.24 g, 0.805 mmol). Heat at 190 °C for 1 h. Cool the reaction mixture to room temperature, quench with ice-cold water, and extract in ethyl acetate (3 × 50 mL). Wash with brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue through (200–400) silica using ethyl acetate and cyclohexane (30:70) to give 2,7-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (0.14 g, 58.74%) as a light brown solid.

[0296] 1¹H NMR (400MHz, methanol-d⁴) δppm 7.15 (s, ¹H), 6.81 (d, ¹H), 3.45–3.53 (m, 2H), 2.70 (s, ³H), 2.45 (s, ³H), 2.23–2.36 (m, 2H), 1.98–2.11 (m, 2H)

[0297] Step 3: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2,7-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (1.016)

[0298]

[0299] Potassium carbonate (0.088 g, 0.63 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.048 g, 0.253 mmol) were added to a solution of 2,8-dimethyl-4-(4,4,4-trifluorobutyl)quinazolin-5-ol (60 mg, 0.211 mmol) in N,N-dimethylformamide (1.2 mL). The mixture was heated to 50 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 30 mL). The extract was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica through ethyl acetate and cyclohexane (10:90) to give 5-(5-chloropyrimidin-2-yl)oxy-2,7-dimethyl-4-(4,4,4-trifluorobutyl)quinazoline (0.040 g, 48.6%) as a grayish-white solid.

[0300] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.55(s, 2H), 7.70(s, 1H), 7.12(s, 1H), 3.28(t, 2H), 2.84(s, 3H), 2.57(s, 3H), 2.12–2.26(m, 2H), 1.97–2.06(m, 2H)

[0301] Example 13: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (1.035)

[0302]

[0303] Step 1: Synthesis of 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline

[0304]

[0305] Acetone (0.66 mL, 9.03 mmol) and potassium hydroxide (0.21 g, 3.61 mmol) were added to 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one (0.45 g, 1.806 mmol) in ethanol (9.0 mL). The mixture was heated to 85 °C for 5 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 100 mL). The mixture was washed with a saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200–400) silica using ethyl acetate and cyclohexane (5:95) to give 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (0.31 g, 63.3%) as a yellow oil.

[0306] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.84 (d, 1H), 7.58 (td, 1H), 7.16 (ddd, 1H), 7.10 (s, 1H), 3.19 (td, 2H), 2.70 (s, 3H), 2.15–2.27 (m, 2H), 1.94–2.05 (m, 2H)

[0307] Step 2: Synthesis of 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline

[0308]

[0309] A solution of 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (0.29 g, 1.069 mmol) in methanol (2.6 mL) and N,N-dimethylformamide (2 mL) was added to a solution of 25% sodium methoxide (0.37 mL, 1.60 mmol). The reaction mixture was heated to 90 °C for 18 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 50 mL). The mixture was washed with a saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200–400) silica using ethyl acetate and cyclohexane (10:90) to give 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (0.18 g, 59.42%) as a pale yellow oil.

[0310] 1¹H NMR (400MHz, chloroform-d) δppm 7.64 (dd, 1H), 7.55 (t, 1H), 7.00 (s, 1H), 6.84 (d, 1H), 3.96 (s, 3H), 3.23–3.29 (m, 2H), 2.66 (s, 3H), 2.13–2.24 (m, 2H), 1.91–1.98 (m, 2H).

[0311] Step 3: Synthesis of 2-methyl-4-(4,4,4-trifluorobutyl)quinoline-5-ol

[0312]

[0313] Add pyridine-1-onium hydrochloride (1.68 g, 14.12 mmol) to 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (0.16 g, 0.565 mmol). Heat at 180 °C for 2 h. Cool the reaction mixture to room temperature, quench with ice-cold water and then with 2N hydrochloric acid, extract in ethyl acetate (3 × 50 mL), wash with brine (50 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by passing it through (200–400) silica using ethyl acetate and cyclohexane (15:85) to give 2-methyl-4-(4,4,4-trifluorobutyl)quinoline-5-ol (0.075 g, 47.34%) as a colloidal substance.

[0314] 1 ¹H NMR (400MHz, methanol-d⁴) δppm 7.41-7.49 (m, 2H), 7.12 (s, 1H), 6.86 (dd, 1H), 3.33-3.39 (m, 2H), 2.62 (s, 3H), 2.15-2.37 (m, 2H), 1.90-2.07 (m, 2H).

[0315] Step 4: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (1.035)

[0316]

[0317] Potassium carbonate (0.019 g, 0.14 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.018 g, 0.093 mmol) were added to a solution of 2-methyl-4-(4,4,4-trifluorobutyl)quinoline-5-ol (25 mg, 0.093 mmol) in N,N-dimethylformamide (0.5 mL). The mixture was heated to 50 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 30 mL). The mixture was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200–400) silica using ethyl acetate and cyclohexane (10:90) to give 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (24 mg, 48.6%) as a grayish-white solid.

[0318] 1 ¹H NMR: (400MHz, chloroform-d) δppm 8.50(s, 2H), 7.99(d, 1H), 7.67(t, 1H), 7.21(d, 1H), 7.08(s, 1H), 3.02–3.11(m, 2H), 2.70(s, 3H), 2.08–2.22(m, 2H), 1.81–1.96(m, 2H).

[0319] Example 14: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline (1.015)

[0320]

[0321] Step 1: Synthesis of 8-bromo-5-methoxy-2-(trifluoromethyl)-1H-quinoline-4-one

[0322]

[0323] A mixture of ethyl-4,4,4-trifluoroacetoacetate (4.3283 g, 23.51 mmol) and polyphosphoric acid (9.76 mL) was heated to 100 °C for 15 minutes. 2-Bromo-5-methoxyaniline (5 g, 23.51 mmol) was added dropwise to the reactants. The reactants were refluxed at 150 °C for 3 h. The reaction mixture was cooled to room temperature and slowly poured into a solution of sodium hydroxide (20 g in 100 mL of water). The resulting solid was filtered off. The filtrate was acidified with concentrated hydrochloric acid. The resulting solid was filtered, washed with water, and dried under vacuum to give 8-bromo-5-methoxy-2-(trifluoromethyl)-1H-quinoline-4-one (3.48 g, 46.0%) as a grayish-white solid.

[0324] 1 H NMR(400MHz,DMSO-d6)δppm 8.09(d,1H),7.28(s,1H),7.03(d,1H),3.99(s,3H)

[0325] Step 2: Synthesis of 5-methoxy-2-(trifluoromethyl)quinoline-4-ol

[0326]

[0327] At -78 °C, n-butyllithium (2.0 mol / L) in hexane (8.8 mL, 18 mmol) was added dropwise to a solution of 1.9 g (5.9 mmol) of 8-bromo-5-methoxy-2-(trifluoromethyl)quinoline-4-ol in tetrahydrofuran (19 mL). After stirring at -70 °C for 1 h, methanol (5 mL / g, 9.5 mL) was added. The reaction mixture was stirred at -70 °C for 1 h and slowly raised to room temperature, stirred for 3 h, and then cooled to 5 °C. The mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3 × 200 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.5 g (100%) of 5-methoxy-2-(trifluoromethyl)quinoline-4-ol as a grayish-white solid.

[0328] 1 ¹H NMR (400MHz, chloroform-d) δppm 9.89–10.12 (m, 1H), 7.79 (dd, 1H), 7.64 (t, 1H), 7.11 (s, 1H), 6.93 (d, 1H), 4.13 (s, 3H).

[0329] Step 3: Synthesis of 4-bromo-5-methoxy-2-(trifluoromethyl)quinoline

[0330]

[0331] Phosphorus tribromooxy (1.8 g, 6.2 mmol) was added to 5-methoxy-2-(trifluoromethyl)quinoline-4-ol (1.5 g, 6.2 mmol). The mixture was heated to 150 °C for 3 h. The reaction mixture was cooled to room temperature and poured into a saturated sodium bicarbonate solution. Extraction was performed in ethyl acetate (3 × 200 mL), washed with a saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing through (200–400) silica using ethyl acetate and cyclohexane (10:90) to give 4-bromo-5-methoxy-2-(trifluoromethyl)quinoline (0.89 g, 47%) as a pale yellow solid.

[0332] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.97 (s, ¹H), 7.83 (dd, ¹H), 7.73 (t, ¹H), 7.06 (d, ¹H), 4.00 (s, ³H)

[0333] Step 4: Synthesis of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline

[0334]

[0335] Iodine crystals were added to magnesium shavings (0.51 g, 21 mmol) stirred in tetrahydrofuran (10 mL). The reaction was stirred for 10 minutes and heated to reflux. Then a small amount of 1-bromo-4,4,4-trifluorobutane in tetrahydrofuran was added. Heating continued until the color of the solution changed from yellow to gray. The remaining 1-bromo-4,4,4-trifluorobutane (2.0 g, 10.00 mmol) solution in tetrahydrofuran (15 mL) was added dropwise under heating, and the reaction was then heated at 75 °C for 1 h, and then allowed to cool to room temperature. At 0 °C, the solution of magnesium bromo(4,4,4-trifluorobutyl) in tetrahydrofuran was added dropwise to an ice-cooled solution of 4-bromo-5-methoxy-2-(trifluoromethyl)quinazoline (0.89 g, 2.91 mmol) and cuprous iodide (I) (0.11 g, 0.058 mmol) in tetrahydrofuran (7 mL), and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (3 × 200 mL). The combined organic matter was washed with brine (50 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to give 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinazoline (0.275 g, 28.04%).

[0336] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.83 (d, 1H), 7.69 (t, 1H), 7.44 (s, 1H), 7.01 (d, 1H), 3.99–4.04 (m, 3H), 3.36–3.43 (m, 2H), 2.14–2.30 (m, 2H), 1.90–2.10 (d, 2H).

[0337] Step 5: Synthesis of 4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-5-ol

[0338]

[0339] A mixture of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline (0.27 g, 0.80 mmol) and pyridin-1-onium hydrochloride (2.38 g, 20.01 mmol) was heated at 180 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water and then with 2N HCl, extracted with ethyl acetate (3 × 50 mL), washed with a brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (15:85) to give 4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-5-ol (0.07 g, 25.97%) as a light brown solid.

[0340] 1 ¹H NMR (400MHz, methanol-d⁴) δppm 7.61-7.67 (m, 2H), 7.54 (s, 1H), 7.05 (dd, 1H), 3.47-3.52 (m, 2H), 2.21-2.36 (m, 2H), 1.95-2.05 (m, 2H).

[0341] Step 6: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline (1.015)

[0342]

[0343] Potassium carbonate (0.035 g, 0.25 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.032 g, 0.167 mmol) were added to a solution of 4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-5-ol (0.054 g, 0.167 mmol) in N,N-dimethylformamide (1.08 mL). The mixture was heated to 55 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 50 mL). The mixture was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (10:90) to obtain 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline (0.05 g, 68.67%), which was a pale yellow gelatinous substance.

[0344] 1¹H NMR (400MHz, chloroform-d) δppm 8.52 (s, 2H), 8.21 (d, 1H), 7.82 (t, 1H), 7.53 (s, 1H), 7.42 (dd, 1H), 3.18–3.25 (m, 2H), 2.14–2.27 (m, 2H), 1.87–1.98 (m, 2H)

[0345] Example 15: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile (1.045)

[0346]

[0347] Step 1: Synthesis of ethyl 5-fluoro-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylate

[0348]

[0349] A solution of 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one (3.0 g, 12.0 mmol) in N,N-dimethylformamide (15.0 mL) was added with cuprous oxide (I) (0.17 g, 1.2 mmol), ethyl-4,4,4-trifluorobut-2-ester (2.2 g, 2.2 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.20 mmol). The mixture was heated to 120 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with ice-cold water (100 mL), extracted with ethyl acetate (3 × 200 mL), washed with a saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (25:75) to obtain ethyl 5-fluoro-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2.7 g, 55%) as a pale yellow oil.

[0350] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.08 (d, 1H), 7.79 (td, 1H), 7.36–7.48 (m, 1H), 4.49 (q, 2H), 3.23 (td, 2H), 2.21–2.33 (m, 2H), 1.98–2.06 (m, 2H), 1.42 (t, 3H).

[0351] Step 2: Synthesis of ethyl 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylate

[0352]

[0353] Sodium methoxide (4.7 mL, 20 mmol) was added to a solution of ethyl 5-fluoro-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2.7 g, 6.8 mmol) in methanol (14 mL) and N,N-dimethylformamide (14 mL). The mixture was heated to 90 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with ice-cold water (100 mL), and extracted with ethyl acetate (3 × 200 mL). The mixture was washed with a brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200–400) silica using ethyl acetate and cyclohexane (25:75) to give ethyl 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2.4 g, 86%) as a yellow oil.

[0354] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.80–7.83 (m, 1H), 7.73 (t, 1H), 7.06 (d, 1H), 4.47 (q, 2H), 4.01 (s, 3H), 3.26–3.39 (m, 2H), 2.23 (m, 3H), 2.00 (m, 2H), 1.41 (t, 2H)

[0355] Step 3: Synthesis of the obtained 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylic acid

[0356]

[0357] A mixture of ethyl 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylic acid (1.8 g, 4.4 mmol) and pyridine-1-onium hydrochloride (10 g, 88 mmol) was heated at 200 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water and then with 2N HCl, extracted with ethyl acetate (4 × 200 mL), washed with a saline solution (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (30:70) to give 0.93 g, 53%, 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylic acid as a pale yellow solid.

[0358] 1¹H NMR (400MHz, DMSO-d⁶) δppm 7.86(t, ¹H), 7.74(d, ¹H), 7.33(d, ¹H), 4.03(s, ³H), 3.22–3.46(m, ²H), 2.35–2.48(m, ²H), 1.80–1.92(m, ²H) One COOH proton is missing.

[0359] Step 4: Synthesis of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxamide

[0360]

[0361] Catalytic N,N-dimethylformamide was added to a stirred solution of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylic acid (0.4 g, 1.05 mmol) in thionyl chloride (8.0 mL, 109 mmol). The reaction mixture was heated at 60 °C for 60 min. The crude mixture obtained after concentration was dissolved in tetrahydrofuran (4 mL) and added dropwise to a stirred ammonia solution (13 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate (3 × 100 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxamide (0.28 g, 70.23%) as a brown gel.

[0362] LCMS: Room temperature: 1.09 min; 381.2 (M+H)

[0363] Step 5: Synthesis of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile

[0364]

[0365] At 0 °C, triethylamine (0.422 mL, 3.01 mmol) was added to a solution of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxamide (0.26 g, 0.684 mmol) in dichloromethane (2.6 mL), followed by the addition of trifluoroacetic anhydride (0.25 mL, 1.71 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-cold water and extracted in ethyl acetate (3 × 100 mL), washed with a saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (5:95) to give 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile (0.112 g, 45.22%) as a yellow oil.

[0366] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.84-7.91 (m, 2H), 7.16 (dd, 1H), 4.07 (s, 3H), 3.70-3.78 (m, 2H), 2.30-2.42 (m, 2H), 1.98-2.07 (m, 2H).

[0367] Step 6: Synthesis of 5-hydroxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile

[0368]

[0369] Lithium chloride (0.1170 g, 2.760 mmol) and p-toluenesulfonic acid (0.480 g, 2.76 mmol) were added to a solution of 5-methoxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile (0.1 g, 0.2760 mmol) in N-methylpyrrolidone (1.5 mL). The mixture was heated at 160 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water and then with 2N hydrochloric acid, extracted with ethyl acetate (3 × 50 mL), washed with a saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica with ethyl acetate and cyclohexane (25:75) to give 5-hydroxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile (0.065 g, 64.93%) as a thick, gel-like substance.

[0370] 1¹H NMR (400MHz, methanol-d⁴) δppm 7.81(t, ¹H), 7.69(dd, ¹H), 7.19(dd, ¹H), 3.74–3.81(m, 2H), 2.30–2.47(m, 2H), 1.98–2.07(m, 2H).

[0371] Step 7: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile (1.045)

[0372]

[0373] Potassium carbonate (0.030 g, 0.215 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.042 g, 0.215 mmol) were added to a solution of 5-hydroxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxynitrile (0.05 g, 0.144 mmol) in isopropanol (1.00 mL). The mixture was heated to 50 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 50 mL). The mixture was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (10:90) to give 5-(5-chloropyrimidin-2-yl)oxy-4-(4,4,4-trifluorobutyl)-2-(trifluoromethyl)quinoline-3-carboxylonitrile (0.029 g, 43.83%) as a grayish-white solid.

[0374] 1 ¹H NMR: 400MHz, chloroform-d) δppm 8.55(s, 2H), 8.24(dd, 1H), 7.99(t, 1H), 7.57(dd, 1H), 3.56-3.64(m, 2H), 2.24-2.38(m, 2H), 1.87-1.97(m, 2H).

[0375] Example 16: Synthesis of 8-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)isoquinoline (1.012)

[0376]

[0377] Step 1: Synthesis of 2-benzoyl-8-methoxy-1H-isoquinoline-1-carboxynitrile

[0378]

[0379] Anhydrous aluminum chloride (0.0042 g, 0.0314 mmol), trimethylsilyl cyanide (1.71 mL, 12.564 mmol), and benzoyl chloride (1.62 mL, 13.821 mmol) were added dropwise to a solution of 8-methoxyisoquinoline (1 g, 6.28 mmol) in dichloromethane (20 mL), followed by dropwise addition of benzoyl chloride (1.62 mL, 13.821 mmol). The reaction mixture was heated at 30 °C. The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was quenched with water (100 mL), stirred for 30 min, and the organic layer was separated. The organic layer was washed with 1 N hydrochloric acid (100 mL), water (100 mL), 1 N sodium hydroxide (100 mL), and finally with water (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a gel-like substance, which was then ground with ether (30 mL × 2) to obtain 2-benzoyl-8-methoxy-1H-isoquinoline-1-carboxynitrile (1.17 g, 64.15%) as a brown solid.

[0380] 1 H NMR (400MHz, chloroform-d) δppm 8.08-8.18(m,1H),7.63-7.73(m,1H),7.44-7.61(m,4H),7.34(t,1H),6.87(d,1H),6.80(d,1H),6.53-6.67(m,1H),5.98(br d,1H).

[0381] Step 2: Synthesis of 8-methoxy-1-(4,4,4-trifluorobutyl)isoquinoline

[0382]

[0383] At -10°C, a solution of 2-benzoyl-8-methoxy-1H-isoquinoline-1-carboxynitrile (1.0 g, 3.4 mmol) and 1-bromo-4,4,4-trifluorobutane (0.79 g, 4.1 mmol) in N,N-dimethylformamide (17 mL) was added dropwise to a suspension of sodium hydride (0.20 g, 4.1 mmol) in N,N-dimethylformamide (17 mL). After the addition was complete, the reaction mixture was allowed to reach room temperature and stirred for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3 × 200 mL), washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200-400) silica using ethyl acetate and cyclohexane (10:90) to give 8-methoxy-1-(4,4,4-trifluorobutyl)isoquinoline (0.33 g, 36%) as a pale yellow solid.

[0384] 1¹H NMR (400MHz, chloroform-d) δppm 8.37(d, 1H), 7.55(t, 1H), 7.44(d, 1H), 7.36(d, 1H), 6.92(d, 1H), 3.99(s, 3H), 3.49–3.57(m, 2H), 2.18–2.30(m, 2H), 2.00–2.13(m, 2H).

[0385] Step 3: Synthesis of 1-(4,4,4-trifluorobutyl)isoquinoline-8-ol

[0386]

[0387] A mixture of 8-methoxy-1-(4,4,4-trifluorobutyl)isoquinoline (0.27 g, 1.00 mmol) and pyridine-1-onium hydrochloride (2.98 g, 25.06 mmol) was heated at 210 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water and then with 2N HCl, extracted with ethyl acetate (3 × 50 mL), washed with a brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (20:80) to give 1-(4,4,4-trifluorobutyl)isoquinoline-8-ol (0.144 g, 54.03%) as a thick, gel-like substance.

[0388] 1 ¹H NMR (400MHz, methanol-d⁴) δppm 8.18 (d, ¹H), 7.51–7.59 (m, 2H), 7.35 (d, ¹H), 7.00 (d, ¹H), 3.53–3.59 (m, 2H), 2.18–2.33 (m, 2H), 1.98–2.06 (m, 2H)

[0389] Step 4: Synthesis of 8-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)isoquinoline (1.012)

[0390]

[0391] Potassium carbonate (0.268 g, 1.88 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.145 g, 0.752 mmol) were added to a solution of 1-(4,4,4-trifluorobutyl)isoquinoline-8-ol (0.16 g, 0.627 mmol) in N,N-dimethylformamide (3.2 mL). The mixture was heated to 60 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with ice-cold water, and extracted in ethyl acetate (3 × 50 mL). The extract was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (10:90) to give 8-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)isoquinoline (0.148 g, 64.18%) as a light brown gel.

[0392] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.52 (s, 2H), 8.45 (d, 1H), 7.77 (dd, 1H) 7.68 (t, 1H), 7.58 (d, 1H), 7.30 (dd, 1H), 3.33–3.39 (m, 2H) 2.11–2.23 (m, 2H) 1.96–2.06 (m, 2H).

[0393] Example 17: Synthesis of 3-chloro-5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (1.040)

[0394]

[0395] Step 1: Synthesis of 3-chloro-5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline

[0396]

[0397] At 0 °C, 1-chloroprop-2-one (0.1782 g, 1.9262 mmol) was added to a solution of 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one (400 mg, 1.6051 mmol) in N,N-dimethylformamide (2 mL), followed by dropwise addition of chloro(trimethyl)silane (1.0 mL, 8.0257 mmol). The mixture was then heated to room temperature overnight and heated at 100 °C for 2 h under MW irradiation. The solution was quenched with water (10 mL), extracted with ethyl acetate (3 × 10 mL), dried over anhydrous (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (30:70) to give a white solid (220 mg, 44%).

[0398] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.89 (d, 1H) 7.58-7.63 (m, 1H) 7.20-7.25 (m, 1H) 3.45 (td, 2H) 2.85 (s, 3H) 2.23-2.36 (m, 2H) 1.90-2.02 (m, 2H)

[0399] Step 2: Synthesis of 3-chloro-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline

[0400]

[0401] Sodium methoxide (2.159 mmol, 25% by mass, 0.4753 g) was added to a solution of 3-chloro-5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (220 mg, 0.7197 mmol) in methanol (2.2 mL) and DMF (2.2 mL), and the mixture was heated to 60 °C for 60 h. The reaction mixture was cooled to room temperature, quenched with an aqueous solution of ammonium chloride (10 mL), extracted with ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (20:80) to give a yellow gelatinous substance (180 mg, 86%).

[0402] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.48–7.63 (m, 2H), 6.89 (dd, 1H), 3.97 (s, 3H), 3.50–3.64 (m, 2H), 2.79 (s, 3H), 2.21–2.37 (m, 2H), 1.89–2.00 (m, 2H)

[0403] Step 3: Synthesis of 3-chloro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-5-ol

[0404]

[0405] A mixture of 3-chloro-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (180 mg, 0.3399 mmol) and pyridine hydrochloride (0.9 mL, 115.562) was heated to 180 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with an aqueous solution of ammonium chloride (10 mL), extracted with ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (20:80) to give a yellow gelatinous substance (30 mg, 29%).

[0406] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.61 (d, 1H), 7.45 (t, 1H), 6.79 (d, 1H), 3.56–3.65 (m, 2H), 2.79 (s, 3H), 2.23–2.34 (m, 2H), 1.96–2.04 (m, 2H)

[0407] Step 4: Synthesis of 3-chloro-5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline (1.040)

[0408]

[0409] Potassium carbonate (41.37 mg, 0.2963 mmol) was added to a solution of 3-chloro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-5-ol (30 mg, 0.09878 mmol) in dimethylformamide (1 mL), followed by the addition of 5-methyl-2-methylsulfonyl-pyrimidine (17 mg, 0.09878 mmol), and the mixture was heated to 50 °C for 2 h. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (3 × 10 mL), washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (20:80) to give a brown solid (16 mg, 38.92%).

[0410] ¹H NMR (400MHz, chloroform-d) δppm: 8.51 (s, 2H), 7.97 (dd, 1H), 7.67 (dd, 1H), 7.21-7.25 (m, 1H), 3.32-3.44 (m, 2H), 2.82 (s, 3H), 2.12-2.29 (m, 2H), 1.70-1.83 (m, 2H)

[0411] Example 18: 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline-7-carboxynitrile (1.018)

[0412]

[0413] Step 1: Synthesis of 1-(4-bromo-2,6-difluoro-phenyl)-5,5,5-trifluoro-pentan-1-ol

[0414]

[0415] Iodine crystals were added to magnesium shavings (1.1 g, 45 mmol) stirred in THF (30 mL). The reaction was stirred for 10 minutes and heated to reflux. Then a small amount of 1-bromo-4,4,4-trifluorobutane in THF was added. Heating continued until the color of the solution changed from yellow to gray. The remaining solution of 1-bromo-4,4,4-trifluorobutane (7.3 g, 38 mmol) in THF (30 mL) was added dropwise under heating, and the reaction was then heated at 75 °C for 1 h, and then cooled to room temperature. At 0 °C, the solution of bromo(4,4,4-trifluorobutyl)magnesium in THF formed above was added dropwise to a cooled solution of 4-bromo-2,6-difluorobenzaldehyde (5 g, 23 mmol) in THF (40 mL), and the reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic matter was washed with brine (100 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to dryness to give 1-(4-bromo-2,6-difluoro-phenyl)-5,5,5-trifluoro-pentan-1-ol (7.4 g, 96%) as a yellow oil.

[0416] ¹H NMR (400MHz, chloroform-d) δppm 7.01–7.19 (m, 2H) 5.00 (dd, 1H) 2.06–2.21 (m, 2H), 1.71–1.95 (m, 2H) 1.49–1.69 (m, 2H) One hydroxyl group is missing.

[0417] Step 2: Synthesis of 1-(4-bromo-2,6-difluoro-phenyl)-5,5,5-trifluoro-pentan-1-one

[0418]

[0419] At 0 °C, (1,1-diacetoxy-3-oxo-1λ5,2-benzyl-1-yl)acetate (10 g, 23 mmol) was added in portions to a solution of 1-(4-bromo-2,6-difluoro-phenyl)-5,5,5-trifluoro-pentan-1-ol (7.5 g, 22 mmol) in acetonitrile (150 mL) over a period of 15 minutes. The resulting mixture was stirred overnight at room temperature. The mixture was then quenched with a solution of sodium thiosulfate (11 g, 66 mmol) in water (100 mL). The mixture was stirred for 10 min, then sodium bicarbonate solution was added to adjust the pH to alkalinity, and the mixture was extracted with ethyl acetate (3 × 100 mL), washed with brine (200 mL), dried over anhydrous (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by passing through (200–400) silica using ethyl acetate and cyclohexane (10:90) to give a yellow liquid (7.5 g, quantitative).

[0420] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.16 (d, 2H), 2.94 (t, 2H), 2.09–2.27 (m, 2H), 1.96–2.02 (m, 2H)

[0421] Step 3: Synthesis of 1-(2-amino-4-bromo-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one

[0422]

[0423] Ammonium hydroxide (88 mL, 660 mmol) was added to a solution of 1-(4-bromo-2,6-difluoro-phenyl)-5,5,5-trifluoro-pentan-1-one (7.5 g, 22 mmol) in acetonitrile (30 mL), and the resulting mixture was heated at 120 °C in an Eyela apparatus for 10 h. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (3 × 100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (10:90) to give a yellow liquid (4 g, 48%).

[0424] 1 ¹H NMR (400MHz, chloroform-d) δppm 6.53 (d, 2H) 6.30-6.50 (br s, 2H) 2.95-3.04 (m, 2H) 2.09-2.23 (m, 2H) 1.93-1.97 (m, 2H)

[0425] Step 4: Synthesis of 7-bromo-5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline

[0426]

[0427] Ammonium acetate (2.2 g, 29 mmol) was added to a suspension of 1-(2-amino-4-bromo-6-fluoro-phenyl)-5,5,5-trifluoro-pentane-1-one (3.5 g, 9.6 mmol) in 2,4-pentanedione (1.2 mL, 12 mmol), and the reaction mixture was stirred at 130 °C for 3 h. The mixture was then quenched in water (50 mL), extracted with ethyl acetate (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (25:75) to give a yellow liquid (1.5 g, 44%).

[0428] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.94–7.96 (m, 1H), 7.36–7.39 (m, 1H), 3.35–3.70 (m, 2H), 2.83 (s, 3H), 2.20–2.35 (m, 2H), 2.06–2.20 (m, 2H)

[0429] Step 5: Synthesis of 7-bromo-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline

[0430]

[0431] Sodium methoxide (2.7 mL, 12 mmol, 25% by mass) was added to a solution of 7-bromo-5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1.4 g, 4.0 mmol) in methanol (11 mL) at 0 °C. The solution was then heated to room temperature overnight, quenched with ice-cold water, and filtered to obtain a precipitate of yellow solid (1.1 g m, 76%).

[0432] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.71 (d, 1H), 6.99 (d, 1H), 4.01 (s, 3H), 3.38–3.46 (m, 2H), 2.79 (s, 3H), 2.22–2.29 (m, 2H), 1.98–2.11 (m, 2H)

[0433] Step 6: Synthesis of 7-bromo-2-methyl-4-(4,4,4-trifluorobutyl)quinazolin-5-ol

[0434]

[0435] A solution of 7-bromo-5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1.1 g, 3.0 mmol) in water (5.5 mL) and hydrobromic acid (48% by mass) was heated at 130 °C for 5 h. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (50:50) to give a yellow solid (400 mg, 38%).

[0436] 1 ¹H NMR (400MHz, chloroform-d) δppm 11.56 (br s, 1H), 7.48 (d, 1H), 7.07 (d, 1H), 3.45 (t, 2H), 2.65 (s, 3H), 2.31–2.45 (m, 2H), 1.88–2.02 (m, 2H)

[0437] Step 7: Synthesis of 7-bromo-5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (1.034)

[0438]

[0439] Potassium carbonate (0.239 g, 1.718 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.3310 g, 1.718 mmol) were added to a solution of 7-bromo-2-methyl-4-(4,4,4-trifluorobutyl)quinazolin-5-ol (200 mg, 0.5727 mmol) in isopropanol (4 mL). The resulting mixture was heated to 50 °C for 16 h. The mixture was then quenched in water (10 mL), extracted in ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (20:80) to give a yellow solid (120 mg, 45.38%).

[0440] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.54 (s, 2H), 8.07 (d, 1H), 7.40 (d, 1H), 3.29 (t, 2H), 2.83 (s, 3H), 2.12–2.24 (m, 2H), 1.96–2.05 (m, 2H)

[0441] Step 8: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazolin-7-carboxynitrile (1.018)

[0442]

[0443] To a solution of 7-bromo-5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinazoline (50 mg, 0.1083 mmol) in N,N-dimethylformamide (1 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.92 mg, 0.02166 mmol), tris(dibenzylideneacetone)dipalladium(0) (10.22 mg, 0.01083 mmol), and then zinc cyanide (19.08 mg, 0.1624 mmol) were added. The reaction mixture was heated to 90 °C for 4 h. The reaction mixture was then quenched in water (10 mL), extracted in ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing it through (200-400) silica using ethyl acetate and cyclohexane (20:80) to give a yellow solid (24 mg, 54.34%).

[0444] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.55(s, 2H), 8.20(d, 1H), 7.47(d, 1H), 3.36(t, 2H), 2.86(s, 3H), 2.15–2.27(m, 2H), 1.99–2.08(m, 2H)

[0445] Example 19: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline (1.042)

[0446]

[0447] Step 1: Synthesis of 5-fluoro-2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline

[0448]

[0449] p-Toluenesulfonic acid (489 mg, 2.80 mmol) was added to a solution of 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one (700 mg, 2.80 mmol) in butan-2-one (2.5 mL, 28.09 mmol). The resulting mixture was heated at 100 °C for 2 h under microwave irradiation. The reactants were then quenched in water (20 mL), extracted in ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (20:80) to give a yellow solid (380 mg, 47.42%).

[0450] Step 2: Synthesis of 5-methoxy-2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline

[0451]

[0452] Sodium methoxide (0.457 mL, 1.998 mmol) was added to a solution of 5-fluoro-2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline (0.38 g, 1.332 mmol) in methanol (3.8 mL) and DMF (1.9 mL) at room temperature. After the addition was complete, the mixture was heated at 80 °C for 12 h. The reaction mixture was then quenched with an aqueous solution of ammonium chloride (10 mL), extracted with ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (20:80) to give a grayish-white solid (190 mg, 47.98%).

[0453] Step 3: Synthesis of 2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline-5-ol

[0454]

[0455] A suspension of 5-methoxy-2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline (0.15 g, 0.5045 mmol) and pyridine hydrochloride (1.500 g, 12.61 mmol) was heated to 180 °C for 3 h. The mixture was then quenched in 1 N hydrochloric acid (20 mL), extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (20:80) to give a yellow substance (110 mg, 73.88%).

[0456] ¹H NMR (400MHz, chloroform-d) δppm 7.42 (br d, 1H) 7.26-7.34 (m, 1H) 6.82 (br d, 1H) 3.38-3.42 (m, 2H) 2.61 (s, 3H) 2.32 (s, 3H) 2.21-2.23 (m, 2H) 1.76-1.94 (m, 2H).

[0457] Step 4: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline (1.042)

[0458]

[0459] 5-Chloro-2-methylsulfonyl-pyrimidine (0.02448 g, 0.1271 mmol) was added to a solution of 2,3-dimethyl-4-(4,4,4-trifluorobutyl)quinoline-5-ol (0.03 g, 0.1059 mmol) and potassium carbonate (0.03149 g, 0.3177 mmol) in N,N-dimethylformamide (1.059 mL). The reaction mixture was then heated at 50 °C for 4 h. The reaction mixture was then quenched with an aqueous solution of ammonium chloride (10 mL), extracted with ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (20:80) to give a grayish-white solid (7 mg, 16.17%).

[0460] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.52 (s, 2H) 7.99 (br d, 1H) 7.62 (t, 1H) 7.14-7.22 (m, 1H) 3.14-3.26 (m, 2H) 2.73 (s, 3H) 2.42 (s, 3H) 2.15-2.29 (m, 2H) 1.69-1.83 (m, 2H)

[0461] Example 20: 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxylonitrile (1.043)

[0462]

[0463] Step 1: Synthesis of 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxylonitrile

[0464]

[0465] At 0 °C, 3-oxobutyronitrile (0.066 g, 0.80 mmol) was added dropwise to a solution of 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one (200 mg, 0.80257 mmol) in N,N-dimethylformamide (2 mL), followed by dropwise addition of chloro(trimethyl)silane (0.52 mL, 4.01 mmol). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was slowly added to crushed ice. The precipitated solid was filtered and dried under high vacuum to obtain a yellow solid (200 mg, 84%).

[0466] 1¹H NMR (400MHz, chloroform-d) δppm 7.89 (d, 1H), 7.76 (td, 1H), 7.27–7.33 (m, 1H), 3.47–3.54 (m, 2H), 2.92 (s, 3H), 2.26–2.39 (m, 2H), 1.98–2.06 (m, 2H)

[0467] Step 2: Synthesis of 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile

[0468]

[0469] Sodium methoxide (0.4457 g, 2.025 mmol, 25% by mass) was added to a solution of 5-fluoro-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile (200 mg, 0.6750 mmol) in methanol (2 mL) and dimethylformamide (2 mL) at room temperature. After the addition was complete, the mixture was heated at 40 °C for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (30:70) to give a yellow solid (120 mg, 57%).

[0470] LCMS: Room temperature: 1.51 min; 30 g (M+H)

[0471] Step 3: Synthesis of 5-hydroxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile

[0472]

[0473] Lithium chloride (0.068 g, 1.62 mmol) was added to a mixture of 5-methoxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile (100 mg, 0.32 mmol) and 4-methylbenzenesulfonic acid (0.282 g, 1.62 mmol) in N-methyl-2-pyrrolidone (2 mL). The reaction mixture was heated at 160 °C for 6 h and extracted with ethyl acetate (3 × 20 mL). The organic fraction was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (40:60) to give a yellow solid (40 mg, 42%).

[0474] ¹H NMR (400MHz, chloroform-d) δppm 7.64–7.72 (m, ¹H), 7.58–7.63 (m, ¹H), 6.92 (br d, ¹H), 3.59–3.75 (m, 2H), 2.91 (s, 3H), 2.02–2.35 (m, 2H), 2.04 (br t, 2H)

[0475] Step 4: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile (1.043)

[0476]

[0477] Potassium carbonate (0.043 g, 0.30 mmol) and 5-chloro-2-methylsulfonyl-pyrimidine (0.019 g, 0.11 mmol) were added to a solution of 5-hydroxy-2-methyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile (30 mg, 0.10 mmol) in dimethylformamide (1.5 mL), and the reaction was heated at 50 °C for 2 h. The reaction mixture was quenched with ice-cold water and filtered to obtain a precipitate, which was dried under high vacuum to give a yellow solid (26 mg, 62.70%).

[0478] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.53 (s, 2H), 8.01 (d, 1H), 7.82 (t, 1H), 7.33 (d, 1H), 3.38–3.53 (m, 2H), 2.91 (s, 3H), 2.19–2.33 (m, 2H), 1.83–1.93 (m, 2H)

[0479] Example 21: 5-(5-chloropyrimidin-2-yl)oxy-2-cyclopropyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxylonitrile (1.044)

[0480]

[0481] Step 1: Synthesis of 2-cyclopropyl-5-fluoro-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile

[0482]

[0483] At 0 °C, chloro(trimethyl)silane (1.3 mL, 10.03 mmol) was added to a solution of 1-(2-amino-6-fluoro-phenyl)-5,5,5-trifluoro-pentan-1-one (0.5 g, 2.0064 mmol) and 3-cyclopropyl-3-oxopropionitrile (0.21896 g, 2.0064 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was then quenched with an aqueous solution of ammonium chloride (20 mL), extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (30:70) to give a yellow solid (400 mg, 61.80%).

[0484] 1 ¹H NMR (400MHz, chloroform-d) δppm 7.67-7.80 (m, 1H) 7.57-7.66 (m, 1H) 7.06-7.16 (m, 1H) 3.44 (td, 2H) 2.54-2.74 (m, 1H) 2.20-2.38 (m, 2H) 1.90-2.03 (m, 2H) 1.27-1.31 (m, 2H) 1.12-1.16 (m, 2H)

[0485] Step 2: Synthesis of 2-cyclopropyl-5-hydroxy-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile

[0486]

[0487] Ethanehydroxamic acid (0.1328 g, 1.769 mmol) and potassium carbonate (0.4074 g, 2.948 mmol) were added to a solution of 2-cyclopropyl-5-fluoro-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile (0.19 g, 0.5895 mmol) in dimethyl sulfoxide (3.8 mL). The reaction mixture was heated at 80 °C for 3 h under microwave irradiation. The reaction mixture was cooled to room temperature, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate (50 mL × 4). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (30:70) to give a white solid (400 mg, 61.80%).

[0488] 1¹H NMR (400MHz, chloroform-d) δppm 7.48-7.65 (m, 2H) 6.80 (br d, 1H) 3.64-3.68 (m, 2H) 2.62 (tt, 1H) 2.27-2.46 (m, 2H) 1.97-2.12 (m, 2H) 1.29-1.37 (m, 2H) 1.07-1.22 (m, 2H)

[0489] Step 3: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-cyclopropyl-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile (1.044)

[0490]

[0491] 5-Chloro-2-methylsulfonyl-pyrimidine (0.021 g, 0.11 mmol) was added to a solution of 2-cyclopropyl-5-hydroxy-4-(4,4,4-trifluorobutyl)quinoline-3-carboxynitrile (30 mg, 0.093 mmol), potassium carbonate (0.027 g, 0.28 mmol), and N,N-dimethylformamide (1.405 mL). The reaction mixture was stirred at 50 °C for 2 h, quenched with an aqueous solution of ammonium chloride (20 mL), extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (20:80) to give a yellow solid (14 mg, 34.54%).

[0492] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.57 (s, 2H) 7.91 (dd, 1H) 7.76 (t, 1H) 7.25 (dd, 1H) 3.43-3.51 (m, 2H) 2.60-2.68 (m, 1H) 2.17-2.34 (m, 2H) 1.85-1.95 (m, 2H) 1.34-1.39 (m, 2H) 1.17-1.24 (m, 2H)

[0493] Example 22: 4-But-3-enyl-5-(5-chloropyrimidin-2-yl)oxy-2-(trifluoromethyl)quinazoline (1.028)

[0494]

[0495] Step 1: Synthesis of 4-but-3-enyl-5-methoxy-2-(trifluoromethyl)quinazoline

[0496]

[0497] Under nitrogen atmosphere and at room temperature, 2 g (8.76 mmol) of 5-methoxy-2-(trifluoromethyl)quinazoline in 20 mL of tetrahydrofuran was added to a solution of lanthanum(III) bis(lithium chloride) complex (20 mL, 10.518 mmol) in 20 mL of tetrahydrofuran. The mixture was cooled to 0 °C and magnesium bromo(but-3-enyl)bromo (50 mL, 26.296 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-but-3-enyl-5-methoxy-2-(trifluoromethyl)-3,4-dihydroquinazoline (2.4 g m). The mixture (1.246 g, 3.944 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.74 g, 11.83 mmol) in a single batch. The reaction mixture was stirred for 2 h, then quenched with 2 M sodium hydroxide solution (20 mL), extracted with ethyl acetate (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing through (200–400) silica using ethyl acetate and cyclohexane (40:60) to give (630 mg, 56.58%).

[0498] 1 ¹H NMR (400MHz, chloroform-d) 7.88 (t, ¹H) 7.75 (d, ¹H) 7.09 (d, ¹H) 5.85-6.12 (m, ¹H) 5.09-5.16 (m, ¹H) 5.04 (br d, ¹H) 4.06 (s, ³H) 3.57-3.67 (m, ²H) 2.59 (br dd, ²H)

[0499] Step 2: Synthesis of 4-but-3-enyl-2-(trifluoromethyl)quinazoline-5-ol

[0500]

[0501] At 0 °C, boron tribromide (2.4 mL, 2.44 mmol) in dichloromethane was added dropwise to a solution of 230 mg (0.81 mmol) of 4-but-3-enyl-5-methoxy-2-(trifluoromethyl)quinazoline in dichloromethane (2.3 mL). The reaction mixture was stirred at room temperature for 1 hour and quenched with an aqueous solution of sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica through ethyl acetate and cyclohexane (40:60) to give a dark green solid (179 mg, 81.92%).

[0502] 1 H NMR(400MHz, chloroform-d)δppm 7.68-7.80(m,2H)7.10(dd,1H)5.98(d,1H)5.09(dd,1H)4.99(dd,1H)3.65-3.75(m,2H)2.64(br dd,2H)

[0503] Step 3: Synthesis of 4-but-3-enyl-5-(5-chloropyrimidin-2-yl)oxy-2-(trifluoromethyl)quinazoline (1.028)

[0504]

[0505] To a solution of 4-but-3-enyl-2-(trifluoromethyl)quinazoline-5-ol (288 mg, 1.074 mmol) in isopropanol (3 mL), 5-chloro-2-methylsulfonyl-pyrimidine (0.310 g, 1.611 mmol) and potassium carbonate (0.445 g, 3.221 mmol) were added. The reaction mixture was then heated at 50 °C for 16 h, quenched with an aqueous solution of ammonium chloride (20 mL), extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by passing (200–400) silica using ethyl acetate and cyclohexane (20:80) to give a yellow solid (150 mg, 36.68%).

[0506] 1 ¹H NMR (400MHz, chloroform-d) δppm 8.53 (s, 2H), 8.14 (d, 1H), 7.99 (t, 1H), 7.48 (d, 1H), 5.86 (dd, 1H), 4.90–5.02 (m, 2H), 3.44–3.50 (m, 2H), 2.57 (td, 2H)

[0507] Example 23: 5-(5-chloropyrimidin-2-yl)oxy-2-isopropyl-4-(4,4,4-trifluorobutyl)quinazoline (1.050)

[0508]

[0509] Step 1: Synthesis of 5-methoxy-1H-quinazolin-2,4-dione

[0510]

[0511] Sodium cyanate (4.15 g, 61.3 mmol) was added to a suspension of 2-amino-6-methoxy-benzoic acid (5.03 g, 30.1 mmol) in water (120 mL) and acetic acid (3.5 mL, 61 mmol) at 35 °C, and the resulting mixture was stirred for 0.5 h. The mixture was treated with sodium hydroxide (50% by mass, in water, 45 mL, 873 mmol) to obtain a homogeneous solution, which was then heated to 70 °C and stirred for 4 h. After completion, the mixture was ice-cooled, acidified with concentrated hydrochloric acid, and the precipitate was collected and dried to give 5-methoxy-1H-quinazolin-2,4-dione (5.14 g, 84%) as a grayish-white solid.

[0512] 1H NMR (400MHz, DMSO-d6) δ = 10.91 (br s, 2H), 7.51 (t, 1H), 6.72 (d, 1H), 6.70 (d, 1H), 3.81 (s, 3H)

[0513] Step 2: Synthesis of 2,4-dichloro-5-methoxy-quinazoline

[0514]

[0515] A suspension of 5-methoxy-1H-quinazolin-2,4-dione (5.136 g, 25.39 mmol) in acetonitrile (25 mL) and phosphoryl chloride (7.5 mL, 79 mmol) was stirred at 90 °C for 17 hours under a nitrogen atmosphere. Afterward, the mixture was concentrated and the residue was subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 2,4-dichloro-5-methoxy-quinazolin (3.45 g, 56%) as a white solid.

[0516] ¹H NMR (400 MHz, chloroform) δ = 7.86 (t, ¹H), 7.56 (dd, ¹H), 7.03 (d, ¹H), 4.04 (s, ³H)

[0517] Step 3: Synthesis of 2-chloro-5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline

[0518]

[0519] Iodine crystals were added to a mixture of stirred magnesium shavings (250 mg, 10.29 mmol) in tetrahydrofuran (8.5 mL). The reaction was heated to 50 °C and a small amount of 1-bromo-4,4,4-trifluorobutane in tetrahydrofuran was added. Upon activation, the remaining 1-bromo-4,4,4-trifluorobutane (0.52 mL, 4.1 mmol) was added dropwise, and the mixture was stirred at 50 °C for one hour. At 0 °C, the above solution was added dropwise to a solution of 2,4-dichloro-5-methoxy-quinazoline (514 mg, 2.13 mmol) and cuprous iodide (I) (81 mg, 0.43 mmol) in tetrahydrofuran (8.5 mL). The mixture was stirred for 15 minutes, quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and concentrated. The residue was subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 2-chloro-5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (514 mg, 71%) as a grayish-white solid.

[0520] ¹H NMR (400MHz, chloroform) δ=7.80(t,¹H),7.55(dd,¹H),6.98(d,¹H),4.04(s,³H),3.54-3.48(m,²H),2.36-2.21(m,²H),2.15-2.05(m,²H)

[0521] Step 4: Synthesis of 2-isopropyl-5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline

[0522]

[0523] A solution of 2-chloro-5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (149 mg, 0.46 mmol) and ferric acetylacetone (III) (19 mg, 0.05 mmol) in tetrahydrofuran (3.0 mL) and NMP (0.3 mL) was ice-cooled, treated with isopropylmagnesium chloride (2.0 M, in THF, 0.70 mL, 1.4 mmol) and stirred for 5 min. The mixture was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate and concentrated. The residue was subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 2-isopropyl-5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (97 mg, 64%) as a yellow oil.

[0524] ¹H NMR (400 MHz, chloroform) δ = 7.70 (t, ¹H), 7.55 (dd, ¹H), 6.88 (d, ¹H), 4.00 (s, ³H), 3.50 (t, 2H), 3.26 (spt, ¹H), 2.36–2.21 (m, 2H), 2.18–2.08 (m, 2H), 1.40 (d, 6H)

[0525] Step 5: Synthesis of 2-isopropyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol

[0526]

[0527] A solution of 2-isopropyl-5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (97 mg, 0.31 mmol) in NMP (0.8 mL) was treated with 1-dodecylthiol (190 μL, 0.78 mmol) and sodium hydroxide (50% by mass, in water, 40 μL, 0.78 mmol), and then stirred at 100 °C for one hour. The mixture was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and concentrated. The residue was subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 2-isopropyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (52 mg, 53%) as a beige solid.

[0528] ¹H NMR (400MHz, chloroform) δ=7.57-7.46(m, 2H), 6.92(d, 1H), 3.71(t, 2H), 3.35(spt, 1H), 2.38-2.17(m, 4H), 1.43(d, 6H)

[0529] Step 6: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-isopropyl-4-(4,4,4-trifluorobutyl)quinazoline (1.050)

[0530]

[0531] A mixture of 2-isopropyl-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (52 mg, 0.17 mmol), 5-chloro-2-(methanesulfonyl)pyrimidine (106 mg, 0.55 mmol), and potassium carbonate (71 mg, 0.51 mmol) in propan-2-ol (1.0 mL) was stirred at 50 °C for 7 hours. After completion, the mixture was diluted with water, extracted with ethyl acetate, and concentrated. The residue was subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 5-(5-chloropyrimidin-2-yl)oxy-2-isopropyl-4-(4,4,4-trifluorobutyl)quinazoline (51 mg, 71%) as a beige solid.

[0532] ¹H NMR (400 MHz, chloroform) δ = 8.53 (s, 2H), 7.93 (d, 1H), 7.82 (t, 1H), 7.25 (d, 1H), 3.40–3.24 (m, 3H), 2.30–2.14 (m, 2H), 2.14–2.03 (m, 2H), 1.41 (d, 6H)

[0533] Example 24: 5-(5-chloropyrimidin-2-yl)oxy-2-methoxy-4-(4,4,4-trifluorobutyl)(1.014)

[0534]

[0535] Step 1: Synthesis of 2-bromo-4-(4,4,4-trifluorobutyl)quinazoline-5-ol

[0536]

[0537] A solution of 2-chloro-5-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (1.03 g, 3.38 mmol) in chloroform (11 mL) was treated with boron tribromide (1.0 M, in dichloromethane, 10 mL, 10 mmol) and stirred at 60 °C for 18 hours. The mixture was quenched with water, alkalized to pH 5, and extracted with ethyl acetate. The organic matter was concentrated and subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 2-bromo-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (889 mg, 71%) as an orange solid.

[0538] ¹H NMR (400MHz, chloroform) δ=7.76-7.66(m, ¹H), 7.59-7.54(m, ¹H), 6.98-6.90(m, ¹H), 6.29(s, ¹H), 3.65-3.51(m, 2H), 2.37-2.22(m, 2H), 2.21-2.09(m, 2H)

[0539] Step 2: Synthesis of 2-[[2-bromo-4-(4,4,4-trifluorobutyl)quinazolin-5-yl]oxymethoxy]ethyl-trimethyl-silane]

[0540]

[0541] A mixture of 2-bromo-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (889 mg, 2.3875 mmol), potassium carbonate (501 mg, 3.6249 mmol), and acetonitrile (6 mL) was treated with 2-(trimethylsilyl)ethoxymethyl chloride (550 μL, 2.95 mmol) and stirred at room temperature for one hour. The mixture was concentrated and subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 2-[[2-bromo-4-(4,4,4-trifluorobutyl)quinazoline-5-yl]oxymethoxy]ethyl-trimethylsilane (948 mg, 81%) as a yellow oil.

[0542] ¹H NMR (400MHz, chloroform) δ=7.82-7.74(m, ¹H), 7.60(dd, ¹H), 7.33-7.28(m, ¹H), 5.45(s, 2H), 3.86-3.77(m, 2H), 3.56-3.47(m, 2H), 2.38-2.22(m, 2H), 2.19-2.07(m, 2H), 1.05-0.95(m, 2H), 0.00(s, 9H)

[0543] Step 3: Synthesis of 2-methoxy-4-(4,4,4-trifluorobutyl)quinazoline-5-ol

[0544]

[0545] A solution of 2-[[2-bromo-4-(4,4,4-trifluorobutyl)quinazolin-5-yl]oxymethoxy]ethyl-trimethyl-silane (111 mg, 0.227 mmol) and sodium methoxide (0.5 M, in MeOH, 1.0 mL, 0.5 mmol) in methanol (1.0 mL) was stirred at room temperature for 17 hours.

[0546] After completion, the mixture was treated with 2M hydrochloric acid (2 mL, 4.0 mmol) and stirred at room temperature for 3 hours, followed by stirring at 60 °C for another 2.5 hours. The mixture was diluted with water, extracted with ethyl acetate, and concentrated. The residue was subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 2-methoxy-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (40 mg, 59%) as a pale yellow solid.

[0547] ¹H NMR (400 MHz, chloroform) δ = 7.60–7.53 (m, ¹H), 7.4 (dd, ¹H), 6.69 (dd, ¹H), 5.75 (s, ¹H), 4.10 (s, ³H), 3.51 (t, ²H), 2.33–2.20 (m, ²H), 2.20–2.09 (m, ²H)

[0548] Step 4: Synthesis of 5-(5-chloropyrimidin-2-yl)oxy-2-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (1.014)

[0549]

[0550] A mixture of 2-methoxy-4-(4,4,4-trifluorobutyl)quinazoline-5-ol (40 mg, 0.1328 mmol), 5-chloro-2-(methanesulfonyl)pyrimidine (79 mg, 0.41013 mmol), potassium carbonate (56 mg, 0.40518 mmol), and propan-2-ol (1.0 mL) was stirred at 50 °C for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, and concentrated. The residue was subjected to rapid column chromatography (ethyl acetate and cyclohexane) to give 5-(5-chloropyrimidin-2-yl)oxy-2-methoxy-4-(4,4,4-trifluorobutyl)quinazoline (28 mg, 50%) as a beige solid.

[0551] Table 1 – Examples of the herbicidal compounds of the present invention.

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573] Biological examples

[0574] Seeds of various test species were sown in standard soil in pots: Amaranthus retoflexus (AMARE), Echinochloa crus-galli (ECHCG), and Setaria faberi (SETFA). After one day (pre-emergence) or eight days (post-emergence) of cultivation under controlled conditions in a greenhouse (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 a rate of 250 g / ha. These 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. Biological activity is shown in the table below on a five-point scale (5 = 81%-100%; 4 = 61%-80%; 3 = 41%-60%; 2 = 21%-40%; 1 = 0%-20%).

[0575] Table B1 Post-emergence Tests

[0576] compound AMARE ECHCG SETFA 1.001 3 4 4 1.002 3 2 3 1.003 5 3 3 1.005 5 5 5 1.006 5 3 3 1.007 3 1 1 1.008 3 1 1 1.009 1 1 1 1.011 5 5 5 1.012 4 4 4 1.013 3 4 4 1.014 5 5 5 1.015 5 4 4 1.019 4 3 2 1.020 4 5 5 1.021 5 4 4 1.022 4 4 4 1.025 4 5 4 1.026 4 3 4 1.027 4 1 1 1.028 5 4 4 1.029 4 1 2 1.031 4 3 3 1.032 5 3 3 1.033 4 3 3 1.036 4 3 2 1.037 5 3 3 1.043 2 1 2 1.046 4 3 2 1.050 5 2 3

[0577] Table B2 Pre-emergence Test

[0578]

[0579]

Claims

1. A compound having formula (I): Or its agronomically acceptable salt. in Y 1 It is CR 3 ; Y 2 It is N; R 1 Choose from the group consisting of: hydrogen, halogens, C1-C3 alkyl groups and C1-C3 haloalkyl groups; R 2 Selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy-, C1-C3 haloalkoxy- and C1-C3 haloalkyl; R 3 Choose from the group consisting of: hydrogen, halogen, -CN, nitro, C1-C4 alkyl, C2-C4 alkenyl-, C2-C4 alkynyl-, C1-C4 haloalkyl-, C1-C4 alkoxy-, C1-C4 haloalkoxy-, and -S(O). n C1-C4 alkyl; Each R 5 Independently selected from the group consisting of: 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 groups and -S(O) p C1-C4 haloalkyl; R 6 Independently selected from the group consisting of: hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl-, C1-C6 alkoxy-, C1-C6 haloalkoxy- and C3-C6 cycloalkyl-; X 1 It is CH2 or O; Z 1 It is N; Z 2 It is N; R 9 Choose from the group consisting of C1-C6 haloalkyl- and pyrimidin-2-yl groups, wherein the pyrimidin-2-yl group is optionally substituted with one or two halogens; n = 0, 1, or 2; and p = 0, 1, or 2.

2. The compound according to claim 1, wherein, R 1 and R 2 They're all hydrogen.

3. The compound according to claim 1, wherein, R 3 It is chlorine.

4. The compound according to claim 1, wherein, n＝0。 5. The compound according to claim 1, wherein, R 6 Choose from the following groups: hydrogen, methyl, and CF3.

6. The compound according to claim 1, wherein, X 1 It is O.

7. The compound according to claim 1, wherein, R 9 It is a C1-C6 haloalkyl-.

8. A herbicidal composition comprising the compound according to any one of claims 1 to 7 and an agriculturally acceptable formulation adjuvant.

9. The herbicidal composition according to claim 8, further comprising at least one additional pest control agent.

10. The herbicidal composition according to claim 9, wherein, The other pest control agent mentioned is a herbicide or a herbicide safener.

11. 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 8 to 10.

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

Images