Picolinamide compounds with fungicidal activity

Information

  • Patent Grant
  • 10588318
  • Patent Number
    10,588,318
  • Date Filed
    Friday, April 13, 2018
    6 years ago
  • Date Issued
    Tuesday, March 17, 2020
    4 years ago
Abstract
This disclosure relates to picolinamides of Formula I and their use as fungicides.
Description
BACKGROUND & SUMMARY

Fungicides are compounds, of natural or synthetic origin, which act to protect and/or cure plants against damage caused by agriculturally relevant fungi. Generally, no single fungicide is useful in all situations. Consequently, research is ongoing to produce fungicides that may have better performance, are easier to use, and cost less.


The present disclosure relates to picolinamides and their use as fungicides. The compounds of the present disclosure may offer protection against ascomycetes, basidiomycetes, deuteromycetes and oomycetes.


One embodiment of the present disclosure may include compounds of Formula I:




embedded image


in which: X is hydrogen or C(O)R5;


Y is hydrogen, C(O)R5, or Q;


Q is




embedded image


wherein: Z is N or CH;


R1 is hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R8;


R2 is methyl;


R3 is chosen from aryl or heteroaryl, each optionally substituted with 0, 1 or multiple R8;


R4 is chosen from hydrogen, halo, hydroxyl, alkyl or alkoxy;


R5 is chosen from alkoxy or benzyloxy, each optionally substituted with 0, 1, or multiple R8;


R6 is chosen from hydrogen, alkoxy, or halo, each optionally substituted with 0, 1, or multiple R8;


R7 is chosen from hydrogen, —C(O)R9, or —CH2OC(O)R9;


R8 is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkynyl, alkoxy, cyano or heterocyclyl, each optionally substituted with 0, 1, or multiple R10:


R9 is chosen from alkyl, alkoxy, or aryl, each optionally substituted with 0, 1, or multiple R8;


R10 is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, or heterocyclyl;


R11 is chosen from hydrogen or alkyl, substituted with 0, 1, or multiple R8;


R12 is chosen from aryl or heteroaryl, each optionally substituted with 0, 1 or multiple R8.


Another embodiment of the present disclosure may include a fungicidal composition for the control or prevention of fungal attack comprising the compounds described above and a phytologically acceptable carrier material.


Yet another embodiment of the present disclosure may include a method for the control or prevention of fungal attack on a plant, the method including the steps of applying a fungicidally effective amount of one or more of the compounds described above to at least one of the fungus, the plant, and an area adjacent to the plant.


It will be understood by those skilled in the art that the following terms may include generic “R”-groups within their definitions, e.g., “the term alkoxy refers to an —OR substituent”. It is also understood that within the definitions for the following terms, these “R” groups are included for illustration purposes and should not be construed as limiting or being limited by substitutions about Formula I.


The term “alkyl” refers to a branched, unbranched, or saturated cyclic carbon chain, including, but not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.


The term “alkenyl” refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including, but not limited to, ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.


The term “alkynyl” refers to a branched or unbranched carbon chain containing one or more triple bonds including, but not limited to, propynyl, butynyl, and the like.


The terms “aryl” and “Ar” refer to any aromatic ring, mono- or bi-cyclic, containing 0 heteroatoms.


The term “heterocyclyl” refers to any aromatic or non-aromatic ring, mono- or bi-cyclic, containing one or more heteroatoms.


The term “alkoxy” refers to an —OR substituent.


The term “acyloxy” refers to an —OC(O)R substituent.


The term “cyano” refers to a —C≡N substituent.


The term “hydroxyl” refers to an —OH substituent.


The term “amino” refers to a —N(R)2 substituent.


The term “arylalkoxy” refers to —O(CH2)nAr where n is an integer selected from the list 1, 2, 3, 4, 5, or 6.


The term “haloalkoxy” refers to an —OR—X substituent, wherein X is Cl, F, Br, or I, or any combination thereof.


The term “haloalkyl” refers to an alkyl, which is substituted with Cl, F, I, or Br or any combination thereof.


The term “halogen” or “halo” refers to one or more halogen atoms, defined as F, Cl, Br, and I.


The term “nitro” refers to a —NO2 substituent.


The term thioalkyl refers to an —SR substituent.


Throughout the disclosure, reference to the compounds of Formula I is read as also including all stereoisomers, for example diastereomers, enantiomers, and mixtures thereof. In another embodiment, Formula I is read as also including salts or hydrates thereof. Exemplary salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, trifluoroacetate, and trifluoromethane sulfonate.


It is also understood by those skilled in the art that additional substitution is allowable, unless otherwise noted, as long as the rules of chemical bonding and strain energy are satisfied and the product still exhibits fungicidal activity.


Another embodiment of the present disclosure is a use of a compound of Formula I, for protection of a plant against attack by a phytopathogenic organism or the treatment of a plant infested by a phytopathogenic organism, comprising the application of a compound of Formula I, or a composition comprising the compound to soil, a plant, a part of a plant, foliage, and/or roots.


Additionally, another embodiment of the present disclosure is a composition useful for protecting a plant against attack by a phytopathogenic organism and/or treatment of a plant infested by a phytopathogenic organism comprising a compound of Formula I and a phytologically acceptable carrier material.







DETAILED DESCRIPTION

The compounds of the present disclosure may be applied by any of a variety of known techniques, either as the compounds or as formulations comprising the compounds. For example, the compounds may be applied to the roots or foliage of plants for the control of various fungi, without damaging the commercial value of the plants. The materials may be applied in the form of any of the generally used formulation types, for example, as solutions, dusts, wettable powders, flowable concentrate, or emulsifiable concentrates.


Preferably, the compounds of the present disclosure are applied in the form of a formulation, comprising one or more of the compounds of Formula I with a phytologically acceptable carrier. Concentrated formulations may be dispersed in water, or other liquids, for application, or formulations may be dust-like or granular, which may then be applied without further treatment. The formulations can be prepared according to procedures that are conventional in the agricultural chemical art.


The present disclosure contemplates all vehicles by which one or more of the compounds may be formulated for delivery and use as a fungicide. Typically, formulations are applied as aqueous suspensions or emulsions. Such suspensions or emulsions may be produced from water-soluble, water-suspendible, or emulsifiable formulations which are solids, usually known as wettable powders; or liquids, usually known as emulsifiable concentrates, aqueous suspensions, or suspension concentrates. As will be readily appreciated, any material to which these compounds may be added may be used, provided it yields the desired utility without significant interference with the activity of these compounds as antifungal agents.


Wettable powders, which may be compacted to form water-dispersible granules, comprise an intimate mixture of one or more of the compounds of Formula I, an inert carrier and surfactants. The concentration of the compound in the wettable powder may be from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 weight percent to about 75 weight percent. In the preparation of wettable powder formulations, the compounds may be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earths, purified silicates or the like. In such operations, the finely divided carrier and surfactants are typically blended with the compound(s) and milled.


Emulsifiable concentrates of the compounds of Formula I may comprise a convenient concentration, such as from about 1 weight percent to about 50 weight percent of the compound, in a suitable liquid, based on the total weight of the concentrate. The compounds may be dissolved in an inert carrier, which is either a water-miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers. The concentrates may be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Useful organic solvents include aromatics, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, for example, terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.


Emulsifiers which may be advantageously employed herein may be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a blend of two or more emulsifiers. Examples of nonionic emulsifiers useful in preparing the emulsifiable concentrates include the polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as the ethoxylated alkyl phenols and carboxylic esters solubilized with the polyol or polyoxyalkylene. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulfonic acids, oil-soluble salts or sulfated polyglycol ethers and appropriate salts of phosphated polyglycol ether.


Representative organic liquids which may be employed in preparing the emulsifiable concentrates of the compounds of the present disclosure are the aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dimethyl amides of fatty glycols and glycol derivatives such as the n-butyl ether, ethyl ether or methyl ether of diethylene glycol, the methyl ether of triethylene glycol, petroleum fractions or hydrocarbons such as mineral oil, aromatic solvents, paraffinic oils, and the like; vegetable oils such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil and the like; esters of the above vegetable oils; and the like. Mixtures of two or more organic liquids may also be employed in the preparation of the emulsifiable concentrate. Organic liquids include xylene, and propyl benzene fractions, with xylene being most preferred in some cases. Surface-active dispersing agents are typically employed in liquid formulations and in an amount of from 0.1 to 20 percent by weight based on the combined weight of the dispersing agent with one or more of the compounds. The formulations can also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.


Aqueous suspensions comprise suspensions of one or more water-insoluble compounds of Formula I, dispersed in an aqueous vehicle at a concentration in the range from about 1 to about 50 weight percent, based on the total weight of the aqueous suspension. Suspensions are prepared by finely grinding one or more of the compounds, and vigorously mixing the ground material into a vehicle comprised of water and surfactants chosen from the same types discussed above. Other components, such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous vehicle.


The compounds of Formula I can also be applied as granular formulations, which are particularly useful for applications to the soil. Granular formulations generally contain from about 0.5 to about 10 weight percent, based on the total weight of the granular formulation of the compound(s), dispersed in an inert carrier which consists entirely or in large part of coarsely divided inert material such as attapulgite, bentonite, diatomite, clay or a similar inexpensive substance. Such formulations are usually prepared by dissolving the compounds in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. A suitable solvent is a solvent in which the compound is substantially or completely soluble. Such formulations may also be prepared by making a dough or paste of the carrier and the compound and solvent, and crushing and drying to obtain the desired granular particle.


Dusts containing the compounds of Formula I may be prepared by intimately mixing one or more of the compounds in powdered form with a suitable dusty agricultural carrier, such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.


The formulations may additionally contain adjuvant surfactants to enhance deposition, wetting, and penetration of the compounds onto the target crop and organism. These adjuvant surfactants may optionally be employed as a component of the formulation or as a tank mix. The amount of adjuvant surfactant will typically vary from 0.01 to 1.0 percent by volume, based on a spray-volume of water, preferably 0.05 to 0.5 volume percent. Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of the esters or sulfosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines, blends of surfactants with mineral or vegetable oils, crop oil concentrate (mineral oil (85%)+emulsifiers (15%)); nonylphenol ethoxylate; benzylcocoalkyldimethyl quaternary ammonium salt; blend of petroleum hydrocarbon, alkyl esters, organic acid, and anionic surfactant; C9-C11 alkylpolyglycoside; phosphated alcohol ethoxylate; natural primary alcohol (C12-C16) ethoxylate; di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap; nonylphenol ethoxylate+urea ammonium nitrate; emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8EO); tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. The formulations may also include oil-in-water emulsions such as those disclosed in U.S. patent application Ser. No. 11/495,228, the disclosure of which is expressly incorporated by reference herein.


The formulations may optionally include combinations that contain other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, herbicides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds. Accordingly, in such embodiments, the other pesticidal compound is employed as a supplemental toxicant for the same or for a different pesticidal use. The compounds of Formula I and the pesticidal compound in the combination can generally be present in a weight ratio of from 1:100 to 100:1.


The compounds of the present disclosure may also be combined with other fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure are often applied in conjunction with one or more other fungicides to control a wider variety of undesirable diseases. When used in conjunction with other fungicide(s), the presently claimed compounds may be formulated with the other fungicide(s), tank-mixed with the other fungicide(s) or applied sequentially with the other fungicide(s). Such other fungicides may include 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin, Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis, Bacillus subtilis strain QST713, benalaxyl, benomyl, benthiavalicarb-isopropyl, benzovindiflupyr, benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole, bupirimate, calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chlazafenone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate, copper oxychloride, copper sulfate, copper sulfate (tribasic), coumoxystrobin, cuprous oxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine, dipymetitrone, dithianon, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, enestrobin, enestroburin, enoxastrobin, epoxiconazole, ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenaminostrobin, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flufenoxystrobin, flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil, flutriafol, fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadine triacetate, iminoctadine tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone, iprobenfos, iprodione, iprovalicarb, isofetamid, isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, laminarin, mancopper, mancozeb, mandestrobin, mandipropamid, maneb, mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl, oxathiapiprolin, oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, pentachlorophenol, pentachlorophenyl laurate, penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide, picarbutrazox, picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, potassium hydroxyquinoline sulfate, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyraziflumid, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyrisoxazole, pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract, sedaxane, silthiofam, simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils, tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolprocarb, tolylfluanid, triadimefon, triadimenol, triazoxide, triclopyricarb, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, valifenalate, valiphenal, vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum, Gliocladium spp., Phlebiopsis gigantea, Streptomyces griseoviridis, Trichoderma spp., (RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane, 2-(2-heptadecyl-2-imidazolin-1-yl)ethanol, 2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide, 2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride, 2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine, azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox, bentaluron, benzamacril, benzamacril-isobutyl, benzamorf, binapacryl, bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox, climbazole, copper bis(3-phenylsalicylate), copper zinc chromate, cufraneb, cupric hydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram, decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin, halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozolin, N-3,5-dichlorophenyl-succinimide, N-3-nitrophenylitaconimide, natamycin, N-ethylmercurio-4-toluenesulfonanilide, nickel bis(dimethyldithiocarbamate), OCH, phenylmercury dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb, prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor, pyroxyfur, quinacetol, quinacetol sulfate, quinazamid, quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid, triamiphos, triarimol, triazbutil, trichlamide, urbacid, zarilamid, and any combinations thereof.


Additionally, the compounds described herein may be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more other pesticides to control a wider variety of undesirable pests. When used in conjunction with other pesticides, the presently claimed compounds may be formulated with the other pesticide(s), tank-mixed with the other pesticide(s) or applied sequentially with the other pesticide(s). Typical insecticides include, but are not limited to: 1,2-dichloropropane, abamectin, acephate, acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile, afidopyropen, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan, amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine, athidathion, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron, borax, boric acid, broflanilide, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide, cinerin I, cinerin II, cinerins, cismethrin, clacyfos, cloethocarb, closantel, clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyclaniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos, diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos, dicloromezotiaz, dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, doramectin, ecdysterone, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane, eprinomectin, esdepallethrine, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion, fenthion, fenthion-ethyl, fenvalerate, fipronil, flometoquin, flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, flufenprox, flufiprole, fluhexafon, flupyradifurone, fluvalinate, fonofos, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD, heptachlor, heptafluthrin, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin, isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane, isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kappa-bifenthrin, kappa-tefluthrin, kelevan, kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride, mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion, methiocarb, methocrotophos, methomyl, methoprene, methoxychlor, methoxyfenozide, methyl bromide, methyl isothiocyanate, methylchloroform, methylene chloride, metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, molosultap, momfluorothrin, monocrotophos, monomehypo, monosultap, morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron, noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl, penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp′-DDT, prallethrin, precocene I, precocene II, precocene I, primidophos, profenofos, profluralin, promacyl, promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, protrifenbute, pyflubumide, pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyriminostrobin, pyrimitate, pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla, schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron, sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide, tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetramethrin, tetramethylfluthrin, tetraniliprole, theta-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam oxalate, thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium, thiosultap-monosodium, thuringiensin, tioxazafen, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumezopyrim, triflumuron, trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb, zeta-cypermethrin, zolaprofos, and any combinations thereof.


Additionally, the compounds described herein may be combined with herbicides that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more herbicides to control a wide variety of undesirable plants. When used in conjunction with herbicides, the presently claimed compounds may be formulated with the herbicide(s), tank-mixed with the herbicide(s) or applied sequentially with the herbicide(s). Typical herbicides include, but are not limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB; 2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor, acifluorfen, aclonifen, acrolein, alachlor, allidochlor, alloxydim, allyl alcohol, alorac, ametridione, ametryn, amibuzin, amicarbazone, amidosulfuron, aminocyclopyrachlor, aminopyralid, amiprofos-methyl, amitrole, ammonium sulfamate, anilofos, anisuron, asulam, atraton, atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC, beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate, bensulfuron, bensulide, bentazone, benzadox, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron, bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil, bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon, butachlor, butafenacil, butamifos, butenachlor, buthidazole, buthiuron, butralin, butroxydim, buturon, butylate, cacodylic acid, cafenstrole, calcium chlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide, carboxazole, chlorprocarb, carfentrazone, CDEA, CEPC, chlomethoxyfen, chloramben, chloranocryl, chlorazifop, chlorazine, chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlornitrofen, chloropon, chlorotoluron, chloroxuron, chloroxynil, chlorpropham, chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron, cisanilide, clethodim, cliodinate, clodinafop, clofop, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, cloransulam, CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron, cyanatryn, cyanazine, cycloate, cyclopyrimorate, cyclosulfamuron, cycloxydim, cycluron, cyhalofop, cyperquat, cyprazine, cyprazole, cypromid, daimuron, dalapon, dazomet, delachlor, desmedipham, desmetryn, di-allate, dicamba, dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorprop-P, diclofop, diclosulam, diethamquat, diethatyl, difenopenten, difenoxuron, difenzoquat, diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimexano, dimidazon, dinitramine, dinofenate, dinoprop, dinosam, dinoseb, dinoterb, diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron, DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon, esprocarb, ethalfluralin, ethametsulfuron, ethidimuron, ethiolate, ethofumesate, ethoxyfen, ethoxysulfuron, etinofen, etnipromid, etobenzanid, EXD, fenasulam, fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone, fenquinotrione, fenteracol, fenthiaprop, fentrazamide, fenuron, ferrous sulfate, flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop, fluazifop-P, fluazolate, flucarbazone, flucetosulfuron, fluchloralin, flufenacet, flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac, flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen, fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil, flupropanate, flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen, glufosinate, glufosinate-P, glyphosate, halauxifen, halosafen, halosulfuron, haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate, hexazinone, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil, iodomethane, iodosulfuron, iofensulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam, isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin, isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole, isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron, MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb, mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam, metamifop, metamitron, metazachlor, metazosulfuron, metflurazon, methabenzthiazuron, methalpropalin, methazole, methiobencarb, methiozolin, methiuron, methometon, methoprotryne, methyl bromide, methyl isothiocyanate, methyldymron, metobenzuron, metobromuron, metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate, monalide, monisouron, monochloroacetic acid, monolinuron, monuron, morfamquat, MSMA, naproanilide, napropamide, napropamide-M, naptalam, neburon, nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen, norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon, oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat, pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol, pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate, picloram, picolinafen, pinoxaden, piperophos, potassium arsenite, potassium azide, potassium cyanate, pretilachlor, primisulfuron, procyazine, prodiamine, profluazol, profluralin, profoxydim, proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron, propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor, pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate, pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor, pyridafol, pyrdate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron, saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim, siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodium azide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone, sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA, tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn, tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin, thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb, tiafenacil, tiocarbazil, tioclorim, tolpyralate, topramezone, tralkoxydim, triafamone, tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr, tridiphane, trietazine, trifloxysulfuron, trifludimoxazin, trifluralin, triflusulfuron, trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan, tritac, tritosulfuron, vernolate, and xylachlor.


Another embodiment of the present disclosure is a method for the control or prevention of fungal attack. This method comprises applying to the soil, plant, roots, foliage, or locus of the fungus, or to a locus in which the infestation is to be prevented (for example applying to cereal or grape plants), a fungicidally effective amount of one or more of the compounds of Formula I. The compounds are suitable for treatment of various plants at fungicidal levels, while exhibiting low phytotoxicity. The compounds may be useful both in a protectant and/or an eradicant fashion.


The compounds have been found to have significant fungicidal effect particularly for agricultural use. Many of the compounds are particularly effective for use with agricultural crops and horticultural plants.


It will be understood by those skilled in the art that the efficacy of the compound for the foregoing fungi establishes the general utility of the compounds as fungicides.


The compounds have broad ranges of activity against fungal pathogens. Exemplary pathogens may include, but are not limited to, causing agent of wheat leaf blotch (Zymoseptoria tritici), wheat brown rust (Puccinia triticina), wheat stripe rust (Puccinia striiformis), scab of apple (Venturia inaequalis), powdery mildew of grapevine (Uncimula necator), barley scald (Rhynchosporium secalis), blast of rice (Pyricularia oryzae), rust of soybean (Phakopsora pachyrhizi), glume blotch of wheat (Leptosphaeria nodorum), powdery mildew of wheat (Blumreria graminis f. sp. tritici), powdery mildew of barley (Blumeria graminis f. sp. hordei), powdery mildew of cucurbits (Erysiphe cichoracearum), anthracnose of cucurbits (Colletotrichum lagenarium), leaf spot of beet (Cercospora beticola), early blight of tomato (Alternaria solani), and spot blotch of barley (Cochliobolus sativus). The exact amount of the active material to be applied is dependent not only on the specific active material being applied, but also on the particular action desired, the fungal species to be controlled, and the stage of growth thereof, as well as the part of the plant or other product to be contacted with the compound. Thus, all the compounds, and formulations containing the same, may not be equally effective at similar concentrations or against the same fungal species.


The compounds are effective in use with plants in a disease-inhibiting and phytologically acceptable amount. The term “disease-inhibiting and phytologically acceptable amount” refers to an amount of a compound that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm being preferred. The exact concentration of compound required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climate conditions, and the like. A suitable application rate is typically in the range from about 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per square meter, g/m2).


Any range or desired value given herein may be extended or altered without losing the effects sought, as is apparent to the skilled person for an understanding of the teachings herein.


The compounds of Formula I may be made using well-known chemical procedures. Intermediates not specifically mentioned in this disclosure are either commercially available, may be made by routes disclosed in the chemical literature, or may be readily synthesized from commercial starting materials utilizing standard procedures.


General Schemes

The following schemes illustrate approaches to generating picolinamide compounds of Formula I. The following descriptions and examples are provided for illustrative purposes and should not be construed as limiting in terms of substituents or substitution patterns.


Compounds of Formula 1.1, wherein R3 and R12 are as originally defined and are equivalent, can be prepared by the methods shown in Scheme 1, step a. The compound of Formula 1.0 can be treated with an organometallic nucleophile such as phenylmagnesium bromide (PhMgBr) in a polar aprotic solvent such as tetrahydrofuran (THF) at a temperature of about 0° C. to 23° C. to afford compounds of Formula 1.1, wherein R3 and R12 are as previously defined, as shown in a.




embedded image


Compounds of Formula 2.2, wherein R3 is as originally defined and may or may not be equal to R12, can be prepared by the methods shown in Scheme 2, steps a-c. Compounds of Formula 2.2, wherein R3 and R12 are as previously defined but not an electron-deficient aryl or heteroaryl group and may or may not be equivalent, can be obtained by treating the compounds of Formula 2.0, wherein R3 and R12 are as previously defined but not an electron-deficient aryl or heteroaryl group and may or may not be equivalent, with a mixture of a hydride reagent, such as triethylsilane (Et3SiH), and an acid, such as 2,2,2-trifluoroacetic acid (TFA) in a halogenated solvent such as dichloromethane (DCM) at a temperature of about 0° C. to 23° C., as depicted in a. Alternatively, compounds of Formula 2.1, wherein R3 and R12 are an electron-deficient aryl or heteroaryl group and may or may not be equivalent, can be obtained by treating the compounds of Formula 2.0, wherein R3 and R12 are an electron-deficient aryl or heteroaryl group and may or may not be equivalent, with a base, such as sodium hydride (NaH), and a catalyst, such as imidazole, in a polar aprotic solvent such as THF at a temperature of about 23° C., followed by sequential addition of carbon disulfide (CS2) and an alkyl iodide, such as iodomethane (MeI), as depicted in b. Compounds of Formula 2.2, wherein R3 and R12 are an electron-deficient aryl or heteroaryl group and may or may not be equivalent, can be obtained by treating the compounds of Formula 2.1, wherein R3 and R12 are as previously defined and may or may not be equivalent, with a tin reagent, such as tributyltin hydride, and a radical initiator, such as azobisisobutyronitrile (AIBN), in a nonpolar solvent such as toluene at a temperature of about 115° C., as depicted in c.




embedded image


Compounds of Formula 3.1, wherein R3 and R12 are as originally defined and may or may not be equivalent, can be prepared according to the method outlined in Scheme 3, step a. Compounds of Formula 3.1, wherein R3 and R12 are as originally defined and may or may not be equivalent, can be prepared from compounds of Formula 3.0, wherein R3 and R12 are as previously defined and may or may not be equivalent, by treating with a base, such as NaH and an alkyl halide, such as MeI, in a polar aprotic solvent like N,N-dimethylformamide (DMF) at a temperature of about 0° C. to 23° C., as depicted in a.




embedded image


Compounds of Formula 4.1, wherein R3 and R12 are as originally defined and may or may not be equivalent, can be prepared according to the method outlined in Scheme 4, step a. Compounds of Formula 4.1, wherein R3 and R12 are as originally defined and may or may not be equivalent, can be prepared from compounds of Formula 4.0, wherein R3 and R12 are as previously defined and may or may not be equivalent, by treating with a fluorination reagent, such as (diethylamino)sulfur trifluoride (DAST), in a halogenated solvent such as DCM at a temperature of about 0° C. to 23° C., as depicted in a.




embedded image


Compounds of Formula 5.3, wherein R3, R4, and R12 are as originally defined and R3 may or may not be equivalent to R12, can be prepared according to the methods outlined in Scheme 5, steps a-c. Compounds of Formula 5.3, wherein R3, R4, and R12 are as originally defined and R3 may or may not be equivalent to R12, can be prepared from compounds of Formula 5.0, wherein R3, R4, and R12 are as originally defined and R3 may or may not be equivalent to R12, by treating with a catalyst such as palladium on carbon (Pd/C) in a mixture of an unsaturated hydrocarbon solvent, such as cyclohexene, and a polar protic solvent, such as ethanol (EtOH), at an elevated temperature of about 65° C., as shown in a. Alternatively, compounds of Formula 5.3, wherein R3 and R12 are an electron-deficient aryl or heteroaryl group and may or may not be equivalent and R4 is hydroxyl (OH) or alkoxy, can be obtained by treating compounds of Formula 5.1, wherein R3, R4, and R12 are as previously defined and R3 may or may not be equivalent to R12, with a mixture of a hydride reagent, such as Et3SiH, and an acid, such as TFA in a halogenated solvent such as DCM at a temperature of about 0° C. to 23° C., as indicated in b. Additionally, compounds of Formula 5.3, wherein R3 and R12 are as originally defined but not an electron-deficient aryl or heteroaryl group and may or may not be equivalent, and R4 is a proton (H), can be obtained by treating the compounds of Formula 5.2, wherein R3, R4, and R12 are as previously defined and R3 may or may not be equivalent to R12, with a mixture of a hydride reagent, such as Et3SiH, and an acid, such as TFA in a halogenated solvent such as DCM at a temperature of about 0° C. to 23° C., as depicted in c.




embedded image


Compounds of Formula 6.2, wherein R3 and R12 are an electron-deficient aryl or heteroaryl group and equivalent, can be prepared according to the methods outlined in Scheme 6, steps a-b. Compounds of Formula 6.1, wherein R3 and R12 are as described previously, can be prepared from compound of Formula 6.0, by treating with an aryl bromide, such as 4-bromobenzonitrile, in the presence of a Pd catalyst, such as XPhos Pd G3 (CAS #1445085-55-1, commercially available from Sigma-Aldrich), in a polar aprotic solvent such as THF at a temperature of about 55° C., as indicated in a. Compounds of Formula 6.2, wherein R3 and R12 are as described previously, can be prepared from compound of Formula 6.1, wherein R3 and R12 are as described previously, by treating with a hydride reagent, such as borane dimethyl sulfide complex, in the presence of a catalyst, such as (R)-(+)-2-Methyl-CBS-oxazaborolidine, in a polar protic solvent, such as methanol (MeOH), at a temperature of about 0° C., as indicated in b.




embedded image


Compounds of Formula 7.2, wherein R3 and R12 are as originally defined and equivalent, can be prepared according to the methods outlined in Scheme 7, steps a-b. Compounds of Formula 7.1, wherein R3 and R12 are as described previously, can be prepared from compounds of Formula 7.0, by treating with a catalyst, such as SbCl5, in a halogenated solvent such as DCM at a temperature of about 23° C., as indicated in a. Compounds of Formula 7.2, wherein R3 and R12 are as described previously, can be prepared from compound of Formula 7.1, wherein R3 and R12 are as described previously, by treating with a hydride reagent, such as borane dimethyl sulfide complex, in the presence of a catalyst, such as (R)-(+)-2-Methyl-CBS-oxazaborolidine, in a polar protic solvent, such as methanol (MeOH), at a temperature of about 23° C., as indicated in b.




embedded image


Compounds of Formula 8.1, wherein n is either 0 or 1, and W is either CH2 or O, can be prepared according to the method outlined in Scheme 8, step a. Compounds of Formula 8.1, wherein n is either 0 or 1, and W is either CH2 or 0, can be prepared from compounds of Formula 8.0, wherein n is either 0 or 1, and W is either CH2 or O, by treating with a base, such as n-butyllithium (n-BuLi), and an aldehyde, such as acetaldehyde, in a polar aprotic solvent such as THF at a temperature of about −78° C. to 23° C., as indicated in a.




embedded image


Compounds of Formula 9.1, wherein R3 and R12 are as originally defined, can be prepared according to the method outlined in Scheme 9, step a. Compounds of Formula 9.1, wherein R3 and R12 are as originally defined, can be prepared from compounds of Formula 9.0, wherein R3 is as originally defined (Formula 9.0 is either commerically available, or could be prepared from asymmetric Shi epoxidation of the corresponding E-olefin precursor, as reported in Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224), by treating with a pre-mixed suspension of a copper(I) salt, such as copper iodide (CuI), and an organometallic nucleophile, such as 4-(trifluoromethyl)phenylmagnesium bromide in a polar aprotic solvent such as THF, at a temperature of about −78° C. to 23° C., as shown in a.




embedded image


Compounds of Formula 10.2, wherein R1, R2, R3, R4 and R12 are as originally defined, can be prepared according to the method outlined in Scheme 10, step a. Compounds of Formula 10.0, wherein R1 is as originally defined, can be treated with alcohols of Formula 10.1, wherein R2, R3, R4 and R12 are as originally defined, and a coupling reagent such as 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine hydrochloride (EDC), and a catalyst such as N,N-dimethylpyridin-4-amine (DMAP) in a halogenated solvent like DCM to afford compounds of Formula 10.2, wherein R1, R2, R3, R4 and R12 are as previously defined, as shown in a.




embedded image


Compounds of Formula 11.2, wherein R1, R2, R3, R4, R6, R12 and Z are as originally defined, can be prepared according to the methods outlined in Scheme 11, steps a-b. As depicted in a, compounds of Formula 11.2, wherein R1, R2, R3, R4 and R12 are as originally defined, can be subjected to an acid, such as a 4 normal (N) solution of hydrogen chloride (HCl) in dioxane, in a halogenated solvent such as DCM to afford compounds of Formula 9.0, wherein R1, R2, R3, R4 and R12 are as originally defined, as shown in a.


Compounds of Formula 11.0, wherein R1, R2, R3, R4 and R12 are as originally defined, can be treated with compounds of Formula 11.1, wherein R6 and Z are as originally defined, in the presence of a base, such as diisopropylethylamine (DIPEA), and a peptide coupling reagent, such as benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), in an halogenated solvent like DCM, to afford compounds of Formula 11.2, wherein R1, R2, R3, R4, R6, R12 and Z are as originally defined, as shown in b.




embedded image


Compounds of Formula 12.0, wherein R1, R2, R3, R4, R6, R7, R12 and Z are as originally defined, can be prepared according to the method outlined in Scheme 12, step a. As shown in a, compounds of Formula 11.2, wherein R1, R2, R3, R4, R6, R12 and Z are as originally defined, can be treated with an appropriate alkyl halide with or without a reagent such as sodium iodide (NaI) and an alkali carbonate base, such as sodium carbonate (Na2CO3) or potassium carbonate (K2CO3), in a solvent like acetone at a temperature of about 55° C., or by treatment with an acyl halide in the presence of an amine base, such as pyridine, triethylamine (Et3N), DMAP, or mixtures thereof, in an aprotic solvent such as DCM, at a temperature of about 23° C., to afford compounds of Formula 12.0 wherein R1, R2, R3, R4, R6, R7, R12 and Z are as originally defined.




embedded image


EXAMPLES

The chemistry in the following examples may be conducted using either enantiomer of 2-((tert-butoxycarbonyl)amino)propanoic acid (Boc-Ala-OH) or either protected (PMB or Bn) or unprotected enantiomer of ethyl lactate.


Example 1: Preparation of(S)-2-(benzyloxy)-1,1-bis(4-fluorophenyl)propan-1-ol



embedded image


To a solution of(S)-ethyl 2-(benzyloxy)propanoate (2.08 grams (g), 10.0 millimoles (mmol)) in tetrahydrofuran (THF; 20 milliliters (mL)) at 0° C. was slowly added (4-fluorophenyl)magnesium bromide (31.3 mL, 25.0 mmol, 0.8 molar (M) in THF) over a 10 minute (min) period. The reaction vessel was allowed to warm slowly to room temperature over 2 hours (h), and the reaction mixture was quenched by careful addition of saturated (sat.) aqueous (aq.) ammonium chloride (NH4Cl; 50 mL). The mixture was diluted with diethyl ether (Et2O; 50 mL), the phases were separated, and the aq. phase was extracted with Et2O (2×50 mL). The combined organic phases were washed with sat. aq. sodium chloride (NaCl, brine; 100 mL), dried over sodium sulfate (Na2SO4), filtered, and concentrated. The resulting oil was purified by flash column chromatography (silica gel (SiO2), 045% acetone in hexanes) to afford the title compound (3.28 g, 93%) as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.47-7.38 (m, 2H), 7.38-7.27 (m, 5H), 7.17-7.09 (m, 2H), 7.04-6.89 (m, 4H), 4.64 (dd, J=11.4, 0.7 Hz, 1H), 4.51-4.38 (m, 2H), 3.12 (s, 1H), 1.11 (d, J=6.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −116.19, −116.41; ESIMS m/z 377 ([M+Na]+).


Example 2A: Preparation of (S)-4,4′-(2-(benzyloxy)propane-1,1-diyl)bis(fluorobenzene)



embedded image


To a solution of(S)-2-(benzyloxy)-1,1-bis(4-fluorophenyl)propan-1-ol (709 milligrams (mg), 2.00 mmol) in dichloromethane (DCM; 20 mL) at 0° C. was added triethylsilane (Et3SiH; 3.19 mL, 20.0 mmol) followed by 2,2,2-trifluoroacetic acid (TFA; 1.53 mL, 20.0 mmol). The mixture was stirred at 0° C. for 1 h. The resulting solution was quenched by careful addition of sat. aq. sodium bicarbonate (NaHCO3; 20 mL). The phases were separated, and the aq. phase was extracted with DCM (2×30 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→10% acetone in hexanes) to afford the title compound (627 mg, 92%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.31-7.22 (m, 5H), 7.21-7.16 (m, 2H), 7.10-7.03 (m, 2H), 7.00-6.91 (m, 4H), 4.54 (dd, J=11.5, 0.7 Hz, 1H), 4.31 (dd, =11.6, 0.8 Hz, 1H), 4.14 (dq, J=8.1, 6.1 Hz, 1H), 3.93 (d, J=8.1 Hz, 1H), 1.18 (d, J=6.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −116.60, −117.10; ESIMS (m z) 361 ([M+Na]+).


Example 2B: Preparation of (S)-(2-(benzyloxy)-1-methoxypropane-1,1-diyl)dibenzene



embedded image


To a suspension of sodium hydride (NaH; 52.0 mg, 1.30 mmol, 60% weight per weight (w/w) in mineral oil) in N,N-dimethylformamide (DMF; 3 mL) at 0° C. was added a solution of (S)-2-(benzyloxy)-1,1-diphenylpropan-1-ol (318 mg, 1 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 30 min and then cooled to 0° C. Iodomethane (MeI; 93.0 microliters (μL), 1.50 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The resulting solution was quenched by careful addition of sat. aq. NaHCO3 (10 mL). The mixture was diluted with diethyl ether (Et2O; 10 mL), the phases were separated, and the aq. phase was extracted with Et2O (2×10 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→5% acetone in hexanes) to afford the title compound (295 mg, 89%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.47-7.41 (m, 2H), 7.40-7.35 (m, 2H), 7.33-7.18 (m, 11H), 4.69 (d, J=11.9 Hz, 1H), 4.54 (d, J=12.3 Hz, 1H), 4.50 (q, J=6.1 Hz, 1H), 3.13 (s, 3H), 1.10 (d, J=6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.96, 141.31, 138.79, 129.13, 128.54, 128.14, 127.61, 127.16, 127.08, 126.95, 126.69, 99.99, 85.35, 78.13, 70.80, 52.46, 13.65; ESIMS (m/z) 333 ([M+H]+).


Example 2C: Preparation of (S)-(2-(benzyloxy)-1-fluoropropane-1,1-diyl)dibenzene



embedded image


To a solution of (S)-2-(benzyloxy)-1,1-diphenylpropan-1-ol (300 mg, 0.942 mmol) in DCM (5 mL) at 0° C. was added (diethylamino)sulfur trifluoride (DAST; 1.88 mL, 1.88 mmol, 1 M in DCM). The reaction was slowly warmed to room temperature over 3 h. The resulting solution was quenched by careful addition of sat. aq. NaHCO3 (5 mL). The phases were separated, and the aq. phase was extracted with DCM (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→10% acetone in hexanes) to afford the title compound (300 mg, 98%) as a colorless oil; 1H NMR (400 MHz. CDCl3) δ 7.58-7.49 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.20 (m, 9H), 7.09-6.99 (m, 2H), 4.47 (d, J=11.7 Hz, 1H), 4.37-4.25 (m, 2H), 1.26 (dd, J=6.3, 1.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.23 (d, J=22.7 Hz), 141.00 (d, J=23.5 Hz), 138.03, 128.21, 128.16, 127.90 (d, J=1.5 Hz), 127.80, 127.72 (d, J=1.7 Hz), 127.52, 127.42 (d, J=1.3 Hz), 126.23 (d, 0.1=9.6 Hz), 125.93 (d, J=8.7 Hz), 99.96 (d, J=180.8 Hz), 78.91 (d, J=26.9 Hz), 71.68, 14.47 (d, J=3.6 Hz); 19F NMR (376 MHz, CDCl3) δ −159.80.


Example 2D, Step 1: Preparation of (S)—O-(2-(benzyloxy)-1,1-bis(3,4,5-trifluorophenyl)propyl)S-methyl carbonodithioate



embedded image


To a solution of(S)-2-(benzyloxy)-1,1-bis(3,4,5-trifluorophenyl)propan-1-ol (496 mg, 1.16 mmol) in anhydrous THF (5.8 mL) was added NaH (93.0 mg, 2.33 mmol), followed by imidazole (3.96 mg, 0.0580 mmol), and the reaction mixture was stirred at ambient temperature for 1 h. Carbon disulfide (562 μL, 9.30 mmol) was added via syringe in one portion, followed by MeI (579 μL, 9.30 mmol), and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with Et2O (5 mL) and quenched with sat. aq. NH4Cl (10 mL). The layers were separated, and the aq. layer was extracted with Et2O (3×10 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), filtered and concentrated to afford an orange/brown oil. The crude oil was purified by flash column chromatography (SiO2, 0→50% ethyl acetate (EtOAc) in hexanes) to afford the title compound (627 mg, 94%) as a clear, bright yellow colored oil; 1H NMR (400 MHz, CDCl3) δ 7.40-7.27 (m, 3H), 7.24-7.16 (m, 2H), 7.02 (dd, J=9.1, 6.6 Hz, 2H), 6.96 (dd, J=8.8, 6.5 Hz, 2H), 5.44 (q, J=6.1 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.51 (d, J=11.6 Hz, 1H), 2.49 (s, 3H), 1.16 (d, J=6.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −133.89 (d, J=20.7 Hz), −134.73 (d, J=20.6 Hz), −159.83 (t, J=20.6 Hz), −160.56 (t, J=20.7 Hz); (Thin film) 2922, 1721, 1622, 1595, 1526, 1436, 1344, 1241, 1217, 1197, 1119, 1088, 1040, 965, 908, 861, 822, 730, 712, 697, 672 cm−1.


Example 2D, Step 2: Preparation of (S)-5,5′-(2-(benzyloxy)propane-1,1-diyl)bis(1,2,3-trifluorobenzene)



embedded image


A solution of (S)—O-(2-(benzyloxy)-1,1-bis(3,4,5-trifluorophenyl)propyl)S-methyl carbonodithioate (598 mg, 1.16 mmol) in toluene (200 mL) was degassed by a freeze-pump-thaw procedure (3 cycles using liquid nitrogen (N2)) under an atmosphere of N2. Tributyltin hydride (3.12 mL, 11.6 mmol) was then added, the reaction flask was fitted with a reflux condenser, and the reaction mixture was heated to a light reflux (115° C.). A solution of azobisisobutyronitrile (AIBN; 0.200 g, 1.22 mmol) in degassed toluene (3 cycles via liquid N2; 32 mL) was added via syringe down the reflux condenser over 3 h. Once slow addition of the AIBN was complete, the reaction mixture was stirred at reflux overnight. The solvent was removed in vacuo to provide a pale yellow oil. The crude oil was purified by flash column chromatography (SiO2, 0→30% EtOAc in hexanes) to afford the title compound (358 mg, 72%) as a clear, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=6.6 Hz, 3H), 7.17-7.06 (m, 2H), 6.92 (dd, J=8.5, 6.5 Hz, 2H), 6.79 (dd, J=8.3, 6.4 Hz, 2H), 4.59 (d, J=11.7 Hz, 1H), 4.31 (d, J=11.7 Hz, 1H), 4.02 (p, J=6.2 Hz, 1H), 3.76 (d, J=6.8 Hz, 1H), 1.19 (d, J=6.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −133.80 (d, J=20.5 Hz), −134.34 (d, J=20.5 Hz), −162.54 (t, J=20.5 Hz), −162.84 (t, J=20.5 Hz); (Thin film) 2871, 1621, 1526, 1445, 1345, 1262, 1235, 1116, 1096, 1043, 859, 802, 728, 698, 679 cm−1.


Example 3A: Preparation of (S)-1,1-bis(4-fluorophenyl)propan-2-ol



embedded image


To a solution of (S)-4,4′-(2-(benzyloxy)propane-1,1-diyl)bis(fluorobenzene) (575 mg, 1.70 mmol) in ethanol (EtOH; 11 mL) and cyclohexene (5.5 mL) at room temperature was added palladium on carbon (Pd/C; 362 mg, 0.0850 mmol, 2.5% w/w of Pd). The reaction mixture was stirred at 65° C. for 2 h, cooled to room temperature, filtered through a plug of Celite®, and concentrated to afford the title compound (415 mg, 98%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 2H), 7.25-7.18 (m, 2H), 7.09-6.93 (m, 4H), 4.47 (dqd, J=8.2, 6.1, 3.3 Hz, 1H), 3.80 (d, J=8.3 Hz, 1H), 1.55 (d, J=3.3 Hz, 1H), 1.19 (d, J=6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.90 (d, J=23.3 Hz), 160.46 (d, J=23.1 Hz), 138.15 (d, J=3.1 Hz), 136.94 (d, J=3.6 Hz), 130.14 (d, J=7.8 Hz), 129.55 (d, J=7.8 Hz), 115.70 (d, J=18.8 Hz), 115.49 (d, J=18.8 Hz), 70.07, 58.61, 21.63; 19F NMR (376 MHz, CDCl3) δ −115.84, −116.19.


Example 3B: Preparation of(S)-1,1-bis(2-fluorophenyl)propane-1,2-diol



embedded image


To a solution of (S)-1,1-bis(2-fluorophenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol (790 mg, 2.06 mmol) in DCM (20 mL) at 0° C. was added Et3SiH (3.28 mL, 20.6 mmol) followed by TFA (1.57 mL, 20.6 mmol). The mixture was stirred at 0° C. for 1 h. The resulting solution was quenched by careful addition of sat. aq. NaHCO3 (20 mL). The phases were separated, and the aq. phase was extracted with DCM (2×30 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→10% acetone in hexanes) to afford the title compound (388 mg, 71%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.90-7.77 (m, 1H), 7.70 (tt, J=8.2, 1.5 Hz, 1H), 7.31-7.10 (m, 4H), 6.97 (ddd, J=12.7, 8.1, 1.3 Hz, 1H), 6.88 (ddd, J=11.8, 8.0, 1.4 Hz, 1H), 5.11 (qd, J=6.3, 2.3 Hz, 1H), 3.49 (s, 1H), 2.27 (s, 1H), 1.09 (d, J=6.3 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −112.90 (d, J=8.3 Hz), −113.92 (d, J=8.4 Hz); ESIMS (m/z) 551 ([2M+Na]+).


Example 3C: Preparation of(S)-1,1-bis(4-bromophenyl)propan-2-ol



embedded image


To a solution of(S)-1,1-bis(4-bromophenyl)-2-((4-methoxybenzyl)oxy)propan-1-ol (1.80 g, 3.56 mmol) in DCM (18 mL) at 0° C. was added Et3SiH (5.68 mL, 35.6 mmol) followed by TFA (2.72 mL, 35.6 mmol). The mixture was warmed slowly to room temperature over 3 h. The resulting solution was quenched by careful addition of sat. aq. NaHCO3 (20 mL). The phases were separated, and the aq. phase was extracted with DCM (2×30 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→10% acetone in hexanes) to afford the title compound (742 mg, 560/%) as a colorless oil; 1H NMR (300 MHz, CDCl3) 7.51-7.36 (m, 4H), 7.25-7.17 (m, 2H), 7.18-7.06 (m, 2H), 4.48 (dq, J=8.2, 6.1 Hz, 1H), 3.76 (d, J=8.2 Hz, 1H), 2.80 (s, 1H), 1.19 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 140.94, 139.85, 131.98, 131.85, 130.39, 129.84, 121.06, 120.72, 69.82, 58.91, 21.65; (Thin film) 3390, 3024, 2969, 2900, 1486, 1072 cm−1.


Example 3D, Step 1: Preparation of (S) 1,1-bis(4-((trimethylsilyl)ethynyl)-phenyl)propan-2-ol



embedded image


To a solution of(S)-1,1-bis(4-bromophenyl)propan-2-ol (1.01 g, 2.72 mmol) in THF (9 mL) was added bis(triphenylphosphine)palladium dichloride (0.095 g, 0.136 mmol) and copper(I) iodide (CuI; 0.026 g, 0.136 mmol). The mixture was sparged with N2 for 20 min, and triethylamine (Et3N; 4.53 mL) was added dropwise. To the resulting mixture was added ethynyltrimethylsilane (1.15 mL, 8.15 mmol) dropwise, and the mixture was heated to reflux and stirred overnight. The mixture was cooled to room temperature, and the reaction was quenched with sat. aq. NaHCO3. The products were extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was then purified by flash column chromatography (SiO2, 0→20% acetone in hexanes) to provide the title compound (495 mg, 45%) as a brown foam; 1H NMR (400 MHz, CDCl3) δ 7.48-7.42 (m, 2H), 7.42-7.37 (m, 2H), 7.33-7.27 (m, 2H), 7.24-7.17 (m, 2H), 4.51 (dqd, J=12.2, 6.1, 3.5 Hz, 1H), 3.81 (d, J=8.3 Hz, 1H), 1.60 (d, J=3.8 Hz, 1H), 1.18 (d, J=6.1 Hz, 3H), 0.26 (s, 9H), 0.26 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 142.55, 141.48, 132.42, 132.29, 128.69, 128.15, 121.90, 121.57, 104.76, 104.71, 94.49, 94.33, 69.76, 59.96, 21.55, 0.00; (Thin film) 3397, 2960, 2156, 1501, 1248, 861, 840 cm−1, HRMS-ESI (m/z) [M+H]+ calcd for C25H33OSi2, 405.2064; found, 405.2070.


Example 3D, Step 2: Preparation of(S)-1,1-bis(4-ethynylphenyl)propan-2-ol



embedded image


To a solution of(S)-1,1-bis(4-((trimethylsilyl)ethynyl)phenyl)propan-2-ol (0.470 g, 1.16 mmol) in methanol (MeOH; 5.8 mL) was added potassium carbonate (K2CO3; 0.482 g, 3.48 mmol). The mixture was stirred for 1 h at room temperature and then filtered through Celite®. The filter cake was washed with MeOH, and the filtrate was concentrated. The crude material was purified by flash column chromatography (SiO2, 0→20% acetone in hexanes) to provide the title compound (288 mg, 95%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.48-7.43 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.29 (m, 2H), 7.24-7.19 (m, 2H), 4.51 (dqd, J=8.3, 6.1, 3.7 Hz, 1H), 3.82 (d, J=8.3 Hz, 1H), 3.05 (s, 1H), 3.04 (s, 1H), 1.63-1.55 (m, 1H), 1.18 (d, J=6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.84, 141.82, 132.60, 132.48, 128.74, 128.22, 120.87, 120.57, 83.31, 83.29, 77.39, 77.29, 69.73, 59.96, 21.66; (Thin film) 3436, 3280, 2968, 2106, 1499, 1075, 825 cm−1; HRMS-ESI (m/z) [M+H]+ calcd for C19H17O, 261.1274; found, 261.1272.


Example 3D, Step 3: Preparation of (S)-1,1-bis(4-ethylphenyl)propan-2-ol



embedded image


To a solution of(S)-1,1-bis(4-ethynylphenyl)propan-2-ol (0.144 g, 0.553 mmol) in EtOAc (2.8 mL) was added palladium (5% weight (wt) on carbon, dry basis; 0.235 g, 0.055 mmol). The mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through Celite®, and the filter cake was washed with EtOAc. The combined filtrate was then concentrated, and the crude residue was purified by flash column chromatography (SiO2, 0425% acetone in hexanes) to provide the title compound (97.0 mg, 65%) as a clear oil; 1H NMR (400 MHz, CDCl3) δ 7.33-7.25 (m, 2H), 7.22-7.15 (m, 2H), 7.18-7.11 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 4.51 (dqd, J=8.7, 6.1, 2.5 Hz, 1H), 3.74 (d, J=8.9 Hz, 1H), 2.65-2.53 (m, 4H), 1.68 (d, J=2.8 Hz, 1H), 1.23-1.14 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 142.74, 142.33, 139.94, 138.91, 128.48, 128.40, 128.07, 128.02, 70.19, 60.02, 28.41, 28.39, 21.37, 15.47, 15.46; (Thin film) 3421, 2963, 1510, 1110, 821 cm−1; HRMS-ESI (m/z) ([M+Na]+) calcd for C19H24NaO, 291.1719; found, 291.1725.


Example 3E: Preparation of 1-(9H-xanthen-9-yl)ethanol



embedded image


To a solution of 9H-xanthene (364 mg, 2.00 mmol) in THF (10 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes; 0.880 mL, 2.20 mmol). The mixture was stirred at −78° C. for 30 min. Acetaldehyde (0.226 mL, 4.00 mmol) was added, and the reaction mixture was warmed slowly to room temperature overnight. The resulting solution was quenched by careful addition of sat. aq. NH4Cl (10 mL). The phases were separated, and the aq. phase was extracted with Et2O (2×15 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→10% acetone in hexanes) to afford the title compound (216 mg, 48%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.33-7.22 (m, 4H), 7.17-7.04 (m, 4H), 3.99 (d, J=5.1 Hz, 1H), 3.96-3.82 (m, 1H), 1.54 (d, J=6.0 Hz, 1H), 1.00 (d, J=6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 152.94, 152.65, 129.54, 129.30, 128.19, 128.17, 123.18, 123.14, 122.48, 121.73, 116.59, 116.41, 73.07, 47.06, 18.81; ESIMS (m z) 475 ([2M+Na]).


Example 3F: Preparation of (1S,2S)-1-phenyl-1-(4-(trifluoromethyl)phenyl)propan-2-ol



embedded image


To a mixture of magnesium turnings (102 mg, 4.20 mmol) in Et2O (4 mL) was added 1-bromo-4-(trifluoromethyl)benzene (0.588 mL, 4.20 mmol) at room temperature, followed by MeI (5 μL). Upon warming to a gentle boil using a heat gun, the mixture turned a yellow/brown color. The reaction was then stirred in a water bath at room temperature for 30 min until almost all the magnesium was consumed. This was added to a suspension of copper(I) iodide (CuI; 400 mg, 2.10 mmol) in Et2O (4 mL) at −78° C. The reaction was stirred at −20° C. for 30 min, then cooled to −78° C., and (2S,3S)-2-methyl-3-phenyloxirane (0.201 mL, 1.50 mmol) was added. The resulting mixture was warmed slowly to room temperature overnight. The resulting solution was quenched by careful addition of sat. aq. NH4Cl (10 mL). The phases were separated, and the aq. phase was extracted with Et2O (2×15 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→10% acetone in hexanes) to afford the title compound (390 mg, 94%) as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.60-7.50 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.33 (m, 4H), 7.30-7.23 (m, 1H), 4.58 (dqd, J=8.4, 6.1, 3.5 Hz, 1H), 3.88 (d, J=8.5 Hz, 1H), 1.65 (d, J=3.6 Hz, 1H), 1.20 (d, J=6.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −62.49; ESIMS (m/z) 263 ([M−OH]+).


Example 3G, Step 1: Preparation of 4,4′-(2-oxopropane-1,1-diyl)dibenzonitrile



embedded image


To a suspension of 4-bromobenzonitrile (546 mg, 3.00 mmol) and cesium carbonate (977 mg, 3.00 mmol) in THF (10 mL) under an N2 atmosphere was added acetone (1.10 mL, 15.00 mmol), followed by X-Phos Pd G3 (50.8 mg, 0.060 mmol). Then, the vial was sealed and heated to 55° C. for 4 days. The reaction was diluted with EtOAc (30 mL) and washed with sat. NH4Cl (3×10 mL), water (15 mL), and brine (15 mL). Then the organic phase was dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→40% EtOAc in hexanes) to afford the title compound (174 mg, 22%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, 0.1=8.4 Hz, 4H), 7.34 (d, J=8.3 Hz, 4H), 5.21 (s, 1H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 203.68, 142.15, 132.75, 129.64, 118.21, 112.00, 64.25, 30.43; ESIMS m/z 261 ([M+H]+).


Example 3G, Step 2: Preparation of (S)-4,4′-(2-hydroxypropane-1,1-diyl)dibenzonitrile



embedded image


To a solution of 4,4′-(2-oxopropane-1,1-diyl)dibenzonitrile (174 mg, 0.668 mmol) in toluene (4.5 mL) was added (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 M solution in toluene, 66.8 μL, 0.067 mmol). Then, the reaction was cooled to 0° C. and a solution of BH3-DMS (69.8 μl, 0.735 mmol) in 0.5 mL toluene was added over 2 min. The flask was left to stir at 0° C. After 2 h, the reaction was quenched with methanol (0.5 mL), diluted with EtOAc and added water. Phases were separated and the aqueous phase was extracted with EtOAc×2. The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→50% EtOAc in hexanes) to afford the title compound (99.7 mg, 57%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ d 7.60 (dd, J=8.4, 6.8 Hz, 4H), 7.51-7.46 (m, 2H), 7.43-7.37 (m, 2H), 4.63-4.47 (m, 1H), 3.97 (d, J=7.5 Hz, 1H), 1.97 (d, J=3.8 Hz, 1H), 1.21 (d, J=6.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 146.91, 145.86, 132.60, 132.45, 129.90, 129.19, 118.58, 118.51, 110.96, 110.92, 69.19, 59.56, 22.27; ESIMS m/z 263 ([M+H]+).


Example 3H, Step 1: Preparation of 3,3-diphenylbutan-2-one



embedded image


To a magnetically stirred mixture of 2,3-diphenylbutane-2,3-diol (500 mg, 2.06 mmol) in DCM (10 mL) was added antimony pentachloride (26.5 μL, 0.206 mmol) under air atmosphere. The reaction mixture was stirred at 25° C. for 1 h and then was quenched by slow addition of sat. aq. NaHCO3. The resulting mixture was diluted with water and additional DCM, and the organic layer was separated by passing through a phase separator. The resulting oil was purified by flash column chromatography (SiO2, 0→5% acetone in hexanes) to afford the title compound (330 mg, 71%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.36-7.31 (m, 4H), 7.30-7.25 (m, 2H), 7.23-7.15 (m, 4H), 2.11 (s, 3H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 209.16, 143.59, 128.36, 126.91, 62.32, 27.62, 26.42; ESIMS m/z 225 ([M+H]+).


Example 3H, Step 2: Preparation of (S)-3,3-diphenylbutan-2-ol



embedded image


To a solution of 3,3-diphenylbutan-2-one (150 mg, 0.669 mmol) in toluene 4.5 mL) was added (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 M solution in toluene, 134 μL, 0.134 mmol). Then, a solution of BH3-DMS (70.2 μL, 0.702 mmol) in 0.5 mL of toluene was added to the reaction mixture over 2 min. The flask was left to stir at room temperature. After 1 h, the reaction was quenched with methanol (0.5 mL). DCM and water were added, and the phases were separated. The aqueous phase was extracted with DCM (2×). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by flash column chromatography (SiO2, 0→20% acetone in hexanes) to afford the title compound (150 mg, 99%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ d 7.39-7.17 (m, 10H), 4.70-4.61 (m, 1H), 1.67 (s, 3H), 1.51 (d, J=4.9 Hz, 1H), 1.11 (d, J=6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 147.30, 145.86, 128.40, 128.15, 128.05, 127.79, 126.20, 126.01, 72.28, 51.77, 23.26, 18.39; ESIMS m/z 227 ([M+H]+).


Example 31, Step 1: Preparation of (S)-1,1-bis(2,3-dimethoxyphenyl)propane-1,2-diol



embedded image


To a solution of isopropylmagnesium lithium chloride (1.3 M in THF, 6.1 mL, 8.00 mmol) was added THF (2 mL) and 1-bromo-2,3-dimethoxybenzene (1.74 g, 8.00 mmol). The resulting brown solution was heated to a gentle reflux (75° C. external temp) for 2.5 h, then cooled to 0° C. in an ice water bath. (S)-methyl 2-hydroxypropanoate (0.191 ml, 2 mmol) was then added dropwise via syringe. The reaction was stirred at 0° C. for 1 h, then removed from the cold bath and stirred overnight at rt. The reaction was cooled to 0° C. in an ice water bath, diluted with water (20 mL), brine (20 mL), and Et2O (40 mL), and was quenched with 1 N HCl (8 mL). The phases were separated, and the aqueous phase was extracted with Et2O (20 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated to provide an oil. Purification by automated silica gel column chromatography (5-50% EtOAc in hexanes) provided the title compound (568 mg, 82%) as a yellow, crystalline solid; 1H NMR (300 MHz, CDCl3) δ 7.43 (td, J=8.0, 1.5 Hz, 2H), 7.11 (td, J=8.1, 4.9 Hz, 2H), 6.83 (dd, J=8.1, 1.4 Hz, 2H), 5.06-4.82 (m, 1H), 4.74 (d, J=1.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.20 (s, 3H), 3.04 (s, 3H), 2.86 (d, J=9.5 Hz, 1H), 0.97 (d, J=6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 152.89, 152.82, 146.94, 145.53, 139.56, 138.92, 123.32, 123.26, 122.01, 119.01, 111.30, 79.20, 77.22, 60.07, 59.26, 55.77, 55.64, 18.34; HRMS-ESI (m/z) ([M+Na]+) calcd for C19H24O6Na, 371.1465; found, 371.1456.


Example 31, Step 2: Preparation of 1,1-bis(2,3-dimethoxyphenyl)propan-2-one



embedded image


To a solution of(S)-1,1-bis(2,3-dimethoxyphenyl)propane-1,2-diol (560 mg, 1.61 mmol) in anhydrous CH2Cl2 (8 mL) at 0° C. was added triethylsilane (770 μl, 4.82 mmol) and trifluoroacetic acid (TFA, 124 μL, 1.61 mmol). The resulting solution was stirred at 0° C. for 2 h, then removed from the cold bath and stirred for 2 h. TFA (248 μL, 3.2 mmol) was added, and the reaction was then stirred overnight at rt. The reaction was diluted with water (25 mL) and extracted with CH2Cl2 (3×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to provide an oil. Purification by automated silica gel column chromatography (5-25% acetone in hexanes) provided the title compound (396 mg, 75%) as a white solid; 1H NMR (300 MHz, CDCl3) δ 6.99 (t, J=8.0 Hz, 2H), 6.87 (dd, J=8.2, 1.5 Hz, 2H), 6.67-6.54 (m, 2H), 5.86 (s, 1H), 3.87 (s, 6H), 3.75 (s, 6H), 2.25 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 207.18, 152.69, 147.02, 132.23, 123.74, 121.61, 111.64, 60.36, 55.74, 51.96, 29.80; HRMS-ESI (m/z) ([M+Na]+) calcd for C19H22O5Na, 353.1359; found, 353.1353.


Example 31, Step 3: Preparation of 1,1-bis(2,3-dimethoxyphenyl)propan-2-ol



embedded image


To a solution of 1,1-bis(2,3-dimethoxyphenyl)propan-2-one (356 mg, 1.08 mmol) in methanol (3.5 mL) was added sodium borohydride (61 mg, 1.6 mmol). The resulting solution was stirred at rt for 20 h, then was quenched with sat'd NH4Cl (1 mL), diluted with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to provide the title compound (360 mg, 100%) as an oil; 1H NMR (300 MHz, CDCl3) δ 7.16-6.88 (m, 4H), 6.79 (ddd, J=9.6, 7.8, 1.9 Hz, 2H), 4.81 (d, J=8.3 Hz, 1H), 4.53-4.32 (m, 1H), 3.84 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.04 (d, J=4.2 Hz, 1H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 152.98, 152.83, 147.71, 147.04, 136.17, 135.33, 123.94, 123.62, 120.96, 120.84, 110.76, 110.48, 70.32, 60.26, 60.20, 55.66, 55.63, 45.11, 21.80; IR (neat film) 3451, 2935, 2833, 1582, 1473, 1428, 1266, 1215, 1167, 1125, 1088, 1068, 1004, 964, 908, 835, 809, 787, 748, 728.


Example 4A: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl 2-((tert-butoxycarbonyl)amino)-propanoate



embedded image


To a solution of (S)-1,1-diphenylpropan-2-ol (317 mg, 1.493 mmol) in DCM (15 mL) at 0° C. were added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (Boc-Ala-OH; 311 mg, 1.64 mmol) and N,N-dimethylpyridin-4-amine (DMAP; 18.2 mg, 0.149 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDC; 573 mg, 2.99 mmol), and the reaction mixture was stirred at room temperature overnight and concentrated to give a yellow oil. The crude material was purified by flash column chromatography (SiO2, 1→10% acetone in hexanes) to afford the title compound (433 mg, 75%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.42-7.07 (m, 10H), 5.80 (dq, J=10.1, 6.1 Hz, 1H), 4.97 (d, J=8.0 Hz, 1H), 4.19-4.06 (m, 1H), 4.03 (d, J=10.1 Hz, 1H), 1.41 (s, 9H), 1.23 (d, J=6.1 Hz, 3H), 0.76 (d, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) 172.83, 154.96, 141.52, 141.26, 128.79, 128.50, 128.10, 128.08, 126.91, 126.67, 79.62, 73.10, 57.98, 49.21, 28.33, 19.31, 17.98; ESIMS m/z 384 ([M+H]+).


Example 5, Step 1: Preparation of(S)-1-(((S)-1,1-diphenylpropan-2-yl)oxy)-1-oxopropan-2-aminium chloride



embedded image


To a solution of (S)—(S)-1,1-diphenylpropan-2-yl 2-((tert-butoxycarbonyl)amino)propanoate (Cmpd 2; 433 mg, 1.13 mmol) in DCM (6 mL) was added a 4 N solution of HCl in dioxane (2.8 mL, 11.3 mmol), and the mixture was stirred for 3 h at room temperature. The solvent was evaporated under a stream of N2 to provide the title compound (360 mg, 100%) as a white solid: ESIMS (nm/z) 284 ([M+H]+).


Example 5, Step 2: Preparation of(S)—(S)-1,1-diphenylpropan-2-yl 2-(3-hydroxy-4-methoxypicolinamido)propanoate



embedded image


To a solution of (S)-1-(((S)-1,1-diphenylpropan-2-yl)oxy)-1-oxopropan-2-aminium chloride (Cmpd 46; 361 mg, 1.13 mmol) and 3-hydroxy-4-methoxypicolinic acid (210 mg, 1.24 mmol) in DCM (I 1 mL) were added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP; 646 mg, 1.24 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA; 0.651 mL, 3.72 mmol), and the reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated and the crude oil was purified by flash column chromatography (SiO2, 1→50% acetone in hexanes) to afford the title compound (340 mg, 70%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 12.10 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.98 (d, J=5.2 Hz, 1H), 7.38-7.06 (m, 10H), 6.86 (d, J=5.3, 1H), 5.83 (dq, J=10.1, 6.1 Hz, 1H), 4.52 (dq, J=8.1, 7.2 Hz, 1H), 4.06 (d, J=10.2 Hz, 1H), 3.93 (s, 3H), 1.26 (d, J=6.1 Hz, 3H), 0.97 (d, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.67, 168.53, 155.34, 148.72, 141.38, 141.13, 140.40, 130.48, 128.80, 128.50, 128.10, 128.03, 126.95, 126.70, 109.39, 73.57, 57.93, 56.07, 47.85, 19.24, 17.61; HRMS-ESI (m/z) ([M+H]+) calcd for C25H27N2O5, 435.1920; found, 435.1925.


Example 6A: Preparation of (S)—(S)(S)-1,1-diphenylpropan-2-yl 2-(3-acetoxy-4-methoxypicolinamido)propanoate



embedded image


To a solution of(S)—(S)-1,1-diphenylpropan-2-yl 2-(3-hydroxy-4-methoxypicolinamido)-propanoate (Cmpd 90; 70.0 mg, 0.161 mmol), Et3N (44.9 μL, 0.332 mmol), and DMAP (3.94 mg, 0.032 mmol) in DCM (3.2 mL) was added acetyl chloride (17.2 μL, 0.242 mmol) at room temperature, and the reaction mixture was stirred for 2 h. The solvent was evaporated, and the resulting crude oil was purified by flash column chromatography (SiO2, 1→40% acetone in hexanes) to afford the title compound (75.0 mg, 97%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=7.8 Hz, 1H), 8.30 (d, J=5.4 Hz, 1H), 7.38-7.10 (m, 10H), 6.97 (d, J=5.4 Hz, 1H), 5.82 (dq, J=10.0, 6.2 Hz, 1H), 4.52 (dt, J=8.2, 7.1 Hz, 1H), 4.05 (d, J=10.1 Hz, 1H), 3.87 (s, 3H), 2.37 (s, 3H), 1.24 (d, J=6.1 Hz, 3H), 0.89 (d, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) 172.23, 168.89, 162.28, 159.42, 146.66, 141.55, 141.44, 141.25, 137.45, 128.77, 128.50, 128.13, 128.11, 126.89, 126.67, 109.73, 73.32, 57.90, 56.27, 47.85, 20.75, 19.25, 17.92; HRMS-ESI (m/z) ([M+H]+) calcd for C27H29N2O6, 477.2025; found, 477.2019.


Example 6B: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl 2-(3-(acetoxymethoxy)-4-methoxypicolinamido)propanoate



embedded image


To a suspension of(S)—(S)-1,1-diphenylpropan-2-yl 2-(3-hydroxy-4-methoxypicolinamido)-propanoate (Cmpd 90; 100 mg, 0.230 mmol) and K2CO3 (63.6 mg, 0.460 mmol) in acetone (4.6 mL) was added bromomethyl acetate (33.9 μL, 0.345 mmol) at room temperature, and the mixture was heated to 55° C. for 3 h and then cooled to room temperature. The solvent was evaporated and the resulting crude material was purified by flash column chromatography (SiO2, 1→40% acetone in hexanes) to afford the title compound (94.0 mg, 80% yield) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=5.4 Hz, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.34-7.09 (m, 10H), 6.92 (d, J=5.4 Hz, 1H), 5.83 (dq, J=10.1, 6.2 Hz, 1H), 5.72 (d, J=0.7 Hz, 2H), 4.60-4.49 (m, 1H), 4.06 (d, J=10.1 Hz, 1H), 3.88 (s, 3H), 2.05 (s, 3H), 1.25 (d, J=6.1 Hz, 3H), 0.91 (d, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.33, 170.25, 162.88, 160.24, 145.70, 143.91, 142.54, 141.48, 141.25, 128.76, 128.49, 128.12, 128.09, 126.89, 126.65, 109.56, 89.50, 73.27, 57.92, 56.17, 48.07, 20.86, 19.25, 17.73; HRMS-ESI (m/z) [M+H]+ calcd for C28H31N2O7, 507.2131; found, 507.2125.


Example 6C: Preparation of (S)—(S)-1,1-diphenylpropan-2-yl 2-(3-((isobutyryloxy)methoxy)-4-methoxypicolinamido)propanoate



embedded image


To a solution of (S)—(S)-1, l-diphenylpropan-2-yl 2-(3-hydroxy-4-methoxypicolinamido)-propanoate (Cmpd 90; 100 mg, 0.230 mmol) in acetone (4.6 mL) were added sodium carbonate (Na2CO3; 73.2 mg, 0.690 mmol), sodium iodide (NaI; 6.90 mg, 0.046 mmol) and chloromethyl 2-ethoxyacetate (62.9 mg, 0.460 mmol). The mixture was heated to 55° C. overnight and then cooled to room temperature, and the solvent was evaporated. The resulting residue was purified by flash column chromatography (SiO2, 2→30% acetone in hexanes) to afford the title compound (79.0 mg, 64%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=7.9 Hz, 1H), 8.25 (d, J=5.3 Hz, 1H), 7.36-7.08 (m, 10H), 6.92 (d, J=5.4 Hz, 1H), 5.83 (dq, J=10.1, 6.2 Hz, 1H), 5.79-5.69 (m, 2H), 4.62-4.44 (m, 1H), 4.06 (d, J=10.1 Hz, 1H), 3.86 (s, 3H), 2.53 (hept, J=7.0 Hz, 1H), 1.25 (d, J=6.2 Hz, 3H), 1.13 (d, J=7.0 Hz, 6H), 0.91 (d, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) 176.22, 172.34, 162.85, 160.23, 145.55, 144.16, 142.18, 141.48, 141.26, 128.76, 128.49, 128.12, 128.09, 126.89, 126.65, 109.48, 89.90, 73.26, 57.93, 56.12, 48.07, 33.85, 19.26, 18.68, 17.74; HRMS-ESI (m/z) ([M+H]+) calcd for C30H35N2O7, 535.2444; found, 535.2431.


Example A: Evaluation of Fungicidal Activity: Leaf Blotch of Wheat (Zyrnoseptoria tritici; Bayer Code SEPTTR)

Technical grades of materials were dissolved in acetone, which were then mixed with nine volumes of water (H2O) containing 110 ppm Triton X-100. The fungicide solutions were applied onto wheat seedlings using an automated booth sprayer to run-off. All sprayed plants were allowed to air dry prior to further handling. All fungicides were evaluated using the aforementioned method for their activity vs. all target diseases, unless stated otherwise. Wheat leaf blotch and brown rust activity were also evaluated using track spray applications, in which case the fungicides were formulated as EC formulations, containing 0.1% Trycol 5941 in the spray solutions.


Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Zymoseptoria tritici either prior to or after fungicide treatments. After inoculation the plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two to three days in a lighted dew chamber at 20° C.) to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 20° C. for disease to develop. When disease symptoms were fully expressed on the 1st leaves of untreated plants, infection levels were assessed on a scale of 0 to 100 percent disease severity. Percent disease control was calculated using the ratio of disease severity on treated plants relative to untreated plants.


Example B: Evaluation of Fungicidal Activity: Wheat Brown Rust (Puccinia triticina; Synonym: Puccinia recondita f. sp. tritici; Bayer Code PUCCRT)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Puccinia triticina either prior to or after fungicide treatments. After inoculation the plants were kept in a dark dew room at 22° C. with 100% relative humidity overnight to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 24° C. for disease to develop. Fungicide formulation, application and disease assessment followed the procedures as described in the Example A.


Example C: Evaluation of Fungicidal Activity: Wheat Glume Blotch (Leptosphaeria nodorum; Bayer code LEPTNO)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Leptosphaeria nodorum 24 h after fungicide treatments. After inoculation the plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two days in a lighted dew chamber at 20° C.) to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 20° C. for disease to develop. Fungicide formulation, application and disease assessment followed the procedures as described in the Example A.


Example D: Evaluation of Fungicidal Activity: Apple Scab (Venturia inaequalis; Bayer Code VENTIN)

Apple seedlings (variety McIntosh) were grown in soil-less Metro mix, with one plant per pot. Seedlings with two expanding young leaves at the top (older leaves at bottom of the plants were trimmed) were used in the test. Plants were inoculated with a spore suspension of Venturia inaequalis 24 h after fungicide treatment and kept in a 22° C. dew chamber with 100% relative humidity for 48 h, and then moved to a greenhouse set at 20° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.


Example E: Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets (Cercospora beticola; Bayer Code CERCBE)

Sugar beet plants (variety HH88) were grown in soil-less Metro mix and trimmed regularly to maintain a uniform plant size prior to test. Plants were inoculated with a spore suspension 24 h after fungicide treatments. Inoculated plants were kept in a dew chamber at 22° C. for 48 h then incubated in a greenhouse set at 24° C. under a clear plastic hood with bottom ventilation until disease symptoms were fully expressed. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.


Example F: Evaluation of Fungicidal Activity: Asian Soybean Rust (Phakopsora pachyrhizi; Bayer Code PHAKPA)

Technical grades of materials were dissolved in acetone, which were then mixed with nine volumes of H2O containing 0.011% Tween 20. The fungicide solutions were applied onto soybean seedlings using an automated booth sprayer to run-off. All sprayed plants were allowed to air dry prior to further handling.


Soybean plants (variety Williams 82) were grown in soil-less Metro mix, with one plant per pot. Two weeks old seedlings were used for testing. Plants were inoculated either 3 days prior to or 1 day after fungicide treatments. Plants were incubated for 24 h in a dark dew room at 22° C. and 100% relative humidity then transferred to a growth room at 23° C. for disease to develop. Disease severity was assessed on the sprayed leaves.


Example G: Evaluation of Fungicidal Activity: Barley Scald (Rhyncosporium secalis Bayer Code RHYNSE)

Barley seedlings (variety Harrington) were propagated in soil-less Metro mix, with each pot having 8 to 12 plants, and used in the test when the first leaf was fully emerged. Test plants were inoculated by an aqueous spore suspension of Rhyncosporium secalis 24 h after fungicide treatments. After inoculation the plants were kept in a dew room at 22° C. with 100% relative humidity for 48 h. The plants were then transferred to a greenhouse set at 20° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.


Example H: Evaluation of Fungicidal Activity: Rice Blast (Pyricularia oryzae; Bayer Code PYRIOR)

Rice seedlings (variety Japonica) were propagated in soil-less Metro mix, with each pot having 8 to 14 plants, and used in the test when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Pyricularia oryzae 24 h after fungicide treatments. After inoculation the plants were kept in a dew room at 22° C. with 100% relative humidity for 48 h to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 24° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.


Example I: Evaluation of Fungicidal Activity: Tomato Early Blight (Alternaria solani; Bayer Code ALTESO)

Tomato plants (variety Outdoor Girl) were propagated in soil-less Metro mix, with each pot having one plant, and used when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Alternaria solani 24 h after fungicide treatments. After inoculation the plants were kept in a dew room at 22° C. with 100% relative humidity for 48 h to permit spores to germinate and infect the leaf. The plants were then transferred to a growth room at 22° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.


Example J: Evaluation of Fungicidal Activity: Cucumber Anthracnose (Colletotrichum lagenarium; Bayer Code COLLLA)

Cucumber seedlings (variety Bush Pickle) were propagated in soil-less Metro mix, with each pot having one plant, and used in the test when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Colletotrichum lagenarium 24 hr after fungicide treatments. After inoculation the plants were kept in a dew room at 22° C. with 100% relative humidity for 48 hr to permit spores to germinate and infect the leaf. The plants were then transferred to a growth room set at 22° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.









TABLE 1







Compound Structure, Preparation Method, and Appearance












Prepared





According-



*Cmpd.

To



No.
Structure
Example
Appearance













1


embedded image


Example 1; Example 3A; Example 4A
White Solid





2


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





3


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





4


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear, Colorless Oil





5


embedded image


Example 1; Example 2B; Example 3A; Example 4A
Colorless Oil





6


embedded image


Example 1; Example 2B; Example 3A; Example 4 A
Colorless Oil





7


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





8


embedded image


Example 1; Example 2C; Example 3A; Example 4A
Colorless Oil





9


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





10


embedded image


Example 1; Example 2 A; Example 3A; Example 4A
Colorless Oil





11


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





12


embedded image


Example 3E; Example 4A
Colorless Oil





13


embedded image


Example 3E; Example 4A
Colorless Oil





14


embedded image


Example 1; Example 3C; Example 4A
Colorless Oil





15


embedded image


Example 1; Example 3C; Example 4A
Colorless Oil





16


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





18


embedded image


Example 3F; Example 4A
Colorless Oil





19


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





20


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear Oil





21


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear Oil





22


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear Oil





23


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear Oil





24


embedded image


Example 1; Example 3C; Example 4A
Sticky Wax





25


embedded image


Example 1; Example 3C; Example 4A
Sticky Wax





26


embedded image


Example 1; Example 3C; Example 4A
Sticky Wax





27


embedded image


Example 1; Example 3C; Example 4A
Sticky Wax





28


embedded image


Example 1; Example 3C; Example 3D, Steps 1-2; Example 4A
White Foam





29


embedded image


Example 1; Example 3C; Example 3D, Steps 1-3; Example 4A
Sticky Wax





31


embedded image


Example 3F; Example 4A
Clear Oil





33


embedded image


Example 1; Example 3B; Example 4A
White Solid





34


embedded image


Example 1; Example 3B; Example 4A
White Solid





35


embedded image


Example 1; Example 2A; Example 3A; Example 4A
White Solid





36


embedded image


Example 1; Example 3B; Example 4A
White Foam





37


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear, Colorless Oil





38


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear, Colorless Oil





39


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear, Colorless Oil





40


embedded image


Example 1; Example 2A; Example 3A; Example 4A
White Foam





43


embedded image


Example 1; Example 2A; Example 3A; Example 4A
White Solid





44


embedded image


Example 1; Example 2A; Example 3A; Example 4A
White Solid





45


embedded image


Example 5, Step 1
White Solid





46


embedded image


Example 5, Step 1
Colorless Oil





47


embedded image


Example 5, Step 1
Colorless Oil





48


embedded image


Example 5, Step 1
Pale Yellow Oil





49


embedded image


Example 5, Step 1
Colorless Oil





50


embedded image


Example 5, Step 1
Colorless Oil





51


embedded image


Example 5, Step 1
Colorless Oil





52


embedded image


Example 5, Step 1
Colorless Oil





53


embedded image


Example 5, Step 1
Colorless Oil





54


embedded image


Example 5, Step 1
Colorless Oil





55


embedded image


Example 5, Step 1
Colorless Oil





56


embedded image


Example 5, Step 1
Colorless Oil





57


embedded image


Example 5, Step 1
Colorless Oil





58


embedded image


Example 5, Step 1
Colorless Oil





59


embedded image


Example 5, Step 1
Colorless Oil





60


embedded image


Example 5, Step 1
Colorless Oil





61


embedded image


Example 5, Step 1
White Solid





63


embedded image


Example 5, Step 1
Colorless Oil





64


embedded image


Example 5, Step 1
Colorless Oil





65


embedded image


Example 5, Step 1
Sticky Oil





66


embedded image


Example 5, Step 1
Sticky Oil





67


embedded image


Example 5, Step 1
Sticky Oil





68


embedded image


Example 5, Step 1
Sticky Wax





69


embedded image


Example 5, Step 1
Sticky Wax





70


embedded image


Example 5, Step 1
Sticky Wax





71


embedded image


Example 5, Step 1
White Solid





72


embedded image


Example 5, Step 1
White Solid





73


embedded image


Example 5, Step 1
White Solid





74


embedded image


Example 5, Step 1
White Solid





75


embedded image


Example 5, Step 1
White Solid





77


embedded image


Example 5, Step 1
White Solid





78


embedded image


Example 5, Step 1
White Solid





79


embedded image


Example 5, Step 1
White Solid





80


embedded image


Example 1; Example 3B; Example 4A; Example 5, Step 1
Sticky Oil





81


embedded image


Example 5, Step 1
Sticky Oil





83


embedded image


Example 5, Step 1
Colorless Oil





84


embedded image


Example 5, Step 1
Clear, Colorless Oil





85


embedded image


Example 5, Step 1
Clear, Colorless Oil





86


embedded image


Example 5, Step 1
White Solid





87


embedded image


Example 5, Step 1
White Solid





88


embedded image


Example 5, Step 1
White Solid





89


embedded image


Example 5, Step 2
White Solid





90


embedded image


Example 5, Step 2
White Foam





91


embedded image


Example 5, Step 2
Colorless Oil





92


embedded image


Example 5, Step 2
White Foam





93


embedded image


Example 5, Step 2
White Foam





95


embedded image


Example 5, Step 2
Colorless Oil





96


embedded image


Example 5, Step 2
White Foam





97


embedded image


Example 5, Step 2
Colorless Oil





98


embedded image


Example 5, Step 2
Colorless Oil





99


embedded image


Example 5, Step 2
Colorless Oil





100


embedded image


Example 5, Step 2
Colorless Oil





101


embedded image


Example 5, Step 2
Colorless Oil





102


embedded image


Example 5, Step 2
Colorless Oil





103


embedded image


Example 5, Step 2
Colorless Oil





104


embedded image


Example 5, Step 2
Colorless Oil





105


embedded image


Example 5, Step 2
Colorless Oil





106


embedded image


Example 5, Step 2
Colorless Gel





107


embedded image


Example 5, Step 2
Colorless Gel





109


embedded image


Example 5, Step 2
Colorless Oil





110


embedded image


Example 5, Step 2
Clear, Colorless Oil





111


embedded image


Example 5, Step 2
Clear, Colorless Oil





112


embedded image


Example 5, Step 2
Clear, Colorless Oil





113


embedded image


Example 5, Step 2
White Solid





114


embedded image


Example 5, Step 2
White Solid





115


embedded image


Example 5, Step 2
White Solid





116


embedded image


Example 5, Step 2
White Solid





117


embedded image


Example 5, Step 2
White Foam





118


embedded image


Example 5, Step 2
White Foam





119


embedded image


Example 5, Step 2
White Foam





120


embedded image


Example 5, Step 2
White Foam





121


embedded image


Example 5, Step 2
White Foam





122


embedded image


Example 5, Step 2
White Foam





123


embedded image


Example 5, Step 2
White Foam





124


embedded image


Example 5, Step 2
White Foam





125


embedded image


Example 5, Step 2
White Solid





127


embedded image


Example 5, Step 2
White Solid





128


embedded image


Example 5, Step 2
White Solid





129


embedded image


Example 5, Step 2
White Solid





130


embedded image


Example 5, Step 2
Clear, Colorless Oil





131


embedded image


Example 5, Step 2
Clear, Colorless Oil





132


embedded image


Example 5, Step 2
Colorless Foam





133


embedded image


Example 5, Step 2
Colorless Foam





135


embedded image


Example 5, Step 2
Colorless Tacky Semi- Solid





136


embedded image


Example 5, Step 2
White Foam





137


embedded image


Example 5, Step 2
White Foam





138


embedded image


Example 6B
Colorless Semi-Solid





139


embedded image


Example 6A
Colorless Oil





140


embedded image


Example 6A
White Foam





141


embedded image


Example 6B
White Foam





142


embedded image


Example 6C
White Foam





143


embedded image


Example 6A
Colorless Oil





144


embedded image


Example 6B
Colorless Oil





145


embedded image


Example 6A
Colorless Oil





146


embedded image


Example 6B
Colorless Oil





147


embedded image


Example 6B
Colorless Oil





148


embedded image


Example 6B
Colorless Oil





149


embedded image


Example 6B
Colorless Oil





150


embedded image


Example 6A
Colorless Oil





152


embedded image


Example 6A
Colorless Oil





153


embedded image


Example 6B
Colorless Oil





155


embedded image


Example 6A
Colorless Oil





156


embedded image


Example 6A
Colorless Oil





157


embedded image


Example 6A
Colorless Oil





158


embedded image


Example 6B
Colorless Oil





159


embedded image


Example 6B
Colorless Oil





160


embedded image


Example 6B
Colorless Oil





161


embedded image


Example 6A
Colorless Oil





162


embedded image


Example 6A
Colorless Oil





163


embedded image


Example 6B
Colorless Oil





164


embedded image


Example 6B
Colorless Oil





165


embedded image


Example 6A
Colorless Oil





166


embedded image


Example 6A
Colorless Oil





167


embedded image


Example 6A
Colorless Oil





168


embedded image


Example 6A
Colorless Oil





169


embedded image


Example 6B
Colorless Oil





170


embedded image


Example 6B
Colorless Oil





171


embedded image


Example 6B
Colorless Oil





173


embedded image


Example 6A
Colorless Oil





174


embedded image


Example 6A
Colorless Oil





175


embedded image


Example 6B
Colorless Oil





176


embedded image


Example 6B
Colorless Oil





178


embedded image


Example 6B
Clear, Colorless Oil





179


embedded image


Example 6B
Clear, Colorless Oil





180


embedded image


Example 6B
Clear, Colorless Oil





181


embedded image


Example 6B
White Foam





182


embedded image


Example 6A
Colorless Oil





183


embedded image


Example 6B
White Solid





184


embedded image


Example 6B
White Solid





185


embedded image


Example 6B
White Solid





186


embedded image


Example 6B
White Solid





187


embedded image


Example 6A
White Solid





188


embedded image


Example 6A
White Solid





189


embedded image


Example 6A
White Solid





190


embedded image


Example 6A
White Solid





191


embedded image


Example 6B
White Solid





192


embedded image


Example 6B
While Foam





193


embedded image


Example 6B
Sticky Wax





194


embedded image


Example 6B
White Foam





195


embedded image


Example 6B
White Foam





196


embedded image


Example 6B
White Foam





197


embedded image


Example 6B
White Foam





198


embedded image


Example 6B
Sticky Wax





199


embedded image


Example 6B
White Solid





201


embedded image


Example 6B
White Solid





202


embedded image


Example 6B
White Solid





203


embedded image


Example 6B
White Solid





204


embedded image


Example 6A
White Solid





206


embedded image


Example 6A
White Solid





207


embedded image


Example 6A
White Solid





208


embedded image


Example 6A
Clear Colorless Oil





209


embedded image


Example 6A
Slightly Cloudy Colorless Oil





210


embedded image


Example 6A
Slightly Cloudy Colorless Oil





211


embedded image


Example 6C
Clear Colorless Oil





212


embedded image


Example 6C
Colorless Clear Film And Opaque Oil





213


embedded image


Example 6A
Clear Colorless Viscous Oil And Semi- Solid





214


embedded image


Example 6B
Clear, Colorless Oil





215


embedded image


Example 6A
Pale Yellow Oil





216


embedded image


Example 6A
Pale Yellow Oil





217


embedded image


Example 6A
Pale Yellow Oil





218


embedded image


Example 6B
Pale Yellow Oil





219


embedded image


Example 6B
Pale Yellow Oil





220


embedded image


Example 6B
Pale Yellow Oil





221


embedded image


Example 6B
While Foam





222


embedded image


Example 6B
While Foam





223


embedded image


Example 6A
While Foam





224


embedded image


Example 6A
While Foam





225


embedded image


Example 6B
Slightly Opaque Colorless Oil





226


embedded image


Example 1; Example 2D, Steps 1- 2; Example 3A; Example 4A
While Semi- Solid





227


embedded image


Example 5, Step 1
White Glass





228


embedded image


Example 5, Step 2
Colorless Foam





229


embedded image


Example 6A
Clear, Colorless Oil





230


embedded image


Example 6B
Clear, Colorless Oil





232


embedded image


Example 5, Step 1
White Semi- Solid





233


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Clear, Colorless Viscous Oil





234


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





235


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





236


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





237


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





238


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Slightly Cloudy Colorless Viscous Oil





239


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Slightly Cloudy Colorless Viscous Oil





240


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Foam





241


embedded image


Example 3H Steps 1-2; Example 4A.
Colorless Oil





242


embedded image


Example 3G, Steps 1 and 2; Example 4A
Colorless Oil





243


embedded image


Example 3G, Steps 1 and 2; Example 4A
Colorless Oil





244


embedded image


Example 4A
Colorless Oil





245


embedded image


Example 1; Example 3C; Exasnple 4A.
White Foam





246


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Foam





247


embedded image


Example 1; Example 3C; Example 4A.
White Foam





248


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Foam





249


embedded image


Example 3G, Steps 1 and 2; Example 4A
White Foam





250


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Semisolid





251


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Semisolid





252


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Semisolid





253


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





254


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





255


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





256


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





257


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Clear, Colorless Oil





258


embedded image


Example 3I; Example 4A
White Foam





259


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Foam





260


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Colorless Oil





261


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Colorless Oil





262


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Colorless Oil





263


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Colorless Oil





264


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
White Foam





265


embedded image


Example 1; Example 2A: Example 3A; Example 4A.
Colorless Oil





266


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Sticky Wax





267


embedded image


Example 1; Example 2A; Example 3A; Example 4A.
Sticky Wax.





268


embedded image


Example 3I, Example 4A
Oil





269


embedded image


Example 3I, Example 4A
Oil





270


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





271


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





272


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





273


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





274


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





275


embedded image


Example 3F; Example 4A
Colorless Oil





276


embedded image


Example 3F; Example 4A
Colorless Oil





277


embedded image


Example 3F; Example 4A
Colorless Oil





278


embedded image


Example 3F; Example 4A
Colorless Oil





279


embedded image


Example 3F; Example 4A
Colorless Oil





280


embedded image


Example 3F; Example 4A
Colorless Oil





281


embedded image


Example 3F; Example 4A
Colorless Oil





282


embedded image


Example 3F; Example 4A
Colorless Oil





283


embedded image


Example 3F; Example 4A
Colorless Oil





284


embedded image


Example 3F; Example 4A
Colorless Oil





285


embedded image


Example 3F; Example 4A
Colorless Oil





286


embedded image


Example 3F; Example 4A
Colorless Oil





287


embedded image


Example 3F; Example 4A
Colorless Oil





288


embedded image


Example 3F; Example 4A
White Foam





289


embedded image


Example 3F; Example 4A
Yellow Sticky Wax





290


embedded image


Example 3F; Example 4A
White Foam





291


embedded image


Example 3F; Example 4A
Yellow Sticky Wax





292


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





293


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





294


embedded image


Example 1; Example 2A; Example 3A; Example 4A
Colorless Oil





295


embedded image


Example 3F; Example 4A
Colorless Oil





296


embedded image


Example 3F; Example 4A
Colorless Oil





297


embedded image


Example 3F; Example 4A
Colorless Oil





298


embedded image


Example 3F; Example 4A
Colorless Oil





299


embedded image


Example 3F; Example 4A
Colorless Oil





300


embedded image


Example 3F; Example 4A
Colorless Oil





301


embedded image


Example 3F; Example 4A
Colorless Oil





302


embedded image


Example 3F; Example 4A
Colorless Oil





303


embedded image


Example 3F; Example 4A
Colorless Oil





304


embedded image


Example 3F; Example 4A
Colorless Oil





305


embedded image


Example 3F; Example 4A
Colorless Oil





306


embedded image


Example 3F; Example 4A
Colorless Oil





307


embedded image


Example 3F; Example 4A
Colorless Oil





308


embedded image


Example 3F; Example 4A
Thick Oil





309


embedded image


Example 3F; Example 4A
Colorless Oil





310


embedded image


Example 5, Step 1.
White Powder





311


embedded image


Example 5, Step 1.
White Powder





312


embedded image


Example 5, Step 1.
Clear, Colorless Thick Oil





313


embedded image


Example 5, Step 1.
White Powder





314


embedded image


Example 5, Step 1.
White Semi- Solid





315


embedded image


Example 5, Step 1.
White Semi- Solid





316


embedded image


Example 5, Step 1.
Clear Glass





317


embedded image


Example 1; Example 2A; Example 3A; Example 4A. Example 5, step 1.
Pale Purple Sticky Wax





318


embedded image


Example 5 Step 1.
Colorless Oil





319


embedded image


Example 5, Step 1
White Foam





320


embedded image


Example 5, Step 1
White Foam





321


embedded image


Example 5, Step 1
White Solid





322


embedded image


Example 5, Step 1.
Colorless Oil





323


embedded image


Example 5, Step 1.
Yellow Oil





324


embedded image


Example 5, Step 1.
Yellow Oil





325


embedded image


Example 5, Step 1.
Yellow Oil





326


embedded image


Example 5, Step 1.
Yellow Oil





327


embedded image


Example 5, Step 1
White Foam





328


embedded image


Example 5, Step 1
White Foam





329


embedded image


Example 5, Step 1
White Foam





330


embedded image


Example 5, Step 1
White Foam





331


embedded image


Example 5, Step 1
White Foam





332


embedded image


Example 5, Step 1
Clear, Colorless Oil





333


embedded image


Example 5, Step 1.
Light Brown Oil





334


embedded image


Example 5, Step 1.
Pale Yellow Oil





335


embedded image


Example 5, Step 1.
Pale Yellow Oil





336


embedded image


Example 5, Step 1.
White Powdery Solid





337


embedded image


Example 5, Step 1.
Clear, Colorless Oil





338


embedded image


Example 5, Step 1.
Whitc Powdery Solid





339


embedded image


Example 5, Step 1.
Clear, Colorless Oil





340


embedded image


Example 5, Step 1.
Whitc Solid





341


embedded image


Example 5, Step 1.
Thick Oil





342


embedded image


Example 5, Step 1.
White Solid





343


embedded image


Example 5, Step 1.
White Solid





344


embedded image


Example 5, Step 1.
White Solid





345


embedded image


Example 5, Step 1.
White Solid





346


embedded image


Example 5, Step 1.
Thick Oil





347


embedded image


Example 5, Step 1.
White Solid





348


embedded image


Example 5, Step 1.
White Solid





349


embedded image


Example 5, Step 1
Oil





350


embedded image


Example 5, Step 1
Oil





351


embedded image


Example 5, Step 1
Oil





352


embedded image


Example 5, Step 1
Colorless Oil





353


embedded image


Example 5, Step 1
Colorless Oil





354


embedded image


Example 5, Step 1
Colorless Oil





355


embedded image


Example 5, Step 1
Colorless Oil





356


embedded image


Example 5, Step 1
Colorless Oil





357


embedded image


Example 5, Step 1
Colorless Oil





358


embedded image


Example 5, Step 1
Colorless Oil





359


embedded image


Example 5, Step 1
Colorless Oil





360


embedded image


Example 5, Step 1
Colorless Oil





361


embedded image


Example 5, Step 1
Colorless Foam





362


embedded image


Example 5, Step 1
Colorless Foam





363


embedded image


Example 5, Step 1
Colorless Oil





364


embedded image


Example 5, Step 1
Colorless Oil





365


embedded image


Example 5, Step 1
White Foam





366


embedded image


Example 5, Step 1.
Sticky Wax





367


embedded image


Example 5, Step 1.
Sticky Wax





368


embedded image


Example 5, Step 1.
Sticky Wax





369


embedded image


Example 5, Step 1.
Sticky Wax





370


embedded image


Example 5, Step 1.
White Foam





371


embedded image


Example 5, Step 1
White Foam





372


embedded image


Example 5, Step 1
White Foam





373


embedded image


Example 5, Step 1
White Foam





374


embedded image


Example 5, Step 1
White Foam





375


embedded image


Example 5, Step 1
Colorless Oil





376


embedded image


Example 5, Step 1
Colorless Oil





377


embedded image


Example 5, Step 1.
Thick Oil





378


embedded image


Example 5, Step 1.
Thick Oil





379


embedded image


Example 5, Step 1.
White Solid





380


embedded image


Example 5, Step 1.
Thick Oil





381


embedded image


Example 5, Step 1.
Thick Oil





382


embedded image


Example 5, Step 1.
White Foam





383


embedded image


Example 5, Step 1.
White Solid





384


embedded image


Example 5, Step 1.
White Foam





385


embedded image


Example 5, Step 1.
White Foam





386


embedded image


Example 5 Step 2.
Matte White Solid And Clear Oil





387


embedded image


Example 5 Step 2.
Matte White Solid And Clear Oil





388


embedded image


Example 5, Step 2.
Clear, Colorless Oil





389


embedded image


Example 5, Step 2.
Colorless Foam





390


embedded image


Example 5, Step 2.
Colorless Foam





391


embedded image


Example 5, Step 2.
Clear, Colorless Oil





392


embedded image


Example 5, Step 2.
Semi Solid





393


embedded image


Example 5, Step 2.
White Foam





394


embedded image


Example 5 Step 2.
Colorless Foamy Oil





395


embedded image


Example 5, Step 2.
White Foam





396


embedded image


Example 5, Step 2
White Foam





397


embedded image


Example 5, Step 2
White Foam





398


embedded image


Example 5, Step 2
White Foam





399


embedded image


Example 5, Step 2.
White Foam





400


embedded image


Example 5, Step 2.
White Foam





401


embedded image


Example 5, Step 2.
White Foam





402


embedded image


Example 5, Step 2.
White Foam





403


embedded image


Example 5, Step 2
Colorless Oil





404


embedded image


Example 5, Step 2
Colorless Oil





405


embedded image


Example 5, Step 2
White Foam





406


embedded image


Example 5, Step 2
White Foam





407


embedded image


Example 5, Step 2
White Foam





408


embedded image


Example 5, Step 2
White Foam





409


embedded image


Example 5, Step 2
White Foam





410


embedded image


Example 5, Step 2
White Foam





411


embedded image


Example 5, Step 2
White Foam





412


embedded image


Example 5, Step 2
Oil





413


embedded image


Example 5, Step 2
White Foam





414


embedded image


Example 5, Step 2.
Thick Oil





415


embedded image


Example 5, Step 2.
White Foam





416


embedded image


Example 5, Step 2.
White Foam





417


embedded image


Example 5, Step 2.
White Foam





418


embedded image


Example 5, Step 2.
White Foam





419


embedded image


Example 5, Step 2.
White Foam





420


embedded image


Example 5, Step 2.
Colorless Foam





421


embedded image


Example 5, Step 2.
Clear, Colorless Oil





422


embedded image


Example 5, Step 2.
Clear, Colorless Oil





423


embedded image


Example 5, Step 2.
Colorless Foam





424


embedded image


Example 5, Step 2.
Colorless Foam





425


embedded image


Example 5, Step 2.
Clear, Colorless Oil





426


embedded image


Example 5, Step 2.
Clear, Colorless Oil





427


embedded image


Example 5, Step 2.
Clear, Colorless Oil





428


embedded image


Example 5, Step 2.
White Foam





429


embedded image


Example 5, Step 2.
Sticky Wax





430


embedded image


Example 5, Step 2
Colorless Gel





431


embedded image


Example 5, Step 2
Colorless Gel





432


embedded image


Example 5, Step 2
Colorless Gel





433


embedded image


Example 5, Step 2
Colorless Gel





434


embedded image


Example 5, Step 2
Colorless Oil





435


embedded image


Example 5, Step 2
Colorless Oil





436


embedded image


Example 5, Step 2
Colorless Oil





437


embedded image


Example 5, Step 2
Colorless Oil





438


embedded image


Example 5, Step 2
Colorless Foam





439


embedded image


Example 5, Step 2
Colorless Foam





440


embedded image


Example 5, Step 2
Colorless Oil





441


embedded image


Example 5, Step 2
Colorless Oil





442


embedded image


Example 5, Step 2
White Foam





443


embedded image


Example 5, Step 2.
White Foam





444


embedded image


Example 5, Step 2.
White Foam





445


embedded image


Example 5, Step 2.
White Foam





446


embedded image


Example 5, Step 2.
White Foam





447


embedded image


Example 5, Step 2
White Foam





448


embedded image


Example 5, Step 2
White Foam





449


embedded image


Example 5, Step 2
White Foam





450


embedded image


Example 5, Step 2
White Foam





451


embedded image


Example 5, Step 2
White Foam





452


embedded image


Example 5, Step 2
Colorless Oil





453


embedded image


Example 5, Step 2
Colorless Oil





454


embedded image


Example 5, Step 2.
White Foam





455


embedded image


Example 5, Step 2.
White Foam





456


embedded image


Example 5, Step 2.
White Foam





457


embedded image


Example 5, Step 2.
White Foam





458


embedded image


Example 5, Step 2.
White Foam





459


embedded image


Example 5, Step 2.
White Foam





460


embedded image


Example 5, Step 2.
White Foam





461


embedded image


Example 5, Step 2.
White Foam





462


embedded image


Example 6B.
Slightly Opaque Colorless Viscous Oil





463


embedded image


Example 6B.
White Foam Slightly Opaque Colorless Viscous Oil





464


embedded image


Example 6B.
Yellow Oil





465


embedded image


Example 6B.
Clear, Colorless Oil





466


embedded image


Example 6B.
Pale Yellow Oil





467


embedded image


Example 6B.
Pale Yellow Oil





468


embedded image


Example 6A.
Fluffy White Powder





469


embedded image


Example 6A.
Clear, Colorless Oil





470


embedded image


Example 6A.
Clear, Colorless Oil





471


embedded image


Example 6A.
Clear, Colorless Oil





472


embedded image


Example 6B.
White Foam





473


embedded image


Example 6B.
Sticky Wax





474


embedded image


Example 6B.
Colorless Oil





475


embedded image


Example 6A.
White Foam





476


embedded image


Example 6B.
White Foam





477


embedded image


Example 6A.
White Foam





478


embedded image


Example 6A.
White Foam





479


embedded image


Example 6A.
White Foam





480


embedded image


Example 6B.
White Foam





481


embedded image


Example 6B.
White Foam





482


embedded image


Example 6B.
White Foam





483


embedded image


Example 6B.
White Foam





484


embedded image


Example 6B.
White Foam





485


embedded image


Example 6A
Colorless Oil





486


embedded image


Example 6A
Colorless Oil





487


embedded image


Example 6B
Colorless Oil





488


embedded image


Example 6A.
White Foam





489


embedded image


Example 6A.
White Foam





490


embedded image


Example 6A.
White Wax





491


embedded image


Example 6A.
White Foam





492


embedded image


Example 6A.
White Foam





493


embedded image


Example 6B
White Foam





494


embedded image


Example 6C
White Foam





495


embedded image


Example 6A
White Foam





496


embedded image


Example 6A
White Foam





497


embedded image


Example 6A
Colorless Film





498


embedded image


Example 6A.
White Foam





499


embedded image


Example 6A.
White Foam





500


embedded image


Example 6A.
White Foam





501


embedded image


Example 6A.
White Foam





502


embedded image


Example 6A.
White Foam





503


embedded image


Example 6A.
White Foam





504


embedded image


Example 6A.
White Foam





505


embedded image


Example 6A.
Clear, Colorless Oil





506


embedded image


Example 6A.
Clear, Colorless Oil





507


embedded image


Example 6A.
Clear, Colorless Oil





508


embedded image


Example 6A.
Clear, Colorless Oil





509


embedded image


Example 6A.
Clear, Colorless Oil





510


embedded image


Example 6A.
Clear, Colorless Oil





511


embedded image


Example 6A.
Clear, Colorless Oil





512


embedded image


Example 6A.
Clear, Colorless Oil





513


embedded image


Example 6B.
Clear, Colorless Oil





514


embedded image


Example 6B.
Clear, Colorless Oil





515


embedded image


Example 6B.
Clear, Colorless Oil





516


embedded image


Example 6B.
Clear, Colorless Oil





517


embedded image


Example 6B.
Clear, Colorless Oil





518


embedded image


Example 6B.
Clear, Colorless Oil





519


embedded image


Example 6B.
Clear, Colorless Oil





520


embedded image


Example 6B.
Clear, Colorless Oil





521


embedded image


Example 6A.
White Foam





522


embedded image


Example 6A.
Sticky White Foam





523


embedded image


Example 6A
Colorless Oil





524


embedded image


Example 6A
Colorless Oil





525


embedded image


Example 6A
Colorless Oil





526


embedded image


Example 6A
Colorless Oil





527


embedded image


Example 6A
Colorless Foam





528


embedded image


Example 6A
Colorless Foam





529


embedded image


Example 6A
Colorless Foam





530


embedded image


Example 6A
Colorless Foam





531


embedded image


Example 6A
Colorless Oil





532


embedded image


Example 6A
Colorless Oil





533


embedded image


Example 6A
Colorless Oil





534


embedded image


Example 6A
Colorless Oil





535


embedded image


Example 6A.
White Foam





536


embedded image


Example 6A.
White Foam





537


embedded image


Example 6A.
White Foam





538


embedded image


Example 6A.
White Foam





539


embedded image


Example 6A.
White Foam





540


embedded image


Example 6A.
White Foam





541


embedded image


Example 6A.
White Foam





542


embedded image


Example 6A.
White Foam





543


embedded image


Example 6A.
White Foam





544


embedded image


Example 6A.
White Foam





545


embedded image


Example 6A.
White Foam





546


embedded image


Example 6A.
White Foam





547


embedded image


Example 6A.
White Foam





548


embedded image


Example 6A.
White Foam





549


embedded image


Example 6A.
White Foam





550


embedded image


Example 6A.
White Foam





551


embedded image


Example 6A.
White Foam





552


embedded image


Example 6A.
White Foam





553


embedded image


Example 6A
Colorless Foam





554


embedded image


Example 6A
Colorless Foam





*Cmpd. No. — Compound Number














Lengthy table referenced here




US10588318-20200317-T00001


Please refer to the end of the specification for access instructions.














Lengthy table referenced here




US10588318-20200317-T00002


Please refer to the end of the specification for access instructions.














Lengthy table referenced here




US10588318-20200317-T00003


Please refer to the end of the specification for access instructions.














Lengthy table referenced here




US10588318-20200317-T00004


Please refer to the end of the specification for access instructions.














Lengthy table referenced here




US10588318-20200317-T00005


Please refer to the end of the specification for access instructions.














Lengthy table referenced here




US10588318-20200317-T00006


Please refer to the end of the specification for access instructions.














LENGTHY TABLES




The patent contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).





Claims
  • 1. A compound of Formula I
  • 2. The compound according to claim 1, wherein X and Y are hydrogen.
  • 3. The compound according to claim 2, wherein R1 and R11 are independently chosen from hydrogen or alkyl.
  • 4. The compound according to claim 2, wherein R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8.
  • 5. The compound according to claim 2, wherein R4 is H.
  • 6. The compound according to claim 2, wherein R1 and R11 are independently chosen from hydrogen or alkyl, R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8, and R4 is H.
  • 7. The compound according to claim 1, wherein X is C(O)R5 and Y is hydrogen.
  • 8. The compound according to claim 7, wherein R1 and R11 are independently chosen from hydrogen or alkyl.
  • 9. The compound according to claim 7, wherein R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8.
  • 10. The compound according to claim 7, wherein R4 is H.
  • 11. The compound according to claim 7, wherein R1 and R11 are independently chosen from hydrogen or alkyl, R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8, and R4 is H.
  • 12. The compound according to claim 1, wherein X is hydrogen and Y is Q.
  • 13. The compound according to claim 12, wherein Z is N.
  • 14. The compound according to claim 13, wherein R6 is alkoxy.
  • 15. The compound according to claim 14, wherein R7 is hydrogen.
  • 16. The compound according to claim 15, wherein R1 and R11 are independently chosen from hydrogen or alkyl.
  • 17. The compound according to claim 15, wherein R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8.
  • 18. The compound according to claim 15, wherein R4 is H.
  • 19. The compound according to claim 15, wherein R1 and R11 are independently chosen from hydrogen or alkyl, R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8, and R4 is H.
  • 20. The compound according to claim 14, wherein R7 is chosen from —C(O)R9, or —CH2OC(O)R9.
  • 21. The compound according to claim 20, wherein R1 and R11 are independently chosen from hydrogen or alkyl.
  • 22. The compound according to claim 20, wherein R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8.
  • 23. The compound according to claim 20, wherein R4 is H.
  • 24. The compound according to claim 20, wherein R1 and R11 are independently chosen from hydrogen or alkyl, R3 and R12 are independently aryl, each substituted with 0, 1 or multiple R8, and R4 is H.
  • 25. The compound according to claim 24, wherein R9 is chosen from —CH3, +CH2OCH2CH3, —CH2CH2OCH3, —CH(CH3)2, —CH2CH2CH2CH3, or -cyclopropyl.
  • 26. A composition for the control of a fungal pathogen including mixtures of at least one of the compounds of claim 1 and another pesticide selected from the group consisting of fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides and combinations thereof.
  • 27. A composition for the control of a fungal pathogen including mixtures of at least one of the compounds of claim 15 and another pesticide selected from the group consisting of fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides and combinations thereof.
  • 28. A composition for the control of a fungal pathogen including mixtures of at least one of the compounds of claim 20 and another pesticide selected from the group consisting of fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides and combinations thereof.
  • 29. A method for the control of fungal attack on a plant, the method including the step of: applying a fungicidally effective amount of at least one of the compounds of claim 1 to at least one of the plant, an area adjacent to the plant, soil adapted to support growth of the plant, a root of the plant, and foliage of the plant.
  • 30. A method for the control of fungal attack on a plant, the method including the step of: applying a fungicidally effective amount of at least one of the compositions of claim 26 to at least one of the plant, an area adjacent to the plant, soil adapted to support growth of the plant, a root of the plant, and foliage of the plant.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 15/036,314 filed May 12, 2016, which is a U.S. National Phase Patent Application based on International Application No. PCT/US2015/066760 filed Dec. 18, 2015, which claims the benefit of U.S. Provisional Patent Application Ser. Nos. 62/098,120 filed Dec. 30, 2014 and 62/098,122 filed Dec. 30, 2014, which are expressly incorporated by reference herein.

US Referenced Citations (128)
Number Name Date Kind
4051173 Schacht Sep 1977 A
4588735 Spatz May 1986 A
4628120 Tsuchihashi et al. Dec 1986 A
4832729 Shigematsu et al. May 1989 A
4859639 Sterzel Aug 1989 A
5342835 Pepin et al. Aug 1994 A
5401871 Talley Mar 1995 A
5475132 Pepin et al. Dec 1995 A
5563165 Talley Oct 1996 A
5760068 Talley et al. Jun 1998 A
5852042 Jakobi Dec 1998 A
6355660 Ricks Mar 2002 B1
6410572 Schelberger Jun 2002 B1
6436421 Schindler Aug 2002 B1
6521622 Ricks Feb 2003 B1
6706740 Ricks Mar 2004 B2
6861390 Meyer Mar 2005 B2
6903219 Niyaz Jun 2005 B2
6916932 Meyer Jul 2005 B2
6927225 Ricks Aug 2005 B2
6953807 Hutin et al. Oct 2005 B2
7034035 Ricks Apr 2006 B2
7183278 Imamura Feb 2007 B1
7241804 Hockenberry Jul 2007 B1
7250389 Sakanaka Jul 2007 B1
RE39991 Ricks Jan 2008 E
7442672 Muller Dec 2008 B2
7458581 Derrer Dec 2008 B1
7459581 Derrer Dec 2008 B2
7560565 Bacque Jul 2009 B2
7927617 Koltzenburg Apr 2011 B2
8008231 Leatherman Aug 2011 B2
8153819 Dietz Apr 2012 B2
8236962 Hoekstra Aug 2012 B2
8349877 Brix Jan 2013 B2
8415274 Wachendorff-Neumann Apr 2013 B2
8465562 Chen Jun 2013 B2
8470840 Klittich Jun 2013 B2
8476193 Keeney Jul 2013 B2
8580959 Devasthale Nov 2013 B2
8586550 Lee et al. Nov 2013 B2
8604215 Phiasivongsa Dec 2013 B2
8748431 Sulzer-Mosse Jun 2014 B2
8785479 Meyer Jul 2014 B2
8835462 Meyer Sep 2014 B2
8883811 Owen Nov 2014 B2
8916579 Boebel Dec 2014 B2
9006259 Boebel Jan 2015 B2
9084418 Ehr Jul 2015 B2
9131690 Meyer Sep 2015 B2
9144239 Meyer Sep 2015 B2
9155305 Gary Oct 2015 B2
9156816 Ito Oct 2015 B2
9179674 Martin Nov 2015 B2
9185911 Inami Nov 2015 B2
9198419 Owen Dec 2015 B2
9247741 DeLorbe Feb 2016 B2
9265253 Li Feb 2016 B2
9265255 Funke Feb 2016 B2
9271496 Kemmitt Mar 2016 B2
9271497 Lorsbach Mar 2016 B2
9414596 Hoekstra et al. Aug 2016 B2
9439422 Martin Sep 2016 B2
9482661 Ross Nov 2016 B2
9549555 DeLorbe Jan 2017 B2
9549556 DeKorver Jan 2017 B2
9629365 Li Apr 2017 B2
9681664 Lalonde Jun 2017 B2
9686984 DeKorver Jun 2017 B2
9700047 Lu Jul 2017 B2
9750248 Ouimette Sep 2017 B2
9828408 Kalayanov et al. Nov 2017 B2
9840475 Lorsbach Dec 2017 B2
9936697 Hopkins Apr 2018 B2
9955690 Owen May 2018 B2
9955691 Boebel May 2018 B2
9974304 DeKorver May 2018 B2
10015964 Ogawa et al. Jul 2018 B2
10015966 Taggi et al. Jul 2018 B2
10035772 Whiteker Jul 2018 B2
10040764 Whiteker Aug 2018 B2
10111432 Rigoli Oct 2018 B2
10172358 DeKorver Jan 2019 B2
10182568 Bravo-Altamirano Jan 2019 B2
10231452 DeKorver Mar 2019 B2
10244754 Rigoli et al. Apr 2019 B2
10358423 Whiteker et al. Jul 2019 B2
20020119979 Degenhardt Aug 2002 A1
20020177578 Ricks Nov 2002 A1
20030018052 Ricks Jan 2003 A1
20030022902 Ricks Jan 2003 A1
20030022903 Ricks Jan 2003 A1
20050239873 Hockenberry Oct 2005 A1
20060167281 Meijer Jul 2006 A1
20070010401 Noon Jan 2007 A1
20070066629 Tormo i Blasco Mar 2007 A1
20090203770 Hockenberry Aug 2009 A1
20090306142 Carson Dec 2009 A1
20100016163 Keiper Jan 2010 A1
20110070278 Lopez Mar 2011 A1
20110082162 Lorsbach Apr 2011 A1
20120245031 Gewehr Sep 2012 A1
20130296372 Owen Nov 2013 A1
20140051678 Clement-Schatlo Feb 2014 A1
20140187587 Ouimette et al. Jul 2014 A1
20140357713 Damaj Dec 2014 A1
20150289508 Meyer Oct 2015 A1
20150322051 Lu Nov 2015 A1
20160037774 Schulz Feb 2016 A1
20160183526 Hopkins Jun 2016 A1
20160183527 Hopkins Jun 2016 A1
20160264550 Bindl et al. Sep 2016 A2
20170183324 Li Jun 2017 A1
20170360038 Yao Jun 2017 A1
20170273303 DeKorver Sep 2017 A1
20170273306 Lalonde Sep 2017 A1
20170290333 Bravo-Altamirano Oct 2017 A1
20170295792 Bravo-Altamirano Oct 2017 A1
20170369421 Yao Dec 2017 A1
20180000075 Bravo-Altamirano et al. Jan 2018 A1
20180000080 Buchan Jan 2018 A1
20180000084 Yao Jan 2018 A1
20180000085 Bravo-Altamirano et al. Jan 2018 A1
20180002288 Buchan Jan 2018 A1
20180002319 Wilmot Jan 2018 A1
20180002320 Wilmot Jan 2018 A1
20180037541 Yao Feb 2018 A1
20190059383 Bravo-Altamirano et al. Feb 2019 A1
Foreign Referenced Citations (39)
Number Date Country
2015001862 Oct 2015 CL
1185230 Jan 2005 CN
101530104 Sep 2009 CN
1054011 Nov 2000 EP
1516874 Mar 2005 EP
3141118 Mar 2017 EP
2649699 Jan 1991 FR
19940026884 Sep 1995 JP
1998053583 Feb 1998 JP
H10-045747 Feb 1998 JP
1996010016 Apr 1996 WO
199637472 Nov 1996 WO
199741103 Jun 1997 WO
1997019908 Jun 1997 WO
1998018751 May 1998 WO
1999011127 Nov 1999 WO
2000076979 Dec 2000 WO
200114339 Mar 2001 WO
2004080988 Sep 2004 WO
2005121069 Dec 2005 WO
2008079387 Jul 2008 WO
2012020777 Aug 2011 WO
2012016989 Feb 2012 WO
2016109301 Dec 2012 WO
2013136275 Sep 2013 WO
2014105844 Jul 2014 WO
2016007525 Jul 2015 WO
2016109288 Dec 2015 WO
2016109289 Dec 2015 WO
2016109290 Dec 2015 WO
2016109291 Dec 2015 WO
2016109300 Dec 2015 WO
2016109302 Dec 2015 WO
2016109303 Dec 2015 WO
2016109304 Dec 2015 WO
2016109305 Dec 2015 WO
2015005355 Mar 2017 WO
2017116939 Jul 2017 WO
2017116949 Jul 2017 WO
Non-Patent Literature Citations (86)
Entry
International Searching Authority, International Search Report and Written Opinion for PCT/US1567111 dated Mar. 11, 2016, 11 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567113 dated Mar. 11, 2016, 10 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567116 dated Mar. 7, 2016, 8 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567199 dated Mar. 11, 2016, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567200 dated Mar. 2016, 10 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567201 dated Mar. 11, 2016, 8 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567204 dated Mar. 7, 2016, 10 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567206 dated Mar. 7, 2016, 8 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1567207 dated Mar. 11, 2016, 12 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2013039726 dated Sep. 17, 2013, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2013039735 dated Oct. 18, 2013, 8 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2013077472 dated Apr. 16, 2014, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2013077537 dated Apr. 16, 2014, 11 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2014071692 dated Apr. 20, 2015, 6 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2014071695 dated Apr. 17, 2015, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2014071699 dated Apr. 20, 2015, 6 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2014071700 dated Apr. 17, 2015, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2015066760 dated Apr. 14, 2016, 11 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2015066764 dated Apr. 28, 2016, 11 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US20150051598 dated Dec. 6, 2010, 5 pages.
International Searching Authority, International Search Report for PCT/US14/058067, dated Dec. 22, 2014, 4 pages.
International Searching Authority, Written Opinion for PCT/US14/058067, dated Dec. 22, 2014, 5 pages.
International Searching Authority, International Search Report for PCT/US14/058070, dated Dec. 15, 2014, 4 pages.
International Searching Authority, Written Opinion for PCT/US14/058070, dated Dec. 15, 2014, 5 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US2015/067115, dated Mar. 11, 2016, 6 pages.
International Searching Authority, International Search Report PCT/US2000/021523 dated Jul. 7, 2001, 7 pages.
Database Chemabs Online, Chemical Abstracts Service, Columbus Ohio, US: accession No. CA63:16300dXP002164206 (Cited in International Search Report for PCT/US2000/021523).
Anonymous, Synergistic Fungicidal Composition of Heterocyclic Aromatic Amides and Triazoles, ip.com Journal, ip.com, Electronic Publication, West Henrietta, NY, US, Jul. 2004, 11 pages.
Backman, P., Fungicide Formulation: Relationship to Biological Activity, Ann. Rev. Phytopathol, 1978, 16, pp. 211-237.
BASF New Fungicide Xemium Got Full Approval in EU, Agronews, Jul. 18, 2012 [retrieved on Feb. 4, 2014]. Retrieved from the Internet: ,URL:http://news.agropages.com/News/NewsDetail---7386.htm, 1 page.
Bolton, M. et al., “Wheat leaf rust caused by Puccinia triticina,” Molecular Plant Pathology, vol. 9, No. 5, 2008, pp. 563-575 [online] [retrieved on Feb. 3, 2016]. Retrieved from the Internet URL: https://www.researchgate.net/profile/Melvin_Bolton/publication/23483068_Wheat_leaf_rust_caused_by_Puccinia_triticina/links/0646352d94b8d5f2c9000000.pdf.
Davari, M. et al. “Quantum Chemical Investigation of Intramolecular Thione-Thiol Tautomerism of 1, 2, 4-triazole-3-thione and its disubstituted derivatives,” Journal of Molecular Modeling, Sep. 2009, 16(5), pp. 841-855.
Cantacuzene, D., “Optimization of the papain catalyzed esterification of amino acids by alcohols and diols,” Tetrahedron 45, 3 (1989): 741-748.
FRAC Code List: Fungicides Sorted by Mode of Action (including FRAC Code numbering), Fungicide Resistance Action Committee, Dec. 2008, 10 pages.
Fungicidal Mixtures, IP.com Prior Art Database Technical Disclosure, (Jul. 5, 2005), XP055073888, DOI: http://ip.com/pdf/ipcompad/IPCOM000126160D.pdf, 12 pages.
Gisi, U., “Synergistic Interaction of Fungicides in Mixtures,” The American Phytopathology Society, vol. 86, No. 11, 1996, pp. 1273-1279.
Guseynov et al: “Study of the reaction of aminoacetic acid with dihydric alcohols and production of epoxy esters” Chemical Problems, 2009 (1), pp. 188-190.
Hu, Z. et al., “Synthesis of Novel Analogues of Antimycin A3,” Tetrahedron Letters 49 (2008), pp. 5192-5195.
Huang, C. et al., “Synergistic Interactions between Chitinase ChiCW and Fungicides Against Plant Fungal Pathogens,” J. Microbiol. Biotechnol., 2008, 18(4), pp. 784-787.
Kissling, E., “Crop Protection Pipeline Value Jumps to Euro 2.4 Billion,” BASF SE, Mar. 10, 2011 [retrieved on Feb. 4, 2014], Retrieved from the internet: ,URL:http://agro.basf.com/agri/AP-Internet/en/content/news_room/news/basf-crop-protection-pipeline-value, 4 pages.
Koyanagi, T. et al., “Bioisoterism in Agrochemicals,” Synthesis and Chemistry of Agrochemicals IV; Baker, D. et al., ACS Symposium Series; American Chemical Society: Washington, D.C., 1995, pp. 15-24.
Latin, R., et al, “Re-Examining Fungicide Synergism for Dollar Spot Control,” GCM, Jul. 2008, pp. 84-87.
Ueki, M., et al., “UK-2A, B, C, and D, Novel Antifungal Antibiotics from Streptomyces sp. 517-02 I. Fermentation, Isolation, and Biological Properties,” The Journal of Antibiotics, vol. 49, No. 7, Jul. 1996, pp. 639-634.
O'Sullivan, E., et al., “Fungicide Resistance—an Increasing Problem,” Proceedings of National Tillage Conference 2007, Published by Crop Research Centre, Oak Park, Carlow, Jan. 31, 2007, pp. 43-56.
Parker, J.E., et al., “Mechanism of Binding of Prothioconazole to Mycosphaerella graminicola CYP51 Differs from That of Other Azole Antifungals,” Applied and Environmental Microbiology, vol. 77, No. 4, Feb. 2011, pp. 1460-1465.
PubChem: Open Chemistry Database, Substance Record for SID 74383515. Deposit Date Jun. 11, 2009 [retrieved on May 25, 2016] Retrieved from internet. <URL:https://pubchem.ncbi.nlm.nih.gov/substance/74383515#section=Top>, 5 pages.
Science for a Better Life, Bayer CropScience “Positioned for Growth”, Jun. 2008, 22 pages.
Calcium Dodecyl Benzene Sulfonate, CAS 26264-06-2, (http://www.hichem.com/product/showproduct.php?id=334639) Mar. 28, 2013, 6 pages.
Tani, K. et al., “UK2A, B, C, and D, Novel Antifungal Antibiotics—from Streptomyces sp. 517-02.,” The Journal of Antibiotics, vol. 55, No. 3, Mar. 2002, pp. 315-21.
The Merck Index, Twelfth Edition, S. Budavari, Ed., Merck and Co., Inc., Whitehouse Station, NJ, 1996, pp. 2220, 3666, 7937 and 7946.
Usuki, Y., et al., “Semi-synthesis and biological evaluation of analogues of UK-2A, a novel antifungal antibiotic from Streptomyces sp. 517-02,” Bioorganic & Medicinal Chemistry Letters, vol. 15, No. 8, 2005, pp. 2011-2014.
Usuki, Y. et al., “UK-2A, B, C, and D, Novel Antifungal Antibiotics from Streptomyces sp. 517-02 VI (2). Structure-activity Relationships of UK-2A,” Journal of Antibiotics, vol. 55, No. 6, Jun. 2002, pp. 607-610.
Webster's New World Dictionary, Second College Edition, Guralnik, D, Ed., The World Publishing Co., New York, p. 1127 (1972).
Wilson, C.L. et al. “Fruit Volatiles Inhibitory to Monilinia Fruiticola and Botrytis cinerea,” 1987, Plant Disease, vol. 71, No. 4, pp. 316-319.
Goellner et al. “Phakopsora pachyrhizi, the causal agent of Asian soybean rust.” Molecular Plant Pathology, vol. 11, No. 2, pp. 169-177 (2010).
Fujita T, Ed. “Quantitative structure-activity analysis and database-aided bioisosteric structural transformation procedure as methodologies of agrochemical design”; Classical and Three Dimensional QSAR in Agrochemistry, ACS Symposium Series Washington, D.C. vol. 606, pp. 13-34 (1995).
Patani et al. Biosterism: A rational approach in drug design. Chemical Reviews, vol. 96, No. 8, pp. 3147-3176 (1996).
Kendall, S. et al. “Changes in sensitivity to DMI fungicides in Rhynchosporium secalis”. Crop Protection, vol. 12, No. 5, pp. 357-362 (1993).
Cooke et al. “The effect of fungicide programmes based on epoxiconazole on the control and DMI sensitivity of Rhynchosporium secalis in winter barley.” Crop Protection, vol. 23, No. 5, pp. 393-406 (2004).
Shimano et al. “Total synthesis of the antifungal dilactones UK-2A and UK-3a: The determination of their relative and absolute configurations, analog synthesis and antifungal activities”. Tetrahedron, vol. 54, pp. 12745-12774 (1998).
Lippard, S. “Chemical Synthesis: The Art of Chemistry”. Nature, vol. 416, p. 587 (2002).
Washburn, W.N., “Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate.” Journal of medicinal chemistry 57, 18 (Aug. 28, 2014): 7509-7522.
Amiri et al. “Sensitivity of Botrytis cinerea field isolates to the novel succinate dehydrogenase inhibitors fluopyram, penthiopyrad, and fluxapuroxad”. Annual Meeting of the American Phytopathological Society, Phytopathology, vol. 102 (2012). (Uploaded in 3 parts due to size restrictions).
Chitwood, D. “Nematicides”. Encyclopedia of Agrochemicals (3), pp. 1104-1115, John Wiley & Sons, New York, NY, http://naldc.nal.usda.gov/download/43874/PDF (2003).
Hanafi et al. “UK2A, B, C, and D, Novel Antifungal Antibiotics from Streptomyces sp 517-02 II. Structural Elucidation.” The Journal of Antibiotics, vol. 49, Issue 12, pp. 1226-1231 (1996).
Shibata et al. “UK1, A Novel Cytotoxic Metabolite from Streptomyces sp. 517-02 II. Structural Elucidation.” The Journal of Antibiotics, vol. 46, Issue 7, pp. 1095-1100 (1993).
Shimano et al. “Enantioselective Total Synthesis of the Antifungal Dilactone, UK-2A: The Determination of the Relative and Absolute Configurations”. Tetrahedron Letters, vol. 39, pp. 4363-4366 (1998).
Stephenson, G., et al. “Glossary of terms relating to pesticides”. Pure and Applied Chemistry, vol. 78, No. 11, pp. 2075-2154, International Union of Pure and Applied Chemistry (2006).
Ueki, M., et al., “UK-1, A Novel Cytotoxic Metabolite from Streptomyces sp. 517-02 I. Taxonomy, Fermentation, Isolation, Physico-chemical and Biological Properties.” The Journal of Antibiotics, vol. 46, No. 7, pp. 1089-1094 (1993).
Ueki et al. “UK-3A, A Novel Antifungal Antibiotic from Streptomyces sp. 517-02: Fermentation, Isolation, Structural Elucidation and Biological Properties”. The Journal of Antibiotics, vol. 50, Issue 7, pp. 551-555 (1997).
Ueki et al. “The mode of action of UK-2A and UK-3A, Novel antifungal antibiotics from Streptomyces sp. 517-02”. The Journal of Antibiotics, vol. 50, Issue 12, pp. 1052-1057 (1997).
International Searching Authority, International Search Report and Written Opinion for PCT/US14/58061 dated Dec. 15, 2014, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1458065 dated Dec. 22, 2014, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1528407 dated Aug. 5, 2015, 8 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1539407 dated Sep. 30, 2015, 9 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1539409 dated Oct. 5, 2015, 10 pages.
International Searching Authority, International Search Report and Written Opinion for PCT/US1544383 dated Mar. 16, 2016, 11 pages.
Carris, L., et al. “Introduction to Fungi,” The American Phytopathological Society. DOI: 10.1094/PHI-I-2012-0426-01, 2012. Available at https://www.apsnet.org/edcenter/intropp/PathogenGroups/Pages/IntroFungi.aspx. 38 pgs.
Gribble, G. “Sodium borohydride in carboxylic acid media: a phenomenal reduction system”. Chemical Society Reviews, vol. 27, pp. 395-404, 1998.
Marcusson, J. et al. “Inhibition of [3H]paroxetine binding by various serotonin uptake inhibitors: Structure-activity relationships”. European Journal of Pharmacology, vol. 215, Issue 2, pp. 191-198, 1992.
Mikami, K., et al. “Catalytic Asymmetric Glyoxylate-ene Reaction: A Practical Access to alpha-Hydroxy Esters in High Enantiomeric Purities”. Journal of the American Chemical Society, vol. 112, Issue 10, pp. 3949-3954, 1990.
Muller, S., et al. “Design and Evaluation of Inclusion Resolutions, Based on Readily Available Host Compounds”. European Journal of Organic Chemistry, pp. 1082-1096, 2005.
Patent Abstracts of Japan vol. 1998, No. 06, Apr. 30, 1998 JP10053583A (Mitsubishi Chem Corp) Feb. 24, 1998 abstract example 20.
Rebiere, F., et al. “Asymmetric Diels-Alder Reaction Catalysed by Some Chiral Lewis Acids”. Tetrahedron Asymmetry, vol. 1, No. 3, pp. 199-214, 1990.
Shionhara, T., et al. “Facile One-Pot Procedure for Et3Al-Promoted Asymmetric Pinacol-Type Rearrangement”. Synthesis, vol. 1, pp. 141-146, 2003.
Wirth, D. “Carboxylic Sulfonic Mixed Anhydrides: General Utility and Application to the Synthesis of Ceftazidime”. Tetrahedron, vol. 49, Issue 8, pp. 1535-1540, 1993.
Related Publications (1)
Number Date Country
20180228159 A1 Aug 2018 US
Provisional Applications (2)
Number Date Country
62098120 Dec 2014 US
62098122 Dec 2014 US
Continuations (1)
Number Date Country
Parent 15036314 US
Child 15953394 US