WO2023247976A1 - Deuterated herbicides based on oxazinones and 6-(trifluoromethyl)pyrimidine-2,4-diones - Google Patents

Deuterated herbicides based on oxazinones and 6-(trifluoromethyl)pyrimidine-2,4-diones Download PDF

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Publication number
WO2023247976A1
WO2023247976A1 PCT/GB2023/051660 GB2023051660W WO2023247976A1 WO 2023247976 A1 WO2023247976 A1 WO 2023247976A1 GB 2023051660 W GB2023051660 W GB 2023051660W WO 2023247976 A1 WO2023247976 A1 WO 2023247976A1
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Prior art keywords
compound
mmol
reaction mixture
compounds
weeds
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PCT/GB2023/051660
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French (fr)
Inventor
Bill Thompson
Alistair Miller
John Street
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Redag Crop Protection Ltd
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Publication of WO2023247976A1 publication Critical patent/WO2023247976A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P13/00—Herbicides; Algicides
    • A01P13/02—Herbicides; Algicides selective
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to compounds which are of use in the field of agriculture as herbicides.
  • EP0170191, EP0176101, EP0640600 and WO 2010/145992 describe benzoxazinone compounds that are useful as herbicides.
  • WO 2019/020987 A1 discloses herbicides comprising a spirofused tricycle core.
  • herbicidal compounds that are more active than prior art compounds. It is an aim of certain embodiments of the invention to provide herbicidal compounds that have a quicker onset of action than prior art compounds. It is an aim of certain embodiments of the invention to provide herbicidal compounds that are more selective than prior art compounds, i.e. they may have better, similar or even lower activity than prior art compounds against weeds but are significantly less active against non-target plant species (e.g. the crops which are being protected). It is an aim of certain embodiments of the invention to provide herbicidal compounds that provide control over a broader spectrum of weed species than prior art compounds.
  • This invention provides compounds that achieve one or more of the above aims.
  • a compound of formula (I) or an agronomically acceptable salt or N-oxide thereof wherein R 1 is independently at each occurrence selected from D and H; R 2 is independently selected from
  • R 3 and R 4 are independently at each occurrence selected from -CD3, -CHD2, -CH2D and -CH3;
  • R 5 is at each occurrence F or is at each occurrence H; or each R 5 together with the carbon atom to which they are attached form cyclopropyl;
  • R 6 is independently selected from D and H;
  • X 1 is independently selected from F, Cl and Br, wherein R 1 , R 2 and R 6 are selected so that at least one group selected from the two R 1 groups, R 2 and R 6 is D or comprises D.
  • the compound of formula (I) is a compound of formula (la): wherein R 1 , R 3 and R 6 are as defined above for compounds of formula (I) and are selected so that at least one group selected from the two R 1 groups, R 3 and R 6 is D or comprises D.
  • the compound of formula (I) is a compound of formula (lb): wherein R 1 , R 3 , R 4 and R 6 are as defined above for compounds of formula (I) and are selected so that at least one group selected from the two R 1 groups, R 3 , R 4 and R 6 is D or comprises D.
  • the compound of formula (I) is a compound of formula (Ic): wherein R 1 and R 6 are as defined above for compounds of formula (I) and are selected so that at least one group selected from the two R 1 groups and R 6 is D.
  • the compound of formula (I), (la), (lb) or (Ic) is not in the form of an agronomically acceptable N-oxide. In an embodiment, the compound of formula (I), (la), (lb) or (Ic) is not in the form of an agronomically acceptable salt or N-oxide.
  • R 1 and R 6 are selected so that at least one group selected from the two R 1 groups and R 6 is D.
  • At least one R 1 is H. It may be that R 1 is at both occurrences H. It may be that at least one R 1 is D. It may be that R 1 is at both occurrences D. Compounds wherein at least one R 1 is D (e.g. wherein R 1 is at both occurrences D) have been shown to display increased potency of herbicidal action than their non-deuterated counterpart.
  • R 3 may be independently selected from -CD3, -CHD2 and -CH2D.
  • R 3 may be independently selected from -CD3 and -CHD2.
  • R 3 may be -CH3.
  • R 3 is -CD 3 .
  • R 4 may be independently selected from -CD3, -CHD2 and -CH2D.
  • R 4 may be independently selected from -CD3 and -CHD2.
  • R 4 may be -CD3.
  • R 4 may be -CH3.
  • R 3 and R 4 are each independently selected from -CD3, -CHD2 and - CH2D. It may be that R 3 and R 4 are each -CD3. It may be that R 3 and R 4 are each -CH3.
  • R 2 may
  • R 5 may be at each occurrence F.
  • R 5 may be at each occurrence H. It may be that each R 5 together with the carbon atom to which they are attached form cyclopropyl.
  • X 1 is F.
  • R 1 when R 1 is at both occurrences H, at least one of R 3 and R 4 (if present) is selected from -CD3, -CHD2 and -CH2D. It may be that when R 1 is at both occurrences H, R 3 is selected from -CD3, -CHD2 and -CH2D. It may be that when R 1 is at both occurrences H, at least one of R 3 and R 4 (if present) is -CD3. It may be that when R 1 is at both occurrences H, R 3 is -CD3.
  • R 1 is at both occurrences D and R 3 is -CD3.
  • R 3 is -CD3.
  • R 5 together with the carbon atom to which they are attached form cyclopropyl. It may be that each R 5 together with the carbon atom to which they are attached form cyclopropyl.
  • the compound of formula (I) is a compound of formula (la) and R 1 is, at at least one occurrence (e.g. at both occurrences), D.
  • the compound of formula (I) is a compound of formula (lb) and R 6 is D.
  • the compound of formula (I) is a compound of formula (lb) and R 1 is at both occurrences D.
  • the compound of formula (I) may be a selected from: Formul
  • agronomically acceptable salt or N-oxide thereof wherein R 6 is independently selected from -CD3, -CHD2, -CH2D and -CH3;
  • R 8 is independently at each occurrence selected from D and H;
  • R 9 is at each occurrence F; or each R 9 together with the carbon atom to which they are attached form cyclopropyl;
  • R 10 is independently selected from -CD3, -CHD2, -CH2D and -CH3;
  • X 2 and X 3 are each independently selected from F, Cl and Br, wherein R 6 and R 7 are selected so that, at least one group selected from R 6 and R 7 comprises D.
  • the compound of formula (II) is a compound of formula (Ila): wherein R 6 and R 8 are as defined above for compounds of formula (II) and are selected so that at least one group selected from R 6 and the two R 8 groups is D or comprises D.
  • the compound of formula (II) is a compound of formula (lib): (lib), wherein R 6 and R 10 are as defined above for compounds of formula (II) and are selected so that at least one group selected from R 6 and R 10 comprises D.
  • the compound of formula (II), (Ila) or (lib) is not in the form of an agronomically acceptable N-oxide. In an embodiment, the compound of formula (II), (Ila) or (lib) is not in the form of an agronomically acceptable salt or N-oxide.
  • R 6 is -CD 3 .
  • R 6 may however be CH3.
  • the compound of formula (II) is a compound of formula (Ila) and R 8 is, at at least one occurrence (e.g. at both occurrences), D.
  • the compound of formula (II) is a compound of formula (Ila) and both R 6 and R 10 are independently selected from -CDs, -CHD2, -CH2D. It may be that the compound of formula (II) is a compound of formula (Ila) and both R 6 and R 10 are independently -CDs.
  • R 10 may be -CD3. Alternatively, R 10 may be -CH3.
  • X 2 and X 3 are each independently selected from F and Cl. In preferred embodiments, X 2 is F. In preferred embodiments, X 3 is Cl. [0046]
  • the compound of formula (II) may be a compound selected from:
  • Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers, e.g. the R- or the S- stereoisomer.
  • geometric cis/trans (or Z/E) isomers are possible.
  • structural isomers are interconvertible via a low energy barrier
  • tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the compounds of the invention may be obtained, stored and/or used in the form of an agronomically acceptable salt.
  • Suitable salts include, but are not limited to, salts of acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of agronomically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids
  • Suitable salts also include salts of inorganic and organic bases, e.g. counterions such as Na, Ca, K, Li, Mg, ammonium, trimethylsulfonium.
  • the compounds may also be obtained, stored and/or used in the form of an N-oxide.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g. 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • the activity of the compounds of the present invention can be assessed by a variety of in silico, in vitro and in vivo assays. In silico analysis of a variety of compounds has been demonstrated to be predictive of ultimate in vitro and even in vivo activity.
  • the present invention also includes all environmentally acceptable isotopically-labelled compounds of formulae (I) and (II), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, bromine, such as 79 Br and 81 Br, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, and sulfur, such as 35 S.
  • isotopes of hydrogen such as 2 H and 3 H
  • carbon such as 11 C, 13 C and 14 C
  • chlorine such as 36 CI
  • fluorine such as 18 F
  • bromine such as 79 Br and 81 Br
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 O and 18 O
  • sulfur such as 35 S.
  • a position designated “D” may be occupied with deuterium at an isotopic purity of 2 H of greater than 50%. Isotopic purity can be determined using conventional analytical methods known to a person skilled in the art, such as mass spectrometry and nuclear magnetic resonance spectroscopy. A position designated “D” may be occupied with deuterium at an isotopic purity of 2 H of at least 90%, e.g. at least 95%. A position designated “D” may be occupied with deuterium at an isotopic purity of 2 H of at least 99%, e.g. at least 99.5%.
  • the compounds of the invention have herbicidal activity.
  • a method for controlling weeds comprising applying a compound according to the first or second aspect of the invention to the weeds themselves or to an area where it is envisioned that the weeds will grow or are growing.
  • the term “weed” is intended to cover a wild plant growing where it is not wanted, usually in competition with cultivated/crop plants.
  • an agronomically effective and substantially non-phytotoxic (to the crop plant) quantity of the compound according to the invention may be applied.
  • the active compound may be applied neat, or in the form of a formulation.
  • the compound may be applied as a foliar application, stem application, drench or drip application (chemigation) to the weed or to the fruit of the weed or to soil or to inert substrate (e.g. inorganic substrates like sand, rockwool, glasswool; expanded minerals like perlite, vermiculite, zeolite or expanded clay), Pumbe, Pyroclastic materials or stuff, synthetic organic substrates (e.g. polyurethane) organic substrates (e.g. peat, composts, tree waste products like coir, wood fibre or chips, tree bark) or to a liquid substrate (e.g. floating hydroponic systems, Nutrient Film Technique, Aeroponics).
  • inert substrate e.g. inorganic substrates like sand, rockwool, glasswool; expanded minerals like perlite, vermiculite, zeolite or expanded clay
  • synthetic organic substrates e.g. polyurethane
  • organic substrates e.g. peat, composts, tree
  • Some compounds of the invention may also have herbicidal activity against a broad spectrum of economically important mono- and dicotyledonous harmful weeds. Some compounds of the invention may have herbicidal activity against monocotyledonous weeds but no activity or little activity against dicotyledonous crops. Other compounds of the invention may have excellent herbicidal activity against dicotyledonous weeds but no activity or little activity against monocotyledonous crops. In both cases, the compounds of the invention are selective through having activity against the target weeds while not affecting the growth of the crops in which they are applied. Other compounds of the invention may have better herbicidal activity against certain monocotyledonous weeds but no activity or little activity against certain monocotyledonous crops.
  • the compounds of the invention may have non-selective activity and be active against both monocotyledonous and dicotyledonous weeds, with effects also on the crops where these weeds are agronomically important.
  • the compounds of the invention may be used for burn-down, post crop harvest, or in preparation of the seed bed prior to sowing the crop.
  • Difficult-to-control perennial weeds which produce shoots from rhizomes, root stocks or other perennial organs may also be controlled by herbicidal compounds.
  • the substances can be applied by the pre-sowing method, the pre-emergence method and/or the post-emergence method.
  • Avena spp. Alopecurus spp., Brachiaria spp., Digitaria spp., Lolium spp., Echinochloa spp., Panicum spp., Phalaris spp., Poa spp., Setaria spp. and also Bromus spp.
  • dicotyledonous weeds that may be controlled by compounds of the invention: Abutilon spp., Amaranthus spp., Chenopodium spp., Chrysanthemum spp., Galium spp. such as Galium aparine, Ipomoea spp., Kochia spp., Lamium spp., Matricaria spp., Pharbitis spp., Polygonum spp., Sida spp., Sinapis spp., Solanum spp., Stellaria spp., Veronica spp. and Viola spp., Xanthium spp., in the case of annuals, and Convolvulus, Cirsium, Rumex and Artemisia in the case of the perennials.
  • the weeds may be broadleaf plants.
  • the weeds may be Alopecurus myosuroides (commonly known as black-grass).
  • the weeds may be Stellaria media (chickweed), Abutilon theophrasti (velvetleaf) or Amaranthus spp.
  • herbicides are not typically conducted in a sterile in vitro laboratory test. Herbicides are typically tested by spraying live weeds or soil where seeds have been sown. There is typically greater variation in results obtained from such testing than might be the case in more controlled testing regimes that have been conducted in vitro.
  • the method may comprise applying the compound in a concentration in the range from 0.1 to 50 g/ha.
  • the method may comprise applying the compound in a concentration in the range from 35 to .05 g/ha
  • the present invention also relates to a herbicidal formulation comprising an effective amount of a compound according to the first or second aspect of the invention.
  • the formulation may further comprise one or more additional herbicides.
  • the term "effective and non-phytotoxic amount” means an amount of herbicide according to the invention which is sufficient to control or destroy any of the targeted weeds present or liable to appear in the crops and which does not have any significant detrimental effect on the crops or indeed has a positive effect on plant vigour and yield in the absence of target organism.
  • the amount will vary depending on the weed or weeds to be controlled, the type of crop, the climatic conditions and the compounds included in the herbicidal formulation. This amount can be determined by systematic field trials, which are within the capabilities of a person skilled in the art.
  • the active compounds of the invention can be formulated as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, microencapsulations in polymeric substances and also as ULV cold and warm fogging formulations.
  • the formulation may be a ready-to-use solution, emulsion, water- or oil-based suspension, powder, wettable powder, paste, soluble powder, dust, soluble granules, granules for broadcasting, suspoemulsion concentrate, natural substance impregnated with active compound, synthetic substance impregnated with active compound, fertilizer or a microencapsulation in polymeric substances.
  • Application may be carried out, for example, by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is also possible to apply the active compounds by the ultra-low volume method or to inject the preparation of active compound or the active compound itself into the soil.
  • Formulations containing the compounds of the invention are produced in a known manner, for example by mixing the compounds with extenders (e.g. liquid solvents and/or solid carriers), optionally with the use of surfactants (e.g. emulsifiers and/or dispersants and/or foam-formers).
  • extenders e.g. liquid solvents and/or solid carriers
  • surfactants e.g. emulsifiers and/or dispersants and/or foam-formers.
  • the formulations are prepared either in factories/production plants or alternatively before or during the application.
  • auxiliaries are substances which are suitable for imparting to the formulation itself and/or to preparations derived therefrom (for example spray liquors) particular properties such as certain technical properties and/or also particular biological properties.
  • suitable auxiliaries are: extenders, solvents and carriers.
  • Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the classes of the aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which, if appropriate, may also be substituted, etherified and/or esterified), the ketones (such as acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, the unsubstituted and substituted amines, amides, lactams (such as N-alkylpyrrolidones) and lactones, the sulfones and sulfoxides (such as dimethyl sulfoxide).
  • aromatic and non-aromatic hydrocarbons such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes
  • the alcohols and polyols
  • suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffins, for example petroleum fractions, alcohols such as butanol or glycol and also their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide and dimethyl sulfoxide.
  • aromatics such as xylene, toluene or alkylnaphthalenes
  • chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride
  • aliphatic hydrocarbons such as cyclohexane
  • Suitable solid carriers are: for example, ammonium salts and ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, and ground synthetic minerals, such as finely divided silica, alumina and silicates;
  • suitable solid carriers for granules are: for example, crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and also synthetic granules of inorganic and organic meals, and granules of organic material such as paper, sawdust, coconut shells, maize cobs and tobacco stalks;
  • suitable emulsifiers and/or foam-formers are: for example, nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkylsulfonates, alkyl sulfates
  • oligo- or polymers for example those derived from vinylic monomers, from acrylic acid, from EO and/or PO alone or in combination with, for example, (poly)alcohols or (poly)amines. It is also possible to employ lignin and its sulfonic acid derivatives, unmodified and modified celluloses, aromatic and/or aliphatic sulfonic acids and their adducts with formaldehyde.
  • Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, as well as natural phospholipids such as cephalins and lecithins, and synthetic phospholipids, can be used in the formulations.
  • Further additives may be mineral and vegetable oils. It is also possible to add colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs, such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue
  • organic dyestuffs such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs
  • trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
  • Other possible additives are perfumes, mineral or vegetable, optionally modified oils and waxes.
  • the formulations may also comprise stabilizers, e.g. low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability.
  • stabilizers e.g. low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability.
  • the formulations generally comprise between 0.01 and 98% by weight of active compound, preferably between 0.1 and 95% and particularly preferably between 0.5 and 90%.
  • the active compounds according to the invention can also be used as a mixture with other known herbicides for example, to improve the activity spectrum or to reduce or slow the development of resistance.
  • a mixture with other known active compounds such as nematicides, acaricides, fungicides, insecticides or bactericides, or with fertilizers and growth regulators, safeners or semiochemicals is also possible.
  • Exemplary application rates of the active compounds according to the invention are: when treating leaves: from 0.1 to 10 000 g/ha, preferably from 10 to 1000 g/ha, particularly preferably from 50 to 300 g/ha (when the application is carried out by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rock wool or perlite are used); when treating the soil: from 0.1 to 10 000 g/ha, preferably from 1 to 5000 g/ha.
  • the formulation may be as described in the ‘Catalogue of pesticide formulation types and international coding system’ (Technical Monograph n° 2, 8th Edition by CropLife International).
  • the formulations according to the invention may be suitable for supporting the growing of any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture and, in particular, cereals (e.g. wheat, barley, rye, millet and oats), maize, cotton, soya beans, rice, potatoes, sunflowers, beans, coffee, beet (for example sugar beet and fodder beet), peanuts, vegetables (e.g. tomatoes, cucumbers, onions and lettuce), lawns, fruit and nut trees (e.g. apples pears peaches nectarines, apricots, hazelnut, pecan, macadamia, pistachio), soft fruit (e.g. strawberries, raspberries, blackcurrants, redcurrants), grapevines, bananas, cocoa and ornamental plants.
  • cereals e.g. wheat, barley, rye, millet and oats
  • maize cotton
  • soya beans rice
  • potatoes e.g. tomatoes,
  • the invention may be as described in one of the following numbered paragraphs: wherein R 1 is independently at each occurrence selected from D and H;
  • R 2 is independently selected from
  • R 3 and R 4 are each independently selected from -CDs, -CHD2, -CH2D and -CH3;
  • R 5 is at each occurrence F; or each R 5 together with the carbon atom to which they are attached form cyclopropyl; and X 1 is independently selected from F, Cl and Br, wherein when R 1 is at both occurrences H, at least one of R 3 and R 4 (if present) is selected from -CD 3 , -CHD 2 and -CH 2 D; or an agronomically acceptable salt or N-oxide thereof.
  • R 3 is independently selected from - CD 3 , -CHD 2 and -CH 2 D.
  • R 6 is independently selected from -CD3, -CHD2 and -CH2D;
  • R 8 is independently at each occurrence selected from D and H;
  • R 9 is at each occurrence F; or each R 9 together with the carbon atom to which they are attached form cyclopropyl;
  • X 2 and X 3 are each independently selected from F, Cl and Br, or an agronomically acceptable salt or N-oxide thereof.
  • a method for controlling weeds comprising applying a compound of any preceding paragraph to the weeds themselves or to an area where it is envisioned that the weeds will grow. 17. A method of paragraph 16, wherein the weeds are Alopecurus myosuroides.
  • a herbicidal formulation comprising an effective amount of a compound of any one of paragraphs 1 to 15.
  • Figure 1 is a bar chart showing % ALOMY necrosis after treatment with various compounds, including compounds of the invention, at a dose of 30 g/ha after 3, 7 and 14 days.
  • Figures 2, 3 and 4 are bar charts showing % STEME, ABUTH and AMARE, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10 and 3 g/ha via a track sprayer at water volumes of 200 and 800 L/ha after 3 and 7 days.
  • Figures 5, 6 and 7 are bar charts showing % STEME, ABUTH and AMARE, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 10, 3, 1 and 0.3 g/ha via a track sprayer at a water volume of 200 L/ha after 3, 7 and 14 days.
  • Figures 8 to 11 are bar charts showing % ALOMY, LOLPE, STEME and ABUTH, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10, 3, 1 g/ha after 3, 7 and 14 days.
  • Figures 12 to 14 are bar charts showing % ALOMY, STEME and ABUTH, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10, 3, 1 g/ha after 3, 7 and 14 days.
  • Figure 15 to 18 are bar charts showing % ALOMY, AMARE, STEME and ABUTH, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10, 3, 1 g/ha after 3, 7 and 14 days.
  • Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.
  • Certain compounds of the invention can be made according to or by methods analogous to the syntheses disclosed in WO 2010/038953 (for tiafenacil derivatives), US 5,344,812 (for benfendizone derivatives), WO 95/32952 (for butafenacil derivatives) and EP195346 (for flupropacil derivatives).
  • Certain compounds of the invention can be made according to or by methods analogous to the general synthetic Schemes A to E, below. Certain compounds of the invention can be made according to or by methods analogous to the methods described in Examples 1 to 15.
  • Mass spectra were run on LC-MS systems using electrospray ionization. These were run using a Waters Acquity Classic LIPLC with PDA and SQ mass detection (LC-MS-1) or a Waters Acquity H-Class LIPLC with PDA and QDA mass detection (LC-MS-2). [M+H] + refers to mono-isotopic molecular weights.
  • NMR spectra were run on either a Bruker Ultrashield 400 MHz or 500MHz NMR spectrometer. Spectra were recorded at 298K and were referenced using the solvent peak.
  • the reaction mixture was allowed to warm slowly to ambient temperature and after 17 hours, the reaction mixture was diluted with water (10 mL).
  • the product was extracted from the aqueous phase with EtOAc (3 x 15 mL).
  • the combined organic phases were washed with brine/water (3 x 10 mL, 1 :1) followed by sat. brine (10 mL), dried over MgSCU, filtered and concentrated to give a brown oil which was concentrated from toluene (2 x 5 mL) followed by CH2CI2 (5 mL) to give a brown solid (300 mg).
  • reaction mixture was heated to 120 °C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with water (25 mL) and then the product was extracted with EtOAc (50 mL then 3 x 25 mL). The combined organic phases were washed with sat. aq. NaHCCh (2 x 50 mL) followed by sat. brine (50 mL), dried over MgSCU, filtered and concentrated to give a red/brown oil (0.72 g). Chromatography on SiC>2 (8 g cartridge) eluting with 2-40 % EtOAc I petroleum ether gave the title compound as a light brown solid (373 mg).
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 15% ethyl acetate in petroleum ether) and then repurified by flash column chromatography on silica (eluting 11% to 20% petroleum ether in acetone) to give the title product as a colourless oil (531 mg).
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 3.5% methanol in dichloromethane) to give the title compound as a yellow oil (65 mg).
  • the crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 30% ethyl acetate in petroleum ether) to give the title compound as a white solid (102 mg).
  • LC-MS-2 (Method 2B): Rt 1.52 mins; mass ion not observed (100% @ 254nm).
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 15% ethyl acetate in petroleum ether) and then repurified by flash column chromatography on silica (eluting 11% to 20% petroleum ether in acetone) to give the title product as a colourless oil (531 mg).
  • reaction mixture was stirred, allowing to warm to room temperature, for 17 h.
  • the reaction mixture was quenched by dropwise addition of water (50 mL) and then the crude product extracted into diethyl ether (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over MgSCU and concentrated in vacuo to give the title compound as a pale yellow oil (1.1 g).
  • Nitric acid (70%, 219 mg, 3.48 mmol) was added dropwise to a solution of ethyl [3- (2-chloro-4-fluorophenoxy)-2-pyridyloxy]acetate (intermediate V1) (1.03 g, 3.16 mmol) in sulfuric acid (18.3 g, 187 mmol) at 0 °C.
  • the reaction mixture was stirred for 2 h then poured into iced water and the crude product extracted into ethyl acetate (2 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo to give the title compound as a yellow solid (1.0 g).
  • Example 7 3-(7-fluoro-3-oxo-4-prop-2-vnyl-spiron,4-benzoxazine-2,T-cyclopropane1-6-yl)-1- (trideuteriomethyl)-6-(trifluoromethyl)pyridine-2, 4-dione
  • Example 2 3-[4-(1, 1-dideuterioprop-2-ynyl)-7-fluoro-3-oxo-spiro[1,4-benzoxazine-2, 1'- cyclopropane]-6-yll-1-methyl-6-(trifluoromethyl)pyrimidine-2, 4-dione
  • Example 3 3-f4-( 1 , 1 -dideuterioprop-2-vnyl)-7-fluoro-3-oxo-spirof 1 ,4-benzoxazine-2, 1 '- cvclopropane1-6-yl1-1-(trideuteriomethyl)-6-(trifluoromethyl)pyrimidine-2, 4-dione
  • Triethylamine (22.1 mg, 0.218 mmol) was added to a solution of 1 ,5-dimethyl-6- thioxo-3-[2,2,7-trifluoro-3-oxo-4-(2-propynyl)-2,4-dihydro-1 ,4-benzoxazin-6-yl]-1 ,3,5- triazinane-2, 4-dione (intermediate Z13) (30 mg, 0.0728 mmol) in methanol-d4 (0.5 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo.
  • Example 5 1, 5-Bis[ Hs methyll- -thioxo-S- , 2, 7-trifluoro-3-oxo-4-(2-propynyl)-2, 4-dihydro- 1 , 4-benzoxazin-6-yll- 1 , 3, 5-triazinane-2, 4-dione
  • the crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 30% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (70 mg).
  • Example 6 1 , 5-Bis[ ( 2H3) meth yl]-6-thioxo-3-[2, 2, 7-trifluoro-3-oxo-4-r(3-2H) -2-prop ynyll-2, 4- di hydro- 1 ,4-benzoxazin-6-yl ⁇ - 1 , 3, 5-triazinane-2, 4-dione
  • Triethylamine (21.8 mg, 0.215 mmol) was added to a solution of Example 5 (30 mg, 0.0717 mmol) in methanol-d4 (0.5 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was diluted with water (10 mL) and the crude product extracted into ethyl acetate (2 x 10 mL). The combined organics were dried over MgSCU and concentrated in vacuo followed by lyophilisation to give the title compound as a white solid (16 mg).
  • reaction mixture was heated to 55 °C before a solution of 1-[( 2 Hs)methyl]-3- methylthiourea (intermediate Z12) (60 mg, 0.562 mmol) in ethyl acetate (1.12 mL) was added.
  • the reaction mixture was heated at 76 °C for 18 h then poured into iced water (200 mL) and 2M HCI (aq.) (30 mL).
  • the crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo.
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 35% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (140 mg).
  • Example 8 1 ,5-Dimethyl-6-thioxo-3-[2,2,7-trifluoro-3-oxo-4-r(1 , 1- 2 H2)-2-propynyl]-2,4- di hydro- 1 ,4-benzoxazin-6-yl ⁇ - 1 , 3, 5-triazinane-2, 4-dione
  • reaction mixture was heated to 55 °C before a solution of 1 ,3-dimethylthiourea (intermediate Z9) (32 mg, 0.302 mmol) in ethyl acetate (0.58 mL) was added.
  • the reaction mixture was heated at 76 °C for 18 h then poured into iced water (20 mL) and 2M HCI (aq.) (5 mL).
  • the crude product was extracted into ethyl acetate (3 x 15 mL). The combined organics were dried over MgSCU and concentrated in vacuo.
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 20% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (55 mg).
  • reaction mixture was heated to 55 °C before a solution of 1,3-bis[( 2 H3)methyl]thiourea (intermediate Z10) (31 mg, 0.279 mmol) in ethyl acetate (0.54 mL) was added.
  • the reaction mixture was heated at 76 °C for 18 h then poured into iced water (20 mL) and 2M HCI (aq.) (5 mL).
  • the crude product was extracted into ethyl acetate (3 x 15 mL). The combined organics were dried over MgSCU and concentrated in vacuo.
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (25 g MODUS silica cartridge, eluting 0 to 28% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (53 mg).
  • Example 10 2-/7-Fluoro-3-oxo-4-[(3- 2 H)-2-propynyll-2,4-dihvdro-1,4-benzoxazin-6-yl ⁇ - 4,5,6, 7-tetrahydro-2H-isoindole- 1 , 3-dione
  • Triethylamine 65 pL, 0.5 mmol
  • Example 11 2-/7-Fluoro-3-oxo-4-[(1 , 1- 2 H2)-2-propynyll-2,4-dihvdro-1,4-benzoxazin-6-yl ⁇ - 4,5,6, 7-tetrahydro-2H-isoindole- 1 , 3-dione
  • Example 12 N-l lsopropyl)-N-( 2 H3)methylaminosulfonyl]2-chloro-4-fluoro-5-l' 1-methyl-2,4- dioxo-6-(trifluoromethyl)-3-pyrimidinyllbenzamide
  • Carbonyldiimidazole 35 mg, 0.28 mmol was added to a solution of 2-chloro-4- fluoro-5-[1-methyl-2,4-dioxo-6-(trifluoromethyl)-3-pyrimidinyl]benzoic acid (intermediate W6) (79 mg, 0.22 mmol) in tetrahydrofuran (1.1 mL).
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (4 g MODUS silica cartridge, eluting 2 to 35% ethyl acetate/petroleum ether) followed by flash column chromatography on the Interchim Puriflash® 450 (5.4 g MODUS Cis cartridge, 5 to 95% acetonitrile in water (0.1% aq. formic acid) followed by lyophilisation to give the title compound as a white solid (7 mg).
  • Example 15 Ethyl [3-(2-chloro-4-fluoro-5- 1-[( 2 H3)methyll-2,4-dioxo-6-(trifluoromethyl)-3- yrimidinyl ⁇ phenoxy)-2-pyridyloxy1acetate [00264] Potassium carbonate (193 mg, 1.40 mmol) was added to a solution of ethyl (3- ⁇ 2- chloro-5-[2,4-dioxo-6-(trifluoromethyl)-3-pyrimidinyl]-4-fluorophenoxy ⁇ -2-pyridyloxy)acetate (intermediate V4) (320 mg, 0.635 mmol) in /V,/V-dimethylformamide (9.6 mL).
  • the reaction mixture was stirred at room temperature for 10 min and iodomethane-d3 (405 mg, 2.79 mmol) was added.
  • the reaction mixture was stirred at room temperature for 19 h then diluted with water (80 mL).
  • the crude product was extracted into dichloromethane (3 x 50 mL). The combined organics were washed with water (50 mL), dried over MgSCU and concentrated in vacuo.
  • the crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 50% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as an off-white solid (59 mg).
  • Comparative Example A can be made according to the process described in WO 2019/020987 A1.
  • the crude product was extracted into dichloromethane (3 x 50 mL). The combined organics were washed with water (50 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 40% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a pink solid (26 mg).
  • Examples 1-3 as well as Comparative Example A were screened at four concentrations (30, 10, 3 and 1 g/ha) against ALOMY.
  • Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer.
  • Examples 2 and 3 as well as Comparative Example A were screened at three concentrations (30, 10 and 3 g/ha) against STEME, ABUTH and AMARE. Application was via a track sprayer at water volumes of 200 or 800 L/ha.
  • Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 20 ml/ m2 (equivalent to 2001/ha) of spray solution or 80ml/m2 (equivalent to 8001/ha) .depending on the experimental objectives, using a track sprayer. The formulation used was 25% acetone and 75% 0.1% Tween 20.
  • Figures 2 to 4 show that both Examples 2 and 3 were better than Comparative Example A, giving better weed control at the lowest concentration (3 g/ha) at an application rate of 200 L/ha (against all tested weeds) and at 800 L/ha (against Amaranthus). This evidence shows that certain compounds of the invention display improved potency over their non-deuterated counterpart.
  • Examples 2 and 3 as well as Comparative Example A were screened at four concentrations (10, 3 ,1 and 0.3 g/ha) against STEME, ABLITH and AMARE. Application was via a track sprayer at a water volume of 200 L/ha.
  • Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 20 ml/ m2 (equivalent to 200l/ha) of spray solution, using a track sprayer. The formulation used was 25% acetone and 75% 0.1% Tween 20.
  • Figures 5 to 7 shows that Example 3 displayed improved activity against the tested weeds.
  • Flumioxazin, Example 10, saflufenacil and Examples 12 to 14 were screened at four concentrations (30, 10, 3 and 1 g/ha) against four weed species, ALOMY, LOLPE, STEME AND .
  • Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer. Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment.
  • Figures 8 to 11 show significant improvement in activity of both Examples 10 and 14 in comparison with their respective parents.
  • Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer. Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment.
  • Figures 12 to 14 shows improved control of the tested weed species by Example 11, compared with the flumioxazin.
  • Examples 4 and 6 also shows some improvement over trifludimoxazin at certain doses against certain weeds.
  • Epyrifenacil and Example 15 were screened at four concentrations (30, 10, 3 and 1 g/ha) against ALOMY, AMARE, STEME and ABUTH.
  • Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer. Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment.

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Abstract

This invention relates to deuterated compounds useful in agriculture as herbicides.

Description

DEUTERATED HERBICIDES BASED ON OXAZINONES AND 6-(TRIFLUOROMETHYL)PYRIMIDINE-2, 4-DIONES
[0001] The present invention relates to compounds which are of use in the field of agriculture as herbicides.
[0002] Given the global increase in demand for food there is an international need for new treatments to reduce food crop losses to disease, insects and weeds. Over 40% of crops are lost before harvest worldwide. Losses have actually increased since the mid-1990s.
[0003] EP0170191, EP0176101, EP0640600 and WO 2010/145992 describe benzoxazinone compounds that are useful as herbicides. WO 2019/020987 A1 discloses herbicides comprising a spirofused tricycle core.
[0004] It is an aim of certain embodiments of the invention to provide herbicidal compounds that are more active than prior art compounds. It is an aim of certain embodiments of the invention to provide herbicidal compounds that have a quicker onset of action than prior art compounds. It is an aim of certain embodiments of the invention to provide herbicidal compounds that are more selective than prior art compounds, i.e. they may have better, similar or even lower activity than prior art compounds against weeds but are significantly less active against non-target plant species (e.g. the crops which are being protected). It is an aim of certain embodiments of the invention to provide herbicidal compounds that provide control over a broader spectrum of weed species than prior art compounds.
[0005] This invention provides compounds that achieve one or more of the above aims.
Summary of the Invention
Formula (I)
[0006] According to a first aspect of the invention is provided a compound of formula (I)
Figure imgf000002_0001
or an agronomically acceptable salt or N-oxide thereof, wherein R1 is independently at each occurrence selected from D and H; R2 is independently selected from
Figure imgf000003_0001
Figure imgf000003_0002
R3 and R4 are independently at each occurrence selected from -CD3, -CHD2, -CH2D and -CH3;
R5 is at each occurrence F or is at each occurrence H; or each R5 together with the carbon atom to which they are attached form cyclopropyl;
R6 is independently selected from D and H; and
X1 is independently selected from F, Cl and Br, wherein R1, R2 and R6 are selected so that at least one group selected from the two R1 groups, R2 and R6 is D or comprises D.
[0007] The inventors of the present invention have found that compounds of Formula (I) exhibit a surprising increase in herbicidal activity in comparison to their non-deuterated counterparts.
[0008] In an embodiment, the compound of formula (I) is a compound of formula (la):
Figure imgf000003_0003
wherein R1, R3 and R6 are as defined above for compounds of formula (I) and are selected so that at least one group selected from the two R1 groups, R3 and R6 is D or comprises D.
[0009] In an embodiment, the compound of formula (I) is a compound of formula (lb):
Figure imgf000004_0001
wherein R1, R3, R4 and R6 are as defined above for compounds of formula (I) and are selected so that at least one group selected from the two R1 groups, R3, R4 and R6 is D or comprises D.
[0010] In an embodiment, the compound of formula (I) is a compound of formula (Ic):
Figure imgf000004_0002
wherein R1 and R6 are as defined above for compounds of formula (I) and are selected so that at least one group selected from the two R1 groups and R6 is D.
[0011] The following embodiments apply to compounds of Formulae (I), (la), (lb) and (Ic). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass that compound may be combined to provide a further embodiment which forms part of the present disclosure.
[0012] In an embodiment, the compound of formula (I), (la), (lb) or (Ic) is not in the form of an agronomically acceptable N-oxide. In an embodiment, the compound of formula (I), (la), (lb) or (Ic) is not in the form of an agronomically acceptable salt or N-oxide.
[0013] It may be that R1 and R6 are selected so that at least one group selected from the two R1 groups and R6 is D.
[0014] It may be that at least one R1 is H. It may be that R1 is at both occurrences H. It may be that at least one R1 is D. It may be that R1 is at both occurrences D. Compounds wherein at least one R1 is D (e.g. wherein R1 is at both occurrences D) have been shown to display increased potency of herbicidal action than their non-deuterated counterpart.
Figure imgf000005_0001
[0017] R3 may be independently selected from -CD3, -CHD2 and -CH2D. R3 may be independently selected from -CD3 and -CHD2. R3 may be -CH3. Preferably, R3 is -CD3.
[0018] R4 may be independently selected from -CD3, -CHD2 and -CH2D. R4 may be independently selected from -CD3 and -CHD2. R4 may be -CD3. R4 may be -CH3.
[0019] It may be that R3 and R4 are each independently selected from -CD3, -CHD2 and - CH2D. It may be that R3 and R4 are each -CD3. It may be that R3 and R4 are each -CH3.
[0020] R2 may
Figure imgf000005_0002
[0021] R5 may be at each occurrence F. R5 may be at each occurrence H. It may be that each R5 together with the carbon atom to which they are attached form cyclopropyl.
[0022] In preferred embodiments, X1 is F.
[0023] It may be that when R1 is at both occurrences H, at least one of R3 and R4 (if present) is selected from -CD3, -CHD2 and -CH2D. It may be that when R1 is at both occurrences H, R3 is selected from -CD3, -CHD2 and -CH2D. It may be that when R1 is at both occurrences H, at least one of R3 and R4 (if present) is -CD3. It may be that when R1 is at both occurrences H, R3 is -CD3.
[0024] It may be that R1 is at both occurrences D and R3 is -CD3. [0025] It may be that when
Figure imgf000006_0001
each R5 together with the carbon atom to which they are attached form cyclopropyl. It may be that
Figure imgf000006_0002
each R5 together with the carbon atom to which they are attached form cyclopropyl.
[0026] It may be that when
Figure imgf000006_0003
each occurrence F. It may be that
Figure imgf000006_0004
each occurrence F and.
[0027] It may be that when
Figure imgf000006_0005
each occurrence H. It may be that
Figure imgf000006_0006
each occurrence H.
[0028] It may be that the compound of formula (I) is a compound of formula (la) and R1 is, at at least one occurrence (e.g. at both occurrences), D.
[0029] It may be that the compound of formula (I) is a compound of formula (lb) and R6 is D. [0030] It may be that the compound of formula (I) is a compound of formula (lb) and R1 is at both occurrences D.
[0031] The compound of formula (I) may be a selected from:
Figure imgf000007_0001
Formul
Figure imgf000008_0001
[0032] According to a second aspect of the invention is provided a compound of formula (II):
Figure imgf000008_0002
agronomically acceptable salt or N-oxide thereof, wherein R6 is independently selected from -CD3, -CHD2, -CH2D and -CH3;
Figure imgf000008_0003
Figure imgf000009_0001
R8 is independently at each occurrence selected from D and H;
R9 is at each occurrence F; or each R9 together with the carbon atom to which they are attached form cyclopropyl;
R10 is independently selected from -CD3, -CHD2, -CH2D and -CH3; and
X2 and X3 are each independently selected from F, Cl and Br, wherein R6 and R7 are selected so that, at least one group selected from R6 and R7 comprises D.
[0033] The inventors of the present invention have found that compounds of Formula (II) exhibit a surprising increase in herbicidal activity in comparison to their non-deuterated counterpart.
[0034] In an embodiment, the compound of formula (II) is a compound of formula (Ila):
Figure imgf000009_0002
wherein R6 and R8 are as defined above for compounds of formula (II) and are selected so that at least one group selected from R6 and the two R8 groups is D or comprises D.
[0035] In an embodiment, the compound of formula (II) is a compound of formula (lib):
Figure imgf000010_0001
(lib), wherein R6 and R10 are as defined above for compounds of formula (II) and are selected so that at least one group selected from R6 and R10 comprises D.
[0036] The following embodiments apply to compounds of Formulae (II), (Ila) and (lib).
These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass that compound may be combined to provide a further embodiment which forms part of the present disclosure.
[0037] In an embodiment, the compound of formula (II), (Ila) or (lib) is not in the form of an agronomically acceptable N-oxide. In an embodiment, the compound of formula (II), (Ila) or (lib) is not in the form of an agronomically acceptable salt or N-oxide.
[0038] Preferably, R6 is -CD3. R6 may however be CH3.
[0039] It may be that each R9 together with the carbon atom to which they are attached form
Figure imgf000010_0002
these embodiments, it may be that at least one R8 is D. Preferably, R8 is at each occurrence D.
[0040] It may be that the compound of formula (II) is a compound of formula (Ila) and R8 is, at at least one occurrence (e.g. at both occurrences), D.
[0041] It may be that the compound of formula (II) is a compound of formula (Ila) and both R6 and R10 are independently selected from -CDs, -CHD2, -CH2D. It may be that the compound of formula (II) is a compound of formula (Ila) and both R6 and R10 are independently -CDs.
Figure imgf000011_0001
y selected from -CD3, -CHD2 and -CH2D. R10 may be -CD3. Alternatively, R10 may be -CH3.
Figure imgf000011_0002
[0045] It may be that X2 and X3 are each independently selected from F and Cl. In preferred embodiments, X2 is F. In preferred embodiments, X3 is Cl. [0046] The compound of formula (II) may be a compound selected from:
Figure imgf000012_0001
Figure imgf000013_0001
Detailed Description
[0047] Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers, e.g. the R- or the S- stereoisomer. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
[0048] Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.
[0049] The compounds of the invention may be obtained, stored and/or used in the form of an agronomically acceptable salt. Suitable salts include, but are not limited to, salts of acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of agronomically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Suitable salts also include salts of inorganic and organic bases, e.g. counterions such as Na, Ca, K, Li, Mg, ammonium, trimethylsulfonium. The compounds may also be obtained, stored and/or used in the form of an N-oxide.
[0050] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
[0051] Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g. 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
[0052] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
[0053] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
[0054] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate.
Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994). [0055] The activity of the compounds of the present invention can be assessed by a variety of in silico, in vitro and in vivo assays. In silico analysis of a variety of compounds has been demonstrated to be predictive of ultimate in vitro and even in vivo activity.
[0056] Unless stated otherwise, the present invention also includes all environmentally acceptable isotopically-labelled compounds of formulae (I) and (II), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
[0057] Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
[0058] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, bromine, such as 79Br and 81 Br, nitrogen, such as 13N and 15N, oxygen, such as 150, 17O and 18O, and sulfur, such as 35S.
[0059] However, in the compounds of the invention, when a position is specifically designated as “D”, this position would be understood by a skilled person to be occupied by deuterium (2H) at an isotopic abundance greater than its natural isotopic abundance (e.g. greater than about 0.015%).
[0060] For example, a position designated “D” may be occupied with deuterium at an isotopic purity of 2H of greater than 50%. Isotopic purity can be determined using conventional analytical methods known to a person skilled in the art, such as mass spectrometry and nuclear magnetic resonance spectroscopy. A position designated “D” may be occupied with deuterium at an isotopic purity of 2H of at least 90%, e.g. at least 95%. A position designated “D” may be occupied with deuterium at an isotopic purity of 2H of at least 99%, e.g. at least 99.5%.
[0061] Throughout the description and claims of this specification, certain plant varieties may be referred to by their binomial nomenclature, EPPO code or common name. The nomenclature of certain referred to plant (weed) varieties is provided in the following table.
Figure imgf000015_0001
[0062] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, means “including but not limited to”, and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.
[0063] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
[0064] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
Herbicides
[0065] The compounds of the invention have herbicidal activity.
[0066] According to another aspect of the present invention, there is provided a method for controlling weeds, the method comprising applying a compound according to the first or second aspect of the invention to the weeds themselves or to an area where it is envisioned that the weeds will grow or are growing. The term “weed” is intended to cover a wild plant growing where it is not wanted, usually in competition with cultivated/crop plants.
[0067] Where crop plants are already growing or have recently been sown, an agronomically effective and substantially non-phytotoxic (to the crop plant) quantity of the compound according to the invention may be applied.
[0068] The active compound may be applied neat, or in the form of a formulation.
[0069] The compound may be applied as a foliar application, stem application, drench or drip application (chemigation) to the weed or to the fruit of the weed or to soil or to inert substrate (e.g. inorganic substrates like sand, rockwool, glasswool; expanded minerals like perlite, vermiculite, zeolite or expanded clay), Pumbe, Pyroclastic materials or stuff, synthetic organic substrates (e.g. polyurethane) organic substrates (e.g. peat, composts, tree waste products like coir, wood fibre or chips, tree bark) or to a liquid substrate (e.g. floating hydroponic systems, Nutrient Film Technique, Aeroponics).
[0070] According to another aspect of the invention, there is provided a use of a compound according to the first or second aspect of the invention as a herbicide.
[0071] Some compounds of the invention may also have herbicidal activity against a broad spectrum of economically important mono- and dicotyledonous harmful weeds. Some compounds of the invention may have herbicidal activity against monocotyledonous weeds but no activity or little activity against dicotyledonous crops. Other compounds of the invention may have excellent herbicidal activity against dicotyledonous weeds but no activity or little activity against monocotyledonous crops. In both cases, the compounds of the invention are selective through having activity against the target weeds while not affecting the growth of the crops in which they are applied. Other compounds of the invention may have better herbicidal activity against certain monocotyledonous weeds but no activity or little activity against certain monocotyledonous crops.
[0072] In other cases, the compounds of the invention may have non-selective activity and be active against both monocotyledonous and dicotyledonous weeds, with effects also on the crops where these weeds are agronomically important. In such cases, the compounds of the invention may be used for burn-down, post crop harvest, or in preparation of the seed bed prior to sowing the crop.
[0073] Difficult-to-control perennial weeds which produce shoots from rhizomes, root stocks or other perennial organs may also be controlled by herbicidal compounds. Here, the substances can be applied by the pre-sowing method, the pre-emergence method and/or the post-emergence method.
[0074] The following are illustrative examples of monocotyledonous weeds that may be controlled by compounds of the invention: Avena spp., Alopecurus spp., Brachiaria spp., Digitaria spp., Lolium spp., Echinochloa spp., Panicum spp., Phalaris spp., Poa spp., Setaria spp. and also Bromus spp. such as Bromus catharticus, Bromus secalinus, Bromus erectus, Bromus tectorum and Bromus japonicus and Cyperus species from the annual group, and, Agropyron, Cynodon, Imperata and Sorghum and also perennial Cyperus species, from the perennial group.
[0075] The following are illustrative examples of dicotyledonous weeds that may be controlled by compounds of the invention: Abutilon spp., Amaranthus spp., Chenopodium spp., Chrysanthemum spp., Galium spp. such as Galium aparine, Ipomoea spp., Kochia spp., Lamium spp., Matricaria spp., Pharbitis spp., Polygonum spp., Sida spp., Sinapis spp., Solanum spp., Stellaria spp., Veronica spp. and Viola spp., Xanthium spp., in the case of annuals, and Convolvulus, Cirsium, Rumex and Artemisia in the case of the perennials.
[0076] The weeds may be broadleaf plants. The weeds may be Alopecurus myosuroides (commonly known as black-grass). The weeds may be Stellaria media (chickweed), Abutilon theophrasti (velvetleaf) or Amaranthus spp.
[0077] If herbicidal compounds are applied to the soil surface before or during germination, the weed seedlings are inhibited or prevented completely from emerging or else the weeds grow until they have reached the cotyledon stage, but then their growth stops, and, eventually, they die completely.
[0078] If herbicidal compounds are applied post-emergence to the green parts of the weeds, growth typically stops following the treatment, and the weed plants remain substantially at the growth stage of the point of time of application, or they die completely, so that in this manner competition from the weeds is eliminated quickly and in a sustained manner.
[0079] The testing of herbicides is not typically conducted in a sterile in vitro laboratory test. Herbicides are typically tested by spraying live weeds or soil where seeds have been sown. There is typically greater variation in results obtained from such testing than might be the case in more controlled testing regimes that have been conducted in vitro.
[0080] The method may comprise applying the compound in a concentration in the range from 0.1 to 50 g/ha. The method may comprise applying the compound in a concentration in the range from 35 to .05 g/ha
Formulation
[0081] In a further aspect, the present invention also relates to a herbicidal formulation comprising an effective amount of a compound according to the first or second aspect of the invention. The formulation may further comprise one or more additional herbicides.
[0082] The term "effective and non-phytotoxic amount" means an amount of herbicide according to the invention which is sufficient to control or destroy any of the targeted weeds present or liable to appear in the crops and which does not have any significant detrimental effect on the crops or indeed has a positive effect on plant vigour and yield in the absence of target organism. The amount will vary depending on the weed or weeds to be controlled, the type of crop, the climatic conditions and the compounds included in the herbicidal formulation. This amount can be determined by systematic field trials, which are within the capabilities of a person skilled in the art.
[0083] Depending on their particular physical and/or chemical properties, the active compounds of the invention can be formulated as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, microencapsulations in polymeric substances and also as ULV cold and warm fogging formulations.
[0084] The formulation may be a ready-to-use solution, emulsion, water- or oil-based suspension, powder, wettable powder, paste, soluble powder, dust, soluble granules, granules for broadcasting, suspoemulsion concentrate, natural substance impregnated with active compound, synthetic substance impregnated with active compound, fertilizer or a microencapsulation in polymeric substances. Application may be carried out, for example, by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is also possible to apply the active compounds by the ultra-low volume method or to inject the preparation of active compound or the active compound itself into the soil.
[0085] Formulations containing the compounds of the invention are produced in a known manner, for example by mixing the compounds with extenders (e.g. liquid solvents and/or solid carriers), optionally with the use of surfactants (e.g. emulsifiers and/or dispersants and/or foam-formers). The formulations are prepared either in factories/production plants or alternatively before or during the application.
[0086] Auxiliaries are substances which are suitable for imparting to the formulation itself and/or to preparations derived therefrom (for example spray liquors) particular properties such as certain technical properties and/or also particular biological properties. Typical suitable auxiliaries are: extenders, solvents and carriers.
[0087] Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the classes of the aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which, if appropriate, may also be substituted, etherified and/or esterified), the ketones (such as acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, the unsubstituted and substituted amines, amides, lactams (such as N-alkylpyrrolidones) and lactones, the sulfones and sulfoxides (such as dimethyl sulfoxide).
[0088] If the extender used is water, it is also possible to use, for example, organic solvents as auxiliary solvents. Essentially, suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffins, for example petroleum fractions, alcohols such as butanol or glycol and also their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide and dimethyl sulfoxide.
[0089] Suitable solid carriers are: for example, ammonium salts and ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, and ground synthetic minerals, such as finely divided silica, alumina and silicates; suitable solid carriers for granules are: for example, crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and also synthetic granules of inorganic and organic meals, and granules of organic material such as paper, sawdust, coconut shells, maize cobs and tobacco stalks; suitable emulsifiers and/or foam-formers are: for example, nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkylsulfonates, alkyl sulfates, arylsulfonates and also protein hydrolysates; suitable dispersants are nonionic and/or ionic substances, for example from the classes of the alcohol-POE and/or -POP ethers, acid and/or POP-POE esters, alkylaryl and/or POP-POE ethers, fat- and/or POP-POE adducts, POE- and/or POP-polyol derivatives, POE- and/or POP-sorbitan- or -sugar adducts, alkyl or aryl sulfates, alkyl- or arylsulfonates and alkyl or aryl phosphates or the corresponding PO- ether adducts. Furthermore, suitable oligo- or polymers, for example those derived from vinylic monomers, from acrylic acid, from EO and/or PO alone or in combination with, for example, (poly)alcohols or (poly)amines. It is also possible to employ lignin and its sulfonic acid derivatives, unmodified and modified celluloses, aromatic and/or aliphatic sulfonic acids and their adducts with formaldehyde.
[0090] Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, as well as natural phospholipids such as cephalins and lecithins, and synthetic phospholipids, can be used in the formulations.
[0091] Further additives may be mineral and vegetable oils. It is also possible to add colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs, such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc. Other possible additives are perfumes, mineral or vegetable, optionally modified oils and waxes.
[0092] The formulations may also comprise stabilizers, e.g. low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability.
[0093] The formulations generally comprise between 0.01 and 98% by weight of active compound, preferably between 0.1 and 95% and particularly preferably between 0.5 and 90%.
[0094] The active compounds according to the invention can also be used as a mixture with other known herbicides for example, to improve the activity spectrum or to reduce or slow the development of resistance.
[0095] A mixture with other known active compounds such as nematicides, acaricides, fungicides, insecticides or bactericides, or with fertilizers and growth regulators, safeners or semiochemicals is also possible.
[0096] Exemplary application rates of the active compounds according to the invention are: when treating leaves: from 0.1 to 10 000 g/ha, preferably from 10 to 1000 g/ha, particularly preferably from 50 to 300 g/ha (when the application is carried out by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rock wool or perlite are used); when treating the soil: from 0.1 to 10 000 g/ha, preferably from 1 to 5000 g/ha.
[0097] Formulations which could be used to administer compounds of the invention are outlined in Experiments 1 to 6, below.
[0098] The formulation may be as described in the ‘Catalogue of pesticide formulation types and international coding system’ (Technical Monograph n° 2, 8th Edition by CropLife International).
[0099] The formulations according to the invention may be suitable for supporting the growing of any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture and, in particular, cereals (e.g. wheat, barley, rye, millet and oats), maize, cotton, soya beans, rice, potatoes, sunflowers, beans, coffee, beet (for example sugar beet and fodder beet), peanuts, vegetables (e.g. tomatoes, cucumbers, onions and lettuce), lawns, fruit and nut trees (e.g. apples pears peaches nectarines, apricots, hazelnut, pecan, macadamia, pistachio), soft fruit (e.g. strawberries, raspberries, blackcurrants, redcurrants), grapevines, bananas, cocoa and ornamental plants.
[00100] The invention may be as described in one of the following numbered paragraphs:
Figure imgf000021_0001
wherein R1 is independently at each occurrence selected from D and H;
R2 is independently selected from
Figure imgf000021_0002
R3 and R4 are each independently selected from -CDs, -CHD2, -CH2D and -CH3;
R5 is at each occurrence F; or each R5 together with the carbon atom to which they are attached form cyclopropyl; and X1 is independently selected from F, Cl and Br, wherein when R1 is at both occurrences H, at least one of R3 and R4 (if present) is selected from -CD3, -CHD2 and -CH2D; or an agronomically acceptable salt or N-oxide thereof.
2. A compound of paragraph 1 , wherein at least one R1 is D.
3. A compound of paragraph 2, wherein R1 is at both occurrences D.
A compound of any preceding paragraph, wherein
Figure imgf000022_0001
5. A compound of any preceding paragraph, wherein R3 is independently selected from - CD3, -CHD2 and -CH2D.
6. A compound of paragraph 5, wherein R3 is -CD3.
7. A compound of any preceding paragraph , wherein X1 is F.
8. A compound of paragraph 1 , wherein the compound is a compound selected from:
Figure imgf000023_0001
wherein R6 is independently selected from -CD3, -CHD2 and -CH2D;
Figure imgf000024_0001
Figure imgf000024_0002
R8 is independently at each occurrence selected from D and H;
R9 is at each occurrence F; or each R9 together with the carbon atom to which they are attached form cyclopropyl; and
X2 and X3 are each independently selected from F, Cl and Br, or an agronomically acceptable salt or N-oxide thereof.
10. A compound of paragraph 9, wherein R6 is -CD3.
11 . A compound of paragraph 9 or paragraph 10, wherein
Figure imgf000024_0003
12. A compound of any one of paragraphs 9 to 11 , wherein R8 is at each occurrence D.
13. A compound of paragraph 9 or paragraph 10, wherein R7 is
Figure imgf000025_0001
14. A compound of any one of paragraphs 9 to 13, wherein X2 is F.
15. A compound of paragraph 9, wherein the compound is a compound selected from:
Figure imgf000025_0002
16. A method for controlling weeds, the method comprising applying a compound of any preceding paragraph to the weeds themselves or to an area where it is envisioned that the weeds will grow. 17. A method of paragraph 16, wherein the weeds are Alopecurus myosuroides.
18. Use of a compound of any one of paragraphs 1 to 15 as a herbicide.
19. A herbicidal formulation comprising an effective amount of a compound of any one of paragraphs 1 to 15.
Description of Figures
[00101] Figure 1 is a bar chart showing % ALOMY necrosis after treatment with various compounds, including compounds of the invention, at a dose of 30 g/ha after 3, 7 and 14 days.
[00102] Figures 2, 3 and 4 are bar charts showing % STEME, ABUTH and AMARE, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10 and 3 g/ha via a track sprayer at water volumes of 200 and 800 L/ha after 3 and 7 days.
[00103] Figures 5, 6 and 7 are bar charts showing % STEME, ABUTH and AMARE, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 10, 3, 1 and 0.3 g/ha via a track sprayer at a water volume of 200 L/ha after 3, 7 and 14 days.
[00104] Figures 8 to 11 are bar charts showing % ALOMY, LOLPE, STEME and ABUTH, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10, 3, 1 g/ha after 3, 7 and 14 days.
[00105] Figures 12 to 14 are bar charts showing % ALOMY, STEME and ABUTH, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10, 3, 1 g/ha after 3, 7 and 14 days.
[00106] Figure 15 to 18 are bar charts showing % ALOMY, AMARE, STEME and ABUTH, respectively, necrosis after treatment with various compounds, including compounds of the invention, at doses of 30, 10, 3, 1 g/ha after 3, 7 and 14 days.
General Synthesis
[00107] The skilled person will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.
[00108] For example, the skilled person will be immediately familiar with standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions); "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure”, MB Smith, J. March, Wiley, (5th edition or later); “Advanced Organic Chemistry, Part B, Reactions and Synthesis”, FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions); "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions); "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions); “Heterocyclic Chemistry”, J. Joule (Wiley 2010 edition or later); "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.
[00109] The skilled person is familiar with a range of strategies for synthesising organic and particularly heterocyclic molecules and these represent common general knowledge as set out in text books such as Warren “Organic Synthesis: The Disconnection Approach”; Mackie and Smith “Guidebook to Organic Chemistry”; and Clayden, Greeves, Warren and Wothers “Organic Chemistry”.
[00110] The skilled chemist will exercise his or her judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection I deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein.
[00111] Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.
[00112] Throughout this specification these abbreviations have the following meanings:
LCMS - liquid chromatography-mass spectrometry
NMR - nuclear magnetic resonance
MS - mass spectrometry sat. - saturated aq. - aqueous
Rt - room temperature PDA - photodiode array
SQ - single quadruple
UPLC - ultra performance liquid chromatography ha - hectare
[00113] Certain compounds of the invention can be made according to or by methods analogous to the syntheses disclosed in WO 2010/038953 (for tiafenacil derivatives), US 5,344,812 (for benfendizone derivatives), WO 95/32952 (for butafenacil derivatives) and EP195346 (for flupropacil derivatives).
[00114] Certain compounds of the invention can be made according to or by methods analogous to the general synthetic Schemes A to E, below. Certain compounds of the invention can be made according to or by methods analogous to the methods described in Examples 1 to 15.
General Synthetic Schemes
[00115] Certain compounds of formula (I) can be made according to General Scheme A.
Figure imgf000028_0001
[00116] Certain compounds of formula (I) can be made according to General Scheme B.
Figure imgf000029_0004
Figure imgf000029_0001
wherein LG/PG is a leaving group or protecting group.
Scheme B
[00117] Certain compounds of formula (II) can be made according to General Scheme C.
Figure imgf000029_0002
Scheme C
[00118] Certain compounds of formula (II) can be made according to General Scheme D.
Figure imgf000029_0003
Scheme D
[00119] Certain compounds of formula (I) can be made according to General Scheme E. romethyl)-
Figure imgf000030_0002
Figure imgf000030_0001
Scheme E
Analytical Procedures
[00120] Mass spectra were run on LC-MS systems using electrospray ionization. These were run using a Waters Acquity Classic LIPLC with PDA and SQ mass detection (LC-MS-1) or a Waters Acquity H-Class LIPLC with PDA and QDA mass detection (LC-MS-2). [M+H]+ refers to mono-isotopic molecular weights.
LC-MS-1 Method 2A
Column: Acquity LIPLC BEH C18 2.1 x 50 mm 1.7 pm
Column Temp: 50 °C
Flow rate: 0.8 mL/min.
Eluents: A: H2O, 0.1 % formic acid, B: MeCN
Gradient: 0.0-1.8 min 2-98% B, 1.8-2.1 min 98% B, 2.1-2.5 98% A.
LC-MS-1 Method 2B
Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 pm
Column Temp: 50 °C
Flow rate: 0.8 mL/min.
Eluents: A: H2O, 0.1 % ammonia B: MeCN Gradient: 0.0-1.8 mins 2-98% B; 1.8-2.1 mins 98% B; 2.1-2.5 mins 98% A.
LC-MS-2 Method 2A
Column: Acquity LIPLC BEH C182.1 x 50 mm 1.7 pm
Column Temp: 50 °C
Flow rate: 0.8 mL/min.
Eluents: A: H2O, B: MeCN, C: 50% H2O I 50% MeCN + 2.0% formic acid
Gradient: 0.0 - 1.7 mins 0-95% B, 5% C; 1.7-2.1 mins 95% B, 5% C
2.1-2.5 mins 95% A, 5% C.
LC-MS-2 Method 2B
Column: Acquity UPLC BEH C182.1 x 50 mm 1.7 pm
Column Temp: 50 °C
Flow rate: 0.8 mL/min.
Eluents: A: H2O, B: MeCN, C: 50% H2O I 50% MeCN + 2.0% ammonia (aq.)
Gradient: 0.0-1.7 mins 0-95% B, 5% C; 1.7-2.1 mins 95% B, 5% C; 2.1-2.5 mins 95% A, 5% C.
[00121] NMR spectra were run on either a Bruker Ultrashield 400 MHz or 500MHz NMR spectrometer. Spectra were recorded at 298K and were referenced using the solvent peak.
Synthetic Intermediates
Intermediate X1: 3-(p-Tolylsulfonyloxy)-1-propyne-d2
Figure imgf000031_0001
[00122] To a suspension of lithium aluminium deuteride (270 mg, 6.42 mmol) in diethyl ether (15 mL) at -40 °C was added a solution of methyl propiolate (1.0 g, 11.89 mmol) in diethyl ether (1.5 mL) dropwise. The reaction mixture was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was cooled to 0 °C and then water (0.5 mL), aq. NaOH (0.5 mL) and water (0.5 mL) were added. After warming to ambient temperature, the reaction mixture was filtered through celite which was washed with Et2O (18.5 mL). The filtrate was dried over MgSO4, filtered and cooled to 0 °C. Potassium hydroxide (2.73 g, 48.64 mmol) followed by 4-methylbenzenesulfonyl chloride (2.28 g, 11.97 mmol) were added and the solution was allowed to warm slowly to ambient temperature over 3 hours before being diluted with water (15 mL) and Et2<D (15 mL). The phases were separated, and the product was extracted from the aqueous phase with Et2<D (3 x 15 mL). The organic phases were combined, dried over MgSCU and concentrated in vacuo. Chromatography on SiC>2 eluting with 14-20% acetone I petroleum ether gave the title compound as a colourless oil (526 mg).
[00123] 1H NMR (400 MHz, Methanol-d) 5 7.80 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 2.99 (s, 1H), 2.46 (s, 3H).
Intermediate X2: 6-amino-4-(1, 1-dideuterioprop-2-vnyl)-7-fluoro-spiro[ 1,4-benzoxazine-2, 1 cyclopropanel-3-one
Figure imgf000032_0001
[00124] To a solution of 6-amino-7-fluoro-spiro[4H-1,4-benzoxazine-2,T-cyclopropane]-3- one (254 mg, 1.22 mmol) in dimethylformamide (1.5 mL) at 0 °C, was added Potassium hydroxide (90 mg, 1.61 mmol) and tetrabutylammonium bromide (5 mg, 0.02 mmol). After 35 minutes, 3-(p-Tolylsulfonyloxy)-1-propyne-d2 (Intermediate X1) (285 mg, 1.34 mmol) was added dropwise and the residual reactant was washed into the reaction with dimethylformamide (1 mL). The reaction mixture was allowed to warm slowly to ambient temperature and after 17 hours, the reaction mixture was diluted with water (10 mL). The product was extracted from the aqueous phase with EtOAc (3 x 15 mL). The combined organic phases were washed with brine/water (3 x 10 mL, 1 :1) followed by sat. brine (10 mL), dried over MgSCU, filtered and concentrated to give a brown oil which was concentrated from toluene (2 x 5 mL) followed by CH2CI2 (5 mL) to give a brown solid (300 mg).
[00125] LC-MS-1 (Method 2B): Rt 1.17 mins; MS m/z 249.1 = [M+H]+ (18% @ 254 nm).
[00126] 1H NMR (400 MHz, Chloroform-d) 56.65 (d, J = 5.8 Hz, 1 H), 6.63 (d, J = 8.0 Hz, 1 H), 2.26 (s, 1 H), 1.42 - 1.37 (m, 2H), 1.22 - 1.14 (m, 2H).
Intermediate X3: 3-[4-( 1, 1-dideuterioprop-2-vnyl)-7-fluoro-3-oxo-spiro[ 1,4-benzoxazine-2, 1 cyclopropanel-6-yll-6-(trifluoromethyl)-1H-pyrimidine-2, 4-dione
Figure imgf000032_0002
[00127] To a solution of 6-amino-4-(1 ,1-dideuterioprop-2-ynyl)-7-fluoro-spiro[1 ,4- benzoxazine-2,1'-cyclopropane]-3-one (Intermediate X2) (300 mg, 1.21 mmol) in acetic acid (7 mL) at ambient temperature, was added 2-(dimethylamino)-4-(trifluoromethyl)-1 ,3-oxazin- 6-one (269 mg, 1.29 mmol). The reaction mixture was heated to 120 °C for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with water (25 mL) and then the product was extracted with EtOAc (50 mL then 3 x 25 mL). The combined organic phases were washed with sat. aq. NaHCCh (2 x 50 mL) followed by sat. brine (50 mL), dried over MgSCU, filtered and concentrated to give a red/brown oil (0.72 g). Chromatography on SiC>2 (8 g cartridge) eluting with 2-40 % EtOAc I petroleum ether gave the title compound as a light brown solid (373 mg).
[00128] LC-MS-1 (Method 2B): Rt 0.60 mins; MS m/z 412.1 = [M+H]+ (66% @ 254 nm).
[00129] 1H NMR (400 MHz, Chloroform-d) 5 8.72 (s, 1 H), 7.03 (d, J = 6.7 Hz, 1 H), 6.82 (d, J = 9.6 Hz, 1 H), 6.28 (s, 1 H), 2.26 (s, 1 H), 1.51 - 1.46 (m, 2H), 1.29 - 1.24 (m, 2H).
Intermediate Z1: A/,A/-Dimethylbromodifluoroacetamide
Figure imgf000033_0001
[00130] Dimethylamine (2M in tetrahydrofuran, 10 mL) was added dropwise to a solution of ethyl bromodifluoroacetate (3.7 g, 18.23 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 18 h then concentrated in vacuo to give the title compound as a colourless liquid (4.38 g).
[00131] LC-MS-2 (Method 2B): Rt 1.10 mins; MS m/z = 203.8 [M+H]+ (100% @ 254nm).
[00132] 1H NMR (400 MHz, CDCh) 6 3.19 (s, 3H), 3.07 (s, 3H).
Intermediate Z2: N, N-Dimethyldifluoro(m-fluorophenoxy)acetamide
Figure imgf000033_0002
[00133] Potassium carbonate (3.30 g, 23.85 mmol) was added to a solution of N,N- dimethylbromodifluoroacetamide (intermediate Z1) (4.38 g, 21.68 mmol) and 3-fluorophenol (2.43 g, 21.68 mmol) in /V,/V-dimethylacetamide (20 mL). The reaction mixture was heated at 100 °C for 1 h and 120 °C for 2 h then, upon cooling, was diluted with water (25 mL) and the crude product extracted into ethyl acetate (2 x 25 mL). The combined organics were washed with 2M NaOH (aq., 20 mL), water (2 x 25 mL), dried over MgSC and concentrated in vacuo to give the title compound as a yellow liquid (3.44 g).
[00134] LC-MS-2 (Method 2A): Rt 1.56 mins; MS m/z = 233.9 [M+H]+ (84% @ 254nm).
[00135] 1H NMR (400 MHz, CDCh) 6 7.32 (tdd, J = 9.1, 6.3, 2.9 Hz, 1H), 7.10 - 6.82 (m, 3H), 3.23 (s, 3H), 3.06 (s, 3H).
Intermediate Z3: N, N-Dimethyldifluoro(5-fluoro-2, 4-dinitrophenoxy)acetamide
Figure imgf000034_0001
[00136] /V,/V-Dimethyldifluoro(m-fluorophenoxy)acetamide (intermediate Z2) (2.44 g, 10.46 mmol) was added to a mixture of sulfuric acid (9.54 g, 97.31 mmol) and fuming nitric acid (3.30 g, 52.32 mmol) at 0 °C The temperature rose to 40 °C and was held at this temperature for a further 3 h. The reaction mixture was then poured into iced water and the crude product extracted into ethyl acetate (2 x 25 mL). The combined organics were washed with sat. aq. NaHCOs (20 mL), water (2 x 25 mL), dried over MgSCU and concentrated in vacuo to give the title compound as a yellow oil (2.37 g).
[00137] LC-MS-2 (Method 2A): Rt 1.34 mins; mass ion not observed (93% @ 254nm).
[00138] 1H NMR (400 MHz, CDCh) 6 8.79 (d, J = 7.5 Hz, 1 H), 7.49 (d, J = 10.9 Hz, 1 H), 3.22 (s, 3H), 3.07 (s, 3H).
Intermediate Z4: 6-Amino-2,2, 7-trifluoro-2,4-dihydro-1,4-benzoxazin-3-one
Figure imgf000034_0002
[00139] Hydrochloric acid (2M aq., 13 mL, 26.04 mmol) and iron powder (1.87 g, 33.56 mmol) were added to a suspension of /V,/V-dimethyldifluoro(5-fluoro-2,4- dinitrophenoxy)acetamide (intermediate Z3) (1.87 g, 5.79 mmol) in ethanol (70 mL) and water (11.8 mL). The reaction mixture was heated to 90 °C for 5 h. Then further 2M hydrochloric acid solution (6 mL) was added, and the reaction mixture was stirred for 30 min. The mixture was then filtered through celite, washed with ethyl acetate. Adjusted the pH of the mixture with 2M sodium hydroxide solution to 9. The crude product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with brine (2 x 25 mL), dried over MgSCU and concentrated in vacuo to give the title compound as a brown solid (746 mg).
[00140] LC-MS-1 (Method 2B): Rt 0.59 mins; MS m/z = 217.2 [M-H]’ (72% @ 254nm). [00141] 1H NMR (400 MHz, DMSO-d6) 5 11.68 (s, 1 H), 7.13 (d, J = 11.1 Hz, 1H), 6.51 (d, J = 8.6 Hz, 1 H), 5.28 (s, 2H).
Intermediate Z5: 6-Amino-2, 2, 7-trifluoro-4-(2-propynyl)-2, 4-dihydro- 1 ,4-benzoxazin-3-one
Figure imgf000035_0001
[00142] Propargyl bromide solution (80% in toluene, 574 mg, 3.86 mmol) was added dropwise to a suspension of 6-amino-2,2,7-trifluoro-2,4-dihydro-1,4-benzoxazin-3-one (intermediate Z4) (766 mg, 3.51 mmol) and potassium carbonate (510 mg, 3.69 mmol) in ethyl acetate (5 mL) at room temperature. The reaction mixture was heated at 78 °C for 3 h then, upon cooling, was diluted with water (20 mL) and the crude product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with 2M HCI (aq.) (15 mL), water (2 x 25 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 25% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (450 mg).
[00143] LC-MS-1 (Method 2B): Rt 1.25 mins; MS m/z = 257.1 [M+H]+ and MS m/z = 255.3 [M-H]- (100% @ 254nm).
[00144] 1H NMR (400 MHz, DMSO-d6) 5 7.25 (d, J = 10.9 Hz, 1 H), 6.83 (d, J = 8.3 Hz, 1 H), 5.41 (s, 2H), 4.72 (s, 2H), 3.46 (s, 1 H).
Intermediate Z6: (1, 1-2H2)-2-Propyn-1-ol
Figure imgf000035_0002
[00145] A solution of methyl propiolate (1.0 g, 11.89 mmol) in diethyl ether (1.5 mL) was added dropwise to a suspension of lithium aluminium deuteride (270 mg, 6.42 mmol) in diethyl ether (15 mL) at - 50 °C. The reaction mixture was stirred, allowing to warm to room temperature, for 16 h. The reaction mixture was cooled to 0 °C and quenched by dropwise addition of water (0.5 mL), sat. aq. NaOH (0.5 mL) and water (0.5 mL). After warming to room temperature, the reaction mixture was filtered through celite and washed with diethyl ether. The filtrate was dried over MgSCU and the solution used directly in the next step.
Intermediate Z7 3-(Tosyloxy)(3,3-2H2)propyne
Figure imgf000036_0001
[00146] Potassium hydroxide (3.33 g, 59.41 mmol) followed by 4-methylbenzenesulfonyl chloride (2.79 g, 14.61 mmol) were added to a solution of (1,1-2H2)-2-propyn-1-ol (intermediate Z6) (690 mg, 11.88 mmol) in diethyl ether (150 mL) at O °C . The solution was allowed to warm slowly to room temperature over 3 h then diluted with water (15 mL) and diethyl ether (15 mL). The crude product was extracted into diethyl ether (3 x 15 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 15% ethyl acetate in petroleum ether) and then repurified by flash column chromatography on silica (eluting 11% to 20% petroleum ether in acetone) to give the title product as a colourless oil (531 mg).
[00147] LC-MS-1 (Method 2B): Rt 1.36 mins; MS m/z = 211.2 [M-H]’ (71% @ 254nm).
[00148] 1H NMR (400 MHz, MeOD) 5 7.80 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 2.99 (s, 1H), 2.46 (s, 3H).
Intermediate Z8: 6-Amino-2,2, 7-trifluoro-4-[(1, 1-2H2)-2-propynyll-2,4-dihvdro-1,4-benzoxazin- 3-one
Figure imgf000036_0002
[00149] A solution of 3-(tosyloxy)(3,3-2H2)propyne (intermediate Z7) (398 mg, 1.88 mmol) in toluene (0.47 mL) was added dropwise to a suspension of 6-amino-2,2,7-trifluoro-2,4- dihydro-1,4-benzoxazin-3-one (intermediate Z4) (372 mg, 1.71 mmol) and potassium carbonate (247 mg, 1.79 mmol) in ethyl acetate (5 mL) at room temperature. The mixture was heated at 78 °C for 4.5 h then, upon cooling, was diluted with water (20 mL) and the crude product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with 2M HCI (aq.) (15 mL), water (2 x 25 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 30% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (130 mg).
[00150] LC-MS-1 (Method 2B): Rt 1.28 mins; MS m/z = 259.1 [M+H]+ and MS m/z = 257.3 [M-H]’ (82% @ 254nm). [00151] 1H NMR (400 MHz, CDCh) 56.93 (d, J = 10.3 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1 H), 3.80 (s, 2H), 2.33 (s, 1 H).
Intermediate Z9: 1 ,3-Dimethylthiourea
Figure imgf000037_0001
[00152] Methylamine (2M in tetrahydrofuran, 70 mg, 2.24 mmol) was added to a solution of 1 ,1'-thiocarbonyldiimidazole (200 mg, 1.12 mmol) in toluene (4 mL) in a sealed vial. The reaction mixture was heated at 110 °C for 16 h then concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (25 g MODUS silica cartridge, eluting 0 to 6.5% methanol in dichloromethane) to give the title compound as a yellow oil (86 mg).
[00153] LC-MS-2 (Method 2A): Rt 0.32 mins; MS m/z = 104.9 [M+H]+ (88% @ 254nm).
[00154] 1H NMR (400 MHz, CDCh) 6 5.79 (s, 2H), 3.03 (s, 6H).
Figure imgf000037_0002
[00155] Sodium hydroxide (180 mg, 4.49 mmol) was added to a solution of 1 ,T- thiocarbonyldiimidazole (400 mg, 2.24 mmol) and trideuteriomethanamine hydrochloride (317 mg, 4.49 mmol) in tetrahydrofuran (12.4 mL) in a sealed vial. The reaction mixture was heated at 90 °C for 16 h then concentrated in vacuo. The residue was diluted with water (25 mL) and the crude product extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 3.5% methanol in dichloromethane) to give the title compound as a yellow oil (65 mg).
[00156] LC-MS-2 (Method 2A): Rt 0.30 mins; MS m/z = 110.8 [M+H]+ (30% @ 254nm).
[00157] 2H NMR (400 MHz, CHCh) 5 3.00 (s, 6H).
Intermediate Z11: Methyl-1 -imidazolecarbothioamide
Figure imgf000037_0003
[00158] Methylamine (2M in tetrahydrofuran, 158 mg, 5.10 mmol) was added to a solution of 1 ,1'-thiocarbonyldiimidazole (1 g, 5.61 mmol) in tetrahydrofuran (5.6 mL) in a sealed vial. The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 3.5% methanol in dichloromethane) to give the title compound as a white solid (438 mg).
[00159] LC-MS-2 (Method 2A): Rt 0.56 mins; MS m/z = 141.9 [M+H]+ (100% @ 254nm).
[00160] 1H NMR (400 MHz, CDCh) 5 9.21 (s, 1H), 8.31 (t, J = 1.2 Hz, 1 H), 7.61 (t, J = 1.5 Hz, 1H), 7.05 - 7.01 (m, 1 H), 3.29 (s, 3H).
Intermediate Z12: 1-[(2H3)Methyl]-3-methylthiourea
Figure imgf000038_0001
[00161] Sodium hydroxide (94 mg, 2.34 mmol) was added to a solution of methyl-1- imidazolecarbothioamide (intermediate Z11) (300 mg, 2.12 mmol) and trideuteriomethanamine hydrochloride (165 mg, 2.34 mmol) in tetrohydrofuran (11.5 mL) in a sealed vial. The reaction mixture was heated at 90 °C for 3 h then concentrated in vacuo. The residue was diluted with water (25 mL) and the crude product extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 4% methanol in dichloromethane) to give the title compound as a colourless oil (61 mg).
[00162] LC-MS-2 (Method 2A): Rt 0.27 mins; MS m/z = 107.9 [M+H]+ (68% @ 254nm).
[00163] 1H NMR (400 MHz, CDCh) 6 5.77 (s, 2H), 3.03 (s, 3H).
[00164] 2H NMR (61 MHz, CHCh) 5 3.04 (s, 3H).
Intermediate Z13 (trifludimoxazin): 1 ,5-Dimethyl-6-thioxo-3-[2,2, 7-trifluoro-3-oxo-4-(2- propynyl)-2, 4-dihydro- 1 ,4-benzoxazin-6-yl]-1 ,3, 5-triazinane-2, 4-dione
Figure imgf000038_0002
[00165] 6-Amino-2,2,7-trifluoro-4-(2-propynyl)-2,4-dihydro-1 ,4-benzoxazin-3-one
(intermediate Z5) (72 mg, 0.281 mmol) was added to a solution of 1 ,1'-carbonyldiimidazole (137 mg, 0.843 mmol) and triethylamine (28 mg, 0.281 mmol) in ethyl acetate (0.3 mL). The reaction mixture was heated to 55 °C before a solution of 1 ,3-dimethylthiourea (intermediate Z9) (35 mg, 0.337 mmol) in ethyl acetate (0.6 mL) was added. The reaction mixture was heated at 76 °C for 18 h then poured into iced water (200 mL) and 2M HCI (aq.) (30 mL). The crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 30% ethyl acetate in petroleum ether) to give the title compound as a white solid (102 mg).
[00166] LC-MS-2 (Method 2B): Rt 1.52 mins; mass ion not observed (100% @ 254nm).
[00167] 1H NMR (400 MHz, CDCh) 6 7.26 (d, = 6.5 Hz, 1 H), 7.17 (d, J = 8.9 Hz, 1 H), 4.76 (d, J = 2.6 Hz, 2H), 3.79 (s, 6H), 2.38 (t, J = 2.6 Hz, 1 H).
Intermediate Y1: (1, 1-2H2)-2-Propyn-1-ol
Figure imgf000039_0001
[00168] A solution of methyl propiolate (1.0 g, 11.89 mmol) in diethyl ether (1.5 mL) was added dropwise to a suspension of lithium aluminium deuteride (270 mg, 6.42 mmol) in diethyl ether (15 mL) at - 50 °C. The reaction mixture was stirred, allowing to warm to room temperature, for 16 h. The reaction mixture was cooled to 0 °C and quenched by dropwise addition of water (0.5 mL), sat. aq. NaOH (0.5 mL) and water (0.5 mL). After warming to room temperature, the reaction mixture was filtered through celite and washed with diethyl ether. The filtrate was dried over MgSCU and the solution used directly in the next step.
Intermediate Y2: 3-(Tosyloxy)(3,3-2H2)propyne
Figure imgf000039_0002
[00169] Potassium hydroxide (3.33 g, 59.41 mmol) followed by 4-methylbenzenesulfonyl chloride (2.79 g, 14.61 mmol) were added to a solution of (1,1-2H2)-2-propyn-1-ol (intermediate Y1) (690 mg, 11.88 mmol) in diethyl ether (150 mL) at 0 °C . The solution was allowed to warm slowly to room temperature over 3 h then diluted with water (15 mL) and diethyl ether (15 mL). The crude product was extracted into diethyl ether (3 x 15 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 15% ethyl acetate in petroleum ether) and then repurified by flash column chromatography on silica (eluting 11% to 20% petroleum ether in acetone) to give the title product as a colourless oil (531 mg).
[00170] LC-MS-1 (Method 2 B): Rt 1.36 mins; MS m/z = 211.2 [M-H]' (71% @ 254nm).
[00171] 1H NMR (400 MHz, MeOD) 5 7.80 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 2.99 (s, 1H), 2.46 (s, 3H).
Intermediate Y3: 7-Fluoro-2,4-dihydro-1,4-benzoxazin-3-one
Figure imgf000040_0001
[00172] 2-Chloroacetyl chloride (6.88 mL, 87 mmol) was added dropwise to a suspension of 2-amino-5-fluorophenol (10.0 g, 79 mmol), potassium carbonate (32.6 g, 236 mmol) and tetrabutylammonium bromide (2.53 g, 7.9 mmol) in acetonitrile (200 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 min followed by reflux temperature for 16 h then concentrated in vacuo. The residue was stirred in water (100 mL), filtered and dried under vacuum to give the title compound as a white solid (12.3 g).
[00173] LC-MS-1 (Method 2B): Rt 1.70 mins; MS m/z = 168.1 [M+H]+ (100% @ 254nm).
[00174] 1H NMR (500 MHz, CDCh) 6 10.70 (s, 1 H), 6.90-6.86 (m, 2H), 6.83-6.78 (td, 1H), 4.59 (s, 2H).
Intermediate Y4: 7-Fluoro-6-nitro-2, 4-dihydro- 1 ,4-benzoxazin-3-one
Figure imgf000040_0002
[00175] A mixture of sulfuric acid (cone., 5 mL) and nitric acid (70%, 1.9 mL) was added dropwise to a solution of 7-fluoro-2,4-dihydro-1,4-benzoxazin-3-one (intermediate Y3) (5.0 g, 29.9 mmol) in sulfuric acid (cone., 10 mL) at -5 °C. The reaction mixture was stirred at 0 °C for 1.5 h then poured into iced water (~ 300 mL), filtered, washed with diethyl ether (~ 20 mL) and dried under vacuum to give the title compound as a brown solid (3.0 g).
[00176] LC-MS-2 (Method 2B): Rt 1.16 mins; MS m/z = 211.0 [M-H]' (100% @ 254nm).
[00177] 1H NMR (400 MHz, DMSO) 5 11.03 (s, 1 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.26 (d, J = 12.2 Hz, 1H), 4.79 (s, 2H).
Intermediate Y5: 6-Amino-7-fluoro-2, 4-dihydro- 1 ,4-benzoxazin-3-one
Figure imgf000041_0001
[00178] Palladium on carbon (10%, 100 mg) was added to a solution of 7-fluoro-6-nitro-2,4- dihydro-1,4-benzoxazin-3-one (intermediate Y4) (1.03 g, 4.855 mmol) in methanol (5 mL) and 1,4-dioxane (30 mL) under nitrogen. The flask was evacuated and filled with hydrogen. The reaction mixture was stirred under balloon of hydrogen for 24 h then filtered through celite and evaporated to give a pale brown solid (806 mg).
[00179] 1H NMR (400 MHz, DMSO) 5 10.50 (s, 1 H), 6.72 (d, J = 11.5 Hz, 1 H), 6.36 (d, J = 8.9 Hz, 1 H), 4.86 (br s, 2H), 4.41 (s, 2H).
Intermediate Y6: 6-Amino-7-fluoro-4-[ ( 1, 1-2H2)-2-propynyl]-2, 4-dihydro- 1 ,4-benzoxazin-3-one
Figure imgf000041_0002
[00180] Potassium hydroxide (81 mg, 1.45 mmol) and tetrabutylammonium bromide (4.6 mg, 0.15 mmol) were added to a solution of 6-amino-7-fluoro-2,4-dihydro-1,4-benzoxazin-3- one (intermediate Y5) (200 mg, 1.098 mmol) in /V,/V-dimethylformamide (1.5 mL) at 0 °C. After 30 min a solution of 3-(tosyloxy)(3,3-2H2)propyne (intermediate Y2) (256 mg, 1.21 mmol) in /V,/V-dimethylformamide (1 mL) was added dropwise and the reaction mixture was stirred for 4 days at room temperature. The reaction mixture was diluted with water (20 mL) and the crude product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with brine (25 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography (eluting 2:2 petroleum ether: ethyl acetate) to give the title compound as a yellow solid (196 mg).
[00181] 1H NMR (400 MHz, CDCh) 66.80-6.70 (m, 2H), 4.56 (s, 2H), 2.27 (s, 1 H).
Intermediate W1: 5-Amino-2-chloro-4-fluorobenzoic acid
Figure imgf000041_0003
[00182] Iron powder (1.0 g, 18.22 mmol) was added to a solution of 2-chloro-4-fluoro-5-nitro- benzoic acid (1.0 g, 4.55 mmol) in acetic acid (5 mL). The reaction mixture was heated at 120 °C for 50 min. Upon cooling the reaction mixture was diluted with water (50 mL) and the crude product extracted into ethyl acetate (100 mL then 4 x 25 mL). The combined organics were washed with brine (50 mL), dried over MgSCU and concentrated in vacuo to give the title compound as an orange oil (0.2 g).
[00183] 1H NMR (400 MHz, CDCh) 6 7.45 (d, J = 9.3 Hz, 1 H), 7.12 (d, J = 10.6 Hz, 1 H).
Intermediate W2: 2-Chloro-5-[2, 4-dioxo-6-(trifluoromethyl)-3-pyrimidinyl]-4-fluorobenzoic acid
Figure imgf000042_0001
[00184] 2-(Dimethylamino)-4-(trifluoromethyl)-1 ,3-oxazin-6-one (235 mg, 1.13 mmol) was added to a solution of 5-amino-2-chloro-4-fluorobenzoic acid (intermediate W1) (0.2 g, 1.06 mmol) in acetic acid (5 mL). The reaction mixture was heated at 120 °C for 5 h and then diluted with toluene (5 mL) and concentrated in vacuo (x 3). The residue was diluted with water (10 mL) and the crude product extracted into ethyl acetate (15 mL then 2 * 10 mL). The combined organics were washed with brine (10 mL), dried over MgSCU and concentrated in vacuo to give the title compound as an orange solid (320 mg).
[00185] LC-MS-2 (Method 2A): Rt 1.17 mins; MS m/z 351.1 = [M-H]’ (84% @ 254nm).
[00186] 1H NMR (400 MHz, DMSO-cfe) 6 8.07 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 9.6 Hz, 1 H), 6.43 (s, 1 H).
Intermediate W3: I2 H3) Methyl 2-chloro-4-fluoro-5-/1-[(2H3)methyll-2,4-dioxo-6- (trifluoromethyl)-3-pyrimidinyl}benzoate
Figure imgf000042_0002
[00187] Potassium carbonate (118 mg, 0.85 mmol) was added to a solution of 2-chloro-5- [2,4-dioxo-6-(trifluoromethyl)-3-pyrimidinyl]-4-fluorobenzoic acid (intermediate W2) (120 mg, 0.34 mmol) in /V,/V-dimethylformamide (1.3 mL). The reaction mixture was stirred for 30 min and then iodomethane-d3 (53 pL, 0.85 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then diluted with water (7.5 mL) and the crude product extracted into ethyl acetate (3 * 10 mL). The combined organics were washed with water/brine (3 * 10 mL, 1 :1), 0.1 M NaOH (10 mL), brine (10 mL), dried over MgSCU and concentrated in vacuo to give the title compound as an orange oil (74 mg).
[00188] LC-MS-2 (Method 2A): Rt 1.57 min, mass ion not observed (76% @ 254nm). [00189] 1H NMR (400 MHz, CDCh) 6 7.91 (d, J = 7.7 Hz, 1 H), 7.39 (d, J = 9.2 Hz, 1 H), 6.37 (s, 1H).
Figure imgf000043_0001
[00190] Boron tribromide (1 M in dichloromethane, 574 pL, 0.57 mmol) was added dropwise to a solution of (2H3)methyl 2-chloro-4-fluoro-5-{1-[(2H3)methyl]-2,4-dioxo-6-(trifluoromethyl)- 3-pyrimidinyl}benzoate (intermediate W3) (74 mg, 0.19 mmol) in dichloromethane (1.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 50 min and then allowed to warm to room temperature. After 16 h, the reaction mixture was poured into iced water (5 mL) and then brine (5 mL) was added. The crude product was extracted into dichloromethane (4 x 10 mL). The organics were combined, dried over MgSCU and concentrated in vacuo to give the title compound as an orange solid (60 mg).
[00191] LC-MS-2 (Method 2A): Rt 1.38 min, MS m/z 368.0 = [M-H]’ (70 % @ 254 nm).
[00192] 1H NMR (400 MHz, DMSO-cfe) 5 8.04 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1 H), 6.60 (s, 1 H).
Intermediate I/I/5: Methyl 2-chloro-4-fluoro-5-[1-methyl-2,4-dioxo-6-(trifluoromethyl)-3- p yrimidin yl] benzoate
Figure imgf000043_0002
[00193] Potassium carbonate (98 mg, 0.71 mmol) was added to a solution of 2-chloro-5-[2,4- dioxo-6-(trifluoromethyl)-3-pyrimidinyl]-4-fluorobenzoic acid (intermediate W2) (100 mg, 0.28 mmol) in /V,/V-dimethylformamide (1.1 mL). The reaction mixture was stirred for 10 min and then iodomethane (44 pL, 0.71 mmol) was added. The reaction mixture was stirred at room temperature for 19 h and then further iodomethane (44 pL, 0.71 mmol) was added. The reaction mixture was stirred for a further 22 h and then diluted with water (5 mL). The crude product was extracted into ethyl acetate (3 x 10 mL). The combined organic phases were washed with water (3 x 5 mL), 0.1 M NaOH (10 mL), brine (10 mL), dried over MgSCU and concentrated in vacuo to give the title compound as a yellow oil (92 mg). [00194] LC-MS-2 (Method 2A): Rt 1.55 min, MS m/z not observed (87 % @ 254 nm).
[00195] 1H NMR (400 MHz, CDCh) 6 7.91 (d, J = 7.7 Hz, 1 H), 7.39 (d, J = 9.2 Hz, 1 H), 6.37 (s, 1H), 3.91 (s, 3H), 3.59 - 3.54 (m, 3H).
Intermediate W6: 2-Chloro-4-fluoro-5-[ 1-methyl-2,4-dioxo-6-(trifluoromethyl)-3- pyrimidinyllbenzoic acid
Figure imgf000044_0001
[00196] Boron tribromide (1 M in dichloromethane, 725 pL, 0.73 mmol) was added dropwise to a solution of methyl 2-chloro-4-fluoro-5-[1-methyl-2,4-dioxo-6-(trifluoromethyl)-3- pyrimidinyl]benzoate (intermediate W5) (92 mg, 0.24 mmol) in dichloromethane (1.2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min and then allowed to warm to room temperature. After 16 h the reaction mixture was poured into iced water (5 mL) and then brine (5 mL) was added. The crude product was extracted into dichloromethane (4 x 10 mL). The organics were combined, dried over MgSCU and concentrated in vacuo to give the title compound as an orange solid (80 mg).
[00197] LC-MS-2 (Method 2A): Rt 1.43 min, MS m/z 365.0 = [M-H]’ (89% @ 254 nm).
[00198] 1H NMR (400 MHz, DMSO-cfe) 6 8.04 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1 H), 6.60 (s, 1H), 3.41 (s, 3H).
Figure imgf000044_0002
[00199] Methyl chloroformate (4.80 g, 50.75 mmol, 3.92 mL) was added to a suspension of isopropylamine (4.4 mL, 50.75 mmol) and potassium carbonate (7.0 g, 50.75 mmol) in dichloromethane (20 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and then heated at reflux temperature for 5 h. Upon cooling the reaction mixture was diluted with water (20 mL) and the product extracted into dichloromethane (2 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo to give the title compound as a pale yellow oil (5.35 g).
[00200] 1H NMR (400 MHz, CDCh) 6 4.47 (br. s, 1H), 3.84 - 3.76 (m, 2H), 3.65 (s, 3H), 1.15 (d, J = 6.5 Hz, 6H).
Intermediate W8: (Isopropyl -N- Haimethylmethoxycarbonylamine
Figure imgf000045_0001
[00201] A solution of (isopropyl)methoxycarbonylamine (intermediate W7) (1.0 g, 8.54 mmol) in tetrahydrofuran (4.5 mL) was added dropwise to a suspension sodium hydride (60% in mineral oil, 1.7 g, 42.68 mmol) in tetrahydrofuran (28.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minand then allowed to warm to room temperature over 55 min. After re-cooling the suspension to 0 °C, iodomethane-d3 (2.7 mL, 42.68 mmol) was added dropwise. The reaction mixture was stirred, allowing to warm to room temperature, for 17 h. The reaction mixture was quenched by dropwise addition of water (50 mL) and then the crude product extracted into diethyl ether (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over MgSCU and concentrated in vacuo to give the title compound as a pale yellow oil (1.1 g).
[00202] 1H NMR (400 MHz, CDCh) 6 4.54 - 4.17 (s, 1H), 3.69 (s, 3H), 1.10 (d, J = 6.8 Hz, 6H).
Figure imgf000045_0002
[00203] A mixture of (isopropyl)-N-(2H3)methylmethoxycarbonylamine (intermediate W8) (1.14 g, 8.50 mmol) and hydrochloric acid (2M aq., 127 mL) was heated at reflux temperature for 10 h. The solution was concentrated in vacuo and then co-evaporated from toluene (2 x 10 mL) followed by dichloromethane (2 x 20 mL) to give the title compound as an orange oil (0.64 g).
[00204] 1H NMR (400 MHz, CDCh) 6 9.43 (br. s, 2H), 3.35 - 3.18 (m, 1 H), 1.45 (d, = 6.5 Hz, 6H).
Figure imgf000045_0003
[00205] A solution of terf-butanol (804 pL, 8.40 mmol) in dichloromethane (1.1 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (690 pL, 7.93 mmol) in dichloromethane (6.7 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hand then triethylamine (2.3 mL, 16.65 mmol) was added dropwise followed by a solution of N- (2H3)methyl(isopropyl)amine hydrochloride (intermediate W9) (640 mg, 5.68 mmol) in dichloromethane (2.20 mL) dropwise. The reaction mixture was stirred at 0 °C for 18 h then diluted with dichloromethane (100 mL) and filtered. The filtrate was washed with water (3 x 20 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow oil (0.91 g).
[00206] 1H NMR (400 MHz, CDCh) 6 7.02 (br. s, 1 H), 4.15 (hept, J = 6.7 Hz, 1 H), 1.48 (s, 9H), 1.18 (d, = 6.7 Hz, 6H).
Intermediate W11: (Isopropyl -N- Haimethylaminosulfoamine
Figure imgf000046_0001
[00207] Ice cold hydrochloric acid (4M aq., 2.3 mL) was added to terf-butyl-(isopropyl)-A/- (2H3)methylaminosulfonylaminoformylate (intermediate W10) (0.98 g, 3.57 mmol) and the reaction mixture was vigorously stirred at room temperature. After 19 h the solution was concentrated in vacuo from toluene (2 x 8 mL). The residue was basified by dropwise addition of sat. aq. NaHCOs (10 mL). The crude product was extracted into ethyl acetate (4 x 10 mL) and the combined organics were dried over MgSCU and concentrated to give the title compound as a yellow oil (0.50 g).
[00208] 1H NMR (400 MHz, CDCh) 6 4.32 (br. s, 2H), 4.18 (hept, = 6.8 Hz, 1 H), 1.18 (d, J = 6.7 Hz, 6H).
Figure imgf000046_0002
[00209] A solution of terf-butanol (507 pL, 5.30 mmol) in dichloromethane (0.7 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (435 pL, 5.00 mmol) in dichloromethane (4.2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then triethylamine (1.5 mL, 10.50 mmol) was added dropwise followed by a solution of N- methyl(isopropyl)amine (388 mg, 5.30 mmol) in dichloromethane (0.7 mL) dropwise. The reaction mixture was stirred at 0 °C for 19 h then diluted with dichloromethane (30 mL) and filtered. The filtrate was washed with water (3 x 10 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow oil (1 .00 g).
[00210] 1H NMR (400 MHz, DMSO-cfe) 6 3.94 (hept, J = 6.8 Hz, 1 H), 2.70 (s, 3H), 1.40 (s, 9H), 1.06 (d, = 6.7 Hz, 6H). Intermediate W13: (Isopropyl)-N-methylaminosulfoamine
Figure imgf000047_0001
[00211] Ice cold hydrochloric acid (4M aq., 2.6 mL) was added to ferf-butyl-(isopropyl)-/V- methylaminosulfonylaminoformylate (intermediate W12) (1.00 g, 3.95 mmol) and the reaction mixture was vigorously stirred at room temperature. After 21 h the solution was concentrated in vacuo from toluene (2 x 8 mL). The residue was basified by dropwise addition of sat. aq. NaHCOs (10 mL). The crude product was extracted into ethyl acetate (4 x 10 mL) and the combined organics were dried over MgSCU and concentrated to give the title compound as a yellow oil (0.40 g).
[00212] 1H NMR (400 MHz, CDCh) 64.31 (s, 2H), 4.18 (hept, = 6.7 Hz, 1 H), 2.74 (s, 3H), 1.18 (d, = 6.7 Hz, 6H).
Intermediate V1: Ethyl [3-(2-chloro-4-fluorophenoxy)-2-pyridyloxy]acetate
Figure imgf000047_0002
[00213] Ethyl diazoacetate (605 mg, 4.51 mmol) was added to a solution of 3-(2-chloro-4- fluorophenoxy)-1,2-dihydro-2-pyridinone (900 mg, 3.76 mmol) and boron trifluoride diethyl etherate (45 mg, 0.317 mmol) in chlorobenzene (12.6 mL). The reaction mixture was heated at 50 °C for 4 h. Upon cooling the reaction mixture was diluted with water (25 mL) and the crude product extracted into ethyl acetate (2 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo to give the title compound as a brown solid (1.08 g).
[00214] 1H NMR (400 MHz, CDCh) 6 7.88 (dt, J = 5.0, 1.6 Hz, 1 H), 7.22 - 7.18 (m, 1 H), 7.12 - 7.04 (m, 1H), 6.95 (tdd, J = 6.1, 3.3, 1.9 Hz, 2H), 6.87 (ddd, J = 7.8, 4.9, 1.8 Hz, 1H), 4.96 (s, 2H), 4.24 - 4.18 (m, 2H), 1.31 - 1.24 (m, 3H).
Intermediate V2: Ethyl [3-(2-chloro-4-fluoro-5-nitrophenoxy)-2-pyridyloxylacetate
Figure imgf000047_0003
[00215] Nitric acid (70%, 219 mg, 3.48 mmol) was added dropwise to a solution of ethyl [3- (2-chloro-4-fluorophenoxy)-2-pyridyloxy]acetate (intermediate V1) (1.03 g, 3.16 mmol) in sulfuric acid (18.3 g, 187 mmol) at 0 °C. The reaction mixture was stirred for 2 h then poured into iced water and the crude product extracted into ethyl acetate (2 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo to give the title compound as a yellow solid (1.0 g).
[00216] LC-MS-2 (Method 2A): Rt 1.68 mins; MS m/z = 370.9 [M+H]+ (84% @ 254nm).
[00217] 1H NMR (400 MHz, CDCh) 6 8.03 (dd, J = 5.0, 1.6 Hz, 1H), 7.53 (d, J = 6.7 Hz, 1 H), 7.46 - 7.37 (m, 2H), 7.01 (dd, J = 7.7, 5.0 Hz, 1H), 4.90 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).
Intermediate V3: Ethyl [3-(5-amino-2-chloro-4-fluorophenoxy)-2-pyridyloxy]acetate
Figure imgf000048_0001
[00218] Ammonium chloride (325 mg, 6.07 mmol) and iron powder (437 mg, 7.83 mmol) were added to a suspension of ethyl [3-(2-chloro-4-fluoro-5-nitrophenoxy)-2- pyridyloxy]acetate (intermediate V2) (500 mg, 1.35 mmol) in ethanol (16.1 mL) and water (2.73 mL). The reaction mixture was heated at 90 °C for 3 h. Upon cooling the mixture was filtered through celite, washing with ethyl acetate. The combined filtrates were concentrated in vacuo and then the residue was diluted with water (25 mL) and the crude product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with brine (3 x 20 mL), dried over MgSCU and concentrated in vacuo to give the title compound as a brown solid (348 mg).
[00219] LC-MS-2 (Method 2B): Rt 1.48 mins; MS m/z = 341.0 [M+H]+ (75% @ 254nm).
[00220] 1H NMR (400 MHz, DMSO) 5 7.90 (s, 1 H), 7.14 (d, J = 98.2 Hz, 3H), 6.35 (s, 1H), 5.44 (s, 2H), 4.95 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.18 (s, 3H).
Intermediate V4: Ethyl (3-/2-chloro-5-[2,4-dioxo-6-(trifluoromethyl)-3-pyrimidinyll-4- fluorophenoxy}-2-pyridyloxy)acetate
Figure imgf000048_0002
[00221] 2-(Dimethylamino)-4-(trifluoromethyl)-1 ,3-oxazin-6-one (167 mg, 0.801 mmol) was added to a solution of ethyl [3-(5-amino-2-chloro-4-fluorophenoxy)-2-pyridyloxy]acetate (intermediate V3) (248 mg, 0.728 mmol) in acetic acid (5.7 mL). The reaction mixture was heated at 120 °C for 3 h. Upon cooling the reaction mixture was diluted with water (25 mL) and the crude product extracted into ethyl acetate (50 mL then 3 x 25 mL). The combined organics were washed with sat. aq. NaHCCh (2 x 50 mL), brine (50 mL), dried over MgSCU and concentrated in vacuo to give the title compound as a brown oil (320 mg).
[00222] 1H NMR (400 MHz, CDCh) 6 7.93 (s, 1 H), 7.35 (dd, J = 15.5, 8.1 Hz, 2H), 7.02 - 6.84 (m, 2H), 6.18 (s, 1 H), 4.92 (s, 2H), 4.15-4.10 (m, 2H), 1.26 (q, J = 7.3 Hz, 3H).
Exemplary Compounds
Example 7: 3-(7-fluoro-3-oxo-4-prop-2-vnyl-spiron,4-benzoxazine-2,T-cyclopropane1-6-yl)-1- (trideuteriomethyl)-6-(trifluoromethyl)pyridine-2, 4-dione
Figure imgf000049_0001
[00223] To a solution of Intermediate Comparative Example A (100 mg, 0.25 mmol) in acetone (2 mL) at ambient temperature was added potassium carbonate (70 mg, 0.50 mmol) and iodomethane-ds (17 pL, 0.27 mmol). The reaction mixture was heated to reflux temperature for 3 hours, cooled and diluted with water (10 mL) and EtOAc (10 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated.
Chromatography on SiO2 (12 g cartridge) eluting with 0-50 % EtOAc I petroleum ether followed by followed by reverse phase chromatography (20 g Cis cartridge) eluting with 30- 70 % MeCN / 0.1 % aqueous ammonia solution gave the title compound as a white solid (3 mg) after lyophilisation.
[00224] LC-MS-1 (Method 2B): Rt 1.40 mins; MS m/z 427.2 = [M+H]+ (98% @ 254nm).
[00225] 1H NMR (500 MHz, Chloroform-d) 5 7.02 (d, J = 6.7 Hz, 1 H), 6.82 (d, J = 9.6 Hz, 1 H), 6.39 (s, 1 H), 4.80 - 4.46 (m, 2H), 2.27 (s, 1 H), 1.51 - 1.38 (m, 2H), 1.33 - 1.20 (m, 2H).
Example 2: 3-[4-(1, 1-dideuterioprop-2-ynyl)-7-fluoro-3-oxo-spiro[1,4-benzoxazine-2, 1'- cyclopropane]-6-yll-1-methyl-6-(trifluoromethyl)pyrimidine-2, 4-dione
Figure imgf000050_0001
[00226] To a solution of 3-[4-(1 ,1-dideuterioprop-2-ynyl)-7-fluoro-3-oxo-spiro[1 ,4- benzoxazine-2,1'-cyclopropane]-6-yl]-6-(trifluoromethyl)-1 H-pyrimidine-2, 4-dione (Intermediate X3) (218 mg, 0.53 mmol) in Dimethylformamide (8 mL) at ambient temperature, was added Potassium carbonate (161 mg, 1.17 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes and then iodomethane (145 pL, 2.33 mmol) was added. The reaction mixture was stirred at ambient temperature for 19 hours and then diluted with water (80 mL) and CH2CI2 (50 mL). The phases were separated and the aqueous phase was extracted with CH2CI2 (3 x 50 mL). The combined organic phases were washed with water (50 mL), dried over Na2SO4, filtered and concentrated. The residue was concentrated from toluene (2 x 50 mL) to give a brown oil (0.49 g). Chromatography on SiC>2 (8 g cartridge) eluting with 2-30 % EtOAc I petroleum ether gave the title compound as a white solid (132 mg).
[00227] LC-MS-1 (Method 2B): Rt 1.37 mins; MS m/z 426.2 = [M+H]+ (100% @ 254 nm).
[00228] 1H NMR (400 MHz, Chloroform-d) 5 7.01 (d, J = 6.7 Hz, 1 H), 6.82 (d, J = 9.6 Hz, 1 H), 6.39 (s, 1 H), 3.58 (s, 3H), 2.26 (s, 1 H), 1.48 (q, J = 4.7 Hz, 2H), 1.27 (q, J = 4.6 Hz, 2H).
Example 3: 3-f4-( 1 , 1 -dideuterioprop-2-vnyl)-7-fluoro-3-oxo-spirof 1 ,4-benzoxazine-2, 1 '- cvclopropane1-6-yl1-1-(trideuteriomethyl)-6-(trifluoromethyl)pyrimidine-2, 4-dione
Figure imgf000050_0002
[00229] To a solution of 3-[4-(1 ,1-dideuterioprop-2-ynyl)-7-fluoro-3-oxo-spiro[1 ,4- benzoxazine-2,T-cyclopropane]-6-yl]-6-(trifluoromethyl)-1 H-pyrimidine-2, 4-dione (Intermediate X3) (218 mg, 0.53 mmol) in Dimethylformamide (8 mL) at ambient temperature, was added Potassium carbonate (161 mg, 1.17 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes and then iodomethane-ds (145 pL, 2.33 mmol) was added. The reaction mixture was stirred at ambient temperature for 19 hours and then diluted with water (80 mL) and CH2CI2 (50 mL). The phases were separated and the aqueous phase was extracted with CH2CI2 (3 x 50 mL). The combined organic phases were washed with water (50 mL), dried over Na2SC>4, filtered and concentrated. The residue was concentrated from toluene (2 x 50 mL) to give a brown oil (0.49 g). Chromatography on SiC>2 (8 g cartridge) eluting with 2-30 % EtOAc / petroleum ether gave the title compound as a white solid (114 mg).
[00230] LC-MS-1 (Method 2B): Rt 1.37 mins; MS m/z 429.2 = [M+H]+ (100% @ 254 nm).
[00231] 1H NMR (400 MHz, Chloroform-d) 6 7.01 (d, = 6.8 Hz, 1 H), 6.81 (d, J = 9.6 Hz, 1 H), 6.39 (s, 1 H), 2.26 (s, 1 H), 1.48 (q, J = 4.7 Hz, 2H), 1 .27 (q, J = 4.8 Hz, 2H).
Example 4: 1,5-Dimethyl-6-thioxo-3- 2,2, 7-trifluoro-3-oxo-4-[(3-2H)-2-propynyl]-2,4-dihvdro- 1 , 4-benzoxazin-6-yl}- 1,3, 5-triazinane-2, 4-dione
Figure imgf000051_0001
[00232] Triethylamine (22.1 mg, 0.218 mmol) was added to a solution of 1 ,5-dimethyl-6- thioxo-3-[2,2,7-trifluoro-3-oxo-4-(2-propynyl)-2,4-dihydro-1 ,4-benzoxazin-6-yl]-1 ,3,5- triazinane-2, 4-dione (intermediate Z13) (30 mg, 0.0728 mmol) in methanol-d4 (0.5 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was diluted with water (10 mL) and the crude product extracted into ethyl acetate (2 x 10 mL). The combined organics were dried over MgSCU and concentrated in vacuo followed by lyophilisation to give the title compound as a white solid (25 mg).
[00233] LC-MS-2 (Method 2B): Rt 1.52 mins; MS m/z = 329.0 (100% @ 254nm). UPLC didn't indicate the mass of the product.
[00234] 1H NMR (400 MHz, CDCh) 6 7.26 (d, = 6.6 Hz, 1 H), 7.17 (d, J = 9.0 Hz, 1 H), 4.76 (s, 2H), 3.80 (s, 6H).
Example 5: 1, 5-Bis[ Hs methyll- -thioxo-S- , 2, 7-trifluoro-3-oxo-4-(2-propynyl)-2, 4-dihydro- 1 , 4-benzoxazin-6-yll- 1 , 3, 5-triazinane-2, 4-dione
Figure imgf000051_0002
[00235] 6-Amino-2,2,7-trifluoro-4-(2-propynyl)-2,4-dihydro-1 ,4-benzoxazin-3-one
(intermediate Z5) (77 mg, 0.301 mmol) was added to a solution of 1 ,1'-carbonyldiimidazole (146 mg, 0.901 mmol) and triethylamine (30.4 mg, 0.301 mmol) in ethyl acetate (0.3 mL). The reaction mixture was heated to 55 °C before a solution of 1,3-bis[(2H3)methyl]thiourea (intermediate Z10) (40 mg, 0.361 mmol) in ethyl acetate (0.7 mL) was added. The reaction mixture was heated at 76 °C for 18h then poured into iced water (200 mL) and 2M HCI (aq.) (30 mL). The crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 30% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (70 mg).
[00236] LC-MS-2 (Method 2B): Rt 1.51 mins; MS m/z = 435.0 (100% @ 254nm). UPLC didn't indicate the mass of the product.
[00237] 1H NMR (400 MHz, CDCh) 6 7.27 (s, 1H), 7.17 (d, J = 8.9 Hz, 1 H), 4.76 (d, J = 2.Q Hz, 2H), 2.38 (t, J = 2.5 Hz, 1 H).
Example 6: 1 , 5-Bis[ ( 2H3) meth yl]-6-thioxo-3-[2, 2, 7-trifluoro-3-oxo-4-r(3-2H) -2-prop ynyll-2, 4- di hydro- 1 ,4-benzoxazin-6-yl}- 1 , 3, 5-triazinane-2, 4-dione
Figure imgf000052_0001
[00238] Triethylamine (21.8 mg, 0.215 mmol) was added to a solution of Example 5 (30 mg, 0.0717 mmol) in methanol-d4 (0.5 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was diluted with water (10 mL) and the crude product extracted into ethyl acetate (2 x 10 mL). The combined organics were dried over MgSCU and concentrated in vacuo followed by lyophilisation to give the title compound as a white solid (16 mg).
[00239] LC-MS-2 (Method 2B): Rt1.48 mins; MS m/z = 297.1 (100% @ 254nm). UPLC didn't indicate the mass of the product.
[00240] 1H NMR (400 MHz, CDCh) 6 7.27-7.25 (m, 1 H), 7.17 (d, J = 8.9 Hz, 1H), 4.76 (s, 2H).
Figure imgf000052_0002
Figure imgf000053_0001
[00241] 6-Amino-2,2,7-trifluoro-4-(2-propynyl)-2,4-dihydro-1 ,4-benzoxazin-3-one (intermediate Z5) (120 mg, 0.468 mmol) was added to a solution of 1 ,1'-carbonyldiimidazole (228 mg, 1.41 mmol) and triethylamine (47.4 mg, 0.468 mmol) in ethyl acetate (0.48 mL). The reaction mixture was heated to 55 °C before a solution of 1-[(2Hs)methyl]-3- methylthiourea (intermediate Z12) (60 mg, 0.562 mmol) in ethyl acetate (1.12 mL) was added. The reaction mixture was heated at 76 °C for 18 h then poured into iced water (200 mL) and 2M HCI (aq.) (30 mL). The crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 35% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (140 mg).
[00242] LC-MS-1 (Method 2B): Rt 1.54 mins; MS m/z = 416.1 [M+H]+ (100% @ 254nm).
[00243] 1H NMR (500 MHz, CDC ) 6 7.27 (s, 1H), 7.17 (d, J = 9.0 Hz, 1 H), 4.76 (s, 2H), 3.79 (s, 3H), 2.38 (t, J = 2.5 Hz, 1 H).
Example 8: 1 ,5-Dimethyl-6-thioxo-3-[2,2,7-trifluoro-3-oxo-4-r(1 , 1-2H2)-2-propynyl]-2,4- di hydro- 1 ,4-benzoxazin-6-yl}- 1 , 3, 5-triazinane-2, 4-dione
Figure imgf000053_0002
[00244] 6-Amino-2,2,7-trifluoro-4-[(1,1-2H2)-2-propynyl]-2,4-dihydro-1 ,4-benzoxazin-3-one (intermediate Z8) (65 mg, 0.252 mmol)was added to a solution of 1 ,1'-carbonyldiimidazole (122 mg, 0.755 mmol) and triethylamine (26 mg, 0.252 mmol) in ethyl acetate (0.26 mL). The reaction mixture was heated to 55 °C before a solution of 1 ,3-dimethylthiourea (intermediate Z9) (32 mg, 0.302 mmol) in ethyl acetate (0.58 mL) was added. The reaction mixture was heated at 76 °C for 18 h then poured into iced water (20 mL) and 2M HCI (aq.) (5 mL). The crude product was extracted into ethyl acetate (3 x 15 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 20% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (55 mg).
[00245] LC-MS-2 (Method 2B): Rt 1.49 mins; MS m/z = 387.0 [M-H]’ (100% @ 254nm). UPLC didn't show the mass of the product.
[00246] 1H NMR (400 MHz, CDCh) 6 7.27-7.16 (m, 1H), 7.17 (d, J = 9.0 Hz, 1H), 3.79 (s, 6H), 2.37 (s, 1 H).
Figure imgf000054_0001
[00247] 6-Amino-2,2,7-trifluoro-4-[(1,1-2H2)-2-propynyl]-2,4-dihydro-1 ,4-benzoxazin-3-one (intermediate Z8) (60 mg, 0.232 mmol) was added to a solution of 1 ,1'-carbonyldiimidazole (113 mg, 0.697 mmol) and triethylamine (24 mg, 0.232 mmol) in ethyl acetate (0.24 mL). The reaction mixture was heated to 55 °C before a solution of 1,3-bis[(2H3)methyl]thiourea (intermediate Z10) (31 mg, 0.279 mmol) in ethyl acetate (0.54 mL) was added. The reaction mixture was heated at 76 °C for 18 h then poured into iced water (20 mL) and 2M HCI (aq.) (5 mL). The crude product was extracted into ethyl acetate (3 x 15 mL). The combined organics were dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (25 g MODUS silica cartridge, eluting 0 to 28% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a white solid (53 mg).
[00248] LC-MS-2 (Method 2B): Rt 1.48 mins; MS m/z = 290.3 [M+H]+ (100% @ 254nm). UPLC didn't show the mass of the product.
[00249] 1H NMR (400 MHz, CDCh) 6 7.27-7.25 (m, 1 H), 7.17 (d, J = 8.9 Hz, 1H), 2.37 (s, 1 H).
Example 10: 2-/7-Fluoro-3-oxo-4-[(3-2H)-2-propynyll-2,4-dihvdro-1,4-benzoxazin-6-yl}- 4,5,6, 7-tetrahydro-2H-isoindole- 1 , 3-dione
Figure imgf000054_0002
[00250] Triethylamine (65 pL, 0.5 mmol) was added to a solution of 2-[7-fluoro-3-oxo-4-(2- propynyl)-2,4-dihydro-1,4-benzoxazin-6-yl]-4,5,6,7-tetrahydro-2/7-isoindole-1 ,3-dione (flumioxazin) (55 mg, 0.15 mmol) in methanol-d4 (10 mL). The reaction mixture was stirred at toom temperature for 16 h then DMSO-d6 (2 mL) added to aid solubility. The reaction mixture was stirred at toom temperature for 24 h then diluted with water (5 mL) and the crude product extracted into ethyl acetate (2 x 10 mL). The combined organics were dried over MgSCU and concentrated in vacuo to give the title compound as an off-white solid (55 mg).
[00251] LC-MS-1 (Method 2B): Rt 1.40 mins; MS m/z 356.2 = [M+H]+ (89% @ 254nm).
1H NMR (400 MHz, CDCh) 6 7.05 (d, = 6.8 Hz, 1 H), 6.90 (d, J = 9.7 Hz, 1 H), 4.67 (m, 4H), 2.44 (m 4H), 1.84 (m, 4H).
Example 11: 2-/7-Fluoro-3-oxo-4-[(1 , 1-2H2)-2-propynyll-2,4-dihvdro-1,4-benzoxazin-6-yl}- 4,5,6, 7-tetrahydro-2H-isoindole- 1 , 3-dione
Figure imgf000055_0001
[00252] 4,5,6,7-Tetrahydroisobenzofuran-1,3-dione (53.406 mg, 351.016 pmol) was added to 6-amino-7-fluoro-4-[(1 , 1 -2H2)-2-propynyl]-2,4-dihydro-1 ,4-benzoxazin-3-one (intermediate Y6) (60 mg, 0.27 mmol) in acetic acid (0.9 mL). The reaction mixture was heated at 80 °C for
6 h then, upon cooling, was added to toluene (10 mL) and concentrated in vacuo. Toluene (10 mL) was added to the residue and the solution was concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (12 g MODUS silica cartridge, eluting 0.1 to 2% ethyl acetate in dichloromethane) to give the desired product as a white solid (90 mg).
[00253] LC-MS-2 (Method 2A): Rt 1.63 mins; mass not observed (100% @ 254nm).
[00254] 1H NMR (500 MHz, Chloroform-d) 57.04 (d, J = 6.8 Hz, 1 H), 6.90 (d, J = 9.6 Hz, 1 H), 4.67 (s, 2H), 2.48 - 2.41 (m, 4H), 2.28 (s, 1 H), 1.87 - 1.81 (m, 4H).
Example 12: N-l lsopropyl)-N-(2H3)methylaminosulfonyl]2-chloro-4-fluoro-5-l' 1-methyl-2,4- dioxo-6-(trifluoromethyl)-3-pyrimidinyllbenzamide
Figure imgf000055_0002
[00255] Carbonyldiimidazole (35 mg, 0.28 mmol) was added to a solution of 2-chloro-4- fluoro-5-[1-methyl-2,4-dioxo-6-(trifluoromethyl)-3-pyrimidinyl]benzoic acid (intermediate W6) (79 mg, 0.22 mmol) in tetrahydrofuran (1.1 mL). The reaction mixture was heated at reflux temperature for 2 h and then cooled to room temperature. A solution of (isopropyl)-A/- (2H3)methylaminosulfoamine (intermediate W11) (34 mg, 0.22 mmol) in tetrahydrofuran (0.15 mL) was added dropwise followed by 1 ,8-diazabicyclo(5.4.0)undec-7-ene (32 pL, 0.22 mmol). The reaction mixture was stirred at room temperature for 22 h and then diluted with water (20 mL) and HCI (2M aq., 5 mL). The crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with brine (2 x 10 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Interchim Puriflash® 450 (20 g MODUS Cis cartridge, 5 to 95% acetonitrile in water (0.1% aq. formic acid) followed by lyophilisation to give the title compound as a white solid (25 mg).
[00256] LC-MS-2 (Method 2A): Rt 1.56 min, MS m/z 503.9 = [M+H]+ (92% @ 254nm).
[00257] 1H NMR (400 MHz, CDCh) 6 8.79 (s, 1 H), 7.74 (d, = 7.5 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 6.37 (s, 1 H), 4.29 (hept, J = 6.7 Hz, 1 H), 3.56 (s, 3H), 1.21 (d, J = 6.7 Hz, 6H).
Figure imgf000056_0001
[00258] Carbonyldiimidazole (13 mg, 0.08 mmol) was added to a solution of [3-(5-carboxy-4- chloro-2-fluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1 ,1-pyrimidinediium-1-yl](2H3)methanuide (intermediate W4) (29 mg, 0.08 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was heated at reflux temperature for 2 h and then cooled to room temperature. (Isopropyl)-A/- methylaminosulfoamine (intermediate W13) (12 mg, 0.08 mmol) was added followed by 1 ,8- diazabicyclo(5.4.0)undec-7-ene (12 pL, 0.08 mmol). The reaction mixture was stirred at room temperature for 25 h and then diluted with water (8 mL) and HCI (2M aq., 2 mL). The crude product was extracted into ethyl acetate (3 x 10 mL). The combined organics were washed with brine (2 x 5 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (4 g MODUS silica cartridge, eluting 2 to 35% ethyl acetate/petroleum ether) followed by flash column chromatography on the Interchim Puriflash® 450 (5.4 g MODUS Cis cartridge, 5 to 95% acetonitrile in water (0.1% aq. formic acid) followed by lyophilisation to give the title compound as a white solid (7 mg).
[00259] LC-MS-2 (Method 2A): Rt 1.56 min, MS m/z 503.9 = [M+H]+ (100% @ 254 nm).
[00260] 1H NMR (400 MHz, CDCh) 6 8.82 (s, 1H), 7.74 (d, = 7.5 Hz, 1 H), 7.38 (d, J = 8.9 Hz, 1H), 6.37 (s, 1 H), 4.30 (hept, J = 6.8 Hz, 2H), 2.96 (s, 3H), 1.21 (d, J = 6.7 Hz, 6H).
Figure imgf000057_0001
[00261] Carbonyldiimidazole (35 mg, 0.22 mmol) was added to a solution of [3-(5-carboxy-4- chloro-2-fluorophenyl)-2,4-dioxo-6-(trifluoromethyl)-1 ,1-pyrimidinediium-1-yl](2H3)methanuide (intermediate W4) (80 mg, 0.22 mmol) in tetrahydrofuran (1.1 mL). The reaction mixture was heated at reflux temperature for 2 h and then cooled to room temperature. A solution of (isopropyl)-/V-(2H3)methylaminosulfoamine (intermediate W11) (34 mg, 0.22 mmol) in tetrahydrofuran (0.15 mL) was added dropwise followed by 1,8-diazabicyclo(5.4.0)undec-7- ene (33 pL, 0.22 mmol). The reaction mixture was stirred at room temperature for 22 h and then diluted with water (20 mL) and HCI (2M aq., 5 mL). The crude product was extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with brine (2 x 10 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Interchim Puriflash® 450 (20 g MODUS Cis cartridge, 5 to 95% acetonitrile in water (0.1% aq. formic acid) followed by lyophilisation to give the title compound as an off-white solid (26 mg).
[00262] LC-MS-2 (Method 2A): Rt 1.56 min, MS m/z 506.9 = [M+H]+ (96% @ 254 nm).
[00263] 1H NMR (400 MHz, CDCh) 6 8.79 (s, 1H), 7.74 (d, = 7.5 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 6.37 (s, 1 H), 4.29 (hept, J = 6.6 Hz, 2H), 1.21 (d, J = 6.7 Hz, 7H).
Example 15: Ethyl [3-(2-chloro-4-fluoro-5- 1-[(2H3)methyll-2,4-dioxo-6-(trifluoromethyl)-3- yrimidinyl}phenoxy)-2-pyridyloxy1acetate
Figure imgf000057_0002
[00264] Potassium carbonate (193 mg, 1.40 mmol) was added to a solution of ethyl (3-{2- chloro-5-[2,4-dioxo-6-(trifluoromethyl)-3-pyrimidinyl]-4-fluorophenoxy}-2-pyridyloxy)acetate (intermediate V4) (320 mg, 0.635 mmol) in /V,/V-dimethylformamide (9.6 mL). The reaction mixture was stirred at room temperature for 10 min and iodomethane-d3 (405 mg, 2.79 mmol) was added. The reaction mixture was stirred at room temperature for 19 h then diluted with water (80 mL). The crude product was extracted into dichloromethane (3 x 50 mL). The combined organics were washed with water (50 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 50% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as an off-white solid (59 mg).
[00265] LC-MS-1 (Method 2B): Rt 1.60 mins; MS m/z = 521.3 [M+H]+ (98% @ 254nm).
[00266] 1H NMR (400 MHz, CDCh) 6 7.92 (dd, J = 5.0, 1.6 Hz, 1 H), 7.37 (d, J = 8.9 Hz, 1 H), 7.31 (dd, J = 7.8, 1.6 Hz, 1H), 6.96 - 6.89 (m, 2H), 6.29 (s, 1 H), 5.01 - 4.82 (m, 2H), 4.16 (qd, J = 7.1, 0.9 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).
Comparative Compounds
Comparative Example A 3-(7-Fluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4- dihydrospiro[benzo[b][1,4loxazine-2, 1 '-cyclopropanl-6-yl)- 1-methyl-6- (trifluoromethyl)pyrimidine-2,4(1H,3H)-dione
Figure imgf000058_0001
[00267] Comparative Example A can be made according to the process described in WO 2019/020987 A1.
Epyrifenacil (ethyl (3-/2-chloro-4-fluoro-5-[ 1-methyl-2,4-dioxo-6-(trifluoromethyl)-3-
Pyrimidinyllphenoxy}-2-pyridyloxy)acetate)
Figure imgf000058_0002
[00268] Potassium carbonate (77 mg, 0.555 mmol) was added to a solution of ethyl (3-{2- chloro-5-[2,4-dioxo-6-(trifluoromethyl)-3-pyrimidinyl]-4-fluorophenoxy}-2-pyridyloxy)acetate (intermediate V4) (127 mg, 0.252 mmol) in /V,/V-dimethylformamide (3.8 mL). The reaction mixture was stirred at room temperature for 10 min and then iodomethane (157 mg, 1.11 mmol) was added. The reaction mixture was stirred at room temperature for 19 h then diluted with water (80 mL). The crude product was extracted into dichloromethane (3 x 50 mL). The combined organics were washed with water (50 mL), dried over MgSCU and concentrated in vacuo. The crude product was purified by flash column chromatography on the Combiflash® Nextgen 300+ (40 g MODUS silica cartridge, eluting 0 to 40% ethyl acetate in petroleum ether) followed by lyophilisation to give the title compound as a pink solid (26 mg).
[00269] LC-MS-2 (Method 2B): Rt 1.61 mins; MS m/z = 517.9 [M+H]+ (98% @ 254nm).
[00270] 1H NMR (400 MHz, CDCh) 6 7.92 (dd, J = 4.9, 1.6 Hz, 1 H), 7.37 (d, J = 8.9 Hz, 1 H), 7.31 (dd, J = 7.8, 1.6 Hz, 1H), 7.03 - 6.77 (m, 2H), 6.29 (s, 1 H), 5.05 - 4.79 (m, 2H), 4.16 (qd, J = 7.2, 0.9 Hz, 2H), 3.51 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).
Biological Activity
Experiment 1 - Testing the herbicidal activity of compounds of the invention
[00271] Examples 1-3 as well as Comparative Example A were screened at four concentrations (30, 10, 3 and 1 g/ha) against ALOMY.
[00272] Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer.
[00273] Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment. The assessment was based on the % necrosis compared to the untreated controls. Results are shown in Figure 1.
[00274] As can be seen from Figure 1 , certain compounds of the invention displayed an earlier onset of action and a clear improvement in performance in the control of blackgrass when compared to Comparative Example A.
Experiment 2 - Track Sprayer
[00275] Examples 2 and 3 as well as Comparative Example A were screened at three concentrations (30, 10 and 3 g/ha) against STEME, ABUTH and AMARE. Application was via a track sprayer at water volumes of 200 or 800 L/ha.
[00276] Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 20 ml/ m2 (equivalent to 2001/ha) of spray solution or 80ml/m2 (equivalent to 8001/ha) .depending on the experimental objectives, using a track sprayer. The formulation used was 25% acetone and 75% 0.1% Tween 20.
[00277] Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment. The assessment was based on the % necrosis compared to the untreated controls.
[00278] Figures 2 to 4 show that both Examples 2 and 3 were better than Comparative Example A, giving better weed control at the lowest concentration (3 g/ha) at an application rate of 200 L/ha (against all tested weeds) and at 800 L/ha (against Amaranthus). This evidence shows that certain compounds of the invention display improved potency over their non-deuterated counterpart.
Experiment 3 - Low Dose
[00279] Examples 2 and 3 as well as Comparative Example A were screened at four concentrations (10, 3 ,1 and 0.3 g/ha) against STEME, ABLITH and AMARE. Application was via a track sprayer at a water volume of 200 L/ha.
[00280] Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 20 ml/ m2 (equivalent to 200l/ha) of spray solution, using a track sprayer. The formulation used was 25% acetone and 75% 0.1% Tween 20.
[00281] Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment. The assessment was based on the % necrosis compared to the untreated controls.
[00282] Figures 5 to 7 shows that Example 3 displayed improved activity against the tested weeds.
Experiment 4 - Herbicidal Activity
[00283] Flumioxazin, Example 10, saflufenacil and Examples 12 to 14 were screened at four concentrations (30, 10, 3 and 1 g/ha) against four weed species, ALOMY, LOLPE, STEME AND .
[00284] Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer. Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment.
[00285] The assessment was based on the % necrosis compared to the untreated controls. Results are shown in Figures 8 to 11.
[00286] Figures 8 to 11 show significant improvement in activity of both Examples 10 and 14 in comparison with their respective parents.
Experiment 5 - Herbicidal Activity
[00287] Flumioxazin and Example 11 as well as trifludimoxazin and Examples 4 to 9 Flumioxazin, Example 10, saflufenacil and Examples 12 to 14 were screened at four (4) concentrations (30, 10, 3 and 1 g/ha) against ALOMY, STEME and ABLITH.
[00288] Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer. Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment.
[00289] The assessment was based on the % necrosis compared to the untreated controls. Results are shown in Figures 12 to 14.
[00290] Figures 12 to 14 shows improved control of the tested weed species by Example 11, compared with the flumioxazin. Examples 4 and 6 also shows some improvement over trifludimoxazin at certain doses against certain weeds.
Experiment 6 - Herbicidal Activity
[00291] Epyrifenacil and Example 15 were screened at four concentrations (30, 10, 3 and 1 g/ha) against ALOMY, AMARE, STEME and ABUTH.
[00292] Seeds were sown in 9 cm pots (5-10 seed per pot) 3 to 4 weeks prior to treatment. Broadleaf weeds were treated at the two true leaf stage and grass weeks when 2-3 leaves present with each replicate pot treated with 2 ml of spray solution. The formulation used was 25% acetone and 75% 0.1% Tween 20. Weeds were sprayed using a handheld atomiser sprayer. Each treatment was replicated three times. The weeds were kept in a glasshouse (uncontrolled conditions) and assessed 3, 7 and 14 days after treatment.
[00293] The assessment was based on the % necrosis compared to the untreated controls. Results are shown in Figures 15 to 18. [00294] Figure 15 shows that Example 15 displays either equivalent or improved activity against the tested weeds compared to epyrifenacil.

Claims

Claims:
1 . A compound of formula (I):
Figure imgf000063_0001
agronomically acceptable salt or N-oxide thereof, wherein R1 is independently at each occurrence selected from D and H;
R2 is independently selected from
Figure imgf000063_0002
and
Figure imgf000063_0003
are independently at each occurrence selected from -CD3, -CHD2, -CH2D and -CH3;
R5 is at each occurrence F or is at each occurrence H; or each R5 together with the carbon atom to which they are attached form cyclopropyl;
R6 is independently selected from D and H; and
X1 is independently selected from F, Cl and Br, wherein R1, R2 and R6 are selected so that at least one group selected from the two R1 groups, R2and R6 is D or comprises D.
2. A compound of claim 1 , wherein at least one R1 is D.
3. A compound of claim 2, wherein R1 is at both occurrences D.
4. A compound of any preceding claim, wherein R6 is D.
A compound of any preceding claim, wherein
Figure imgf000064_0001
A compound of any one of claims 1 to 4, wherein
Figure imgf000064_0002
7. A compound of any preceding claim, wherein R3 is independently selected from -CDs,
-CHD2 and -CH2D.
8. A compound of claim 7, wherein R3 is -CD3.
9. A compound of any one of claims 1 to 4, wherein
Figure imgf000064_0003
10. A compound of any preceding claim, wherein X1 is F.
11. A compound of claim 1 , wherein the compound of Formula (I) is a compound selected from:
Figure imgf000065_0001
12. A compound of formula (II):
Figure imgf000066_0001
agronomically acceptable salt or N-oxide thereof, wherein R6 is independently selected from -CD3, -CHD2, -CH2D, and -CH3;
Figure imgf000066_0002
R8 is independently at each occurrence selected from D and H;
R9 is at each occurrence F; or each R9 together with the carbon atom to which they are attached form cyclopropyl;
R10 is independently selected from -CD3, -CHD2, -CH2D and -CH3; and
X2 and X3 are each independently selected from F, Cl and Br, wherein R6 and R7 are selected so that, at least one group selected from R6 and R7 comprises D.
13. A compound of claim 12, wherein R6 is -CD3.
14. A compound of claim 12 or claim 13, wherein
Figure imgf000067_0001
15. A compound of any one of claims 12 to 14, wherein R8 is at each occurrence D.
16. A compound of claim 12 or claim 13, wherein R7 is
Figure imgf000067_0002
17. A compound of any one of claims 12 to 16, wherein X2 is F.
18. A compound of claim 12, wherein the compound of Formula (II) is a compound selected from:
Figure imgf000067_0003
Figure imgf000068_0001
19. A method for controlling weeds, the method comprising applying a compound of any preceding claim to the weeds themselves or to an area where it is envisioned that the weeds will grow or are growing.
20. A method of claim 19, wherein the weeds are Alopecurus myosuroides, Abutilon theophrasti or Amaranthus retroflexus.
21. Use of a compound of any one of claims 1 to 18 as a herbicide.
22. A herbicidal formulation comprising an effective amount of a compound of any one of claims 1 to 18.
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