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WO2024192147A2 - Protoporphyrinogen oxidase inhibitors - Google Patents

Protoporphyrinogen oxidase inhibitors Download PDF

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Publication number
WO2024192147A2
WO2024192147A2 PCT/US2024/019767 US2024019767W WO2024192147A2 WO 2024192147 A2 WO2024192147 A2 WO 2024192147A2 US 2024019767 W US2024019767 W US 2024019767W WO 2024192147 A2 WO2024192147 A2 WO 2024192147A2
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Prior art keywords
compound
formula
salt
iii
compound according
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PCT/US2024/019767
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French (fr)
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WO2024192147A3 (en
Inventor
Neville John ANTHONY
David Jeffrey Lauffer
Peter STCHUR III
Daniel A. Pearson
Jacqueline Ella Heard
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Enko Chem, Inc.
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Publication of WO2024192147A2 publication Critical patent/WO2024192147A2/en
Publication of WO2024192147A3 publication Critical patent/WO2024192147A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
    • A01N31/14—Ethers
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    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
    • A01N33/18—Nitro compounds
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/48—Nitro-carboxylic acids; Derivatives thereof
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    • A01N39/00—Biocides, pest repellants or attractants, or plant growth regulators containing aryloxy- or arylthio-aliphatic or cycloaliphatic compounds, containing the group or, e.g. phenoxyethylamine, phenylthio-acetonitrile, phenoxyacetone
    • A01N39/02—Aryloxy-carboxylic acids; Derivatives thereof
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    • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
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    • 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
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    • 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
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    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
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    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
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    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to protoporphyrinogen IX oxidase (PPO) inhibitors useful as herbicides.
  • PPO protoporphyrinogen IX oxidase
  • the present invention relates to certain fluorinated phenyl compounds, compositions comprising such compounds, processes for making such compounds and compositions, and methods for using such compounds for crop protection and to control unwanted vegetation.
  • Protox or PPO Herbicides that inhibit protoporphyrinogen oxidase (hereinafter referred to as Protox or PPO; EC:1.3.3.4), a key enzyme in the biosynthesis of protoporphyrin IX, have been used for selective weed control since the 1960s.
  • PPO catalyzes the last common step in chlorophyll and heme biosynthesis, which is the oxidation of protoporphyrinogen IX to protoporphyrin IX [Matringe M. et al., Protoporphyrinogen oxidase as a molecular target for diphenyl ether herbicides, Biochemistry Journal (1989) 260: 231-235].
  • protoporphyrinogen IX in the chloroplast and mitochondria, which is believed to leak into the cytosol where it is oxidized by a peroxidase.
  • protoporphyrin IX When exposed to light, protoporphyrin IX causes formation of singlet oxygen in the cytosol and the formation of other reactive oxygen species, which can cause lipid peroxidation and membrane disruption leading to rapid cell death [Lee H.J. et al., Cellular localization of protoporphyrinogen-oxidizing activities of etiolated barley leaves, Plant Physiology (1993) 102: 881].
  • PPO-inhibiting herbicides include many different structural classes of molecules, including diphenyl ethers (e.g. lactofen, acifluorfen, acifluorfen methyl ester, or oxyfluorfen); oxadiazoles (e.g.
  • cyclic imides e.g. S-23142, N-(4-chloro-2- fluoro-5-propargyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, chlorophthalim, N-(4- chlorophenyl)-3,4,5,6-tetrahydrophthalimide)]; phenyl pyrazoles (e.g. TNPP-ethyl, ethyl 2- [1-(2,3,4-trichlorophenyl)-4-nitropyrazolyl-5-oxy]propionate, M&B 39279); pyridine derivatives (e.g.
  • an agricultural composition including, in some variations, herbicidal compositions
  • the salt is an agriculturally suitable salt.
  • the composition optionally further includes at least one additional active ingredient.
  • the additional active ingredient may be an herbicide and/or herbicide safener.
  • provided are also processes for making the above-identified compounds, salts, and compositions.
  • provided are also methods for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of the invention, its salt, or a composition that includes a compound of the invention as described herein.
  • FIG.1 depicts a Schrodinger Maestro model of the binding configuration of fluorophenyl analog A5 in the active site of PPO.
  • FIG.2 depicts a Schrodinger Maestro model of the binding configuration of fluorophenyl analog A21 in the active site of PPO.
  • R 1 is OR 1a , N(R 1a )2, C(O)OR 1a , C(O)NHS(O)2R 1b , C(O)NHS(O)2N(R 1a )(R 1b ), S(O)2NHR 1a , S(O) 2 NHC(O)R 1b , alkyl, alkenyl, or alkynyl, wherein each alkyl, alkenyl, or alkynyl is substituted with C(O)OR w and optionally substituted with halo; each R 1a is, independently, H, alkyl optionally substituted with C(O)OR 1b , alkyl optionally substituted with C(O)N(R 1c )2, alkenyl, alkynyl, cycloalkyl, C(O)alkyl, C(O)
  • R 1 is OR 1a , N(R 1a ) 2 , C(O)OR 1a , C(O)NHS(O) 2 R 1b , C(O)NHS(O) 2 N(R 1a )(R 1b ), S(O) 2 NHR 1a , S(O) 2 NHC(O)R 1b , C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, or C2-4alkynyl is substituted with C(O)OR w and optionally substituted with halogen; each R 1a is, independently, H, C 1-6 alkyl optionally substituted with C(O)OR 1b , C 1-6 alkyl optionally substituted with C(O)N(R 1c ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloal
  • Ring A of the compounds of formula (I) has at least 4 F.
  • R 4 is H or F and each of R 5 , R 6 , and R 7 is F.
  • Ring A contains 5 F.
  • X is a bond.
  • X is O.
  • each R G1a is, independently, H, C1-4alkyl optionally substituted with C(O)OR G1b , C1-4alkyl optionally substituted with C(O)N(R G1c ) 2 , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C(O)C 1- 4alkyl, C(O)C3-6cycloalkyl, C(O)N(R G1x ), C1-4alkyl, C(O)OCH2C2-4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R G1x , pyridyl optionally substituted with OCH 2 CO 2 R G
  • the compound of formula (G-I) is a compound of formula (G-II): 11 ny-2699290 Attorney Docket No.26327-20012.40
  • R G1a is C1-4alkyl optionally substituted with C(O)OR G1b or C(O)N(R G1c )2.
  • R G1a is pyridyl substituted with OCH 2 CO 2 R G1x .
  • the compound of formula (G-I) is a compound of formula (G-III): [0040]
  • R G1a is, independently, H or S(O) 2 C 1-4 alkyl.
  • R 4 is F. In another further embodiment for any of the compounds of formulas (G-II) or (G- III), R 4 is H. In yet another further embodiment for any of the compounds of formulas (G-II) or (G-III), R 2 is Cl and R 3 is F.
  • R H1 is OR H1a , NHS(O)2R H1b , or NHS(O)2N(R H1a )(R H1b );
  • R H1a is H or C 1-6 alkyl optionally substituted with C(O)OC 1-4 alkyl or C(O)OC 2-4 alkenyl;
  • R H1b is C 1-6 alkyl;
  • R 2 is Cl or OCHF2;
  • R 3 is H or F; and
  • R 4 is H or F.
  • the compound of formula (H-I) is a compound of formula (H- II): [0045]
  • the compound of formula (H-I) is a compound of formula (H-IV): [0046]
  • R 2 is Cl, R 3 is F, and R 4 is F.
  • R 2 is Cl, R 3 is F, and R 4 is H.
  • the compound of formula (K-I) is a compound of formula (K- II): halogen atom.
  • the compound of formula (K-I) is a compound of formula (K-III): halogen atom.
  • R 3 is F.
  • X is Cl.
  • R Kx is H.
  • R Kx is C 1-2 alkyl.
  • R M1 is OR M1a , C(O)OR M1a , C(O)NHS(O) 2 R M1b , S(O) 2 NHR M1a , or S(O) 2 NHC(O)R M1b ; C 1-6 alkyl optionally substituted with C(O)OC 1-2 alkyl, or C 3-6 cycloalkyl; R M1b is C1-6alkyl, or C3-6cycloalkyl; R M2 is Cl or NO 2 ; R 4 is H or F; and R 5 is F or CF3.
  • the compound of formula (M-I) is a compound of formula (M-II): [0053] In a further embodiment, R 5 is F. In another further embodiment, R 5 is CF3. [0054] In another embodiment, the compound of formula (M-I) is a compound of formula (M-III): [0055] In a further embodiment, R 5 is F. In another further embodiment, R 5 is CF3. 15 ny-2699290 Attorney Docket No.26327-20012.40 [0056] In one embodiment, the compound of formula (M-I) is a compound of formula (M-IV): [0057] In a further embodiment, R 5 is F. In another further embodiment, R 5 is CF3.
  • the compound of formula (M-I) is a compound of formula (M-V): [0059] In a further embodiment, R 5 is F. In another further embodiment, R 5 is CF3. [0060] In some aspects, provided are compounds having formula (I): or a salt thereof, wherein: R 1 is OR 1a , N(R 1a )2, C(O)OR 1a , C(O)NHS(O)2R 1b , C(O)NHS(O)2N(R 1a )(R 1b ), S(O)2NHR 1a , S(O) 2 NHC(O)R 1b , C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, or C2-4alkynyl is substituted with C(O)OR w and optionally substituted with halogen; 16 ny-2699290 Attorney Docket No
  • R 1 is not CH 3 , S(O) 2 NHR 1a or S(O) 2 NHC(O)R 1b , and at least one of R 2 or R 3 is not H.
  • each of R 2 and R 3 is not H, and at least one of R 2 and R 3 is not F.
  • R 2 and at least one of R 1 or R 3 is not H.
  • R 1 is not NHCH3.
  • Table 1 Exemplary Compounds 18 ny-2699290 Attorney Docket No.26327-20012.40 19 ny-2699290 Attorney Docket No.26327-20012.40 20 ny-2699290 Attorney Docket No.26327-20012.40 [0064]
  • the invention features a method of controlling undesired vegetation, that includes contacting the vegetation or its environment with a compound of the invention, a salt thereof, or a composition comprising said compound.
  • the invention features a method of controlling undesired vegetation, that includes contacting the vegetation or its environment with a compound of formula (I), a salt thereof, or a composition comprising a compound of formula (I): 21 ny-2699290 Attorney Docket No.26327-20012.40 wherein R 1 is OR 1a , N(R 1a ) 2 , C(O)OR 1a , C(O)NHS(O) 2 R 1b , C(O)NHS(O) 2 N(R 1a )(R 1b ), S(O) 2 NHR 1a , S(O) 2 NHC(O)R 1b , C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, or C2-4alkynyl is substituted with C(O)OR w and optionally substituted with halogen; each R 1a is, independently, H
  • Ring A contains at least 3 F.
  • the method includes a compound of any one of formulas (G- I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M- II), (M-III), (M-IV), or (M-V), or a salt thereof.
  • the method includes a compound found in Table 1, or a salt thereof.
  • the invention features an herbicidal composition that includes a compound of the invention, a salt thereof.
  • the salt may be an agriculturally suitable salt.
  • the agriculturally suitable salt is a salt that exhibits herbicidal activity, or that is or can be converted in plants, water, or soil into a compound or salt with herbicidal activity.
  • the invention features an agricultural composition comprising a compound of the invention, or a salt thereof, and at least one additional component that serves as a carrier.
  • at least one additional component of the agricultural composition is a surfactant or a diluent.
  • the composition is an herbicidal composition.
  • the invention features a method of controlling undesired vegetation, the method comprising contacting the vegetation or its environment with an herbicidally effective amount of a compound of the invention, or agriculturally acceptable salt thereof.
  • the undesired vegetation includes weeds.
  • the undesired vegetation includes protoporphyrinogen IX oxidase (PPO) inhibitor-resistant weeds.
  • the PPO inhibitor-resistant weeds have a dG210 mutation.
  • a compound or composition of the invention is applied at a rate of 1 to 100 g per 10,000 m 2 .
  • contacting the undesired vegetation or its environment with a compound or composition of the invention leads to post-emergence control of the undesired vegetation.
  • the undesired vegetation is at least 60% controlled.
  • the undesired vegetation is at least 80% controlled.
  • the undesired vegetation is at least 90% controlled.
  • contacting the undesired vegetation or its environment with a compound or composition of the invention leads to pre-emergence control of the undesired vegetation.
  • the undesired vegetation is at least 60% controlled.
  • the undesired vegetation is at least 80% controlled.
  • the undesired vegetation is at least 90% controlled.
  • a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog of a base compound, wherein the base compound (i) inhibits protoporphyrinogen oxidase (PPO) and (ii) comprises a terminal cyclic moiety, wherein the fluorophenyl analog replaces the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein the fluorophenyl analog has one or more of the following properties: i) similar or improved inhibition of wild-type PPO, relative to the base compound; ii) similar or improved inhibition of DG210 mutant PPO, relative to the base compound; iii) similar or improved xylem mobility, relative to the base compound; iv) similar or improved phloem mobility, relative to the base compound; or v) similar
  • the base compound comprises a terminal alkyl ester moiety
  • the fluorophenyl analog replaces the terminal alkyl ester moiety with a carboxylic acid moiety.
  • a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog, wherein the fluorophenyl analog comprises a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein (i) when the fluorophenyl analog binds in the active site of protoporphyrinogen oxidase (PPO), the terminal phenyl moiety of the fluorophenyl analog is positioned within close proximity of a phenylalanine residue of the PPO, for example Phe392 in Amaranthus palmeri; or (ii) when the fluorophenyl analog binds in the active site of PPO, the terminal phenyl moiety of the fluorophenyl analog exhibits
  • a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog, wherein the fluorophenyl analog comprises a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein when the fluorophenyl analog binds in the active site of PPO, the terminal phenyl moiety of WKH ⁇ IOXRURSKHQ ⁇ O ⁇ DQDORJ ⁇ H[KLELWV ⁇ D ⁇ - ⁇ VWDFNLQJ ⁇ LQWHUDFWLRQ ⁇ ZLWK ⁇ WKH ⁇ SKHQ ⁇ O ⁇ ULQJ ⁇ RI ⁇ D ⁇ phenylalanine residue in the active site of the PPO, for example Phe392 in Amaranthus palmeri.
  • the fluorophenyl analog exhibits inhibition of wild-type PPO, LQKLELWLRQ ⁇ RI ⁇ * ⁇ PXWDQW ⁇ 332 ⁇ [ ⁇ OHP ⁇ PRELOLW ⁇ SKORHP ⁇ PRELOLW ⁇ RU ⁇ VRLO ⁇ PRELOLW ⁇ RU ⁇ DQ ⁇ combination of the foregoing.
  • the fluorophenyl analog is a compound of formula (A-I): [A] – [B] (A-I) Wherein [A] is a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and [B] is a core structure optionally substituted with one or more mobility targeting moieties.
  • [B] i) binds in the active site of the PPO, and ii) when binding in the active site RI ⁇ WKH ⁇ 332 ⁇ SRVLWLRQV ⁇ WKH ⁇ WHUPLQDO ⁇ SKHQ ⁇ O ⁇ PRLHW ⁇ >$@ ⁇ WR ⁇ H[KLELW ⁇ D ⁇ - ⁇ VWDFNLQJ ⁇ LQWHUDFWLRQ ⁇ with the phenyl ring of a phenylalanine residue in the active site of the PPO, for example Phe392 in Amaranthus palmeri.
  • a compound exhibiting inhibition PPO refers to the compound exhibiting an IC50 of less than 1 ⁇ M for the specified PPO.
  • a compound’s IC 50 for PPO is assessed by the method described in Examples 26 and 27.
  • a compound exhibiting xylem mobility or phloem mobility refers to a compound that is tested in the Setaria italica mobility assay described in Example 33 and causes rapid necrosis representative of PPO inhibition acropetal to or basipetal to the compound application site.
  • a compound’s soil mobility is assessed by the method described in Example 34.
  • the method comprises contacting the undesired vegetation or its environment with an herbicidally effective amount of the fluorophenyl analog.
  • a herbicidally effective amount refers to an amount of the compound, such that the quantity of such compound is capable of producing a controlling or modifying effect on the growth of plants. Controlling or modifying effects include all deviation from natural development, for example killing, retardation, leaf burn, albinism, dwarfing and the like.
  • the fluorophenyl analog is an analog of a base compound that (i) inhibits protoporphyrinogen oxidase (PPO) and (ii) comprises a terminal cyclic moiety, and the fluorophenyl analog replaces the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups.
  • the base compound may be sulfentrazone, which has the following structure: s ulfentrazone .
  • This compound comprises a terminal cyclic moiety, , that may be replaced with a pentafluorophenyl group, arrive at the fluorophenyl analog A1, which has the following structure: 26 ny-2699290 Attorney Docket No.26327-20012.40 Analog A1.
  • the base compound is sulfentrazone, flumioxazin, sulflufencil, fomesan, carfentrazone-ethyl, oxyfluorfen, acifluoren, bifenox, lactofen, pyraflufen-ethyl, tiafenacil, oxadiazon, pentoxazone, oxadiargyl, butafenacil, cinidon-ethyl, trifludimoxazin, or epyrifenacil.
  • the terminal cyclic moiety in the base compound is , [0091]
  • the base compound in addition to replacing the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups, the base compound may further be modified with one or more additional changes.
  • a mobility enhancing moiety may further be added to the base compound to arrive at the fluorophenyl analog.
  • the mobility enhancing moiety may improve xylem mobility, phloem mobility and/or soil mobility in the fluorophenyl analog as compared to the base compound.
  • the fluorophenyl analog is a compound of formula (A-I): [A] – [B] (A-I) Wherein [A] is a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and [B] is a core structure optionally substituted with one or more mobility targeting moieties.
  • [B] i) binds in the active site of the PPO, and ii) when binding in the active site 27 ny-2699290 Attorney Docket No.26327-20012.40 RI ⁇ WKH ⁇ 332 ⁇ SRVLWLRQV ⁇ WKH ⁇ WHUPLQDO ⁇ SKHQ ⁇ O ⁇ PRLHW ⁇ >$@ ⁇ WR ⁇ H[KLELW ⁇ D ⁇ - ⁇ VWDFNLQJ ⁇ LQWHUDFWLRQ ⁇ with the phenyl ring of a phenylalanine residue in the active site of the PPO, for example Phe392 in Amaranthus palmeri.
  • the core structure of [B] is selected from some embodiments of formula (A-I), the core structure is selected from the group consisting [0094]
  • the one or more mobility targeting moieties are configured to selectively enhance xylem mobility.
  • the one or more mobility targeting moieties are configured to selectively enhance phloem mobility.
  • the one or more mobility targeting moieties are configured to enhance both xylem and phloem mobility.
  • the one or more mobility targeting moieties are each 28 ny-2699290 Attorney Docket No.26327-20012.40 [0095] In some embodiments of formula (A-I), [B] is selected from the group consisting 29 ny-2699290 Attorney Docket No.26327-20012.40 . [0096] In some embodiments, the terminal phenyl moiety is substituted with 4 fluoro groups. In some embodiments, the terminal phenyl moiety is selected from the group consisting A1 , wherein R is H or -OCH 3 . In some embodiments R A1 is H. In some embodiments R A1 is -OCH3.
  • the terminal phenyl moiety [0097] In some embodiments of formula (A-I), [A] is a terminal phenyl moiety is substituted with 4 fluoro groups. In some embodiments of formula (A-I), [A] is selected from the group consisting , wh A1 erein R is H or - OCH3. In some embodiments R A1 is H. In some embodiments R A1 is -OCH3. In some embodiments of formula 30 ny-2699290 Attorney Docket No.26327-20012.40 [0098] In some embodiments, the terminal phenyl moiety is substituted with 5 fluoro groups.
  • the terminal phenyl moiety [0099] In some embodiments of formula (A-I), [A] is a terminal phenyl moiety substituted with 5 fluoro groups.
  • formula Definitions [0100] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains,” “containing,” “characterized by,” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, or method that includes or comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.
  • seedling used either alone or in a combination of words means a young plant developing from the embryo of a seed.
  • broadleaf used either alone or in terms such as “broadleaf weed” means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, or hexyl isomers.
  • Alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl, and hexenyl isomers.
  • Alkenyl also includes polyenes such as 1,2- propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl, and the different butynyl, pentynyl, and hexynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5- hexadiynyl.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy, and hexyloxy isomers.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • halogen or “halo” either alone or in compound words such as “haloalkyl,” or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine, or iodine.
  • C1-4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl
  • C 2 alkoxyalkyl designates CH 3 OCH 2 -
  • C 3 32 ny-2699290 Attorney Docket No.26327-20012.40 alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2-, or CH3CH2OCH2-
  • C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 - and CH3CH2OCH2CH2-.
  • the substituents are independently selected from the group of defined substituents, e.g., (R 1 ) m , where m is 0, 1, 2 or 3. Further, when the subscript indicates a range, e.g. (R)i-j, then the number of substituents may be selected from the integers between ‘i’ and ‘j’ inclusive.
  • substituents which can be hydrogen (H), for example, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to the group being unsubstituted.
  • variable group When a variable group is shown to be optionally attached to a position, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be “not substituted” or “unsubstituted,” then hydrogen atoms are attached to take up any free valency.
  • “Aromatic” indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the ring plane, and thaW ⁇ Q ⁇ HOHFWURQV ⁇ ZKHUH ⁇ Q ⁇ LV ⁇ D ⁇ positive integer, are associated with the ring to comply with Hückel's rule.
  • aromatic ring system denotes a carbocyclic or heterocyclic ring system in which at least one ring of the ring system is aromatic.
  • nonaromatic ring system denotes a carbocyclic or heterocyclic ring system that may be fully saturated, as well as partially or fully unsaturated, provided that none of the rings in the ring system are aromatic.
  • optionally substituted in connection with the heterocyclic rings refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated.
  • Preferred cations are the ions of the alkali metals, preferably of lithium, sodium and potassium, of the alkaline earth metals, preferably of calcium and magnesium, and of the transition metals, preferably of manganese, copper, zinc and iron, further ammonium and substituted ammonium in which one to four hydrogen atoms are replaced by C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 - alkoxy-C 1 -C 4 -alkyl, phenyl, or benzyl - preferably ammonium, methylammonium, isopropylammonium, dimethylammonium, diethylammonium, diisopropylammonium, trimethylammonium, triethylammonium, tris(isopropyl)ammonium, heptylammoni
  • Anions of useful acid addition salts are primarily chloride, bromide, fluoride, iodide, hydrogensulfate, methylsulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and also the anions of C1-C4-alkanoic acids - preferably formate, acetate, propionate, and butyrate.
  • the terms "undesirable vegetation” and “harmful plants” are synonyms.
  • stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers.
  • Stereoisomers are isomers of identical constitution but differing in the arrangement of their atoms in space and include enantiomers, diastereomers, cis-trans isomers (also known as geometric isomers) and atropisomers.
  • Atropisomers result from restricted rotation about single bonds where the rotational barrier is high enough to permit isolation of the isomeric species.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s).
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • Compounds of the invention typically exist in more than one form, and the formulas of the invention thus include all crystalline and non-crystalline forms of the compounds they represent.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e., different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice.
  • Polymorphs can differ in such chemical, physical, and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate, and biological availability.
  • a polymorph of a compound of the invention can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound.
  • Preparation and isolation of a particular polymorph of a compound of a compound of the invention can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
  • crystallization using selected solvents and temperatures.
  • salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms.
  • salts of compounds of the invention are useful for control of undesired vegetation (i.e., are agriculturally suitable).
  • the salts of compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic, or valeric acids.
  • inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic, or valeric acids.
  • salts also include those formed with organic or inorganic bases such as pyridine, triethylamine, or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium, or barium.
  • the invention features processes and intermediates for preparing compounds of the invention. These compounds can be prepared by general methods known in the art of synthetic organic chemistry. One or more of the following methods and variations as described in Schemes 1 to 10 can be used. [0122] In one general example, some compounds of formula (G-II) can be prepared as shown in Scheme 1.
  • Scheme 1 36 ny-2699290 Attorney Docket No.26327-20012.40 [0123] Accordingly, as shown in Step 1 of Scheme 1, where R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein, Prot is a phenol protecting group, and (R y O)2B is a boronic acid or boronate, a compound of formula (a) can be reacted with a fluorinated benzene analog containing leaving group L 1 (e.g., Br, I, or OTf) utilizing typical Suzuki conditions with a metal catalyst such as Pd, to provide a compound of formula (c).
  • L 1 e.g., Br, I, or OTf
  • a highly fluorinated benzene can be arylated directly with an arene of formula (b) using a metal catalyst (e.g., Pd or Cu) to provide a compound of formula (c).
  • a metal catalyst e.g., Pd or Cu
  • the phenol protecting group of a compound of formula (c) can be removed to produce a phenol of formula (d), which can subsequently be alkylated, acylated, or sulfonated with a compound of formula R G1a -L 2 as shown in Step 4, where L 2 is a leaving group such as a halogen, sulfonate, or a reactive intermediate in a Mitsinobu reaction, to form a compound of formula (e), which is a compound of formula (G-II) when R G1a , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein.
  • one R G1a group can be transformed into another R G1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides).
  • synthetic manipulations e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides.
  • some compounds formula (G-II) can be prepared as shown in Scheme 2.
  • the nitro group can be subsequently reduced (e.g., with iron powder) to produce a of formula (g).
  • an amine of formula (g) can be reacted with sodium nitrite in sulfuric acid to produce a phenol of formula (h) which can subsequently be alkylated, acylated, or sulfonated with compounds of formula R G1a -L 2 as shown in Step 4, where L 2 is a leaving group such as a halogen, sulfonate, or a reactive intermediate in a Mitsinobu reaction, to form compounds of formula (i), which are compounds of formula (G-II) when R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein and R G1a is phenyl or pyridyl optionally substituted with OCH2CO2R G1x , where R G1x is H or C1-6alkyl.
  • one R G1a group can be transformed into another R G1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides).
  • synthetic manipulations e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides.
  • some compounds of formula (G-III) can be prepared as shown in Scheme 3.
  • a highly fluorinated benzene can be arylated directly with an arene of formula (k) using a metal catalyst (e.g., Pd or Cu) to provide a compound of formula (m).
  • a metal catalyst e.g., Pd or Cu
  • the nitro group of a compound of formula (m) can be reduced (e.g., with sodium thiosulfate) to form of formula (n), which can subsequently alkylated, acylated, or sulfonated with a compound of formula R G1a -L 2 as shown in Step 4, where L 2 is a leaving group such as a halogen or sulfonate, to form a compound of formula (o), which is a compound of formula (G-III) when R 1a , R 2 , R 3 and R 4 are as described elsewhere herein and R 5 , R 6 , and R 7 are each F.
  • the compound of formula (n) can be reacted with an aldehyde of formula R G1a CHO in a reductive amination reaction to produce a compound of formula (o).
  • one R G1a group can be transformed into another R G1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides).
  • some compounds of formulas (H-II), (H-III), and (H- IV) can be prepared as shown in Scheme 4.
  • a highly fluorinated benzene can be arylated directly with an arene of formula (q) using a metal catalyst (e.g., Pd or Cu) to provide a compound of formula (r).
  • a metal catalyst e.g., Pd or Cu
  • the carboxylic acid protecting group of a compound of formula (r) can be removed to produce a carboxylic acid of formula (s), which can subsequently be alkylated with a compound of formula R H1a -L 2 as shown in Step 4, where L 2 is a leaving group such as a halogen, sulfonate, or a reactive intermediate in a Mitsinobu reaction, to form a compound of formula (t), which is a compound of formula (H-II) when R 1a , R 2 , R 3 , and R 4 are as described elsewhere herein and R 5 , R 6 , and R 7 are each F.
  • L 2 is a leaving group such as a halogen, sulfonate, or a reactive intermediate in a Mitsinobu reaction
  • one R H1a group can be transformed into another R H1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides).
  • a compound of formula (s) can be transformed into an active ester or an acyl halide (such as those known in the art used to prepare amides) and subsequently reacted with a sulfonamide of formula H 2 NS(O) 2 R H1b or H 2 NS(O) 2 N(R H1a )N(R H1b ) to form a compound of formula (u) or (v), respectively.
  • Compounds of formula (u) and compounds of formula (v) are compounds of formula (H-III) or (H-IV), respectively, where R H1a , R H1b , R 2 , R 3 , and R 4 are as described elsewhere herein and R 5 , R 6 , and R 7 are each F.
  • a compound of formula (w) can be reacted with a fluorinated benzene analog containing leaving group L 1 (e.g., Br, I, or OTf) utilizing typical Suzuki conditions with a metal catalyst such as Pd, to provide a compound of formula (x).
  • L 1 e.g., Br, I, or OTf
  • the compound of formula (x) can be nitrated (e.g., with nitric acid in sulfuric acid) to form a compound of formula (y), the nitro group of which can be subsequently reduced (e.g., with Fe powder) to form a compound of formula (z), as shown in Step 3.
  • a compound of formula (z) can be reacted 41 ny-2699290 Attorney Docket No.26327-20012.40 with a vinyl carboxylic ester to form a compound for formula (aa), which is a compound of formula (K-II) when X 1 is H and R 4 , R 5 , R 6 , and R 7 are each F.
  • the carboxylic ester of a compound of formula (aa) can by saponified (e.g., with LiOH) to form a compound of formula (ab).
  • a compound of formula (x) can be brominated or iodinated via reaction with N-bromosuccinimide or N-iodosuccinimide, respectively, to form a compound of formula (ad).
  • the compound of formula (ad) can be cross-coupled with a vinyl carboxylic ester, using a metal catalyst such as Pd, to form a compound of formula (ae), which is a compound of formula (K-III) where X 1 is H and R 3 , R 4 , R 5 , R 6 , and R 7 are each F.
  • a metal catalyst such as Pd
  • Subsequent hydrogenation results in a compound of formula (af), which is a compound of formula (K-II) when R x is X 1 is H and R 3 , R 4 , R 5 , R 6 , and R 7 are each F.
  • the ester of a compound of formula (af) can be saponified (e.g., with LiOH) to form a compound of formula (ag).
  • a compound of formula (ae) can be saponified to form a compound of formula (ah).
  • some compounds of formula (K-III) can be prepared as shown in Scheme 7.
  • a boronate or boronic acid of formula (aj) can be formed from a phenyl bromide of formula (ai) by procedures known to those skilled in the art (e.g., via the reaction of the bromide with triethylborate or (BPin)2).
  • the aldehyde boronate/boronic acid of formula (aj) can be reacted with a pentafluorobenzene having leaving group L 1 , which can be I, Br, or OTf, to form a compound of formula (ak).
  • L 1 which can be I, Br, or OTf
  • the aldehyde of formula (ak) can then be condensed with an alkyl 2-haloacetate to form a compound of formula (am), which is a compound of formula (K-III) when X 1 is halogen and R 3 , R 4 , R 5 , R 6 , and R 7 are each F.
  • the compound of formula (am) can then be saponified to form a compound of formula (an).
  • the compounds of formula (ao) (which are compounds of formula (M-I) when R 1 is OR M1a or of formula (M-II) when R 1 is OR 1a , R 2 is NO 2 , R 3 is H, and R 4 is F) can be prepared as shown in Scheme 8.
  • compounds of formula (as) can be prepared by reacting a monoprotected resorcinol of formula (aq) with a polyfluorinated benzene of formula (ar).
  • Prot is CH 3 and can be removed with a Lewis acid such as BBr3.
  • Step 3 Removal of Prot and subsequent O-alkylation with R M1a -L 2 , as shown in Step 3, where R M1a is as described elsewhere herein and L 2 is a leaving group such as a halogen or sulfonate, produces a compound of formula (at), which is a compound of formula (M-II) when R M1 is OR M1a , R 2 is NO2, R 3 is H, and R 4 , R 6 , and R 7 are each F. [0138] In another general example, some compounds of formulas (M-III) and (M-IV) can be prepared as shown in Scheme 9.
  • the resulting compound of formula (av) can be O-alkylated with a compound of formula R M1a -L 2 , where R M1a is as described elsewhere herein and L 2 is a leaving group such as a halogen or sulfonate, produces a compound of formula (ax).
  • the compound of formula (av) can be transformed into an active ester or an acyl halide (such as those known in the art used to prepare esters or amides) to produce the compound of formula (aw), where L 3 is a leaving group intermediate of an active ester or is a fluorine or chlorine.
  • reaction of a compound of formula (aw) with and alcohol of formula R M1a -OH or a sulfonamide of formula H 2 NS(O) 2 R M1b forms compounds of formula (ax) or (ay), respectively.
  • Compounds of formula (ax) are compounds of formula (M-III) when R M1 is C(O)OR M1a , R 2 is NO2, R 3 is H, and R 4 , R 6 , and R 7 are each F.
  • Compounds of formula (ay) are compounds of formula (M-III) when R M1 is C(O)OR M1a , R 2 is NO2, R 3 is H, and R 4 , R 6 , and R 7 are each F.
  • Scheme 10 [0141] Accordingly, as shown in Step 1 of Scheme 10, compounds of formula (ba) can be prepared by reacting phenols of formula (az) with a polyfluorinated benzene of formula (ar) under basic conditions, where L 1 , R 2 , R 3 , R 4 , and R 5 are as described elsewhere herein.
  • Step 2 subsequent reaction of a compound of formula (ba) with benzyl mercaptan produces a compound of formula (bb), which, as shown in Step 3, is subsequently transformed into a sulfonyl chloride of formula (bc) via reaction with oxidizing chlorinating agents such as 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione. Reaction of compounds of formula (bc) with ammonia produces a compound of formula (bd).
  • a method of preparing a compound of formula (G-II), or a salt thereof comprising: 46 ny-2699290 Attorney Docket No.26327-20012.40 reacting a boronic acid or boronate of formula (a), where R y is H, C1-4alkyl, or two R y O and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a tetrafluoro or pentafluoro benzene having leaving group L 1 , which can be iodine, bromine, or a sulfonate, to provide a compound of formula (c), reacting a protected phenol of formula (b) with tetrafluorobenzene or pentafluorobenzene under catalytic conditions to also provide a compound of formula (c); ; removing protecting group Prot from a compound of formula (c), then reacting the
  • the compound of formula (e) is a compound of formula (G-II), when each of R 5 , R 6 , and R 7 are F.
  • a method of preparing a compound of formula (j), or a salt thereof comprising: 47 ny-2699290 Attorney Docket No.26327-20012.40 reacting a compound of formula (d) with a nitrobenzene or nitropyridine of formula (e), under basic conditions to produce a compound of formula (f), where Q 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein and where L 3 is a halogen or sulfonate, ; reducing the nitro group of a compound of formula (f) to an amine of formula (g), transforming aniline of formula (g) to a phenol of formula (h), reacting a phenol of formula (h) with alkylating agent R G1a -
  • a method of preparing a compound of formula (III) as described herein, or a salt thereof comprising: reacting a boronic acid or boronate of formula (j), where R y is H, C 1-4 alkyl, or two R y O and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a fluorinated benzene having leaving group L 1 , which can be iodine, bromine, or a sulfonate, to provide a compound of formula (m), , or reacting a nitrobenzene of formula (m) with tetrafluorobenzene or pentafluorobenzene to provide a compound of formula (n); reducing the nitro group of the compound of formula (n) to an amine to produce a compound of formula (o), then react
  • R 5 , R 6 , and R 7 are each F and the compound of formula (o) is a compound of formula (G-III) 49 ny-2699290 Attorney Docket No.26327-20012.40 [0145]
  • a method of preparing a compound of formulas (s), (t), (u), or (v) comprising: reacting a boronic acid or boronate of formula (p), where R y is H, C 1-4 alkyl, or two R y O and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a tetrafluoro or pentafluoro benzene having leaving group L 1 , which can be iodine, bromine, or a sulfonate, to provide a compound of formula (r), reacting a protected carboxylic acid of formula (q) with tetrafluorobenzene or pentafluor
  • the compound of formula (t) is a compound of formula (H-II) when R 5 , R 6 , and R 7 are each F.
  • a method of preparing a compound of formula (u) or a compound of formula (v) comprising: reacting a boronic acid or boronate of formula (p), where R y is H, C1-4alkyl, or two R y O and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a polyfluorinated benzene having leaving group L 1 , which can be iodine, bromine, or a sulfonate, to provide a compound of formula (r), , or reacting a protected carboxylic acid of formula (q) with a polyfluorinated benzene under catalytic conditions to also provide a compound of
  • the compound of formula (u) is a compound of formula (H-III) when R 5 , R 6 , and R 7 are each F.
  • the compound of formula (v) is a compound of formula (H-IV) when R 5 , R 6 , and R 7 are each F.
  • a method of preparing a compound of formulas (aa) and (ab) comprising: reacting a boronic acid or boronate of formula (w), where R y is H, C 1-4 alkyl, or two R y O and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a pentafluoro benzene having leaving group L 1 , which can be iodine, bromine, or a sulfonate, to provide a compound of formula (x), nitrating the compound of formula (x) to provide a compound of formula (y), reducing the nitro group of a compound of formula (y) to form a compound of formula (z), 52 ny-2699290 Attorney Docket No.26327-20012.40 reacting the aniline of formula (z) with an alkyl vinylcarboxalate under Sandmeyer-like conditions with a copper(I
  • the compound of formula (aa), which is a compound of formula (K-II) when X 1 is halogen, R Kx is C 1-2 alkyl, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F, can be saponified to form a compound of formula (ab), which is a compound of formula (K-II) when X 1 is halogen, R Kx is H, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F.
  • a method of preparing a compound of formulas (ae) and (af) comprising: reacting a compound of formula (x) with N-bromosuccinimide or N- iodosuccinimide to form a compound of formula (ad), reacting the compound of formula (ad) with an alkyl vinylcarboxylate, under cross-coupling conditions using a metal catalyst such as palladium, to form a compound of formula (ae), 53 ny-2699290 Attorney Docket No.26327-20012.40 hydrogenating a compound of formula (ae) to form a compound of formula (af), , where R Kx , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein.
  • the compound of formula (af), which is a compound of formula (K-II), where X 1 is H, R Kx is C 1-2 alkyl, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F, can be saponified to form a compound of formula (ag), which is a compound of formula (K-II) where each of X 1 and R x is H, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F.
  • the compound of formula (ae), which is a compound of formula (K-III) where X 1 is H, R Kx is C 1-2 alkyl, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F, can be saponified to form a compound of formula (ah), where X 1 is H, R Kx is H, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F.
  • a method of preparing a compound of formula (am) comprising: reacting a boronic acid or boronate of formula (aj), where R y is H, C1-4alkyl, or two R y O and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a polyfluoro benzene having leaving group L 1 , which can be iodine, bromine, or a sulfonate, to provide a compound of formula (ak), 54 ny-2699290 Attorney Docket No.26327-20012.40 condensing the aldehyde of formula (ak) with an alkyl 2-haloacetate to form a compound of formula (am), , where X 1 is halogen and R Kx , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein.
  • the compound of formula (am), which is a compound of formula (K-III) where R Kx is C 1-2 alkyl, X 1 is halogen, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F, can be saponified to form a compound of formula (an), which is a compound of formula (K-III) where R Kx is H, X 1 is halogen, each of R 3 and R 4 is H or F, and each of R 5 , R 6 , and R 7 is F.
  • a method of preparing a compound of formula (at) comprising: reacting a polyfluorinated phenol of formula (ap), as shown below, with protected phenol (ao), where L 1 is a leaving group such as a halogen or a sulfonate, to provide a compound of formula (as), ; and 55 ny-2699290 Attorney Docket No.26327-20012.40 removing protecting group Prot from a compound of formula (as), then reacting the resulting phenol with alkylating agent R M1a -L 2 , where L 2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (at), , where R M1a , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein.
  • the compound of formula (at) is a compound of formula (M-II) when R M1a is as described elsewhere herein, R 2 is NO 2 , R 3 is H, each of R 4 , R 6 , and R 7 is F, and R 5 is F or CF 3 .
  • a method of preparing a compound of formula (at) comprising: reacting a monoprotected resorcinol of formula (aq), as shown below, with a polyfluorinated benzene of formula (ar) to provide a compound of formula (as), removing protecting group Prot from a compound of formula (as), then reacting the resulting phenol with alkylating agent R M1a -L 2 , where L 2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (at), , where R M1a , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein.
  • the compound of formula (at) is a compound 56 ny-2699290 Attorney Docket No.26327-20012.40 of formula (M-II) when R M1a is as described elsewhere herein, R 2 is NO2, R 3 is H, each of R 4 , R 6 , and R 7 is F, and R 5 is F or CF3.
  • a method of preparing a compound of formula (ax) comprising: reacting a fluorinated phenol of formula (ap) with a protected benzoic acid of formula (au), where L 1 is a leaving group such as a halogen or a sulfonate, followed by removal of the protecting group to provide a compound of formula (av), alkylating a compound of formula (av) with a compound having formula L 2 -R M1a , where L 2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (ax), and R 7 are as described elsewhere herein.
  • the compound of formula (at) is a compound of formula (M-III) when R M1a is as described elsewhere herein, R 2 is NO2, R 3 is H, each of R 4 , R 6 , and R 7 is F, and R 5 is F or CF3.
  • a compound of formula (M-III) can be formed by reacting a carboxylic acid of formula (av) with an activating agent, where L 3 is a leaving group such as F, Cl, OBt, OAt, or is the result of reacting the carboxylic acid with a carbodiimide, to provide a compound of formula (aw), 57 ny-2699290 Attorney Docket No.26327-20012.40 reacting an active ester of formula (aw) with an alcohol of formula R M1a -OH, to provide a compound of formula (ax), and R 7 are as described elsewhere herein.
  • an activating agent where L 3 is a leaving group such as F, Cl, OBt, OAt, or is the result of reacting the carboxylic acid with a carbodiimide
  • the compound of formula (at) is a compound of formula (M-III) when R M1a is as described elsewhere herein, R 2 is NO 2 , R 3 is H, each of R 4 , R 6 , and R 7 is F, and R 5 is F or CF3.
  • a method of preparing a compound of formula (ay) comprising: reacting a carboxylic acid of formula (av) with an activating agent to provide a compound of formula (aw), where L 3 is a leaving group such as F, Cl, OBt, OAt, or is the result of reacting the carboxylic acid with a carbodiimide, reacting a compound of formula (aw) with a sulfonamide of formula R 1b S(O) 2 NH 2 , to provide a compound of formula (ay), 58 ny-2699290 Attorney Docket No.26327-20012.40 , where R M1b , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described elsewhere herein.
  • a method of preparing a compound of formula (be) comprising: reacting a phenol of formula (az) with a fluorinated benzene of formula (ar) to provide a compound of formula (ba), reacting a compound of formula (aw), where L 1 is a leaving group such as a halogen or a sulfonate, with benzyl mercaptan to provide a compound of formula (ax), ; reacting a compound of formula (bb) with 1,3-dichloro-5,5- dimethylimidazolidine-2,4-dione to provide a compound of formula (bc), 59 ny-2699290 Attorney Docket No.26327-20012.
  • compositions [0164]
  • a compound of this disclosure including an agriculturally suitable salt thereof, may be used as an herbicidal active ingredient in a formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents, and liquid diluents, which serves as a carrier.
  • the formulation ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application, and environmental factors such as soil type, moisture, and temperature.
  • compositions provided here are herbicides.
  • the compositions comprise a compound of this disclosure that controls or modifies the growth of plants.
  • the compositions comprise a herbicidally effective amount of the compound, such that the quantity of such compound is capable of producing a controlling or modifying effect on the growth of plants. Controlling or modifying effects include all deviation from natural development, for example killing, retardation, leaf burn, albinism, dwarfing and the like.
  • Liquid formulations include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions, oil-in -water emulsions, flowable 62 ny-2699290 Attorney Docket No.26327-20012.40 concentrates and/or suspoemulsions), and the like, which optionally can be thickened into gels.
  • the general types of aqueous liquid formulations are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion, oil-in-water emulsion, flowable concentrate, and suspoemulsion.
  • nonaqueous liquid formulations are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate, and oil dispersion.
  • solid formulations are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings), and the like, which can be water- dispersible ("wettable") or water-soluble. Films and coatings formed from film-forming solutions or flowable suspensions are particularly useful for seed treatment.
  • Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation. Alternatively, the entire formulation of active ingredient can be encapsulated (or "overcoated”). Encapsulation can control or delay release of the active ingredient.
  • Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water, but occasionally another suitable medium like an aromatic or paraffinic hydrocarbon or vegetable oil. Spray volumes can range from about from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant.
  • Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting.
  • the formulations will typically contain effective amounts of active ingredient, diluent, and surfactant within the following approximate ranges, shown in Table 2, which add up to 100 percent by weight. 63 ny-2699290 Attorney Docket No.26327-20012.40 Table 2.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
  • Liquid diluents include, for example, water; N,N-dimethylalkanamides (e.g., N,N- dimethylformamide); limonene; dimethyl sulfoxide; N-alkylpyrrolidones (e.g., N- methylpyrrolidinone); alkyl phosphates (e.g., triethyl phosphate); ethylene glycol; triethylene glycol; propylene glycol; dipropylene glycol; polypropylene glycol; propylene carbonate; butylene carbonate; paraffins (e.g., white mineral oils, normal paraffins, isoparaffins); alkylbenzenes; alkylnaphthalenes; glycerine; glycerol triacetate; sorbitol; aromatic hydrocarbons; dearomatized aliphatics; alkylbenzenes; alkylnaphthalenes; ketones such as cyclohe
  • Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22) such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut, and palm kernel), animal- sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof.
  • plant seed and fruit oils e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut, and palm kernel
  • animal- sourced fats e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil
  • Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources and can be purified by distillation. Typical liquid diluents are described in C. Marsden & S. Mann, Solvents Guide, Cleaver-Hume Press, London, 1963. [0173] Surfactants can be classified as nonionic, anionic, or cationic.
  • Nonionic surfactants useful for the present formulations include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides, and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor, and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates, and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from prop
  • Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxyl
  • Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines, and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts, and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
  • amines such as N-alkyl propanediamines, tripropylenetriamines, and dipropylenetetramines, and ethoxyl
  • Nonionic, anionic, and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon' s Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
  • Formulations of the present invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents, or surfactants).
  • Such formulation auxiliaries and additives may control the following: pH (buffers), foaming during processing 66 ny-2699290 Attorney Docket No.26327-20012.40 (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes.
  • Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone- vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers, and waxes.
  • formulation auxiliaries and additives include those listed in McCutcheon's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
  • the compounds of the invention and any other active ingredients are typically incorporated into the present formulations by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent.
  • Solutions including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid formulations intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2,000 microns can be wet milled using media mills to obtain particles with average diameters below 3 microns. Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. Pat. No.3,060,084) or further processed by spray drying to form water-dispersible granules.
  • Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill).
  • Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, “Agglomeration,” Chemical Engineering, December 4, 1967, pp 147-48, Perry 's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and PCT Publication WO 91/13546.
  • Pellets can be prepared as described in U.S. Pat. No. 4,172,714.
  • Water-dispersible and water-soluble granules can be prepared as taught in U.S. Pat. Nos.4,144,050 and 3,920,442 and German Pat. No.3,246,493. Tablets can be prepared as taught in U.S. Pat. Nos.5,180,587, 5,232,701, and 5,208,030. Films can be prepared as taught in Great Britain Pat. No.2,095,558 and U.S. Pat. No.3,299,566. 67 ny-2699290 Attorney Docket No.26327-20012.40 [0179] For further information regarding the art of formulation, see T. S.
  • Woods “The Formulator's Toolbox - Product Forms for Modern Agriculture” in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp.120-133. See also U.S. Pat. No.3,235,361, Col.6, line 16 through Col.7, line 19 and Examples 10-41; U.S. Pat. No.3,309,192, Col.5, line 43 through Col.7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. Pat.
  • the compounds of the invention generally show highest activity for postemergence weed control (e.g., applied after weed seedlings emerge from the soil) and preemergence weed control (e.g., applied before weed seedlings emerge from the soil). Many of them have utility for broad- spectrum pre- and/or postemergence weed control in areas where complete control of all vegetation is desired such as around fuel storage tanks, industrial storage areas, parking lots, drive-in theaters, airfields, riverbanks, irrigation, and other waterways, around billboards and highway and railroad structures.
  • a method of controlling undesired vegetation comprising applying a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V), or a salt thereof (including an agriculturally suitable salt thereof).
  • 68 ny-2699290 Attorney Docket No.26327-20012.40 the compound is applied at low application rates.
  • the compound is applied at a rate of 1 to 10,000 g per 10,000 m 2 , 2 to 5,000 g per 10,000 m 2 , 5 to 2,000 g per 10,000 m 2 , 1 to 1000 g per 10,000 m 2 , 1 to 500 g per 10,000 m 2 , 1 to 100 g per 10,000 m 2 , 1 to 75 g per 10,000 m 2 , 15 to 1000 g per 10,000 m 2 , 15 to 100 g per 10,000 m 2 , 15 to 75 g per 10,000 m 2 , or 15 to 60 g per 10,000 m 2 .
  • the application of the compound at the aforementioned application rates leads to postemergence control of the undesired vegetation and/or preemergence control of the undesired vegetation.
  • the application of the compound, including at the aforementioned application rate leads to burndown.
  • burndown refers to when an herbicide is used to reduce weed presence at the time of treatment. Burndown is often used in minimum or no-till fields because the weeds cannot be managed by tilling the soil. The burndown application may be used post-harvest and/or prior to crop emergence. Burndown may be useful against weeds that emerge between growing seasons.
  • the application of the compound, including at the aforementioned application rate imparts residual control.
  • the undesired vegetation is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% controlled.
  • the undesired vegetation is a weed.
  • the undesired vegetation is a PPO inhibitor-resistant weed.
  • Examples of crop fields treated by the compounds in the present invention include edible crop fields such as peanut fields, soybean fields, corn fields, and wheat fields, feed crop fields such as sorghum fields and oat fields, industrial crop fields such as cotton fields and rape fields, and sugar crop fields such as sugarcane fields and sugar beet fields.
  • crop fields treated by the compounds herein include corn, soybean, wheat, and cotton fields.
  • Examples of vegetable fields treated by the compounds in the present invention include fields for cultivation of solanaceous vegetables (eggplants, tomatoes, bell peppers, capsicums, potatoes, and the like), fields for cultivation of cucurbitaceous vegetables (cucumbers, pumpkins, zucchini, watermelons, melons, and the like), fields for cultivation of cruciferous vegetables (radishes, turnips, horseradishes, kohlrabies, Chinese cabbages, cabbages, mustard, broccolis, cauliflowers, and the like), fields for cultivation of asteraceous vegetables (burdocks, garland chrysanthemums, artichokes, lettuces, and the like), fields for cultivation of liliaceous vegetables (leeks, onions, garlics, and asparagus), fields for cultivation of apiaceous vegetables (carrots, parsley, celery, parsnips, and the like), fields for cultivation of chenopodiaceous vegetables (spinach,
  • Examples of the land under perennial crops in the present invention include orchards, tea fields, mulberry fields, coffee fields, banana fields, palm fields, flowering tree firms, flowering tree fields, planting stock fields, nursery fields, forest lands, and gardens.
  • Examples of the orchard trees in the present invention include pomaceous fruits (apples, pears, Japanese pears, Chinese quinces, quinces, and the like), stone fruits (peaches, plums, nectarines, Japanese apricots, cherries, apricots, prunes, and the like), citrus fruits (Citrus unshiu, oranges, lemons, limes, grapefruits, and the like), nut trees (chestnuts, walnuts, hazelnut trees, almonds, pistachios, cashew nut trees, macadamia nut trees, and the like), berry fruits (grapes, blueberries, cranberries, blackberries, raspberries, and the like), Japanese persimmons, olives, and loquats.
  • Examples of the non-crop land in the present invention include athletic fields, empty lots, railroad edges, parks, parking lots, road edges, dry riverbeds, lands under a power line, residential lands, and factory sites.
  • the crop cultivated in the crop field in the present invention is not limited as long as the crop is a variety generally cultivated as a crop.
  • the plant of the above-mentioned variety may be a plant that can be produced by natural crossing, a plant that can be generated by mutation, an F1 hybrid plant, or a transgenic plant (also referred to as a genetically-modified plant).
  • the plant generally has properties such as obtaining of the tolerance to an herbicide, accumulation of a toxic substance against a 70 ny-2699290 Attorney Docket No.26327-20012.40 pest, suppression of the susceptibility to a disease, increase in the yield potential, improvement in the tolerance to a biotic and an abiotic stressors, accumulation of a substance, and improvement in the preservability and the processability.
  • An F1 hybrid plant is a first-generation hybrid obtained by crossing varieties of two different strains, and generally has a heterotic property with a trait superior to that of either of the parents.
  • a transgenic plant has a foreign gene introduced from another organism or the like such as a microorganism and has a property that cannot be easily obtained by cross breeding, mutagenesis, or natural recombination in a natural environment.
  • Examples of the techniques for producing the above-mentioned plants include conventional breeding techniques; genetic engineering techniques; genome breeding techniques; new breeding techniques; and genome editing techniques.
  • Conventional breeding techniques are for obtaining a plant having a desirable property by mutation or crossing.
  • Genetic engineering techniques include techniques for imparting a new property to a target organism by extracting a target gene (DNA) from another organism (for example, a microorganism) and introducing the target gene into the genome of the target organism.
  • Genome breeding techniques are for improving breeding efficiency using genomic information, and examples of the genome breeding techniques include DNA marker (also called genomic marker or genetic marker) breeding techniques and genomic selection.
  • DNA marker breeding is a method in which a progeny having a target useful trait gene is selected from a large number of crossed progenies using a DNA marker that is a DNA sequence that serves as a marker of the location of the specific useful trait gene on the genome. In the method, the crossed progeny is analyzed when it is an infant plant using a DNA marker to effectively shorten the time required for the breeding.
  • Genomic selection is a technique in which a prediction formula is created from a phenotype and genomic information obtained in advance to predict the property from the prediction formula and the genomic information without evaluating the phenotype and is a technique that can contribute to improving breeding efficiency.
  • new breeding techniques is a general term for breed improvement (breeding) techniques that combine molecular biological techniques.
  • Examples of the new breeding techniques include cisgenesis/intragenesis, oligonucleotide-directed mutagenesis, RNA-dependent DNA 71 ny-2699290 Attorney Docket No.26327-20012.40 methylation, genome editing, grafting on a GM rootstock or a scion, reverse breeding, agroinfiltration, and seed production technology (SPT).
  • the genome editing technique is for converting genetic information in a sequence-specific manner, and it is possible to delete a base sequence, substitute an amino acid sequence, introduce a foreign gene, and the like using the technique.
  • Examples of the tool include sequence-specific genome modification techniques such as a zinc finger nuclease capable of sequence-specific DNA cleavage (Zinc- Finger, ZFN), TALEN, CRISPR-Cas9, CRISPER-Cpf1, Meganuclease, and CAS9 Nickase and Target-AID created by modifying the aforementioned tools.
  • sequence-specific genome modification techniques such as a zinc finger nuclease capable of sequence-specific DNA cleavage (Zinc- Finger, ZFN), TALEN, CRISPR-Cas9, CRISPER-Cpf1, Meganuclease, and CAS9 Nickase and Target-AID created by modifying the aforementioned tools.
  • Examples of the above-mentioned plants include plants listed in the database of the registered genetically-modified crops (GM Approval Database) in the electronic information site of International Service for the Acquisition of Agri-biotech Applications (ISAAA) (http://www.isaaa.org/).
  • herbicide-tolerant plants More specific examples are herbicide-tolerant plants, pest-resistant plants, disease-resistant plants, plants modified in the quality (for example, with increase or decrease in the content or change in the composition) of the products (for example, starch, amino acids, and fatty acids), fertility trait-modified plants, abiotic stress-tolerant plants, and plants modified in the trait related to the growth or the yield.
  • Mechanisms of obtaining herbicide tolerance include reduction in the affinity between the agent and its target, rapid metabolism (decomposition, modification, and the like) of the agent by an expressed enzyme that inactivates the agent, or inhibition of incorporation or translocation of the agent in the plant body.
  • Examples of the plants to which herbicide tolerance has been imparted by genetic engineering technique include plants to which tolerance has been imparted to 4-hydroxyphenylpyruvate dioxygenase (hereinafter abbreviated as HPPD) inhibitors such as isoxaflutole and mesotrione, acetolactate synthase (hereinafter abbreviated as ALS) inhibitors such as imidazolinone herbicides containing imazethapyr and sulfonylurea herbicides containing thifensulfuron-methyl, 5- enolpyruvylshikimate-3-phosphate synthase (hereinafter abbreviated as EPSP) inhibitors such as glyphosate, glutamine synthase inhibitors such as glufosinate, auxin herbicides such as 2,4-D and dicamba, and oxynyl herbicides containing bromoxynil.
  • HPPD 4-hydroxyphenylpyruvate dioxygenase
  • glyphosate herbicide-tolerant plants one or more genes are introduced from: a glyphosate-tolerant EPSPS gene (CP4 epsps) from Agrobacterium tumefaciens strain CP4; a glyphosate metabolizing enzyme gene (gat4601, gat4621) in which the metabolic activity of the glyphosate metabolizing enzyme (glyphosate N-acetyltransferase) gene from Bacillus licheniformis is enhanced by a shuffling technique; a glyphosate metabolizing enzyme (glyphosate oxidase gene, goxv247) from Ochrobacterum anthropi strain LBAA; and EPSPS genes from maize having a glyphosate-tolerant mutation (mepsps, 2mepsps).
  • CP4 epsps CP4 epsps
  • a glyphosate metabolizing enzyme gene gat4601, gat4621
  • Main examples of the plants are alfalfa (Medicago sativa), Argentine canola (Brassica napus), cotton (Gossypium hirsutum L.), creeping bentgrass (Agrostis stolonifera), maize (Zea mays L.), polish canola (Brassica rapa), potato (Solanum tuberosum L.), soybean (Glycine max L.), sugar beet (Beta vulgaris), and wheat (Triticum aestivum).
  • Some glyphosate-tolerant transgenic plants are commercially available.
  • the genetically-modified plant in which the glyphosate-tolerant EPSPS from the Agrobacterium is expressed is commercially available with a trade name such as “Roundup Ready®”
  • the genetically-modified plant in which the glyphosate metabolizing enzyme that is from Bacillus and has the metabolic activity enhanced by a shuffling technique is expressed is commercially available with a trade name such as “Optimum® GAT®, or “Optimum® Gly canola”
  • the genetically-modified plant in which the EPSPS that is from maize and has glyphosate-tolerant mutation is expressed is commercially available with the trade name “GlyTol®”.
  • glufosinate herbicide-tolerant plants one or more genes are introduced from: a phosphinothricin N-acetyltransferase (PAT) gene (bar) that is a glufosinate metabolizing enzyme from Streptomyces hygroscopicus; a phosphinothricin N-acetyltransferase (PAT) enzyme gene (pat) that is a glufosinate metabolizing enzyme from Streptomyces viridochromogenes; and a synthesized pat gene (pat syn) from Streptomyces viridochromogenes strain Tu494.
  • PAT phosphinothricin N-acetyltransferase
  • Main examples of the plants include Argentine canola (Brassica napus), chicory (Cichorium intybus), cotton (Gossypium hirsutum L.), maize (Zea mays L.), polish canola (Brassica rapa), rice (Oryza sativa L.), soybean (Glycine max L.), and sugar beet (Beta vulgaris).
  • Argentine canola Brainssica napus
  • chicory Cichorium intybus
  • cotton Gossypium hirsutum L.
  • maize Zea mays L.
  • polish canola Brassica rapa
  • rice Oryza sativa L.
  • soybean Glycine max L.
  • sugar beet Beta vulgaris
  • a genetically-modified 73 ny-2699290 Attorney Docket No.26327-20012.40 plant from a glufosinate metabolizing enzyme (bar) from Streptomyces hygroscopicus and from Streptomyces viridochromogenes is commercially available with trade names such as “LibertyLink®”, “InVigor®”, or “WideStrike®”.
  • oxynil herbicide-tolerant plants are known.
  • Argentine canola Brain canola
  • cotton Gossypium hirsutum L.
  • tobacco Naturala tabacum L.
  • the plants are commercially available with a trade name such as “Navigator® canola” or “BXN®”.
  • ALS herbicide-tolerant plants are also known.
  • Examples include carnations (Dianthus caryophyllus), which are obtained by introduction of an ALS herbicide-tolerant ALS gene (surB) as a selection marker from tobacco (Nicotiana tabacum) and are commercially available with the trade names “Moondust®”, “Moonshadow®”, “Moonshade®”, “Moonlite®”, “Moonaqua®”, “Moonvista®”, “Moonique®”, “Moonpearl®”, “Moonberry®”, and “Moonvelvet®”; flax (Linum usitatissumum L.), into which an ALS herbicide-tolerant ALS gene (als) from Arabidopsis thaliana is introduced is commercially available with the trade name “CDC Triffid Flax”; sulfonylurea herbicide- tolerant and an imidazolinone herbicide-tolerant maize (Zea mays L.) into which an ALS herbicide-tolerant ALS gene (zm-hra) from maize is introduced is commercially
  • ALS herbicide- tolerant ALS gene S4-HrA
  • HPPD herbicide-tolerant plants are also known.
  • a soybean into which a mesotrione-tolerant HPPD gene (avhppd-03) from an oat (Avena sativa) and a phinothricin N-acetyltransferase (PAT) enzyme gene (pat) are simultaneously introduced.
  • a soybean tolerant to mesotrione into which a glufosinate metabolizing enzyme from Streptomyces viridochromogenes is introduced is commercially available.
  • 2,4-D-tolerant plants include: maize into which an aryloxyalkanoate dioxygenase gene (aad-1) for a 2,4-D metabolizing enzyme from Sphingobium herbicidovorans is introduced is commercially available with the trade name “Enlist® Maize”; and soybean and cotton into which an aryloxyalkanoate dioxygenase gene (aad-12) for a 2,4-D metabolizing enzyme from Delftia acidovorans is introduced is commercially available with the trade name “Enlist® Soybean”.
  • Dicamba-tolerant plants include: soybean and cotton into which a dicamba monooxygenase gene (dmo) having a dicamba metabolizing enzyme from Stenotrophomonas maltophilia strain DI-6 is introduced; and a soybean (Glycine max L.) into which a glyphosate-tolerant EPSPS gene (CP4 epsps) from Agrobacterium tumefaciens strain CP4 is introduced simultaneously with the above-mentioned gene is commercially available with the trade name “Genuity® Roundup ReadyTM 2 Xtend®”.
  • glyphosate-tolerant maize “Roundup Ready® Corn”, “Roundup Ready® 2”, “Agrisure® GT”, “Agrisure® GT/CB/LL”, “Agrisure® GT/RW”, “Agrisure® 3000GT”, “YieldGardTM VTTM Rootworm/RR2”, and “YieldGardTM VTTM Triple”; the glyphosate-tolerant soybeans “Roundup Ready® Soybean” and “Optimum® GAT”; the glyphosate-tolerant cotton “Roundup Ready® Cotton” and “Roundup Ready® Flex”; the glyphosate-tolerant canola “Roundup Ready® Canola”; the glyphosate-tolerant alfalfa “Roundup Ready® Alfalfa”, the glyphosate-tolerant rice “Roundup Ready® Rice”; the glufo
  • Additional plants modified with respect to a herbicide are widely known, and the examples of the plants include alfalfa, apples, barley, eucalyptuses, flax, grapes, lentils, rape, peas, potatoes, rice, sugar beet, sunflowers, tobacco, tomato, turfgrass, and wheat that are tolerant to glyphosate (see, for example, U.S. Pat. Nos.
  • the rice tolerant to an imidazolinone herbicide is especially known, and examples of the rice include rice having specific mutation (for example, S653N, S654K, A122T, S653(At)N, S654(At)K, and A122(At)T) in the acetolactate synthase gene (acetohydroxyacid synthase gene) (see, for example, US 2003/0217381, and WO200520673); and the examples include barley, sugar cane, rice, maize, tobacco, soybeans, cotton, rape, sugar beet, wheat, and potatoes that are tolerant to an HPPD inhibitor herbicide (for example, an isoxazole herbicide such as isoxaflutole, a triketone herbicide such as sulcotrione or mesotrione, a pyrazole herbicide such as pyrazolynate,
  • an HPPD inhibitor herbicide for example, an isoxazole herbicide such as isoxaflutole,
  • Examples of the plants to which herbicide tolerance has been imparted by a classical technique or a genome breeding technique include the rice “Clearfield® Rice”, the wheat “Clearfield® Wheat”, the sunflower “Clearfield® Sunflower”, the lentil “Clearfield® lentils”, and the canola “Clearfield® canola” (manufactured by BASF SE) that are tolerant to an imidazolinone-based ALS inhibitor herbicide such as imazethapyr or imazamox; the soybean “STS® soybean” that is tolerant to a sulfonyl-based ALS inhibitor herbicide such as thifensulfuron-methyl; the sethoxydim-tolerant maize “SR® corn” and ‘Poast Protected® corn” that are tolerant to an acetyl-CoA carboxylase inhibitor such as a trionoxime herbicide or an aryloxy phenoxypropionic acid herbicide;
  • RTDS® corresponds to oligonucleotide-directed mutagenesis of the genome editing technique, and by RTDS, it is possible to introduce mutation in a DNA in a plant via Gene Repair Oligonucleotide (GRON), that is, a chimeric oligonucleotide of the DNA and the RNA without cutting the DNA.
  • GRON Gene Repair Oligonucleotide
  • examples of the plants include maize in which herbicide tolerance and phytic acid content have been reduced by deleting the endogenous gene IPK1 using zinc finger nuclease (see, for example, Nature 459, 437-441 2009); and rice to which herbicide tolerance has been imparted using CRISPR-Cas9 (see, for example, Rice, 7, 52014).
  • examples of the crop tolerant to a specific PPO inhibitor include crops to which PPO having a reduced affinity for the inhibitor is imparted by a genetic engineering technique.
  • the crop may have a substance that detoxifies and decomposes the PPO inhibitor by cytochrome P450 monooxygenase alone or in combination with the above-mentioned PPO.
  • tolerant crops are described in, for example, patent documents such as WO2011085221, WO2012080975, WO2014030090, WO2015022640, WO2015022636, WO2015022639, WO2015092706, WO2016203377, WO2017198859, WO2018019860, WO2018022777, WO2017112589, WO2017087672, WO2017039969, and WO2017023778, and non-patent document Li & Nicholl in Pest Management Science (2005), Vol.61, pgs.277-285.
  • Examples of the plants to which herbicide tolerance has been imparted by a new breeding technique in which the property of a GM rootstock is imparted to a scion by a breeding technique in which grafting is used include the non-transgenic soybean scion to which glyphosate tolerance is imparted using the glyphosate-tolerant soybean Roundup Ready® as a rootstock (see Jiang, et al., in Weed Technology (2013) Vol.27, pgs.412-416).
  • the above-mentioned plants include strains to which two or more traits are imparted among abiotic stress tolerance, disease resistance, herbicide tolerance, pest resistance, a growth trait, a yield trait, nutrient uptake, product quality, a fertility trait, and the like as described above using a genetic engineering technique, a classical breeding technique, a genome breeding technique, a new breeding technique, a genome editing technique, or the 77 ny-2699290 Attorney Docket No.26327-20012.40 like, and strains to which two or more of the properties of the parent strains are imparted by crossing plants having the same or different properties.
  • Examples of the commercially available plants to which tolerance to two or more herbicides are imparted include the cotton “GlyTolTM LibertyLinkTM” and “GlyTolTM LibertyLinkTM” that are tolerant to glyphosate and glufosinate; the maize “Roundup ReadyTM LibertyLinkTM Maize” that is tolerant to glyphosate and glufosinate; the soybean “EnlistTM Soybean” that is tolerant to glufosinate and 2,4-D; the soybean “Genuity® Roundup Ready (trademark) 2 Xtend (trademark)” that is tolerant to glyphosate and dicamba; the maize and the soybean “OptimumGATTM” that are tolerant to glyphosate and an ALS inhibitor; the genetically modified soybeans “Enlist E3TM” and “EnlistTM Roundup Ready® 2 Yield” that are tolerant to three herbicides of glyphosate, glufosinate, and 2,4-D; the genetically modified soybean
  • the cotton tolerant to glufosinate and 2,4-D the cotton tolerant to both glufosinate and dicamba, the maize tolerant to both glyphosate and 2,4-D, the soybean tolerant to both glyphosate and an HPPD herbicide, and the genetically modified maize tolerant to glyphosate, glufosinate, 2,4-D, an aryloxyphenoxypropionate (FOPs) herbicide, and a cyclohexanedione (DIMs) herbicide have been also developed.
  • FOPs aryloxyphenoxypropionate
  • DIMs cyclohexanedione
  • Examples of the commercially available plants to which herbicide tolerance and pest resistance are imparted include the maize “YieldGard Roundup Ready®” and “YieldGard Roundup Ready® 2” that are tolerant to glyphosate and resistant to a corn borer; the maize “Agrisure® CB/LL” that is tolerant to glufosinate and resistant to a corn borer; the maize “Yield Gard® VT Root worm/RR2” that is tolerant to glyphosate and resistant to a corn rootworm; the maize “Yield Gard® VT Triple” that is tolerant to glyphosate and resistant to a corn rootworm and a corn borer; the maize “Herculex® I” that is tolerant to glufosinate and resistant to a lepidopteran maize pest (Cry1F) (for example, resistance to a western bean cutworm, a corn borer, a black cutworm, and a fall armyworm); the maize “Cry1
  • a composition of the invention is applied to a place where weeds are growing or likely to grow.
  • the method of applying the present composition include a method of spraying the present composition on soil and a method of spraying the present composition on weeds.
  • the application rate of a composition of the invention is generally 1 to 10,000 g per 10,000 m 2 , 2 to 5,000 g per 10,000 m 2 , 5 to 2,000 g per 10,000 m 2 , 1 to 1000 g per 10,000 m 2 , 1 to 500 g per 10,000 m 2 , 1 to 100 g per 10,000 m 2 , 1 to 75 g per 10,000 m 2 , 15 to 1000 g per 10,000 m 2 , 15 to 100 g per 10,000 m 2 , 15 to 75 g per 10,000 m 2 , or 15 to 60 g per 10,000 m 2 , in terms of the total amount of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V),
  • the application rate of a composition of the invention is generally 1 to 10,000 g per 10,000 m 2 , 2 to 5,000 g per 10,000 m 2 , 5 to 2,000 g per 10,000 m 2 , 1 to 1000 g per 10,000 m 2 , 1 to 500 g per 10,000 m 2 , 1 to 100 g per 10,000 m 2 , 1 to 75 g per 10,000 m 2 , 15 to 1000 g per 10,000 m 2 , 15 to 100 g per 10,000 m 2 , 15 to 75 g per 10,000 m 2 , or 15 to 60 g per 10,000 m 2 , in terms of the total amount of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V)
  • an adjuvant may be mixed in a composition of the invention, followed by application.
  • the type of the adjuvant is not particularly limited, and 79 ny-2699290 Attorney Docket No.26327-20012.40 examples of the adjuvant include oil-based adjuvants such as Agri-Dex® and methylated seed oil (MSO), non-ions (esters or ethers of polyoxyethylene) such as Induce, anions (substituted sulfonates) such as Gramine S, cations (polyoxyethylene amines) such as Genamin® T 200BM, and organic silicons such as Silwet® L77.
  • oil-based adjuvants such as Agri-Dex® and methylated seed oil (MSO)
  • non-ions esters or ethers of polyoxyethylene
  • MSO methylated seed oil
  • anions substituted sulfonates
  • Gramine S cations
  • Genamin® T 200BM Genamin® T 200BM
  • the pH and the hardness of the spray liquid prepared when a composition of the invention is applied are not particularly limited, and the pH is usually in the range of 5 to 9, and the hardness is usually in the range of 0 to 500.
  • the time period for applying a composition of the invention is not particularly limited, and is usually in the range of 5:00 AM to 9:00 PM, and the photon flux density is XVXDOO ⁇ WR ⁇ PRO ⁇ P 2 /s.
  • a composition of the invention When a composition of the invention is applied to a crop field, it may be applied before sowing a crop seed, simultaneously with sowing a crop seed, and/or after sowing a crop seed.
  • the frequency of the application of a composition of the invention is once before, simultaneously with, or after sowing a crop seed, twice excluding before the sowing, excluding simultaneously with the sowing, or excluding after the sowing, or three times at all the timing.
  • a composition of the invention is applied before sowing a crop seed, it is applied from 50 days before to immediately before the sowing, preferably from 30 days before to immediately before the sowing, more preferably from 20 days before to immediately before the sowing, and still more preferably from 10 days before to immediately before the sowing.
  • a composition of the invention is applied after sowing a crop seed, it is usually applied from immediately after the sowing to before flowering.
  • composition is more preferably applied from immediately after the sowing to before the emergence, or from 1 to 6 leaf stages of the crop.
  • a composition of the invention is applied simultaneously with sowing a crop seed is the case where a sowing machine and a sprayer are integrated with each other.
  • a carrier such as a solid carrier or a liquid carrier
  • an auxiliary agent for formulation such as a surfactant is added if necessary to prepare a formulation.
  • Preferable formulation types are aqueous liquid suspension formulations, oil-based suspension formulations, wettable powders, water dispersible granules, granules, water-based emulsions, oil-based emulsions, and emulsifiable concentrates, and more preferable formulation type is emulsifiable concentrates.
  • Examples of the method of applying a composition of the invention in a cultivation area include a method of spraying it on the soil in the cultivation area and a method of spraying the present composition on a weeds that are growing.
  • the composition is usually diluted with water, followed by spraying.
  • the spray volume is not particularly limited, and is usually 50 to 1,000 L/ha, preferably 100 to 500 L/ha, and more preferably 140 to 300 L/ha.
  • Specific examples of the weed species to be controlled by the present composition include, but are not limited to, the weed species described below.
  • Urticaceae weeds to be controlled include Urtica urens.
  • Polygonaceae weeds to be controlled include Polygonum convolvulus, Polygonum lapathifolium, Polygonum pensylvanicum, Polygonum persicaria, Polygonum longisetum, Polygonum aviculare, Polygonum arenastrum, Polygonum cuspidatum, Rumex japonicus, Rumex crispus, Rumex obtusifolius, and Rumex acetosa.
  • Portulacaceae weeds to be controlled include Portulaca oleracea.
  • Caryophyllaceae weeds to be controlled include Stellaria media, Stellaria aquatica, Cerastium holosteoides, Cerastium glomeratum, Spergula arvensis, and Silene gallica. 81 ny-2699290 Attorney Docket No.26327-20012.40 [0227] Molluginaceae weeds to be controlled include Mollugo verticillate. [0228] Chenopodiaceae weeds to be controlled include Chenopodium album, Chenopodium ambrosioides, Kochia scoparia, Salsola kali, and Atriplex spp.
  • Amaranthaceae weeds to be controlled include Amaranthus retroflexus, Amaranthus viridis, Amaranthus lividus, Amaranthus spinosus, Amaranthus hybridus, Amaranthus palmeri, Amaranthus patulus, Waterhemp (Amaranthus tuberculatus, Amaranthus rudis, or Amaranthus tamariscinus), Amaranthus blitoides, Amaranthus deflexus, Amaranthus quitensis, Alternanthera philoxeroides, Alternanthera sessilis, and Alternanthera tenella.
  • Papaveraceae weeds to be controlled include Papaver rhoeas, Papaver dubium, and Argemone Mexicana.
  • Brassicaceae weeds to be controlled include Raphanus raphanistrum, Raphanus sativus, Sinapis arvensis, Capsella bursa-pastoris, Brassica juncea, Brassica napus, Descurainia pinnata, Rorippa islandica, Rorippa sylvestris, Thlaspi arvense, Myagrum rugosum, Lepidium virginicum, and Coronopus didymus.
  • Capparaceae weeds to be controlled include Cleome affinis.
  • Fabaceae weeds to be controlled include Aeschynomene indica, Aeschynomene rudis, Sesbania exaltata, Cassia obtusifolia, Cassia occidentalis, Desmodium tortuosum, Desmodium adscendens, Desmodium illinoense, Trifolium repens, Pueraria lobata, Vicia angustifolia, Indigofera hirsuta, Indigofera truxillensis, and Vigna sinensis.
  • Oxalidaceae weeds to be controlled include Oxalis corniculata, Oxalis strica, and Oxalis oxyptera.
  • Geraniaceae weeds to be controlled include Geranium carolinense and Erodium cicutarium.
  • Euphorbiaceae weeds to be controlled include Euphorbia helioscopia, Euphorbia maculata, Euphorbia humistrata, Euphorbia esula, Euphorbia heterophylla, Euphorbia brasiliensis, Acalypha australis, Croton glandulosus, Croton lobatus, Phyllanthus corcovadensis, and Ricinus communis.
  • Malvaceae weeds to be controlled include Abutilon theophrasti, Sida rhombiforia, Sida cordifolia, Sida spinosa, Sida glaziovii, Sida santaremnensis, Hibiscus trionum, Anoda cristata, and Malvastrum coromandelianum.
  • Onagraceae weeds to be controlled include Ludwigia epilobioides, Ludwigia octovalvis, Ludwigia decurre, Oenothera biennis, and Oenothera laciniata.
  • Sterculiaceae weeds to be controlled include Waltheria indica.
  • Violaceae weeds to be controlled include Viola arvensis and Viola tricolor.
  • Cucurbitaceae weeds to be controlled include Sicyos angulatus, Echinocystis lobata, and Momordica charantia.
  • Lythraceae weeds to be controlled include Ammannia multiflora, Ammannia auriculata, Ammannia coccinea, Lythrum salicaria, and Rotala indica.
  • Elatinaceae weeds to be controlled include Elatine triandra and Elatine californica.
  • Apiaceae weeds to be controlled include Oenanthe javanica, Daucus carota, and Conium maculatum.
  • Ceratophyllaceae weeds to be controlled include Ceratophyllum demersum.
  • Cabombaceae weeds to be controlled include Cabomba caroliniana.
  • Haloragaceae weeds to be controlled include Myriophyllum aquaticum, Myriophyllum verticillatum, Myriophyllum spicatum, and Myriophyllum heterophyllum.
  • Sapindaceae weeds to be controlled include Cardiospermum halicacabum.
  • Primulaceae weeds to be controlled include Anagallis arvensis.
  • Asclepiadaceae weeds to be controlled include Asclepias syriaca, and Ampelamus albidus.
  • Rubiaceae weeds to be controlled include Galium aparine, Galium spurium var. echinospermon, Spermacoce latifolia, Richardia brasiliensis, and Borreria alata.
  • Convolvulaceae weeds to be controlled include Ipomoea nil, Ipomoea hederacea, Ipomoea purpurea, Ipomoea hederacea var.
  • Boraginaceae weeds to be controlled include Myosotis arvensis.
  • Lamiaceae weeds to be controlled include Lamium purpureum, Lamium amplexicaule, Leonotis nepetaefolia, Hyptis suaveolens, Hyptis lophanta, Leonurus sibiricus, and Stachys arvensis.
  • Solanaceae weeds to be controlled include Datura stramonium, Solanum nigrum, Solanum americanum, Solanum ptycanthum, Solanum sarrachoides, Solanum rostratum, Solanum aculeatissimum, Solanum sisymbriifolium, Solanum carolinense, Physalis angulata, Physalis subglabrata, and Nicandra physaloides.
  • Scrophulariaceae weeds to be controlled include Veronica hederaefolia, Veronica persica, Veronica arvensis, Lindernia procumbens, Lindernia dubia, Lindernia angustifolia, Bacopa rotundifolia, Dopatrium junceum, and Gratiola japonica.
  • Plantaginaceae weeds to be controlled include Plantago asiatica, Plantago lanceolata, Plantago major, and Callitriche palustris.
  • Asteraceae weeds to be controlled include Xanthium pensylvanicum, Xanthium occidentale, Xanthium italicum, Helianthus annuus, Matricaria chamomilla, Matricaria perforata, Chrysanthemum segetum, Matricaria matricarioides, Artemisia princeps, Artemisia vulgaris, Artemisia verlotorum, Solidago altissima, Taraxacum officinale, Galinsoga ciliata, Galinsoga parviflora, Senecio vulgaris, Senecio brasiliensis, Senecio grisebachii, Conyza bonariensis, Conyza smatrensis, Conyza canadensis, Ambrosia artemisiaefolia, Ambrosia trifida, Bidens tripartita, Bidens pilosa, Bidens frondosa, Bi
  • Alismataceae weeds to be controlled include Sagittaria pygmaea, Sagittaria trifolia, Sagittaria sagittifolia, Sagittaria montevidensis, Sagittaria aginashi, Alisma canaliculatum, and Alisma plantago-aquatica.
  • Limnocharitaceae weeds to be controlled include Limnocharis flava.
  • Hydrocharitaceae weeds to be controlled include Limnobium spongia, Hydrilla verticillata, and Najas guadalupensis.
  • Araceae weeds to be controlled include Pistia stratiotes.
  • Lemnaceae weeds to be controlled include Lemna aoukikusa, Spirodela polyrhiza, and Wolffia spp.
  • Potamogetonaceae to be controlled include Potamogeton distinctus, Potamogeton crispus, Potamogeton illinoensis, and Stuckenia pectinata.
  • Liliaceae weeds to be controlled include Allium canadense, Allium vineale, and Allium macrostemon.
  • Pontederiaceae weeds to be controlled include Eichhornia crassipes, Heteranthera limosa, Monochoria korsakowii, and Monochoria vaginalis.
  • Commelinaceae weeds to be controlled include Commelina communis, Commelina bengharensis, Commelina erecta, and Murdannia keisak.
  • Poaceae weeds to be controlled include Echinochloa crus-galli, Echinochloa oryzicola, Echinochloa crus-galli var formosensis, Echinochloa oryzoides, Echinochloa colona, Echinochloa crus-pavonis, Setaria viridis, Setaria faberi, Setaria glauca, Setaria geniculata, Digitaria ciliaris, Digitaria sanguinalis, Digitaria horizontalis, Digitaria insularis, Eleusine indica, Poa annua, Poa trivialis, Poa pratensis, Alospecurus aequalis, Alopecurus myosuroides, Avena fatua, Sorghum halepense, Sorghum vulgare, Agropyron repens, Lolium multiflorum, Lolium perenne, Lolium rigidum, Bromus catharticus, Bro
  • Cyperaceae weeds to be controlled include Cyperus microiria, Cyperus iria, Cyperus compressus, Cyperus difformis, Cyperus flaccidus, Cyperus globosus, Cyperus nipponics, Cyperus odoratus, Cyperus serotinus, Cyperus rotundus, Cyperus esculentus, Kyllinga gracillima, Kyllinga brevifolia, Fimbristylis miliacea, Fimbristylis dichotoma, Eleocharis acicularis, Eleocharis kuroguwai, Schoenoplectiella hotarui, Schoenoplectiella juncoides, Schoenoplectiella wallichii, Schoenoplectiella mucronatus, Schoenoplectiella triangulatus, Schoenoplectiella nipponicus, Schoenoplectiella triqueter,
  • Equisetaceae weeds to be controlled include Equisetum arvense, and Equisetum palustre.
  • Salviniaceae weeds to be controlled include Salvinia natans.
  • Azollaceae weeds to be controlled include Azolla japonica and Azolla imbricata.
  • Marsileaceae weeds to be controlled include Marsilea quadrifolia.
  • weeds to be controlled include Pithophora, Cladophora, Bryophyta, Marchantiophyta, Anthocerotophyta, Cyanobacteria, Pteridophyta, sucker of perennial crops (pomaceous fruits, nut trees, citruses, Humulus lupulus, grapes, and the like).
  • 86 ny-2699290 Attorney Docket No.26327-20012.40
  • mutations within the species are not particularly limited. That is, the weeds include weeds having reduced sensitivity to a specific herbicide.
  • the reduced sensitivity may be attributed to a mutation at a target site (target site mutation) or may be attributed to any factors other than the target site mutation (non-target site mutation).
  • Examples of the factor of the reduced sensitivity due to a non- target site mutation include increased metabolism, malabsorption, translocation dysfunction, and excretion to out of system.
  • Examples of the factor of the increased metabolism include the enhanced activity of a metabolizing enzyme such as cytochrome P450 monooxygenase, aryl acylamidase, esterase, or glutathione S-transferase.
  • Examples of the excretion to out of system include transport to the vacuole by an ABC transporter.
  • Examples of the weeds having reduced sensitivity due to a target site mutation include weeds having any one of or two or more of the following amino acid substitutions in the ALS gene: Ala122Thr, Ala122Val, Ala122Tyr, Pro197Ser, Pro197His, Pro197Thr, Pro197Arg, Pro197Leu, Pro197Gln, Pro197Ala, Pro197Ile, Ala205Val, Ala205Phe, Asp376Glu, Arg377His, Trp574Leu, Trp574Gly, Trp574Met, Ser653Thr, Ser653Thr, Ser653Asn, Ser635Ile, Gly654Glu, and Gly645Asp.
  • examples of the weeds having reduced sensitivity due to a target site mutation include weeds having any one of or two or more of the following amino acid substitutions in the ACCase gene: Ile1781Leu, Ile1781Val, Ile1781Thr, Trp1999Cys, Trp1999Leu, Ala2004Val, Trp2027Cys, Ile2041Asn, Ile2041Val, Asp2078Gly, Cys2088Arg, Gly2096Ala, and Gly2096Ser.
  • PPO inhibitor-resistant weeds having one or more mutations selected from an Arg128Leu mutation, an Arg128Met mutation, an Arg128Gly mutation, an Arg128His mutation, a Gly210 deletion mutation, and a Gly399Ala mutation in PPO.
  • the word “PPO” means protoporphyrinogen oxidase. Weeds usually have PPO1 and PPO2 in PPO, and the above-mentioned mutations may be present in either PPO1 or PPO2 or in both. The case where weeds have the mutations in PPO2 is preferable.
  • the word "Arg128Met” means that the mutation is present in the 128th (the number is standardized with PPO2 of Amaranthus palmeri) amino acid.
  • the mutation corresponds to a mutation in the 98th amino acid (Rousonelos, et al., Weed Science (2012) Vol.60, pgs.335-344) and is known as Arg98Leu.
  • Arg98 is equivalent to Arg128 according to the present invention.
  • the Arg128Met mutation and the Arg128Gly mutation in the PPO of the weed to be controlled in the present invention are known in 87 ny-2699290 Attorney Docket No.26327-20012.40 Amaranthus palmeri (Giacomini, et al., Pest Management Science (2017) Vol.73, pgs.1559- 1563), the Arg128His mutation is known in Lolium rigidum (Fernandez-Moreno, et al., Weed Science Society of America (WSSA) annual meeting, 2018), and the Gly399Ala mutation is known in Amaranthus palmeri (Rangani, et al., WSSA annual meeting, 2018).
  • the above-mentioned reported resistant weeds are particularly effectively controlled, but particularly effectively controlled weeds are not limited thereto. That is, other weeds having the amino acid mutation are similarly controlled. Not only Amaranthus palmeri having an Arg128Leu mutation, an Arg128Met mutation, an Arg128Gly mutation, an Arg128His mutation, a Gly210 deletion mutation, or a Gly399Ala mutation, but also, for example, waterhemp having the above-mentioned mutation, Ambrosia artemisiaefolia having the above-mentioned mutation, Lolium rigidum having the above-mentioned mutation, Lolium multiflorum having the above-mentioned mutation, and Euphorbia heterophylla having the above-mentioned mutation are effectively controlled.
  • examples of the weeds having reduced sensitivity due to a target site mutation include weeds having an amino acid substitution such as Thr102Ile, Pro106Ser, Pro106Ala, or Pro106Leu in the EPSP gene.
  • weeds having an amino acid substitution such as Thr102Ile, Pro106Ser, Pro106Ala, or Pro106Leu in the EPSP gene.
  • Eleusine indica, Lolium multiflorum, Lolium rigidum, Digitaria insularis, waterhemp, Echinochloa colona, and the like which are resistant to glyphosate and have one or both of the mutations are effectively controlled.
  • examples of the weeds having reduced sensitivity due to a target site include weeds having increased copies of the EPSP gene and Amaranthus palmeri, waterhemp, Kochia scoparia, and the like which are resistant to glyphosate and have the mutation are particularly effectively controlled.
  • Conyza canadensis, Conyza smatrensis, and Conyza bonariensis which are resistant to glyphosate in which an ABC transporter is involved are also effectively controlled.
  • plant nutritional management in general cultivation of a crop can be performed.
  • the fertilization system may be based on Precision Agriculture or may be conventionally uniform one.
  • controlling effect on weeds is exhibited by using a compound of (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M- I), (M-II), (M-III), (M-IV), or (M-V) and a specific compound in combination.
  • a herbicidal composition including a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of a herbicide compound group B and a safener group C, wherein a weight ratio of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) to the at least one compound selected from the group consisting
  • the present invention also features – [3] the herbicidal composition according to [1] or [2], wherein the safener group C is a group consisting of benoxacor, cloquintocet, cyometrinil, cyprosulfamide, dichlormid, dicyclonone, dietholate, fenchlorazole, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen, mefenpyr, mephenate, naphthalic anhydride, oxabetrinil, 4-(dichloroacetyl)-1-oxa-4-azaspiro[4.5]decane, 2,2,5-trimethyl-3- (dichloroacetyl)-1,3-oxazolidine, and N-(2-methoxybenzoyl)-4- [(methylaminocarbonyl)amino]benzenesulfon-amide.
  • the safener group C is a group consisting
  • the present invention includes – [4] the herbicidal composition according to [1], wherein B-1 is a group consisting of pyrithiobac, pyrithiobac-sodium salt, chlorimuron-ethyl, foramsulfuron, halosulfuron-methyl, nicosulfuron, primisulfuron-methyl, rimsulfuron, trifloxysulfuron-sodium salt, chlorsulfuron, iodosulfuron-methyl-sodium, iofensulfuron sodium, metsulfuron-methyl, prosulfuron, thifensulfuron-methyl, tribenuron- methyl, thiencarbazone-methyl, cloransulam-methyl, flumetsulam, imazamethabenz-methyl, imazamox-ammonium salt, imazapic-ammonium salt, imazapyr-isopropylammonium, imazaquin-am
  • the present invention includes - [5] the herbicidal composition according to [1], wherein B-2 is a group consisting of fenoxaprop-ethyl, fenoxaprop-P-ethyl, fluazifop-butyl, fluazifop-P-butyl, quizalofop-ethyl, quizalofop-P-ethyl, clethodim, and sethoxydim (including agriculturally acceptable salts and derivatives thereof for each).
  • the present invention includes - [6] the herbicidal composition according to [1], wherein B-3 is a group consisting of carfentrazone-ethyl, saflufenacil, sulfentrazone, pyraflufen-ethyl, fluthiacet-methyl, flufenpyr-ethyl, flumiclorac- pentyl, flumioxazin, oxyfluorfen, acifluorfen-sodium salt, fomesafen-sodium salt, lactofen, tiafenacil, and ethyl [(3- ⁇ 2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo- 93 ny-2699290 Attorney Docket No.26327-20012.40 1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy ⁇ pyridin-2-yl)oxy
  • the present invention includes - [7] the herbicidal composition according to [1], wherein B-4 is a group consisting of bicyclopyrone, mesotrione, tembotrione, isoxaflutole, fenquinotrione, topramezone, tolpyralate, lancotrione- sodium salt, 2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4- (trifluoromethyl)benzamide (CAS Registry Number 1400904-50-8), 2-chloro-N-(1-methyl- 1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide (CAS Registry Number 1361139-71-0), and 4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexene-1-yl)carbonyl]- 2-methyl-1,2,4-triazine-3,5
  • the present invention includes - [8] the herbicidal composition according to [1], wherein B-5 is a group consisting of norflurazon and fluridone (including agriculturally acceptable salts and derivatives thereof for each).
  • B-5 is a group consisting of norflurazon and fluridone (including agriculturally acceptable salts and derivatives thereof for each).
  • the present invention includes - [9] the herbicidal composition according to [1], wherein B-6 is a group consisting of bentazone, bromoxynil octanoate, diuron, linuron, fluometuron, simazine, atrazine, ametryn, prometryn, and metribuzin (including agriculturally acceptable salts and derivatives thereof for each).
  • the present invention includes - [10] the herbicidal composition according to [1], wherein B-7 is a group consisting of alachlor, acetochlor, metolachlor, S-metolachlor, dimethenamid, dimethenamid-P, pyroxasulfone, and flufenacet (including agriculturally acceptable salts and derivatives thereof for each).
  • B-7 is a group consisting of alachlor, acetochlor, metolachlor, S-metolachlor, dimethenamid, dimethenamid-P, pyroxasulfone, and flufenacet (including agriculturally acceptable salts and derivatives thereof for each).
  • B-8 is a group consisting of trifluralin, pendimethalin, and ethalfluralin (including agriculturally acceptable salts and derivatives thereof for each).
  • the present invention includes - [12] the herbicidal composition according to [1], wherein B-9 is a group consisting of 2,4-DB, fluroxypyr, fluroxypyr-meptyl, clopyralid-olamine salt, clopyralid-potassium salt, clopyralid- triethylammonium salt, halauxifen, halauxifen-methyl, florpyrauxifen, and florpyrauxifen- benzyl (including agriculturally acceptable salts and derivatives thereof for each).
  • B-9 is a group consisting of 2,4-DB, fluroxypyr, fluroxypyr-meptyl, clopyralid-olamine salt, clopyralid-potassium salt, clopyralid- triethylammonium salt, halauxifen, halauxifen-methyl, florpyrauxifen, and florpyrauxifen- benzyl (including agriculturally acceptable salts and derivatives thereof for
  • the present invention includes - [13] the herbicidal composition according to [1], wherein B-10 is a group consisting of a combination of two or more of glyphosate, glyphosate-isopropylammonium salt, glyphosate-ammonium salt, glyphosate-dimethylamine salt, glyphosate-monoethanolamine salt, glyphosate-potassium salt, and glyphosate-guanidine salt (including agriculturally acceptable salts and derivatives thereof for each).
  • the present invention includes - [14] the herbicidal composition according to [1], wherein the B-11 is a group consisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, and glufosinate-P-sodium salt (including agriculturally acceptable salts and derivatives thereof for each).
  • the present invention includes - [15] the herbicidal composition according to [1], wherein the B-12 is a group consisting of EPTC, diflufenzopyr, diflufenzopyr-sodium salt, clomazone, 2-[(2,4-dichlorophenyl)methyl]-4,4- dimethylisoxazolidin-3-one (CAS Registry Number: 81777-95-9), (3S,4S)-N-(2- fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8), cinmethylin, MSMA, paraquat, paraquat dichloride, diquat, and diquat dibromide (including agriculturally acceptable salts and derivatives thereof for each).
  • the B-12 is a group consisting of EPTC, diflufenzopyr, diflufenzopyr-sodium salt, clomazone, 2-[(2,4
  • the present invention includes - [16] The herbicidal composition according to [1], wherein the safener group C is a group consisting of benoxacor, cyprosulfamide, and isoxadifen-ethyl (including agriculturally acceptable salts and derivatives thereof for each).
  • the present invention also features - [18] A method for controlling weeds, the method including a step of applying a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of the herbicide compound group B and the safener group C simultaneously or sequentially to a place where weeds are growing or to grow.
  • the present invention includes - [19] The method according to [18], wherein a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H- IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and the at 95 ny-2699290 Attorney Docket No.26327-20012.40 least one compound selected from the group consisting of the herbicide compound group B and the safener group C are used at a weight ratio of 1:0.1 to 1:50.
  • the present invention includes - [20] The method according to [18] or [19], wherein the place where weeds are growing or to grow is a crop field. [0299] The present invention also features - [21] A use of the herbicidal composition according to any one of [1] to [16], for controlling weeds.
  • Herbicidal compositions according to the present invention also include a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K- II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of an herbicide compound group B and a safener group C.
  • the method for controlling weeds according to the present invention includes the step of applying the present composition to a place where weeds are growing or likely to grow in a crop field, a vegetable field, a land under perennial crops, a non-crop land, or the like.
  • the present composition may be applied before, simultaneously with, and/or after sowing a crop seed.
  • the present method includes the step of applying a compound of formula (I), (G- I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M- II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of the herbicide compound group B and the safener group C simultaneously or sequentially to a place where weeds are growing or likely to grow.
  • the order of the application is not particularly limited.
  • the present composition is usually a formulation prepared by mixing a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of the herbicide compound group B and the safener group C with a carrier such as a solid carrier or a liquid carrier and adding an auxiliary agent for formulation such as a surfactant if necessary.
  • a carrier such as a solid carrier or a liquid carrier
  • an auxiliary agent for formulation such as a surfactant
  • Preferable formulation types of such a formulation are aqueous liquid suspension concentrates, wettable powders, water dispersible granules, 96 ny-2699290 Attorney Docket No.26327-20012.40 granules, and emulsifiable concentrates.
  • the present composition may be used in combination with a formulation containing another herbicide as an active ingredient.
  • the total content of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H- II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M- V) and the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present composition is within a range of 0.01 to 90% by weight, preferably 1 to 80% by weight.
  • the weight of the at least one compound is represented by the acid equivalent.
  • a mixing ratio of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) to the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present composition is within a range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50 by weight ratio.
  • a ratio of application rates of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M- IV), or (M-V) to the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present method is within a range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50 by weight ratio.
  • the mixing ratio of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M- III), (M-IV), or (M-V) to the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present composition include about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.5, about 1:0.7, about 1:1, about 1:2, about 1:3, about 1:5, about 1:7, about 1:10, about 1:15, about 1:20, about 1:30, and about 1:50 by weight ratio.
  • the ratio of application rates of a compound of formula (I), (G- I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M- II), (M-III), (M-IV), or (M-V) to the at least one compound selected from the group 97 ny-2699290 Attorney Docket No.26327-20012.40 consisting of the herbicide compound group B and the safener group C in the present method include about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:1, about 1:1.2, about 1:1.4, about 1:1.6, about 1:1.8, about 1:2, about 1:2.2, about 1:2.4, about 1:2.6, about 1:2.8, about 1:3, about 1:5, about 1:7, about 1:10, about 1:15, about
  • the word “about” in the preceding paragraph means that the specified ratio includes the ratio in the range increased or decreased by 10% by weight relative to the specified ratio.
  • a ratio of about 1:2 includes a range of 1:1.8 to 1:2.2.
  • particularly preferable examples of the combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H- II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M- V) and the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C and the range of weight ratio thereof include, but are not limited to, the following combinations and the ranges: a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-V) and the at least one compound selected from the group consisting
  • the present composition Before, simultaneously with, and/or after sowing a crop seed treated with one or more compounds selected from the group consisting of an insecticide compound, a nematicide compound, a fungicide compound, and the like, the present composition may be applied to the field in which the crop seed have been sown or is to be sown. [0313] In some embodiments, the present composition may be used in combination with another pesticidally-active compound.
  • insecticide compound examples include neonicotinoid compounds, diamide compounds, carbamate compounds, organophosphorus compounds, biological nematicide compounds, other insecticide compounds and nematicide compounds, azole compounds, strobilurin compounds, metalaxyl compounds, SDHI compounds, and other fungicide compounds and plant growth regulators.
  • ENUMERATED EMBODIMENTS [0314] The following enumerated embodiments are representative of some aspects of the invention. Embodiment A1.
  • R 1 is OR 1a or N(R 1a )2; each R 1a is, independently, H, C1-4alkyl optionally substituted with C(O)OR 1b , C1- 4alkyl optionally substituted with C(O)N(R 1c ) 2 , C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R 1x ), C(O)OCH2C2- 4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R 1x , pyridyl optionally substituted with OCH 2 CO 2 R 1x , or S(O) 2 C 1-4 alkyl optionally substituted
  • Embodiment A2 The compound according to embodiment A1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (II): salt thereof.
  • Embodiment A3. The compound according to embodiment A2, or a salt thereof, wherein R 1a is C 1-4 alkyl optionally substituted with C(O)OR 1b or C(O)N(R 1c ) 2 . 110 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment A4.
  • Embodiment A11 An agricultural composition, comprising: a compound of any one of embodiments A1 to A10, or a salt thereof; and at least one additional component that serves as a carrier.
  • Embodiment A12. The composition of embodiment A11, wherein at least one additional component is a surfactant or a diluent.
  • Embodiment A13 The composition of embodiment A11 or 12, wherein the composition is an herbicidal composition. 111 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment A14.
  • a method of controlling undesired vegetation comprising contacting the undesired vegetation or its environment with a compound of formula (I), or a salt thereof, or an agricultural composition comprising said compound and at least one additional component that serves as a carrier, wherein the compound of formula (I) is: wherein: R 1 is OR 1a or N(R 1a ) 2 ; each R 1a is, independently, H, C 1-4 alkyl optionally substituted with C(O)OR 1b , C 1- 4alkyl optionally substituted with C(O)N(R 1c )2, C2-4alkenyl, C2-4alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R 1x ), C(O)OCH2C2- 4alkenyl, C(O)OCH 2 C 2-4 alkynyl, phenyl optionally substituted with OCH 2 CO 2 R 1x , pyrid
  • Embodiment B1 A compound of formula (I): or a salt thereof, wherein R 1 is OR 1a , NHS(O) 2 R 1b , or NHS(O) 2 N(R 1a )(R 1b ); R 1a is H or C1-6alkyl optionally substituted with C(O)OC1-4alkyl or C(O)OC2-4alkenyl; R 1b is C 1-6 alkyl; R 2 is Cl or OCHF 2 ; R 3 is H or F; and R 4 is H or F.
  • An agricultural composition comprising: a compound of any one of embodiments B1 to B10, or a salt thereof; and at least one additional component that serves as a carrier.
  • 114 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment B12.
  • the composition of embodiment B11, wherein at least one additional component is a surfactant or a diluent.
  • Embodiment B13 The composition of embodiment B11 or B12, wherein the composition is an herbicidal composition.
  • a method of controlling undesired vegetation comprising contacting the undesired vegetation or its environment with a compound of any one of embodiments B1 to B10, a salt thereof, or a composition of any one of embodiments B11 to B13.
  • Embodiment C1 A compound of formula (I): or a salt thereof, wherein: R 1 is C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, each substituted with C(O)OR x and optionally substituted with halo; R x is H or C 1-6 alkyl; R 2 is Cl; R 3 is H or F; R 4 is H or F; and R 5 is OCH 3 or F.
  • Embodiment C2 A compound of formula (I): or a salt thereof, wherein: R 1 is C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, each substituted with C(O)OR x and optionally substituted with halo; R x is H or C 1-6 alky
  • Embodiment C6 The compound according to any one of embodiments C1 to C5, or a salt thereof, wherein R 4 is F.
  • Embodiment C7 The compound according to any one of embodiments C1 to C5, or a salt thereof, wherein R 4 is H.
  • Embodiment C8 The compound according to any one of embodiments C1 to C6, or a salt thereof, wherein R x is H. 116 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment C9.
  • R x is C1-2alkyl.
  • Embodiment C10 The compound according to embodiment C1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof.
  • Embodiment C11 An agricultural composition, comprising: a compound of any one of embodiments C1 to C10, or a salt thereof; and at least one additional component that serves as a carrier.
  • Embodiment C12 The composition of embodiment C11, wherein at least one additional component is a surfactant or a diluent.
  • Embodiment C13 The composition of embodiment C11 or C12, wherein the composition is an herbicidal composition.
  • a method of controlling undesired vegetation comprising contacting the undesired vegetation or its environment with a compound of any one of embodiments C1 to C10, a salt thereof, or a composition of any one of embodiments C11 to C13.
  • R 1 is OR 1a , C(O)OR 1a , C(O)NHS(O) 2 R 1b , S(O) 2 NHR 1a , or S(O) 2 NHC(O)R 1b ;
  • R 1a is H, C1-6alkyl optionally substituted with C(O)OC1-2alkyl, or C3-6cycloalkyl;
  • R 1b is C 1-6 alkyl, or C 3-6 cycloalkyl;
  • R 2 is Cl or NO 2 ;
  • R 3 is H or F; 117 ny-2699290 Attorney Docket No.26327-20012.40
  • Embodiment D2 is OR 1a , C(O)OR 1a , C(O)NHS(O) 2 R 1b , S(O) 2 NHR 1a , or S(O) 2 NHC(O)R 1b ;
  • R 1a is H,
  • Embodiment D1 The compound according to embodiment D1, or a salt thereof, wherein R 3 is H.
  • Embodiment D8. The compound according to any one of embodiments D1 to D7, or a salt thereof, wherein each of R 4 and R 5 is F.
  • Embodiment D9. The compound according to any one of embodiments D1 to D7, or a salt thereof, wherein R 5 is CF3.
  • Embodiment D10. The compound according to any one of embodiments D1 to D7, or a salt thereof, wherein R 5 is F and R 4 is H.
  • Embodiment D11 The compound according to any one of embodiments D1 to D10, or a salt thereof, wherein R 2 is NO2.
  • Embodiment D13 The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (II): 118 ny-2699290 Attorney Docket No.26327-20012.40 salt thereof.
  • Embodiment D14 The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (III): salt thereof.
  • Embodiment D15. 15 The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (IV): salt thereof.
  • Embodiment D16 The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (V): salt thereof.
  • Embodiment D17 The compound according to embodiment D1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof.
  • Embodiment D18 An agricultural composition, comprising: a compound of any one of embodiments D1 to D17, or a salt thereof; and at least one additional component that serves as a carrier. 119 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment D19. The composition of embodiment D18, wherein at least one additional component is a surfactant or a diluent.
  • Embodiment D20 The composition of embodiment D18 or D19, wherein the composition is an herbicidal composition.
  • Embodiment D21. A method of controlling undesired vegetation, comprising contacting the undesired vegetation or its environment with a compound of any one of embodiments D1 to D17, a salt thereof, or a composition of any one of embodiments D18 to D20.
  • R 1 is OR 1a , N(R 1a )2, C(O)OR 1a , C(O)NHS(O)2R 1b , C(O)NHS(O)2N(R 1a )(R 1b ), S(O)2NHR 1a , S(O)2NHC(O)R 1b , C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C 2-4 alkynyl is substituted with C(O)OR x and optionally substituted with halogen; each R 1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR 1b , C1- 6alkyl optionally substituted with C(O)N(R 1c )2, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C
  • Embodiment E2 is O or a bond, wherein when X is a bond, R 1 is not OH, NH 2 , CH 3 , S(O) 2 NHR 1a or S(O) 2 NHC(O)R 1b and at least one of R 2 or R 3 is not H; when X is a bond and R 1 is
  • R 1 is OR G1a or N(R G1a )2; each R G1a is, independently, H, C 1-4 alkyl optionally substituted with C(O)OR G1b , C 1- 4alkyl optionally substituted with C(O)N(R G1c )2, C2-4alkenyl, C2-4alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)N(R G1x ), C1-4alkyl, C(O)OCH 2 C 2-4 alkenyl, C(O)OCH 2 C 2-4 alkynyl, phenyl optionally substituted with OCH 2 CO 2 R
  • Embodiment E8 The compound according to embodiment E7, or a salt thereof, wherein said compounds of formula (G-I) is a compound of formula (G-II): 122 ny-2699290 Attorney Docket No.26327-20012.40 or a salt thereof.
  • Embodiment E9. The compound according to embodiment E8, or a salt thereof, wherein R G1a is C 1-4 alkyl optionally substituted with C(O)OR G1b or C(O)N(R G1c ) 2 .
  • Embodiment E10. The compound according to embodiment E8, or a salt thereof, wherein R G1a is pyridyl substituted with OCH2CO2R G1x .
  • Embodiment E16 The compound according to any one of embodiments E7 to E14, or a salt thereof, wherein R 2 is Cl and R 3 is F.
  • Embodiment E16 The compound according to embodiment E7, or a salt thereof, wherein said compound of formula (I) is a compound of formula (H-I): 123 ny-2699290 Attorney Docket No.26327-20012.40 or a salt thereof, wherein: R H1 is OR H1a , NHS(O)2R H1b , or NHS(O)2N(R H1a )(R H1b ); R H1a is H or C 1-6 alkyl optionally substituted with C(O)OC 1-4 alkyl or C(O)OC 2- 4alkenyl; R H1b is C1-6alkyl; R 2 is Cl or OCHF 2 ; R 3 is H or F; and R 4 is H or F.
  • Embodiment E17 The compound according to embodiment E16, or a salt thereof, wherein R 4 Embodiment E18.
  • Embodiment E20 The compound according to embodiment E16, wherein said compound of formula (H-I) is a compound of formula (H-II): (H-II), or a salt thereof.
  • Embodiment E21 The compound according to embodiment E16, wherein said compound of formula (H-I) is a compound of formula (H-II): (H-II), or a salt thereof.
  • Embodiment E25 The compound according to embodiment E1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (K-I): or a salt thereof, wherein: R K1 is C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, each substituted with C(O)OR Kx and optionally substituted with halo; 125 ny-2699290 Attorney Docket No.26327-20012.40 R 2 is Cl; R 3 is H or F; R 4 is H or F R 5 is OCH3 or F; and R Kx is H or C1-6alkyl.
  • Embodiment E26 The compound according to embodiment E25, or a salt thereof, wherein said compound of formula (K-I) is a compound of formula (K-II): or a salt thereof, wherein: X 1 is H or halo.
  • Embodiment E27 The compound according to embodiment E25, or a salt thereof, wherein said compound of formula (K-I) is a compound of formula (K-III): or a salt thereof, wherein: X 1 is H or halo.
  • Embodiment E28 The compound according to any one of embodiments E25 to E27, or a salt thereof, wherein R 3 is F. 126 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment E29.
  • R M1 is OR M1a , C(O)OR M1a , C(O)NHS(O)2R M1b , S(O)2NHR M1a , or S(O)2NHC(O)R M1b ;
  • R M1a is H, C 1-6 alkyl optionally substituted with C(O)OC 1-2 alkyl, or C 3-6 cycloalkyl;
  • R M1b is C 1-6 alkyl, or C 3-6 cycloalkyl;
  • R M2 is Cl or NO2;
  • R 4 is H or F; and
  • R 5 is F or CF 3 .
  • Embodiment E33 The compound according to embodiment E32, or a salt thereof, wherein R M1 is OR M1a .
  • Embodiment E34 The compound according to embodiment E32, or a salt thereof, wherein R 1 is C(O)OR M1a .
  • Embodiment E35 The compound according to embodiment E32, or a salt thereof, wherein R 1 is C(O)NHS(O) 2 R M1b . 127 ny-2699290 Attorney Docket No.26327-20012.40
  • Embodiment E36 The compound according to embodiment E32, or a salt thereof, wherein R 1 is S(O)2NHR M1a .
  • Embodiment E37 The compound according to embodiment E32, or a salt thereof, wherein R 1 is S(O)2NHR M1a .
  • Embodiment E42 The compound according to any one of embodiments E32 to E41, or a salt thereof, wherein R M1a or R M1b is C1-4alkyl.
  • Embodiment E43 The compound according to embodiment E32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-II): or a salt thereof.
  • Embodiment E44 The compound according to embodiment E32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-III): 128 ny-2699290 Attorney Docket No.26327-20012.40 or a salt thereof.
  • Embodiment E45 The compound according to any one of embodiments E32 to E41, or a salt thereof, wherein R M1a or R M1b is C1-4alkyl.
  • Embodiment E43 The compound according to embodiment E32, or a salt thereof, wherein said compound of formula (M-I) is a compound
  • Embodiment E32 The compound according to embodiment E32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-IV): or a salt thereof.
  • Embodiment E46 The compound according to embodiment E32, wherein said compound of formula (M-I) is a compound of formula (M-V): or a salt thereof.
  • Embodiment E47 The compound according to embodiment E1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof.
  • Embodiment E48 An agricultural composition, comprising: a compound of any one of embodiments E1 to E47, or a salt thereof; and at least one additional component that serves as a carrier.
  • Embodiment E49 The composition of embodiment E48, wherein at least one additional component is a surfactant or a diluent.
  • Embodiment E50 The composition of embodiment E47 or E48, wherein the composition is an herbicidal composition.
  • Embodiment E51 The composition of embodiment E48, wherein the composition is an herbicidal composition.
  • a method of controlling undesired vegetation comprising contacting the undesired vegetation or its environment with a compound of formula (I), or a salt thereof, or an agricultural composition comprising said compound and at least one additional component that serves as a carrier, wherein the compound of formula (I) is: wherein: R 1 is OR 1a , N(R 1a ) 2 , C(O)OR 1a , C(O)NHS(O) 2 R 1b , C(O)NHS(O) 2 N(R 1a )(R 1b ), S(O)2NHR 1a , S(O)2NHC(O)R 1b , C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl is substituted with C(O)OR x and optionally substituted with halogen; each R 1a is, independently, H, C1-6alkyl optionally substituted with C
  • Embodiment E52 The method according to embodiment E51, wherein the compound of formula (I) is a compound of any one of embodiments 1 to 47, or a salt thereof.
  • a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog of a base compound, wherein the base compound (i) inhibits protoporphyrinogen oxidase (PPO) and (ii) comprises a terminal cyclic moiety, wherein the fluorophenyl analog replaces the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein the fluorophenyl analog has one or more of the following properties: (i) similar or improved inhibition of wild-type PPO, relative to the base compound; ⁇ LL ⁇ VLPLODU ⁇ RU ⁇ LPSURYHG ⁇ LQKLELWLRQ ⁇ RI ⁇ * ⁇ PXWDQW ⁇ 332 ⁇ UHODWLYH ⁇ WR ⁇ WKH ⁇ EDVH ⁇ compound; (iii) similar or improved xylem mobility, relative to the base compound; (iv) similar or improved phloem mobility, relative to the base compound;
  • Embodiment F2 131 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment F2.
  • the method of embodiment F1 wherein the base compound comprises a terminal alkyl ester moiety, and wherein the fluorophenyl analog replaces the terminal alkyl ester moiety with a carboxylic acid moiety.
  • Embodiment F3. The method of embodiment F1 or F2, wherein the method comprises contacting the undesired vegetation or its environment with an herbicidally effective amount of the fluorophenyl analog.
  • Embodiment F8 wherein the core structure of [B] is selected from the group consisting .
  • Embodiment F10. The method of any one of embodiments F6 to F9, wherein the one or more mobility targeting moieties selectively enhances xylem mobility.
  • Embodiment F11 The method of any one of embodiments F6 to F9, wherein the one or more mobility targeting moieties selectively enhances phloem mobility.
  • Embodiment F12 The method of any one of embodiments F6 to F9, wherein the one or more mobility targeting moieties selectively enhances both xylem and phloem mobility.
  • a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog, wherein the fluorophenyl analog comprises a terminal phenyl moiety substituted with 4 or 5 fluoro groups, wherein: when the fluorophenyl analog binds in the active site of PPO, the terminal phenyl PRLHW ⁇ RI ⁇ WKH ⁇ IOXRURSKHQ ⁇ O ⁇ DQDORJ ⁇ H[KLELWV ⁇ D ⁇ - ⁇ VWDFNLQJ ⁇ LQWHUDFWLRQ ⁇ ZLWK ⁇ WKH ⁇ SKHQ ⁇ O ⁇ ULQJ ⁇ RI ⁇ a phenylalanine residue of the PPO.
  • Embodiment F17 Embodiment F17.
  • Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a procedure described in other Examples or Steps.
  • 1 H-NMR spectra are reported in ppm downfield from tetramethylsilane; “s” means singlet, “d” means doublet, “t” means triplet, “q” means quartet, “m” means multiplet, “dd” means doublet of doublets, “dt” means doublet of triplets, and “br s” means broad singlet.
  • Mass spectra are reported as the molecular weight of the highest isotopic abundance parent ion (M+1) formed by addition of H + (molecular weight of 1) to the molecule, or (M-1) formed by the loss of H + (molecular weight of 1) from the molecule, observed by using liquid chromatography coupled to a mass spectrometer (LCMS) using either atmospheric pressure chemical ionization (AP+) where "amu” stands for unified atomic mass units or electrospray ionization (ES + ).
  • Step 2 of Scheme 12 to a mixture of methyl 2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) acetate (50 mg, 0.13 mmol) in THF (0.9 mL) and H 2 O (0.3 mL) was added lithium hydroxide (16 mg, 0.39 mmol). The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The aqueous solution was acidified with formic acid to pH 3-4 and then was extracted with ethyl acetate.
  • Step 3 of Scheme 13 to a stirred mixture of 4,6-dichloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-ol (100 mg, 0.30 mmol) in DMF (3 mL) were added K2CO3 (126 mg, 0.91 mmol) and propargyl bromide (108 mg, 0.91 mmol). The resulting mixture was stirred at room temperature, diluted with water, and extracted with ethyl acetate.
  • Step 2 of Scheme 14 to a stirred solution of 3-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)-2-nitropyridine (600 mg, 1.38 mmol) in MeOH (7 mL) and water (1.4 mL) were added Fe powder (385 mg, 6.9 mmol) and NH 4 Cl (738 mg, 13.8 mmol). The resulting mixture was stirred at 80°C for 2 hours, filtered, the filter cake washed with MeOH, and the filtrate concentrated under reduced pressure.
  • Step 3 of Scheme 14 to a stirred solution of 3-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2-amine (350 mg, 0.87 mmol) in H2SO4 (5%, 4 mL) was added NaNO2 (119 mg, 1.73 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere.
  • Step 4 of Scheme 14 To a stirred solution of 3-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2(1H)-one (50 mg, 0.12 mmol) in DCE (3 mL) were added ethyl diazoacetate (70 mg, 0.62 mmol) and BF3.Et2O (catalytic, 2 drops). The resulting mixture was stirred at 85°C for 3 hours under a nitrogen atmosphere, diluted with water, and the aqueous layer was extracted with ethyl acetate.
  • Step 5 of Scheme 15 to a racemic mixture of methyl (2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-prolinate from Step 3 above (120 mg, 0.24 mmol) in DCE (2 mL) was added Me3SnOH (132 mg, 0.73 mmol). The resulting mixture was stirred at 65°C for 16 hours, cooled, diluted water, and acidified with 1M HCl pH 4.
  • Step 3 of Scheme 17 to a solution of 6-chloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-amine (200 mg, 0.68 mmol) in acetonitrile (2 mL) was added N-chlorosuccimide (73 mg, 0.54 mmol) at 20°C. The resulting solution was stirred at 80°C for 16 hours, cooled, and extracted with ethyl acetate.
  • Step 4 of Scheme 18 to a stirred solution of a mixture of 4'-chloro- 2,2',3,4,6-pentafluoro-5'-nitro-1,1'-biphenyl and 4-chloro-2,2',3',4',6'-pentafluoro-3,5-dinitro- 1,1'-biphenyl (200 mg) in MeOH (2 mL) were added AcOH (0.2 mL) and Zn (101 mg, 1.54 mmol). The resulting solution was stirred at 25°C for 2 hours.
  • Example 10 Preparation of isopropyl 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- carboxylate (Compound 2) 154 ny-2699290 Attorney Docket No.26327-20012.40 Scheme 20 [0360] As shown in Step 1 of Scheme 20, to a mixture of methyl 5-bromo-2-chloro-4- fluorobenzoate (1.0 g, 3.74 mmol) in tetrahydrofuran (10 mL) were added lithium hydroxide (269 mg, 11.22 mmol) and water (3 mL).
  • Step 2 of Scheme 20 to a solution of 5-bromo-2-chloro-4- fluorobenzoic acid (930 mg, 3.67 mmol) in DMF (10 mL) were added K 2 CO 3 (1.01 g, 7.34 mmol) and 2-iodopropane (936 mg, 5.50 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate.
  • Step 2 of Scheme 23 To a stirred mixture of methyl 2',3',4',5',6,6'- hexafluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylate (2.0 g, 5.71 mmol) in DCM (100 mL) was added boron tribromide (7.2 g, 28.56 mmol) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours, diluted with water at 0°C, and the aqueous solution extracted with ethyl acetate.
  • Example 14 Preparation of isopropyl 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3- carboxylate (Compound 35), 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-carboxylic acid (Compound 36), and 4-chloro-N-(N,N-dimethylsulfamoyl)-2',3',4',6,6'-pentafluoro-[1,1'- biphenyl]-3-carboxamide (Compound 37)
  • Scheme 23 161 ny-2699290 Attorney Docket No.26327-20012.40 [0372] As shown in Step 1 of Scheme 23, to a solution of 2-chloro-4-fluorobenzoic acid (5.0 g, 28.6 mmol) in concentrated H2SO4 (50 mL) was added 1-iodopyr
  • Step 2 of Scheme 23 To a solution of 2-chloro-4-fluoro-5-iodobenzoic acid (7.00 g, 23.3 mmol) in DMF (70 mL) were added 2-iodopropane (6.34 g, 37.3 mmol) and K 2 CO 3 (6.44 g, 46.6 mmol) at 25°C. The resulting mixture was stirred at 25°C for 16 hours, diluted with water, and extracted with EtOAc.
  • Example 15 Preparation of ethyl (R)-2-chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'- biphenyl]-3-yl)propanoate (Compound 38), ethyl (S)-2-chloro-3-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (Compound 39), (R)-2-chloro-3-(4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (Compound 40), and (S)-2- chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-
  • Step 4 of Scheme 24 to a mixture of 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-amine (400 mg, 1.28 mmol) and ethyl acrylate (218 mg, 2.18 mmol) in acetonitrile (5 mL) were added CuCl2 (207 mg, 1.54 mmol) and t-BuONO (172 mg, 1.66 mmol).
  • Step 2 of Scheme 25 To a stirred mixture of 2-chloro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.0 g, 3.60 mmol) in toluene (20 mL) and H2O (4 mL) were added iodopentafluorobenzene (1.3 g, 4.32 mmol), K3PO4 (1.5 g, 7.20 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.5 g, 0.72 mmol) under an atmosphere of nitrogen.
  • iodopentafluorobenzene 1.3 g, 4.32 mmol
  • K3PO4 1.5 g, 7.20 mmol
  • 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride 0.5 g, 0.72 mmol
  • Step 2 of Scheme 27 to a mixture of methyl 2-nitro-5- (perfluorophenoxy) benzoate (500 mg, 1.38 mmol) in THF (4.5 mL) and water (1.5 mL) was added LiOH (174 mg, 4.15 mmol). The resulting mixture was stirred at room temperature for 16 hours, diluted by the addition of water, and acidified to pH 5 with formic acid. The aqueous solution was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 20 Preparation of 1-ethoxy-1-oxopropan-2-yl 2-chloro-5- (perfluorophenoxy)benzoate (Compound 51) Scheme 29 [0398] As shown in Step 1 of Scheme 29, to a stirred solution of methyl 2-chloro-5- hydroxybenzoate (500 mg, 2.65 mmol) in DMF (5 mL) was added NaH (159.2 mg - 60% by weight in mineral oil 3.98 mmol) in portions at 0°C under a nitrogen atmosphere.
  • the 173 ny-2699290 Attorney Docket No.26327-20012.40 resulting mixture was stirred at 0°C for 30 minutes, followed by the addition of hexafluorobenzene (987 mg, 5.30 mmol) at 0°C.
  • the resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere.
  • the reaction mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 3 of Scheme 29 To a stirred mixture of 2-chloro-5- (perfluorophenoxy)benzoic acid (50 mg, 0.15 mmol), ethyl 2-hydroxypropanoate (26 mg, 0.22 mmol) and PPh 3 (58 mg, 0.22 mmol) in THF (1 mL) was added diisopropylazodicarboxylate (45 mg, 0.22 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for additional 3 hours under nitrogen. The reaction mixture was diluted with water and extracted with ethyl acetate.
  • the resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere.
  • the mixture was quenched by the addition of water and the aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • Example 22 Preparation of 2-nitro-5-(2,3,4,5,6-pentafluorophenoxy)phenol (Compound 55) and 1-(3-ethoxy-4-nitrophenoxy)-2,3,4,5,6-pentafluorobenzene (Compound 56) Scheme 31 [0402] As shown in Step 1 of Scheme 31, to a stirred mixture of 1,2,3,4,5-pentafluoro-6- (3-methoxy-4-nitrophenoxy)benzene (350 mg, 1.044 mmol) in DCM (5 mL) was added BBr3 (2616 mg, 10.44 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere.
  • Step 2 of Scheme 31 To a stirred mixture of 2-nitro-5-(2,3,4,5,6- pentafluorophenoxy)phenol (150 mg, 0.46 mmol) in DMF (5 mL) were added K2CO3 (127 mg, 0.92 mmol) and ethyl iodide (109 mg, 0.70 mmol). The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate.
  • Example 23 Preparation of 2-nitro-5-(perfluorophenoxy)benzenesulfonamide (Compound 57) Scheme 32 176 ny-2699290 Attorney Docket No.26327-20012.40 [0404] As shown in Step 1 of Scheme 32, to a solution of 3-bromo-4-nitrophenol (8.00 g, 36.7 mmol) in DMF (80 mL) was added K2CO3 (10.14 g, 73.4 mmol) followed by stirring the mixture at 10 ⁇ for 1 hour. After cooling to room temperature, hexafluorobenzene (68.3 g, 367 mmol) was added dropwise at 25 ⁇ , followed by stirring the mixture for 3 days at 100 ⁇ .
  • K2CO3 10.14 g, 73.4 mmol
  • Step 2 of Scheme 32 to a degassed solution of benzyl mercaptan (582 mg, 4.68 mmol) and 1-(3-bromo-4-nitrophenoxy)-2,3,4,5,6-pentafluorobenzene (1.80 g, 4.68 mmol) in 1,4-dioxane (20 mL) were added XantPhos (271 mg, 0.46 mmol) and DIEA (1.21 J ⁇ PPRO ⁇ 7KH ⁇ UHVXOWLQJ ⁇ PL[WXUH ⁇ ZDV ⁇ VWLUUHG ⁇ DW ⁇ IRU ⁇ Kours under a nitrogen atmosphere.
  • Example 25 Preparation of N-((2-nitro-5-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy)phenyl)sulfonyl)acetamide (Compound 60) 178 ny-2699290 Attorney Docket No.26327-20012.40 Scheme 34 [0410] As shown in Step 1 of Scheme 34, to a solution of 3-bromo-4-nitrophenol (5.00 g, 22.94 mmol) in DMF (50 mL) was added NaH (1.76 g - 60% by weight in mineral oil, 45.9 mmol) in portions at 0 ⁇ .
  • Example 26 Amaranthus tuberculatum Protoporphyrinogen Oxidase (AmPPO) Expression and Purification
  • AmPPO Amaranthus tuberculatum Protoporphyrinogen Oxidase
  • the coding sequence of AmPPO was optimized for E. coli expression and assembled from synthetic oligonucleotides. Synthetic fragments were introduced into a pET28b vector (Novagen) using restriction-less “Hot Fusion” cloning process (Fu C., et al., ‘Hot Fusion: An Efficient Method to Clone Multiple DNA Fragments as Well as Inverted Repeats without Ligase,’ PLoS One (2014) Vol.9(12), page e115318).
  • the resulting DNA was sequence-YHULILHG ⁇ &RQVWUXFW ⁇ HQFRGLQJ ⁇ PXWDQW ⁇ YHUVLRQ ⁇ * ⁇ -AmPPO) of the enzyme was produced via PCR-based mutagenesis using Q5 mutagenesis kit (NEB).
  • Lysogeny broth LB media, 10 mL
  • kanamyci was inoculated with a single colony of BL21(DE3) competent E. coli transformed with pET28b_PPO_CHis.
  • pET28b_PPO_CHis The culture was grown at 37°C with shaking at 230 rpm overnight.
  • This culture was then used to inoculate 1 L of autoinduction media (AIM) prepared by the method of Fox, B. G., & Blommel, P. G. (2009), Autoinduction of protein expression, ‘Current Protocols in Protein Science,’ Chapter 5, Unit–5.23.
  • AIM autoinduction media
  • the resulting culture was grown at 37°C with shaking at 230 rpm for 4 to 6 hours and an additional 40 to 181 ny-2699290 Attorney Docket No.26327-20012.40 48 hours at 18°C.
  • the culture was collected and centrifuged.
  • the resulting AmPPO enzyme- containing cell pellets were frozen and stored at -80°C for future use.
  • a detergent solution was prepared by mixing together the following: 175 mL of B- PER Thermo Scientific); 75 mL of Y-PER (Thermo Scientific); 15 mL of 1M TRIS buffer, pH 9.0, 15 mL of 5M NaCl; 50 mL of glycerol; 2.5 mL of Triton-X100; and 1 mg of Flavin Adenine Dinucleotide (FAD).
  • a portion of this solution (about 80 mL -100 mL) is set aside and supplemented with imidazole to a final concentration of 10 mM and a pH of pH 8.0.
  • detergent solution was supplemented with Hen Egg White Lysozyme (Gold Bio, 1 mg/mL) and Serratia endonuclease (produced in house) and added to about 45 g of frozen enzyme-containing cell pellets, which were allowed to thaw in the lysis solution with vigorous stirring for 30 minutes at room temperature, then briefly sonicated (30 seconds on 50% power using a VWR brand sonic disruptor). Incubation was continued with stirring for additional 15-30 minutes at 4°C. The lysate was clarified for 35 minutes by centrifugation at 14,000 RPM.
  • Hen Egg White Lysozyme Gold Bio, 1 mg/mL
  • Serratia endonuclease produced in house
  • the resulting clarified lysate was incubated for 1 hour at 4°C with gentle stirring with His-SELECT® resin (Sigma, 20 mL of 50% slurry in 20% ethanol, washed 2x with 30 mM TRIS pH 8.1, 10 % glycerol, 220 mM NaCl).
  • His-SELECT® resin Sigma, 20 mL of 50% slurry in 20% ethanol, washed 2x with 30 mM TRIS pH 8.1, 10 % glycerol, 220 mM NaCl.
  • the resin slurry was transferred to a disposable plastic column and washed with 10 mM Imidazole, 250 mM NaCl, 30 mM TRIS pH 8.5, 10 % glycerol until the bound protein was deemed sufficiently washed away from lysate components (about 6-8 column volumes).
  • Protoporphyrinogen IX is prepared by reduction of protoporphyrin IX (PPIX) with a sodium amalgam as described by Jacobs and Jacobs, Enyzme 28: 206 (1982). 182 ny-2699290 Attorney Docket No.26327-20012.40 Once prepared, the PPGIX solution is kept in the dark and all subsequent manipulations of it are performed in the dark. [0421] The Base Buffer for the assay was 50 mM TRIS pH 8.5, 160 mM NaCl, 2 mM DTT, 0.01% Triton X-100.
  • An antifoam solution was prepared by two serial 1 to 10 dilutions of Antifoam B Emulsion (SigmaAldrich) with Milli-Q water.
  • Buffer A was freshly prepared E ⁇ GLOXWLQJ ⁇ $P332 ⁇ RU ⁇ PXWDQW ⁇ * ⁇ -AmPPO in Base Buffer to 3-8 ug/ml concentration of enzyme.
  • Buffer B was prepared by adding 2 ml of reduced 2 mM PPIX to 60 ml of Base Buffer and adjusting the pH back to 8.5 using glacial acetic acid. Finally, antifoam B (Sigma) was added to 0.01% final concentration. Buffer B was protected from light and used within 3 hours of its preparation.
  • a 384 well, clear bottom plate was used for the assay. Each test compound was dissolved in DMSO to a concentration of 30 mM. The test compounds, tested in triplicate, a butafenacil control, and a DMSO control were dispensed as 1.2 ⁇ L drops into a well of the plate. The wells were diluted with 60 ⁇ L of Buffer A and serially diluted 1 volume to 3 volumes over 7 dilutions by removing 20 ⁇ L from the first well, mixing well with 40 ⁇ L of Buffer A in a second well, removing 20 ⁇ L from the second well, and continuing the dilutions in this manner until there were 8 test wells.
  • IC 50 were calculated using a nonlinear regression Sigmoidal dose-response model (GraphPad Prism, variable slope) with curve bottoms constrained to zero and curve tops constrained to plate-specific Vaverage.
  • Compounds 1 to 3, 5, 7, 9 to 10, 12 to 14, 16 to 19, 22, 25, 27 to 28, 30 to 31, 33 to 35, 37 to 41, 43 to 48, 51 to 52, 54, and 56 to 61 had an IC50 of less than 100 nM in the PPO in vitro assay.
  • Compounds 4, 6, 8, 11, 15, 20 to 21, 23 to 24, 26, 29, 36, 42, 50, 53, and 55 had an IC 50 of less than 1 ⁇ M in this assay.
  • Compounds 10, 14, 19, 27, 35, 45 to 46, and 61 had an IC50 of less than 100 nM in WKH ⁇ * ⁇ 332 ⁇ in vitro assay.
  • PPO susceptible weed seeds were sown in 5” x 5” pots by quadrant containing Miracle-Gro potting mix (Scotts Miracle-Gro Company, Marysville, OH, USA) and grown in a Conviron growth chamber with appropriate growth conditions (temperature of 26/22°C with photoperiod 16/8 h light day/night and light intensity of 300 ⁇ mol m -2 s -1 supplemented by LED lamps). Relative humidity in the growth chamber was maintained at around 65%. Plants were grown until 2-4 leaf stage and thinned to 5-8 plants per quadrant per species.
  • Miracle-Gro potting mix Scotts Miracle-Gro Company, Marysville, OH, USA
  • Post-emergence herbicidal activity of selected compounds of the invention 7 days after the compound application (Entries labeled “--” were not tested) 184 ny-2699290 Attorney Docket No.26327-20012.40 Example 29. Testing the pre-emergence herbicidal activity of compounds of the invention.
  • Selected compounds of the invention were screened at 200 PPM against Amaranthus retroflexus (AMARE).
  • AMARE Amaranthus retroflexus
  • PPO susceptible weed seeds were planted in 5” x 5” pots by quadrant containing custom field soil mix (Sandy loam with 4.7% OM, pH 7.0) and covered with a fine layer of the same soil.
  • Fluorophenyl analogs prepared are listed in Table 5, below, along with the commercial PPO inhibitors from which they were derived. Analogs that also appear in Table 1 are identified by their corresponding compound number. Table 5. Fluorophenyl Analogs and Corresponding Base Compounds 186 ny-2699290 Attorney Docket No.26327-20012.40 187 ny-2699290 Attorney Docket No.26327-20012.40 188 ny-2699290 Attorney Docket No.26327-20012.40 [0432] Fluorophenyl analogs A1, A2, A5-A12, A15-A19, and A21 listed in Table 5, above, were prepared according to the synthetic procedures described in Examples 1-25.
  • Entries in Table 7 marked as “A” have IC50 values of less than or equal to 100 nM; entries marked as “B” have IC50 values greater than 100 nM, but less than or equal to 1 ⁇ M; and entries marked as “C” have IC 50 values greater than 1 ⁇ M.
  • Table 7. Inhibition of WT PPO and ⁇ * ⁇ PPO by Fluorophenyl Analogs 191 ny-2699290 Attorney Docket No.26327-20012.40
  • Example 32 Computational Modeling of Fluorophenyl Analog-PPO Binding [0436] The binding of fluorophenyl analogs A5 and A21 was modeled using Schrodinger Maestro.
  • the PPO model was based upon 1SEZ structure of the Nicotiana tabacum PPO in the protein databank found at https://www.ebi.ac.uk/pdbe/entry/pdb/1sez.
  • An image of the predicted binding configuration for fluorophenyl analog A5 is shown in Fig.1.
  • An image of the predicted binding configuration for fluorophenyl analog A21 is shown in Fig.2.
  • the fluorophenyl moiety in close proximity and oriented parallel to the phenyl ring of the SKHQ ⁇ ODODQLQH ⁇ PRLHW ⁇ 3KH ⁇ RI ⁇ WKH ⁇ 332 ⁇ PRGHO ⁇ LQGLFDWLYH ⁇ RI ⁇ DQ ⁇ DWWUDFWLYH ⁇ - ⁇ VWDFNLQJ ⁇ interaction between the fluorophenyl moiety and the phenylalanine residue.
  • Example 33 Example 33.
  • Xylem and phloem mobility assay [0437] Compounds are tested for leaf penetration, translocation, and herbicidal activity in a grass weed species when applied with or without an adjuvant to increase the compound 192 ny-2699290 Attorney Docket No.26327-20012.40 cuticle penetration.
  • Test compounds are formulated to a final concentration of 1.5 mM in 25% Acetone, 0.1% Tween-20 and 2.5% Ammonium sulphate (AMS) with or without the addition of 1% v/v Crop oil concentrate (COC, Agridex). A total of 6 ⁇ L are applied as 3 x 2 ⁇ L droplets on the adaxial surface of an emerged Setaria Italica leaf for each of the two compound solutions (with and without COC). Six replicate plants are treated with each compound. Treatment consisting of the above formulation excluding active compound are applied as a treatment control (TC). Plants are placed back in the growth chamber and, seven days after treatment, are evaluated for overall % visual injury compared to TC.
  • TC treatment control
  • Plants are also evaluated for rapid necrosis representative of PPO inhibition at the site of, acropetal to, and basipetal to the droplet application site to estimate the general, xylem, and phloem compound mobility, respectively.
  • compounds with necrosis only at the site of action are considered to be poorly mobile whereas necrosis in the emerging leaf indicates symplastic phloem movement and necrosis from leaf base to tip only on the applied leaf indicates apoplastic xylem movement.
  • the data can be presented relative to the TC treatment for which the plant and leaf injury percent is considered 0%.
  • A represents a percentage leaf or plant injury between 80 and 100%; “B” represents a percentage leaf or plant injury of 20-80%; “C” represents a percentage control below 20%.
  • Example 34 Soil Mobility Assay [0440] PPO susceptible weed and crop seeds are planted in 3-inch pots at three different depths (0.5, 1 and 2-inch) containing custom field soil mix (sandy loam with 4.7% OM, pH 7.0) and covered with a fine layer of the same soil. Three replicate pots are treated with each of the compounds. Treatment consisting of the above formulation excluding active compound 193 ny-2699290 Attorney Docket No.26327-20012.40 is applied as a treatment control (TC).
  • TC treatment control
  • Pots are treated with the test compound solution in a laboratory spray chamber fitted with 8003 even fan nozzles calibrated to deliver 187-200 L ha-1 at 269 kPa. All treatments include the following inert ingredients in the final formulation; 1% Agridex (v/v) (crop oil concentrate) and 2.5% Ammonium sulphate (w/v). Compound is incorporated into the soil by simulating rainfall equivalent to 0.2 mm using the same track sprayer. Subsequently, pots are irrigated from the bottom until assessed for % growth and germination inhibition of both the crop and weed species tested. Pots are placed back in the growth chamber and evaluated for % visual growth and germination inhibition compared to TC 17-21 days after treatment (DAT). 194 ny-2699290

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Abstract

The present invention relates to protoporphyrinogen oxidase inhibitors, including compounds of formula (I): where the variables are defined herein. The invention features processes and intermediates for preparing such compounds, compositions comprising them, and their use as herbicides, e.g., for controlling harmful plants. The invention also features methods for controlling unwanted vegetation comprising allowing an herbicidal effective amount of the compounds herein to act on plants, their seed, and/or their habitat.

Description

Attorney Docket No.26327-20012.40 PROTOPORPHYRINOGEN OXIDASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 63/490,163, filed March 14, 2023; U.S. Provisional Patent Application No.63/451,992, filed March 14, 2023; U.S. Provisional Patent Application No.63/490,102, filed March 14, 2023; U.S. Provisional Patent Application No.63/490,097, filed March 14, 2023; U.S. Provisional Patent Application No.63/452,040, filed March 14, 2023; and U.S. Provisional Patent Application No.63/452,027, filed March 14, 2023, each of which is incorporated herein by reference in its entirety. FIELD [0002] The present invention relates to protoporphyrinogen IX oxidase (PPO) inhibitors useful as herbicides. In particular, the present invention relates to certain fluorinated phenyl compounds, compositions comprising such compounds, processes for making such compounds and compositions, and methods for using such compounds for crop protection and to control unwanted vegetation. BACKGROUND [0003] Herbicides that inhibit protoporphyrinogen oxidase (hereinafter referred to as Protox or PPO; EC:1.3.3.4), a key enzyme in the biosynthesis of protoporphyrin IX, have been used for selective weed control since the 1960s. PPO catalyzes the last common step in chlorophyll and heme biosynthesis, which is the oxidation of protoporphyrinogen IX to protoporphyrin IX [Matringe M. et al., Protoporphyrinogen oxidase as a molecular target for diphenyl ether herbicides, Biochemistry Journal (1989) 260: 231-235]. Application of PPO- inhibiting herbicides results in the accumulation of protoporphyrinogen IX in the chloroplast and mitochondria, which is believed to leak into the cytosol where it is oxidized by a peroxidase. When exposed to light, protoporphyrin IX causes formation of singlet oxygen in the cytosol and the formation of other reactive oxygen species, which can cause lipid peroxidation and membrane disruption leading to rapid cell death [Lee H.J. et al., Cellular localization of protoporphyrinogen-oxidizing activities of etiolated barley leaves, Plant Physiology (1993) 102: 881]. 1 ny-2699290 Attorney Docket No.26327-20012.40 [0004] To date, thousands of PPO inhibitors have been reported in the literature, with about 30 currently used as herbicides to decimate weeds in fields [Hao, G. F., et al., Protoporphyrinogen oxidase inhibitor: an ideal target for herbicide discovery, Chimia (2011) 65, 961-969]. PPO-inhibiting herbicides include many different structural classes of molecules, including diphenyl ethers (e.g. lactofen, acifluorfen, acifluorfen methyl ester, or oxyfluorfen); oxadiazoles (e.g. oxadiazon); cyclic imides [e.g. S-23142, N-(4-chloro-2- fluoro-5-propargyloxyphenyl)-3,4,5,6-tetrahydrophthalimide, chlorophthalim, N-(4- chlorophenyl)-3,4,5,6-tetrahydrophthalimide)]; phenyl pyrazoles (e.g. TNPP-ethyl, ethyl 2- [1-(2,3,4-trichlorophenyl)-4-nitropyrazolyl-5-oxy]propionate, M&B 39279); pyridine derivatives (e.g. LS 82-556); and phenopylate and its O-phenylpyrrolidino- and piperidinocarbamate analogs (Krämer W., ed., Modern Crop Protection Compounds, 2nd Ed., Vol 1: Herbicides, (2012) Wiley-VCH, Weinheim, Germany). Many of these compounds competitively inhibit the normal reaction catalyzed by the enzyme, apparently acting as substrate analogs. [0005] The herbicidal properties of these known compounds towards harmful plants, however, are not always entirely satisfactory. Herbicide resistant weeds present a serious problem for efficient weed control because such resistant weeds are increasingly widespread and thus weed control by the application of herbicides is no longer effective, causing a huge problem to farmers. Resistance to PPO herbicides has been slow to evolve (about four decades from first commercialization), and to date has been confirmed in 13 weed species [Heap I, The International Survey of Herbicide Resistant Weeds. Available online: http://www.weedscience.org/ (October 2019)]. The first weed to evolve resistance to PPO herbicides was waterhemp (Amaranthus tuberculatus) in 2001 [Shoup D.E., et al., Common waterhemp (Amaranthus rudis^^UHVLVWDQFH^WR^SURWRSRUSK\ULQRJHQ^R[LGDVH^LQKLELWLQJ^ herbicides Weed Sci. (2003) 51:145–150]. Resistance to PPO herbicides in weedy species has been attrLEXWHG^WR^WDUJHW^VLWH^PXWDWLRQ^LQ^WKH^PPX2 JHQH^^)RU^H[DPSOH^^D^XQLTXH^WDUJHW^VLWH^ amino acid deletion (Gly210) and Arg98Leu substitution confer PPO resistance in waterhemp [Patzoldt W.L., et al., A codon deletion confers resistance to herbicides inhibiting protoporphyrinogen oxidase. Proc. Natl. Acad. Sci. USA (2006) 103:12329–12334] and common ragweed [Rousonelos, et al., Characterization of a common ragweed (Ambrosia artemisiifolia^^SRSXODWLRQ^UHVLVWDQW^WR^$/6^^DQG^332^LQKLELWLQJ^KHUELFLGHV^^Weed Sci. (2012) 60:335–344], respectively. 2 ny-2699290 Attorney Docket No.26327-20012.40 [0006] Thus, there is a need for novel methods to effectively control weeds, including herbicide resistant weeds and in particular PPO resistant weeds, which at the same time is tolerated by the useful plants (crops) in question. BRIEF SUMMARY [0007] Accordingly, in one aspect, provided compounds having formula (I):
Figure imgf000005_0001
or a salt thereof, where X, R1, R2, R3, R4, and R5 are as defined elsewhere herein. [0008] In certain embodiments, provided are compounds having formula (G-I):
Figure imgf000005_0002
or a salt thereof, where RG1, R2, R3, R4, and R5 are as defined elsewhere herein. [0009] In certain embodiments, provided are compounds having formula (G-II):
Figure imgf000005_0003
or a salt thereof, where RG1a, R2, R3, R4, and R5 are as defined elsewhere herein. [0010] In certain embodiments, provided are compounds having formula (G-III): 3 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000006_0001
or a salt thereof, where RG1a, R2, R3, R4, and R5 are as defined elsewhere herein. [0011] In certain embodiments, provided are compounds having formula (H-I):
Figure imgf000006_0002
or a salt thereof, where RH1, R2, R3, and R4 are as defined elsewhere herein. [0012] In certain embodiments, provided are compounds having formula (H-II):
Figure imgf000006_0003
or a salt thereof, where RH1a, R2, R3, and R4 are as defined elsewhere herein. [0013] In certain embodiments, provided are compounds having formula (H-III):
Figure imgf000006_0004
or a salt thereof, where RH1b, R2, R3, and R4 are as defined elsewhere herein. [0014] In certain embodiments, provided are compounds having formula (H-IV): 4 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000007_0001
or a salt thereof, where RH1a, RH1b, R2, R3, and R4 are as defined elsewhere herein. [0015] In certain embodiments, provided are compounds having formula (K-I):
Figure imgf000007_0002
(K-I), or a salt thereof, where RK1, R2, R3, R4, and R5 are as defined elsewhere herein. [0016] In certain embodiments, provided are compounds having formula (K-II):
Figure imgf000007_0003
or a salt thereof, where X1, RKx, and R3 are as defined elsewhere herein. [0017] In certain embodiments, provided are compounds having formula (K-III):
Figure imgf000007_0004
or a salt thereof, where X1, RKx, and R3 are as defined elsewhere herein. [0018] In certain embodiments, provided are compounds having formula (M-I): 5 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000008_0001
(M-I), or a salt thereof, where RM1, R2, R3, R4, and R5 are as defined elsewhere herein. [0019] In certain embodiments, provided are compounds having formula (M-II):
Figure imgf000008_0002
or a salt thereof, where RM1a and R5 are as defined elsewhere herein. [0020] In certain embodiments, provided are compounds having formula (M-III):
Figure imgf000008_0003
or a salt thereof, where RM1a and R5 are as defined elsewhere herein. [0021] In certain embodiments, provided are compounds having formula (M-IV):
Figure imgf000008_0004
or a salt thereof, where RM1b and R5 are as defined elsewhere herein. [0022] In certain embodiments, provided are compounds having formula (M-V): 6 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000009_0001
or a salt thereof, where RM1b and R5 are as defined elsewhere herein. [0023] In other aspects, provided is also an agricultural composition (including, in some variations, herbicidal compositions) that includes a compound of formulas (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M- III), (M-IV), or (M-V), or a salt thereof, in a herbicidally effective amount and at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents (e.g., formulations). In some variations, the salt is an agriculturally suitable salt. In some embodiments, the composition optionally further includes at least one additional active ingredient. In one variation, the additional active ingredient may be an herbicide and/or herbicide safener. [0024] In yet another aspect, provided are also processes for making the above-identified compounds, salts, and compositions. [0025] In certain aspects, provided are compounds that are intermediates for making one or more compounds of the invention, including one or more compounds of Table 1, or a salt thereof. [0026] In yet other aspects, provided are also methods for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of the invention, its salt, or a composition that includes a compound of the invention as described herein. DESCRIPTION OF THE FIGURES [0027] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures. 7 ny-2699290 Attorney Docket No.26327-20012.40 [0028] FIG.1 depicts a Schrodinger Maestro model of the binding configuration of fluorophenyl analog A5 in the active site of PPO. [0029] FIG.2 depicts a Schrodinger Maestro model of the binding configuration of fluorophenyl analog A21 in the active site of PPO. DETAILED DESCRIPTION [0030] In one aspect, provided are compounds having formula (I):
Figure imgf000010_0001
or a salt thereof, wherein: R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, alkyl, alkenyl, or alkynyl, wherein each alkyl, alkenyl, or alkynyl is substituted with C(O)ORw and optionally substituted with halo; each R1a is, independently, H, alkyl optionally substituted with C(O)OR1b, alkyl optionally substituted with C(O)N(R1c)2, alkenyl, alkynyl, cycloalkyl, C(O)alkyl, C(O)cycloalkyl, C(O)NH(R1x), C(O)OCH2alkenyl, C(O)OCH2alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2alkyl optionally substituted with up to 3 F atoms; each R1b is independently, H, alkyl, alkenyl, alkynyl, or cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; R1x is H or alkyl; Rw is H or C1-6alkyl; R2 is H, halo, O(haloalkyl), or NO2; 8 ny-2699290 Attorney Docket No.26327-20012.40 R3 is H, or halo; each of R4, R6, and R7 is H or halo; R5 is H, halo, haloalkyl, or O(alkyl); X is O or a bond; and Ring A contains at least 3 halo, provided that: (1) when X is a bond, then R1 is not CH3, S(O)2NHR1a or S(O)2NHC(O)R1b, and at least one of R2 or R3 is not H; (2) when X is a bond and R1 is OH, OCH3, CO2CH3, CO2CH2CH3, or CH=CHCO2H, then each of R2 and R3 is not H; (3) when X is a bond and R1 is NH2, then each of R2 and R3 is not H, and at least one of R2 and R3 is not F; (4) when X is O, then R2 and at least one of R1 or R3 is not H; and (5) when X is O, then R1 is not NHCH3. [0031] In some variations of the foregoing: R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with C(O)ORw and optionally substituted with halogen; each R1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR1b, C1-6alkyl optionally substituted with C(O)N(R1c)2, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2-4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is , independently, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; 9 ny-2699290 Attorney Docket No.26327-20012.40 R1x is H or C1-6alkyl; Rw is H or C1-6alkyl; R2 is H, F, Cl, OCHF2, or NO2; R3 is H, F, or Cl; each of R4, R6, and R7 is H or F; R5 is H, F, CF3. or OC1-2alkyl; X is O or a bond; and Ring A contains at least 3 F, provided that: (1) when X is a bond, then R1 is not CH3, S(O)2NHR1a or S(O)2NHC(O)R1b, and at least one of R2 or R3 is not H; (2) when X is a bond and R1 is OH, OCH3, CO2CH3, CO2CH2CH3, or CH=CHCO2H, then each of R2 and R3 is not H; (3) when X is a bond and R1 is NH2, then each of R2 and R3 is not H, and at least one of R2 and R3 is not F; (4) when X is O, then R2 and at least one of R1 or R3 is not H; and (5) when X is O, then R1 is not NHCH3. [0032] In one embodiment, Ring A of the compounds of formula (I) has at least 4 F. In a further embodiment, R4 is H or F and each of R5, R6, and R7 is F. [0033] In another embodiment, Ring A contains 5 F. [0034] In another embodiment, X is a bond. [0035] In yet another embodiment, X is O. [0036] In one embodiment, provided are compounds having formula (G-I): 10 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000013_0001
(G-I), where R1 is ORG1a or N(RG1a)2; each RG1a is, independently, H, C1-4alkyl optionally substituted with C(O)ORG1b, C1-4alkyl optionally substituted with C(O)N(RG1c)2, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, C(O)C1- 4alkyl, C(O)C3-6cycloalkyl, C(O)N(RG1x), C1-4alkyl, C(O)OCH2C2-4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2RG1x, pyridyl optionally substituted with OCH2CO2RG1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each RG1b is , independently, H, C1-4alkyl, or C3-6cycloalkyl, wherein each C1-4alkyl or C3- 6cycloalkyl of RG1b is optionally substituted with C(O)ORG1x and up to 4 F atoms; each RG1c is, independently, RG1b, or two RG1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)ORG1x; R1x is H or C1-6alkyl; each of R2 and R3 is, independently, F or Cl; R4 is H or F; and R5 is F or OC1-2alkyl. [0037] In another embodiment, the compound of formula (G-I) is a compound of formula (G-II):
Figure imgf000013_0002
11 ny-2699290 Attorney Docket No.26327-20012.40 [0038] In a further embodiment, RG1a is C1-4alkyl optionally substituted with C(O)ORG1b or C(O)N(RG1c)2. In another further embodiment, RG1a is pyridyl substituted with OCH2CO2RG1x. [0039] In another embodiment, the compound of formula (G-I) is a compound of formula (G-III):
Figure imgf000014_0001
[0040] In a further embodiment, RG1a is, independently, H or S(O)2C1-4alkyl. [0041] In a further embodiment for any of the compounds of formulas (G-II) or (G-III), R4 is F. In another further embodiment for any of the compounds of formulas (G-II) or (G- III), R4 is H. In yet another further embodiment for any of the compounds of formulas (G-II) or (G-III), R2 is Cl and R3 is F. [0042] In another embodiment, provided are compounds having formula (H-I):
Figure imgf000014_0002
RH1 is ORH1a, NHS(O)2RH1b, or NHS(O)2N(RH1a)(RH1b); RH1a is H or C1-6alkyl optionally substituted with C(O)OC1-4alkyl or C(O)OC2-4alkenyl; RH1b is C1-6alkyl; R2 is Cl or OCHF2; R3 is H or F; and R4 is H or F. 12 ny-2699290 Attorney Docket No.26327-20012.40 [0043] In one embodiment, the compound of formula (H-I) is a compound of formula (H- II):
Figure imgf000015_0003
[0045] In another embodiment, the compound of formula (H-I) is a compound of formula (H-IV):
Figure imgf000015_0001
[0046] In a further embodiment for any of the compounds of formulas (H-II), (H-III), or (H-III), R2 is Cl, R3 is F, and R4 is F. In another further embodiment for any of the compounds of formulas (H-II), (H-III), or (H-III), R2 is Cl, R3 is F, and R4 is H. [0047] In another embodiment, provided are compounds having formula (K-I):
Figure imgf000015_0002
(K-I), where 13 ny-2699290 Attorney Docket No.26327-20012.40 RK1 is C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, each substituted with C(O)ORKx and optionally substituted with halogen; R2 is Cl; R3 is H or F; R4 is H or F R5 is OCH3 or F; and RKx is H or C1-6alkyl. [0048] In one embodiment, the compound of formula (K-I) is a compound of formula (K- II):
Figure imgf000016_0001
halogen atom. [0049] In another embodiment, the compound of formula (K-I) is a compound of formula (K-III):
Figure imgf000016_0002
halogen atom. [0050] In a further embodiment for any of the compounds of formulas (K-II) or (K-III), R3 is F. In another further embodiment, X is Cl. In another further embodiment, RKx is H. In yet another further embodiment, RKx is C1-2alkyl. [0051] In another embodiment, provided are compounds having formula (M-I): 14 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000017_0001
RM1 is ORM1a, C(O)ORM1a, C(O)NHS(O)2RM1b, S(O)2NHRM1a, or S(O)2NHC(O)RM1b;
Figure imgf000017_0002
C1-6alkyl optionally substituted with C(O)OC1-2alkyl, or C3-6cycloalkyl; RM1b is C1-6alkyl, or C3-6cycloalkyl; RM2 is Cl or NO2; R4 is H or F; and R5 is F or CF3. [0052] In one embodiment, the compound of formula (M-I) is a compound of formula (M-II):
Figure imgf000017_0003
[0053] In a further embodiment, R5 is F. In another further embodiment, R5 is CF3. [0054] In another embodiment, the compound of formula (M-I) is a compound of formula (M-III):
Figure imgf000017_0004
[0055] In a further embodiment, R5 is F. In another further embodiment, R5 is CF3. 15 ny-2699290 Attorney Docket No.26327-20012.40 [0056] In one embodiment, the compound of formula (M-I) is a compound of formula (M-IV):
Figure imgf000018_0001
[0057] In a further embodiment, R5 is F. In another further embodiment, R5 is CF3. [0058] In one embodiment, the compound of formula (M-I) is a compound of formula (M-V):
Figure imgf000018_0002
[0059] In a further embodiment, R5 is F. In another further embodiment, R5 is CF3. [0060] In some aspects, provided are compounds having formula (I):
Figure imgf000018_0003
or a salt thereof, wherein: R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with C(O)ORw and optionally substituted with halogen; 16 ny-2699290 Attorney Docket No.26327-20012.40 each R1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR1b, C1-6alkyl optionally substituted with C(O)N(R1c)2, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2-4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is , independently, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; R1x is H or C1-6alkyl; Rw is H or C1-6alkyl; R2 is H, F, Cl, OCHF2, or NO2; R3 is H, F, or Cl; each of R4, R6, and R7 is H or F; R5 is H, F, CF3. or OC1-2alkyl; X is O or a bond; and Ring A contains at least 3 F. [0061] In some embodiments of formula (I), when X is a bond, then R1 is not CH3, S(O)2NHR1a or S(O)2NHC(O)R1b, and at least one of R2 or R3 is not H. In some embodiments, when X is a bond and R1 is OH, OCH3, CO2CH3, CO2CH2CH3, or CH=CHCO2H, then each of R2 and R3 is not H. In some embodiments, when X is a bond and R1 is NH2, then each of R2 and R3 is not H, and at least one of R2 and R3 is not F. In some embodiments, when X is O, then R2 and at least one of R1 or R3 is not H. In some embodiments, when X is O, then R1 is not NHCH3. [0062] In some embodiments of formula (I), (1) when X is a bond, then R1 is not CH3, S(O)2NHR1a or S(O)2NHC(O)R1b, and at least one of R2 or R3 is not H; (2) when X is a bond 17 ny-2699290 Attorney Docket No.26327-20012.40 and R1 is OH, OCH3, CO2CH3, CO2CH2CH3, or CH=CHCO2H, then each of R2 and R3 is not H; (3) when X is a bond and R1 is NH2, then each of R2 and R3 is not H, and at least one of R2 and R3 is not F; (4) when X is O, then R2 and at least one of R1 or R3 is not H; and (5) when X is O, then R1 is not NHCH3. [0063] In some aspects, provided is a compound selected from the compounds listed in Table 1 below, or a salt thereof (including an agriculturally suitable salt thereof). Table 1. Exemplary Compounds
Figure imgf000020_0001
18 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000021_0001
19 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000022_0001
20 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000023_0001
[0064] In another aspect, the invention features a method of controlling undesired vegetation, that includes contacting the vegetation or its environment with a compound of the invention, a salt thereof, or a composition comprising said compound. [0065] In another aspect, the invention features a method of controlling undesired vegetation, that includes contacting the vegetation or its environment with a compound of formula (I), a salt thereof, or a composition comprising a compound of formula (I): 21 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000024_0001
wherein R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with C(O)ORw and optionally substituted with halogen; each R1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR1b, C1-6alkyl optionally substituted with C(O)N(R1c)2, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2-4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is , independently, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; R1x is H or C1-6alkyl; Rw is H or C1-6alkyl; R2 is H, F, Cl, OCHF2, or NO2; R3 is H, F, or Cl; each of R4, R6, and R7 is H or F; R5 is H, F, CF3. or OC1-2alkyl; X is O or a bond, wherein when X is a bond R1 is not S(O)2NHR1a or S(O)2NHC(O)R1b; and 22 ny-2699290 Attorney Docket No.26327-20012.40 Ring A contains at least 3 F. [0066] In one embodiment, the method includes a compound of any one of formulas (G- I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M- II), (M-III), (M-IV), or (M-V), or a salt thereof. [0067] In another embodiment, the method includes a compound found in Table 1, or a salt thereof. [0068] In another aspect, the invention features an herbicidal composition that includes a compound of the invention, a salt thereof. [0069] In some variations of the foregoing, the salt may be an agriculturally suitable salt. In certain variations, the agriculturally suitable salt is a salt that exhibits herbicidal activity, or that is or can be converted in plants, water, or soil into a compound or salt with herbicidal activity. [0070] In another aspect, the invention features an agricultural composition comprising a compound of the invention, or a salt thereof, and at least one additional component that serves as a carrier. [0071] In one embodiment, at least one additional component of the agricultural composition is a surfactant or a diluent. [0072] In another embodiment, the composition is an herbicidal composition. [0073] In another aspect, the invention features a method of controlling undesired vegetation, the method comprising contacting the vegetation or its environment with an herbicidally effective amount of a compound of the invention, or agriculturally acceptable salt thereof. [0074] In one embodiment, the undesired vegetation includes weeds. In a further embodiment, the undesired vegetation includes protoporphyrinogen IX oxidase (PPO) inhibitor-resistant weeds. In yet another further embodiment, the PPO inhibitor-resistant weeds have a dG210 mutation. [0075] In one embodiment, a compound or composition of the invention is applied at a rate of 1 to 100 g per 10,000 m2. 23 ny-2699290 Attorney Docket No.26327-20012.40 [0076] In one embodiment, contacting the undesired vegetation or its environment with a compound or composition of the invention leads to post-emergence control of the undesired vegetation. In a further embodiment, the undesired vegetation is at least 60% controlled. In another embodiment the undesired vegetation is at least 80% controlled. In yet another embodiment, the undesired vegetation is at least 90% controlled. [0077] In one embodiment, contacting the undesired vegetation or its environment with a compound or composition of the invention leads to pre-emergence control of the undesired vegetation. In a further embodiment, the undesired vegetation is at least 60% controlled. In another embodiment the undesired vegetation is at least 80% controlled. In yet another embodiment, the undesired vegetation is at least 90% controlled. [0078] In one aspect, provided herein is a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog of a base compound, wherein the base compound (i) inhibits protoporphyrinogen oxidase (PPO) and (ii) comprises a terminal cyclic moiety, wherein the fluorophenyl analog replaces the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein the fluorophenyl analog has one or more of the following properties: i) similar or improved inhibition of wild-type PPO, relative to the base compound; ii) similar or improved inhibition of DG210 mutant PPO, relative to the base compound; iii) similar or improved xylem mobility, relative to the base compound; iv) similar or improved phloem mobility, relative to the base compound; or v) similar or improved soil mobility, relative to the base compound. In some embodiments, the base compound comprises a terminal alkyl ester moiety, and the fluorophenyl analog replaces the terminal alkyl ester moiety with a carboxylic acid moiety. [0079] In another aspect, provided herein is a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog, wherein the fluorophenyl analog comprises a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein (i) when the fluorophenyl analog binds in the active site of protoporphyrinogen oxidase (PPO), the terminal phenyl moiety of the fluorophenyl analog is positioned within close proximity of a phenylalanine residue of the PPO, for example Phe392 in Amaranthus palmeri; or (ii) when the fluorophenyl analog binds in the active site of PPO, the terminal phenyl moiety of the fluorophenyl analog exhibits an attractive interaction with a phenylalanine residue of the PPO; or (iii) when the fluorophenyl analog binds in the active site of PPO, the terminal 24 ny-2699290 Attorney Docket No.26327-20012.40 SKHQ\O^PRLHW\^RI^WKH^IOXRURSKHQ\O^DQDORJ^H[KLELWV^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ZLWK^WKH^SKHQ\O^ ring of a phenylalanine residue in the active site of the PPO, for example Phe392 in Amaranthus palmeri. [0080] In some embodiments, provided herein is a method comprising contacting undesired vegetation or its environment with a fluorophenyl analog, wherein the fluorophenyl analog comprises a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein when the fluorophenyl analog binds in the active site of PPO, the terminal phenyl moiety of WKH^IOXRURSKHQ\O^DQDORJ^H[KLELWV^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ZLWK^WKH^SKHQ\O^ULQJ^RI^D^ phenylalanine residue in the active site of the PPO, for example Phe392 in Amaranthus palmeri. In some embodiments, the fluorophenyl analog exhibits inhibition of wild-type PPO, LQKLELWLRQ^RI^ǻ*^^^^PXWDQW^332^^[\OHP^PRELOLW\^^SKORHP^PRELOLW\^^RU^VRLO^PRELOLW\^^RU^DQ\^ combination of the foregoing. [0081] In some embodiments, the fluorophenyl analog is a compound of formula (A-I): [A] – [B] (A-I) Wherein [A] is a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and [B] is a core structure optionally substituted with one or more mobility targeting moieties. In some embodiments, [B] i) binds in the active site of the PPO, and ii) when binding in the active site RI^WKH^332^^SRVLWLRQV^WKH^WHUPLQDO^SKHQ\O^PRLHW\^>$@^WR^H[KLELW^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ with the phenyl ring of a phenylalanine residue in the active site of the PPO, for example Phe392 in Amaranthus palmeri. [0082] In some variations, a compound exhibiting inhibition PPO refers to the compound exhibiting an IC50 of less than 1 μM for the specified PPO. In some embodiments, a compound’s IC50 for PPO is assessed by the method described in Examples 26 and 27. [0083] In some variations, a compound exhibiting xylem mobility or phloem mobility refers to a compound that is tested in the Setaria italica mobility assay described in Example 33 and causes rapid necrosis representative of PPO inhibition acropetal to or basipetal to the compound application site. [0084] In some embodiments, a compound’s soil mobility is assessed by the method described in Example 34. 25 ny-2699290 Attorney Docket No.26327-20012.40 [0085] In some embodiments, the method comprises contacting the undesired vegetation or its environment with an herbicidally effective amount of the fluorophenyl analog. In some embodiments, a herbicidally effective amount refers to an amount of the compound, such that the quantity of such compound is capable of producing a controlling or modifying effect on the growth of plants. Controlling or modifying effects include all deviation from natural development, for example killing, retardation, leaf burn, albinism, dwarfing and the like. [0086] In some embodiments, when the fluorophenyl analog sits in the active site of PPO, WKH^WHUPLQDO^SKHQ\O^PRLHW\^RI^WKH^IOXRURSKHQ\O^DQDORJ^H[KLELWV^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ with the phenyl ring of a phenylalanine residue of the PPO, for example Phe392 in Amaranthus palmeri. [0087] In some embodiments the fluorophenyl analog is an analog of a base compound that (i) inhibits protoporphyrinogen oxidase (PPO) and (ii) comprises a terminal cyclic moiety, and the fluorophenyl analog replaces the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups. [0088] By way of an example to illustrate the terms “terminal cyclic moiety” and “terminal phenyl moiety”, in some embodiments, the base compound may be sulfentrazone, which has the following structure:
Figure imgf000028_0001
sulfentrazone . This compound comprises a terminal cyclic moiety,
Figure imgf000028_0002
, that may be replaced with a pentafluorophenyl group,
Figure imgf000028_0003
arrive at the fluorophenyl analog A1, which has the following structure: 26 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000029_0001
Analog A1. [0089] In some embodiments, the base compound is sulfentrazone, flumioxazin, sulflufencil, fomesan, carfentrazone-ethyl, oxyfluorfen, acifluoren, bifenox, lactofen, pyraflufen-ethyl, tiafenacil, oxadiazon, pentoxazone, oxadiargyl, butafenacil, cinidon-ethyl, trifludimoxazin, or epyrifenacil. [0090] In some embodiments, the terminal cyclic moiety in the base compound is ,
Figure imgf000029_0002
[0091] In some variations of the foregoing, in addition to replacing the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups, the base compound may further be modified with one or more additional changes. For example, in some variations, a mobility enhancing moiety may further be added to the base compound to arrive at the fluorophenyl analog. In certain variations, the mobility enhancing moiety may improve xylem mobility, phloem mobility and/or soil mobility in the fluorophenyl analog as compared to the base compound. [0092] In some embodiments, the fluorophenyl analog is a compound of formula (A-I): [A] – [B] (A-I) Wherein [A] is a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and [B] is a core structure optionally substituted with one or more mobility targeting moieties. In some embodiments, [B] i) binds in the active site of the PPO, and ii) when binding in the active site 27 ny-2699290 Attorney Docket No.26327-20012.40 RI^WKH^332^^SRVLWLRQV^WKH^WHUPLQDO^SKHQ\O^PRLHW\^>$@^WR^H[KLELW^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ with the phenyl ring of a phenylalanine residue in the active site of the PPO, for example Phe392 in Amaranthus palmeri. [0093] In some embodiments of formula (A-I), the core structure of [B] is selected from
Figure imgf000030_0001
some embodiments of formula (A-I), the core structure is selected from the group consisting
Figure imgf000030_0002
[0094] In some embodiments of formula (A-I), the one or more mobility targeting moieties are configured to selectively enhance xylem mobility. In some embodiments of formula (A-I), the one or more mobility targeting moieties are configured to selectively enhance phloem mobility. In some embodiments of formula (A-I), the one or more mobility targeting moieties are configured to enhance both xylem and phloem mobility. In some embodiments of formula (A-I), the one or more mobility targeting moieties are each
Figure imgf000030_0003
28 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000031_0001
[0095] In some embodiments of formula (A-I), [B] is selected from the group consisting
Figure imgf000031_0002
29 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000032_0001
. [0096] In some embodiments, the terminal phenyl moiety is substituted with 4 fluoro groups. In some embodiments, the terminal phenyl moiety is selected from the group consisting A1
Figure imgf000032_0002
, wherein R is H or -OCH3. In some embodiments RA1 is H. In some embodiments RA1 is -OCH3. In some embodiments, the terminal phenyl moiety
Figure imgf000032_0003
[0097] In some embodiments of formula (A-I), [A] is a terminal phenyl moiety is substituted with 4 fluoro groups. In some embodiments of formula (A-I), [A] is selected from the group consisting , wh A1
Figure imgf000032_0004
erein R is H or - OCH3. In some embodiments RA1 is H. In some embodiments RA1 is -OCH3. In some embodiments of formula
Figure imgf000032_0005
30 ny-2699290 Attorney Docket No.26327-20012.40 [0098] In some embodiments, the terminal phenyl moiety is substituted with 5 fluoro groups. In some embodiments, the terminal phenyl moiety
Figure imgf000033_0001
[0099] In some embodiments of formula (A-I), [A] is a terminal phenyl moiety substituted with 5 fluoro groups. In some embodiments of formula
Figure imgf000033_0002
Definitions [0100] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains,” “containing,” “characterized by,” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, or method that includes or comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method. [0101] The transitional phrase “consisting of” excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of” appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. [0102] Further, unless expressly stated to the contrary, “or” refers to an inclusive ‘or’ and not to an exclusive ‘or.’ For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present). 31 ny-2699290 Attorney Docket No.26327-20012.40 [0103] Also, the indefinite articles “a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular. [0104] As referred to herein, the term “seedling,” used either alone or in a combination of words means a young plant developing from the embryo of a seed. [0105] As referred to herein, the term “broadleaf,” used either alone or in terms such as “broadleaf weed” means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons. [0106] In the above recitations, the term “alkyl,” used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, or hexyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl, and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2- propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl, and the different butynyl, pentynyl, and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5- hexadiynyl. [0107] “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy, and hexyloxy isomers. [0108] “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. [0109] The term “halogen” or “halo” either alone or in compound words such as “haloalkyl,” or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine, or iodine. [0110] The total number of carbon atoms in a substituent group is indicated by the “Ci-Cj” or “Ci-j” prefix, where i and j are numbers from 1 to 10. For example, C1-4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C2 alkoxyalkyl designates CH3OCH2-; C3 32 ny-2699290 Attorney Docket No.26327-20012.40 alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2-, or CH3CH2OCH2-; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2- and CH3CH2OCH2CH2-. [0111] When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, the substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., (R1)m, where m is 0, 1, 2 or 3. Further, when the subscript indicates a range, e.g. (R)i-j, then the number of substituents may be selected from the integers between ‘i’ and ‘j’ inclusive. When a group contains a substituent, which can be hydrogen (H), for example, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to the group being unsubstituted. When a variable group is shown to be optionally attached to a position, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be “not substituted” or “unsubstituted,” then hydrogen atoms are attached to take up any free valency. [0112] “Aromatic” indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the ring plane, and thaW^^^Q^^^^^^ʌ^HOHFWURQV^^ZKHUH^Q^LV^D^ positive integer, are associated with the ring to comply with Hückel's rule. The term “aromatic ring system” denotes a carbocyclic or heterocyclic ring system in which at least one ring of the ring system is aromatic. [0113] The term “nonaromatic ring system” denotes a carbocyclic or heterocyclic ring system that may be fully saturated, as well as partially or fully unsaturated, provided that none of the rings in the ring system are aromatic. [0114] The term “optionally substituted” in connection with the heterocyclic rings refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated. The term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “(un)substituted.” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. 33 ny-2699290 Attorney Docket No.26327-20012.40 [0115] The term “acceptable salt” or “salt” when related to a compound of the invention includes cations or anions. Preferred cations are the ions of the alkali metals, preferably of lithium, sodium and potassium, of the alkaline earth metals, preferably of calcium and magnesium, and of the transition metals, preferably of manganese, copper, zinc and iron, further ammonium and substituted ammonium in which one to four hydrogen atoms are replaced by C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4- alkoxy-C1-C4-alkyl, phenyl, or benzyl - preferably ammonium, methylammonium, isopropylammonium, dimethylammonium, diethylammonium, diisopropylammonium, trimethylammonium, triethylammonium, tris(isopropyl)ammonium, heptylammonium, dodecylammonium, tetradecylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium (olamine salt), 2-(2-hydroxyeth-1-oxy)eth- 1-ylammonium (diglycolamine salt), di(2-hydroxyeth-1-yl)ammonium (diolamine salt), tris(2-hydroxyethyl)ammonium (trolamine salt), tris(2-hydroxypropyl)ammonium, benzylthmethylammonium, benzyltriethylammonium, N,N,N-trimethylethanolammonium (choline salt), furthermore phosphonium ions, sulfonium ions, preferably tri(C1-C4- alkyl)sulfonium, such as trimethylsulfonium, and sulfoxonium ions, preferably tri(C1-C4- alkyl)sulfoxonium, and finally the salts of polybasic amines such as N,N-bis-(3- aminopropyl)methylamine, and diethylenetriamine. [0116] Anions of useful acid addition salts are primarily chloride, bromide, fluoride, iodide, hydrogensulfate, methylsulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and also the anions of C1-C4-alkanoic acids - preferably formate, acetate, propionate, and butyrate. [0117] As used herein, the terms "undesirable vegetation" and "harmful plants" are synonyms. Preparation of Compounds of the Invention [0118] A wide variety of synthetic methods are known in the art to enable preparation of aromatic and nonaromatic heterocyclic rings and ring systems; for extensive reviews see the eight-volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve-volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996. 34 ny-2699290 Attorney Docket No.26327-20012.40 [0119] Compounds of the invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Stereoisomers are isomers of identical constitution but differing in the arrangement of their atoms in space and include enantiomers, diastereomers, cis-trans isomers (also known as geometric isomers) and atropisomers. Atropisomers result from restricted rotation about single bonds where the rotational barrier is high enough to permit isolation of the isomeric species. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form. For a comprehensive discussion of all aspects of stereoisomerism, see Ernest L. Eliel and Samuel H. Stereochemistry of Organic Compounds, John Wiley & Sons, New York, 1994. Compounds of the invention typically exist in more than one form, and the formulas of the invention thus include all crystalline and non-crystalline forms of the compounds they represent. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e., different crystalline types). The term “polymorph” refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical, and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate, and biological availability. One skilled in the art will appreciate that a polymorph of a compound of the invention can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound. Preparation and isolation of a particular polymorph of a compound of a compound of the invention can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures. For a comprehensive discussion of polymorphism see R. Hilfiker, Ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006. 35 ny-2699290 Attorney Docket No.26327-20012.40 [0120] One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus, a wide variety of salts of compounds of the invention are useful for control of undesired vegetation (i.e., are agriculturally suitable). The salts of compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic, or valeric acids. When a compound of the invention contains an acidic moiety such as a carboxylic acid or phenol, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine, or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium, or barium. [0121] Moreover, the invention features processes and intermediates for preparing compounds of the invention. These compounds can be prepared by general methods known in the art of synthetic organic chemistry. One or more of the following methods and variations as described in Schemes 1 to 10 can be used. [0122] In one general example, some compounds of formula (G-II) can be prepared as shown in Scheme 1.
Figure imgf000038_0001
Scheme 1 36 ny-2699290 Attorney Docket No.26327-20012.40 [0123] Accordingly, as shown in Step 1 of Scheme 1, where R2, R3, R4, R5, R6, and R7 are as described elsewhere herein, Prot is a phenol protecting group, and (RyO)2B is a boronic acid or boronate, a compound of formula (a) can be reacted with a fluorinated benzene analog containing leaving group L1 (e.g., Br, I, or OTf) utilizing typical Suzuki conditions with a metal catalyst such as Pd, to provide a compound of formula (c). Alternatively, as shown in Step 2, a highly fluorinated benzene can be arylated directly with an arene of formula (b) using a metal catalyst (e.g., Pd or Cu) to provide a compound of formula (c). See Lafrance, et al., Catalytic Intermolecular Direct Arylation of Perfluorobenzenes, Journal of the American Chemical Society (2006), Vol.128(27), pages 8754 to 8756. As shown in Step 3, the phenol protecting group of a compound of formula (c) can be removed to produce a phenol of formula (d), which can subsequently be alkylated, acylated, or sulfonated with a compound of formula RG1a-L2 as shown in Step 4, where L2 is a leaving group such as a halogen, sulfonate, or a reactive intermediate in a Mitsinobu reaction, to form a compound of formula (e), which is a compound of formula (G-II) when RG1a, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. In some cases, one RG1a group can be transformed into another RG1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides). [0124] In another general example, some compounds formula (G-II) can be prepared as shown in Scheme 2.
Figure imgf000039_0001
Scheme 2 [0125] Accordingly, as shown in Step 1 of Scheme 2, where R2, R3, R4, R5, R6, and R7 are as described elsewhere herein and (RxO)2B is a boronic acid or boronate, a compound of 37 ny-2699290 Attorney Docket No.26327-20012.40 formula (d), is reacted under basic conditions with a nitro benzene or nitro pyridine of formula (e), in which L3 is containing a leaving group (e.g., F, Cl, Br, I, or OTf) and Q1 is CH or N, to provide a compound of formula (f). As shown in Step 2, the nitro group can be subsequently reduced (e.g., with iron powder) to produce a of formula (g). As shown in Step 3, an amine of formula (g) can be reacted with sodium nitrite in sulfuric acid to produce a phenol of formula (h) which can subsequently be alkylated, acylated, or sulfonated with compounds of formula RG1a-L2 as shown in Step 4, where L2 is a leaving group such as a halogen, sulfonate, or a reactive intermediate in a Mitsinobu reaction, to form compounds of formula (i), which are compounds of formula (G-II) when R2, R3, R4, R5, R6, and R7 are as described elsewhere herein and RG1a is phenyl or pyridyl optionally substituted with OCH2CO2RG1x, where RG1x is H or C1-6alkyl. In some cases, one RG1a group can be transformed into another RG1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides). [0126] In another general example, some compounds of formula (G-III) can be prepared as shown in Scheme 3.
Figure imgf000040_0001
Scheme 3 [0127] Accordingly, as shown in Step 1 of Scheme 3, where R2, R3, R4, R5, R6, and R7 are as described elsewhere herein and (RyO)2B is a boronic acid or boronate, a compound of 38 ny-2699290 Attorney Docket No.26327-20012.40 formula (j), can be reacted with a fluorinated benzene analog containing leaving group L1 (e.g., Br, I, or OTf) utilizing typical Suzuki conditions with a metal catalyst such as Pd, to provide a compound of formula (m). Alternatively, as shown in Step 2, a highly fluorinated benzene can be arylated directly with an arene of formula (k) using a metal catalyst (e.g., Pd or Cu) to provide a compound of formula (m). As shown in Step 3, the nitro group of a compound of formula (m) can be reduced (e.g., with sodium thiosulfate) to form of formula (n), which can subsequently alkylated, acylated, or sulfonated with a compound of formula RG1a-L2 as shown in Step 4, where L2 is a leaving group such as a halogen or sulfonate, to form a compound of formula (o), which is a compound of formula (G-III) when R1a, R2, R3 and R4 are as described elsewhere herein and R5, R6, and R7 are each F. In some cases, the compound of formula (n) can be reacted with an aldehyde of formula RG1aCHO in a reductive amination reaction to produce a compound of formula (o). In some cases, one RG1a group can be transformed into another RG1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides). [0128] In another general example, some compounds of formulas (H-II), (H-III), and (H- IV) can be prepared as shown in Scheme 4. 39 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000042_0001
Scheme 4 [0129] Accordingly, as shown in Step 1 of Scheme 4, where R2, R3, R4, R5, R6, and R7 are as described elsewhere herein, Prot is a carboxylic acid protecting group, and (RyO)2B is a boronic acid or boronate, a compound of formula (p) can be reacted with a fluorinated benzene analog containing leaving group L1 (e.g., Br, I, or OTf) utilizing typical Suzuki conditions with a metal catalyst such as Pd, to provide a compound of formula (r). Alternatively, as shown in Step 2, a highly fluorinated benzene can be arylated directly with an arene of formula (q) using a metal catalyst (e.g., Pd or Cu) to provide a compound of formula (r). See Lafrance, et al., Catalytic Intermolecular Direct Arylation of Perfluorobenzenes, Journal of the American Chemical Society (2006), Vol.128(27), pages 8754 to 8756. As shown in Step 3, the carboxylic acid protecting group of a compound of formula (r) can be removed to produce a carboxylic acid of formula (s), which can subsequently be alkylated with a compound of formula RH1a-L2 as shown in Step 4, where L2 is a leaving group such as a halogen, sulfonate, or a reactive intermediate in a Mitsinobu reaction, to form a compound of formula (t), which is a compound of formula (H-II) when R1a, R2, R3, and R4 are as described elsewhere herein and R5, R6, and R7 are each F. In some 40 ny-2699290 Attorney Docket No.26327-20012.40 cases, one RH1a group can be transformed into another RH1a group by synthetic manipulations known to those skilled in the art (e.g., saponification of esters to produce carboxylic acids or a saponification followed by subsequent amidation to form carboxamides). Alternatively, a compound of formula (s) can be transformed into an active ester or an acyl halide (such as those known in the art used to prepare amides) and subsequently reacted with a sulfonamide of formula H2NS(O)2RH1b or H2NS(O)2N(RH1a)N(RH1b) to form a compound of formula (u) or (v), respectively. Compounds of formula (u) and compounds of formula (v) are compounds of formula (H-III) or (H-IV), respectively, where RH1a, RH1b, R2, R3, and R4 are as described elsewhere herein and R5, R6, and R7 are each F. [0130] In another general example, some compounds of formula (K-II) can be prepared as shown in Scheme 5.
Figure imgf000043_0001
Figure imgf000043_0002
Scheme 5 [0131] Accordingly, as shown in Step 1 of Scheme 5, where R3, R4, R5, R6, and R7 are as described elsewhere herein and (RyO)2B is a boronic acid or boronate, a compound of formula (w), can be reacted with a fluorinated benzene analog containing leaving group L1 (e.g., Br, I, or OTf) utilizing typical Suzuki conditions with a metal catalyst such as Pd, to provide a compound of formula (x). As shown in Step 2, the compound of formula (x) can be nitrated (e.g., with nitric acid in sulfuric acid) to form a compound of formula (y), the nitro group of which can be subsequently reduced (e.g., with Fe powder) to form a compound of formula (z), as shown in Step 3. As shown in Step 4, utilizing Sandmeyer-like conditions (e.g., with a copper(II) halide and t-butylnitrite), a compound of formula (z) can be reacted 41 ny-2699290 Attorney Docket No.26327-20012.40 with a vinyl carboxylic ester to form a compound for formula (aa), which is a compound of formula (K-II) when X1 is H and R4, R5, R6, and R7 are each F. As shown in Step 5, the carboxylic ester of a compound of formula (aa) can by saponified (e.g., with LiOH) to form a compound of formula (ab). [0132] In another general example, some compounds of formulas (K-II) and (K-III) can be prepared as shown in Scheme 6.
Figure imgf000044_0001
Figure imgf000044_0002
Scheme 6 [0133] Accordingly, as shown in Step 1 of Scheme 1b, where R3, R4, R5, R6, and R7 are as described elsewhere herein, a compound of formula (x) can be brominated or iodinated via reaction with N-bromosuccinimide or N-iodosuccinimide, respectively, to form a compound of formula (ad). As shown in Step 2, the compound of formula (ad) can be cross-coupled with a vinyl carboxylic ester, using a metal catalyst such as Pd, to form a compound of formula (ae), which is a compound of formula (K-III) where X1 is H and R3, R4, R5, R6, and R7 are each F. Subsequent hydrogenation, as shown in Step 3, results in a compound of formula (af), which is a compound of formula (K-II) when Rx is X1 is H and R3, R4, R5, R6, and R7 are each F. As shown in Step 4, the ester of a compound of formula (af) can be saponified (e.g., with LiOH) to form a compound of formula (ag). Alternatively, as shown in Step 5, a compound of formula (ae) can be saponified to form a compound of formula (ah). [0134] In another general example, some compounds of formula (K-III) can be prepared as shown in Scheme 7. 42 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0005
Figure imgf000045_0003
Figure imgf000045_0004
Scheme 7 [0135] Accordingly, as shown in Step 1 of Scheme 7, a boronate or boronic acid of formula (aj) can be formed from a phenyl bromide of formula (ai) by procedures known to those skilled in the art (e.g., via the reaction of the bromide with triethylborate or (BPin)2). As shown in Step 2, where R3, R4, R5, R6, and R7 are as described elsewhere herein, the aldehyde boronate/boronic acid of formula (aj) can be reacted with a pentafluorobenzene having leaving group L1, which can be I, Br, or OTf, to form a compound of formula (ak). As shown in Step 3, the aldehyde of formula (ak) can then be condensed with an alkyl 2-haloacetate to form a compound of formula (am), which is a compound of formula (K-III) when X1 is halogen and R3, R4, R5, R6, and R7 are each F. The compound of formula (am) can then be saponified to form a compound of formula (an). [0136] In another general example, the compounds of formula (ao) (which are compounds of formula (M-I) when R1 is ORM1a or of formula (M-II) when R1 is OR1a, R2 is NO2, R3 is H, and R4 is F) can be prepared as shown in Scheme 8. 43 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000046_0001
Scheme 8 [0137] Accordingly, as shown in Step 1 of Scheme 8, where R2, R3, R4, R5, R6, and R7 are as described elsewhere herein and leaving group L1 can be a halogen or a sulfonate, compounds of formula (as) can be prepared by reacting an appropriately protected phenol of formula (ao) with a fluorinated phenol of formula (ap) under basic conditions, to form a compound of formula (as). Alternatively, as shown in Step 2, compounds of formula (as) can be prepared by reacting a monoprotected resorcinol of formula (aq) with a polyfluorinated benzene of formula (ar). In some examples, Prot is CH3 and can be removed with a Lewis acid such as BBr3. Removal of Prot and subsequent O-alkylation with RM1a-L2, as shown in Step 3, where RM1a is as described elsewhere herein and L2 is a leaving group such as a halogen or sulfonate, produces a compound of formula (at), which is a compound of formula (M-II) when RM1 is ORM1a, R2 is NO2, R3 is H, and R4, R6, and R7 are each F. [0138] In another general example, some compounds of formulas (M-III) and (M-IV) can be prepared as shown in Scheme 9. 44 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000047_0002
Figure imgf000047_0001
Scheme 9 [0139] Accordingly, as shown in Step 1 of Scheme 9, where R2, R3, R4, R5, R6, and R7 are as described elsewhere herein and leaving group L1 can be a halogen or a sulfonate, compounds of formula (av) can be prepared by reacting an appropriately protected carboxylic acid of formula (au) with a fluorinated phenol of formula (ap) under basic conditions, followed by removal of the protecting group. As shown in Step 3, the resulting compound of formula (av) can be O-alkylated with a compound of formula RM1a-L2, where RM1a is as described elsewhere herein and L2 is a leaving group such as a halogen or sulfonate, produces a compound of formula (ax). Alternatively, the compound of formula (av) can be transformed into an active ester or an acyl halide (such as those known in the art used to prepare esters or amides) to produce the compound of formula (aw), where L3 is a leaving group intermediate of an active ester or is a fluorine or chlorine. As shown in Step 4 or Step 5, reaction of a compound of formula (aw) with and alcohol of formula RM1a-OH or a sulfonamide of formula H2NS(O)2RM1b forms compounds of formula (ax) or (ay), respectively. Compounds of formula (ax) are compounds of formula (M-III) when RM1 is C(O)ORM1a, R2 is NO2, R3 is H, and R4, R6, and R7 are each F. Compounds of formula (ay) are compounds of formula (M-III) when RM1 is C(O)ORM1a, R2 is NO2, R3 is H, and R4, R6, and R7 are each F. 45 ny-2699290 Attorney Docket No.26327-20012.40 [0140] In another general example, some compounds of formula (M-V) can be prepared as shown in Scheme 10.
Figure imgf000048_0001
Scheme 10 [0141] Accordingly, as shown in Step 1 of Scheme 10, compounds of formula (ba) can be prepared by reacting phenols of formula (az) with a polyfluorinated benzene of formula (ar) under basic conditions, where L1, R2, R3, R4, and R5 are as described elsewhere herein. As shown in Step 2, subsequent reaction of a compound of formula (ba) with benzyl mercaptan produces a compound of formula (bb), which, as shown in Step 3, is subsequently transformed into a sulfonyl chloride of formula (bc) via reaction with oxidizing chlorinating agents such as 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione. Reaction of compounds of formula (bc) with ammonia produces a compound of formula (bd). Subsequent N-acylation of the resulting sulfonamide with compounds having formula RM1bC(O)L3, where RM1b and leaving group L3 are as described elsewhere herein, produce compounds of formula (be), which is a compound of formula (M-V) when RM1 is S(O)2NHC(O)RM1b, R2 is NO2, R3 is H, and R4, R6, and R7 are each F. [0142] In one aspect, provided is a method of preparing a compound of formula (G-II), or a salt thereof, comprising: 46 ny-2699290 Attorney Docket No.26327-20012.40 reacting a boronic acid or boronate of formula (a), where Ry is H, C1-4alkyl, or two RyO and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a tetrafluoro or pentafluoro benzene having leaving group L1, which can be iodine, bromine, or a sulfonate, to provide a compound of formula (c),
Figure imgf000049_0001
reacting a protected phenol of formula (b) with tetrafluorobenzene or pentafluorobenzene under catalytic conditions to also provide a compound of formula (c);
Figure imgf000049_0003
; removing protecting group Prot from a compound of formula (c), then reacting the resulting phenol of formula (d) with alkylating agent R1a-L2, where L2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (e),
Figure imgf000049_0002
, where R1a, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. In one embodiment, the compound of formula (e) is a compound of formula (G-II), when each of R5, R6, and R7 are F. [0143] In another aspect, provided is a method of preparing a compound of formula (j), or a salt thereof, comprising: 47 ny-2699290 Attorney Docket No.26327-20012.40 reacting a compound of formula (d) with a nitrobenzene or nitropyridine of formula (e), under basic conditions to produce a compound of formula (f), where Q1, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein and where L3 is a halogen or sulfonate,
Figure imgf000050_0001
; reducing the nitro group of a compound of formula (f) to an amine of formula (g),
Figure imgf000050_0002
transforming aniline of formula (g) to a phenol of formula (h),
Figure imgf000050_0003
reacting a phenol of formula (h) with alkylating agent RG1a-L2, where L2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (i),
Figure imgf000050_0004
, where Q1, RG1a, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. 48 ny-2699290 Attorney Docket No.26327-20012.40 [0144] In another aspect, provided is a method of preparing a compound of formula (III) as described herein, or a salt thereof, comprising: reacting a boronic acid or boronate of formula (j), where Ry is H, C1-4alkyl, or two RyO and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a fluorinated benzene having leaving group L1, which can be iodine, bromine, or a sulfonate, to provide a compound of formula (m),
Figure imgf000051_0001
, or reacting a nitrobenzene of formula (m) with tetrafluorobenzene or pentafluorobenzene to provide a compound of formula (n);
Figure imgf000051_0002
reducing the nitro group of the compound of formula (n) to an amine to produce a compound of formula (o), then reacting the resulting amine of formula (o) with alkylating agent RG1a-L2, where L2 is a leaving group such as a halogen or a sulfonate, or with RG1aCHO in a reductive amination to provide a compound of formula (III),
Figure imgf000051_0003
, wherein RG1a, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. In one embodiment, R5, R6, and R7 are each F and the compound of formula (o) is a compound of formula (G-III) 49 ny-2699290 Attorney Docket No.26327-20012.40 [0145] In another aspect, provided is a method of preparing a compound of formulas (s), (t), (u), or (v) comprising: reacting a boronic acid or boronate of formula (p), where Ry is H, C1-4alkyl, or two RyO and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a tetrafluoro or pentafluoro benzene having leaving group L1, which can be iodine, bromine, or a sulfonate, to provide a compound of formula (r),
Figure imgf000052_0001
reacting a protected carboxylic acid of formula (q) with tetrafluorobenzene or pentafluorobenzene under catalytic conditions to also provide a compound of formula (r);
Figure imgf000052_0002
removing protecting group Prot from a compound of formula (r), then reacting the resulting carboxylic acid of formula (s) with alkylating agent RH1a-L2, where L2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (II),
Figure imgf000052_0003
, where RH1a, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. In one 50 ny-2699290 Attorney Docket No.26327-20012.40 embodiment, the compound of formula (t) is a compound of formula (H-II) when R5, R6, and R7 are each F. [0146] In another aspect, provided is a method of preparing a compound of formula (u) or a compound of formula (v) comprising: reacting a boronic acid or boronate of formula (p), where Ry is H, C1-4alkyl, or two RyO and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a polyfluorinated benzene having leaving group L1, which can be iodine, bromine, or a sulfonate, to provide a compound of formula (r),
Figure imgf000053_0002
, or reacting a protected carboxylic acid of formula (q) with a polyfluorinated benzene under catalytic conditions to also provide a compound of formula (r);
Figure imgf000053_0001
removing protecting group Prot from a compound of formula (r), then preparing an active ester or acyl halide of the resulting carboxylic acid of formula (s) with a sulfonamide of formula H2NS(O)2RH1b or of formula H2NS(O)2N(RH1a)N(RH1b), to provide, respectively, a compound of formula (u) or a compound of formula (v), 51 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000054_0003
, where RH1a, RH1b, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. In one embodiment, the compound of formula (u) is a compound of formula (H-III) when R5, R6, and R7 are each F. In another embodiment, the compound of formula (v) is a compound of formula (H-IV) when R5, R6, and R7 are each F. [0147] In another aspect, provided is a method of preparing a compound of formulas (aa) and (ab) comprising: reacting a boronic acid or boronate of formula (w), where Ry is H, C1-4alkyl, or two RyO and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a pentafluoro benzene having leaving group L1, which can be iodine, bromine, or a sulfonate, to provide a compound of formula (x),
Figure imgf000054_0001
nitrating the compound of formula (x) to provide a compound of formula (y),
Figure imgf000054_0002
reducing the nitro group of a compound of formula (y) to form a compound of formula (z), 52 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000055_0001
reacting the aniline of formula (z) with an alkyl vinylcarboxalate under Sandmeyer-like conditions with a copper(II) halide and t-butylnitrite to form a compound of formula (aa),
Figure imgf000055_0002
, where X1 is a halogen atom and RKx, R3, R4, R5, R6, and R7 are as described elsewhere herein. [0148] In one embodiment, the compound of formula (aa), which is a compound of formula (K-II) when X1 is halogen, RKx is C1-2alkyl, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F, can be saponified to form a compound of formula (ab), which is a compound of formula (K-II) when X1 is halogen, RKx is H, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F. [0149] In another aspect, provided is a method of preparing a compound of formulas (ae) and (af) comprising: reacting a compound of formula (x) with N-bromosuccinimide or N- iodosuccinimide to form a compound of formula (ad),
Figure imgf000055_0003
reacting the compound of formula (ad) with an alkyl vinylcarboxylate, under cross-coupling conditions using a metal catalyst such as palladium, to form a compound of formula (ae), 53 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000056_0001
hydrogenating a compound of formula (ae) to form a compound of formula (af),
Figure imgf000056_0002
, where RKx, R3, R4, R5, R6, and R7 are as described elsewhere herein. [0150] In one embodiment, the compound of formula (af), which is a compound of formula (K-II), where X1 is H, RKx is C1-2alkyl, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F, can be saponified to form a compound of formula (ag), which is a compound of formula (K-II) where each of X1 and Rx is H, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F. [0151] In another embodiment, the compound of formula (ae), which is a compound of formula (K-III) where X1 is H, RKx is C1-2alkyl, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F, can be saponified to form a compound of formula (ah), where X1 is H, RKx is H, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F. [0152] In another aspect, provided is a method of preparing a compound of formula (am) comprising: reacting a boronic acid or boronate of formula (aj), where Ry is H, C1-4alkyl, or two RyO and the intervening B atom form a 5 to 6 membered ring optionally substituted with up to 4 methyl groups, with a polyfluoro benzene having leaving group L1, which can be iodine, bromine, or a sulfonate, to provide a compound of formula (ak), 54 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000057_0001
condensing the aldehyde of formula (ak) with an alkyl 2-haloacetate to form a compound of formula (am),
Figure imgf000057_0002
, where X1 is halogen and RKx, R3, R4, R5, R6, and R7 are as described elsewhere herein. [0153] In one embodiment, the compound of formula (am), which is a compound of formula (K-III) where RKx is C1-2alkyl, X1 is halogen, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F, can be saponified to form a compound of formula (an), which is a compound of formula (K-III) where RKx is H, X1 is halogen, each of R3 and R4 is H or F, and each of R5, R6, and R7 is F. [0154] In another aspect, provided is a method of preparing a compound of formula (at) comprising: reacting a polyfluorinated phenol of formula (ap), as shown below, with protected phenol (ao), where L1 is a leaving group such as a halogen or a sulfonate, to provide a compound of formula (as),
Figure imgf000057_0003
; and 55 ny-2699290 Attorney Docket No.26327-20012.40 removing protecting group Prot from a compound of formula (as), then reacting the resulting phenol with alkylating agent RM1a-L2, where L2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (at),
Figure imgf000058_0001
, where RM1a, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. The compound of formula (at) is a compound of formula (M-II) when RM1a is as described elsewhere herein, R2 is NO2, R3 is H, each of R4, R6, and R7 is F, and R5 is F or CF3. [0155] In another aspect, provided is a method of preparing a compound of formula (at) comprising: reacting a monoprotected resorcinol of formula (aq), as shown below, with a polyfluorinated benzene of formula (ar) to provide a compound of formula (as),
Figure imgf000058_0002
removing protecting group Prot from a compound of formula (as), then reacting the resulting phenol with alkylating agent RM1a-L2, where L2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (at),
Figure imgf000058_0003
, where RM1a, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. The compound of formula (at) is a compound 56 ny-2699290 Attorney Docket No.26327-20012.40 of formula (M-II) when RM1a is as described elsewhere herein, R2 is NO2, R3 is H, each of R4, R6, and R7 is F, and R5 is F or CF3. [0156] In another aspect, provided is a method of preparing a compound of formula (ax) comprising: reacting a fluorinated phenol of formula (ap) with a protected benzoic acid of formula (au), where L1 is a leaving group such as a halogen or a sulfonate, followed by removal of the protecting group to provide a compound of formula (av),
Figure imgf000059_0001
alkylating a compound of formula (av) with a compound having formula L2-RM1a, where L2 is a leaving group such as a halogen, a sulfonate, or is the reactive intermediate in a Mitsinobu reaction, to provide a compound of formula (ax),
Figure imgf000059_0002
and R7 are as described elsewhere herein. The compound of formula (at) is a compound of formula (M-III) when RM1a is as described elsewhere herein, R2 is NO2, R3 is H, each of R4, R6, and R7 is F, and R5 is F or CF3. [0157] Alternatively, a compound of formula (M-III) can be formed by reacting a carboxylic acid of formula (av) with an activating agent, where L3 is a leaving group such as F, Cl, OBt, OAt, or is the result of reacting the carboxylic acid with a carbodiimide, to provide a compound of formula (aw), 57 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000060_0001
reacting an active ester of formula (aw) with an alcohol of formula RM1a-OH, to provide a compound of formula (ax),
Figure imgf000060_0002
and R7 are as described elsewhere herein. The compound of formula (at) is a compound of formula (M-III) when RM1a is as described elsewhere herein, R2 is NO2, R3 is H, each of R4, R6, and R7 is F, and R5 is F or CF3. [0158] In another aspect, provided is a method of preparing a compound of formula (ay) comprising: reacting a carboxylic acid of formula (av) with an activating agent to provide a compound of formula (aw), where L3 is a leaving group such as F, Cl, OBt, OAt, or is the result of reacting the carboxylic acid with a carbodiimide,
Figure imgf000060_0003
reacting a compound of formula (aw) with a sulfonamide of formula R1bS(O)2NH2, to provide a compound of formula (ay), 58 ny-2699290 Attorney Docket No.26327-20012.40 , where RM1b, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. Compounds of formula (M-IV) are formed when RM1b is as described elsewhere herein, R2 is NO2, R3 is H, each of R4, R6, and R7 is F, and R5 is F or CF3. [0159] In another aspect, provided is a method of preparing a compound of formula (be) comprising: reacting a phenol of formula (az) with a fluorinated benzene of formula (ar) to provide a compound of formula (ba),
Figure imgf000061_0001
reacting a compound of formula (aw), where L1 is a leaving group such as a halogen or a sulfonate, with benzyl mercaptan to provide a compound of formula (ax),
Figure imgf000061_0002
; reacting a compound of formula (bb) with 1,3-dichloro-5,5- dimethylimidazolidine-2,4-dione to provide a compound of formula (bc), 59 ny-2699290 Attorney Docket No.26327-20012.40 ; and reacting a compound of formula (bc) with ammonia to provide a compound of formula (bd),
Figure imgf000062_0001
reacting a compound of formula (az) with a compound of formula RM1bC(O)L3, where L3 is a leaving group such as F, Cl, OBt, OAt, or is the result of reacting the carboxylic acid with a carbodiimide, to provide a compound of formula (ba),
Figure imgf000062_0002
, where RM1b, R2, R3, R4, R5, R6, and R7 are as described elsewhere herein. Compounds of formula (M-V) are formed when RM1b is as described elsewhere herein, R2 is NO2, R3 is H, each of R4, R6, and R7 is F, and R5 is F or CF3. [0160] Any of the embodiments and variations described herein for compounds of formulas (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) also applies to intermediates of formulas (c), (d), (e), (f), (g), (h), (i), (m), (n), (o), (r), (s), (t), (u), (v), (x), (y), (z), (aa), (ab), (ad), (ae), (af), (ag), (ah), (ak), (am) (an), (as), (at), (av), (aw), (ax), (ay), (ba), (bb), (bc), (bd), or (be). Synthetic intermediates useful in the preparation of some compounds of formulas (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), 60 ny-2699290 Attorney Docket No.26327-20012.40 (M-II), (M-III), (M-IV), or (M-V) include 2',4'-dichloro-2,3,4,5,6-pentafluoro-5'-methoxy- 1,1'-biphenyl; 3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)-2- nitropyridine; 3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2- amine; 3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2(1H)-one; methyl 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)propanoate; 2-((4- chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)propanoic acid; 4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-amine; 6-chloro-2',3',4',5',6'-pentafluoro-[1,1'- biphenyl]-3-amine; 4,6-dichloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-amine; 4'-chloro- 2,2',3,4,6-pentafluoro-1,1'-biphenyl; 4'-chloro-2,2',3,4,6-pentafluoro-5'-nitro-1,1'-biphenyl; methyl 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-carboxylate; isopropyl 5-bromo- 2-chloro-4-fluorobenzoate; methyl 2',3',4',5',6,6'-hexafluoro-4-methoxy-[1,1'-biphenyl]-3- carboxylate; methyl 2',3',4',5',6,6'-hexafluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate; 4- (difluoromethoxy)-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-carboxylic acid; 4'-chloro- 2,2',3,4,5,6-hexafluoro-1,1'-biphenyl; 4'-chloro-2,2',3,4,5,6-hexafluoro-5'-nitro-1,1'-biphenyl; 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-amine; 4-chloro-2',3',4',5',6'-pentafluoro- [1,1'-biphenyl]-3-carbaldehyde; 5'-bromo-4'-chloro-2,2',3,4,5,6-hexafluoro-1,1'-biphenyl; 4'- chloro-2,2',3,4,5,6-hexafluoro-5'-iodo-1,1'-biphenyl; methyl 2-nitro-5- (perfluorophenoxy)benzoate; methyl 2-chloro-5-(perfluorophenoxy)benzoate; 2-chloro-5- (perfluorophenoxy)benzoic acid; 1-(3-bromo-4-nitrophenoxy)-2,3,4,5,6-pentafluorobenzene; benzyl(2-nitro-5-(perfluorophenoxy)phenyl)sulfane; 2-nitro-5- (perfluorophenoxy)benzenesulfonyl chloride; 1-(3-bromo-4-nitrophenoxy)-2,3,5,6- tetrafluoro-4-(trifluoromethyl)benzene; benzyl(2-nitro-5-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy)phenyl)sulfane; 2-nitro-5-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy)benzenesulfonyl chloride; and 2-nitro-5-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy)benzenesulfonamide. [0161] It is recognized by one skilled in the art that various functional groups can be converted into others to provide different compounds of the invention. For a valuable resource that illustrates the interconversion of functional groups in a simple and straightforward fashion, see Larock, R. C, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Ed., Wiley- VCH, New York, 1999. [0162] It is also recognized that some reagents and reaction conditions described above for preparing compounds of the invention may not be compatible with certain functionalities 61 ny-2699290 Attorney Docket No.26327-20012.40 present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of the invention. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particulars presented to prepare the compounds of the invention. [0163] One skilled in the art will also recognize that compounds of the invention and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents. Compositions [0164] In certain aspects, a compound of this disclosure, including an agriculturally suitable salt thereof, may be used as an herbicidal active ingredient in a formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents, and liquid diluents, which serves as a carrier. The formulation ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application, and environmental factors such as soil type, moisture, and temperature. [0165] In some variations, the compositions provided here are herbicides. In some variations, the compositions comprise a compound of this disclosure that controls or modifies the growth of plants. In certain variations, the compositions comprise a herbicidally effective amount of the compound, such that the quantity of such compound is capable of producing a controlling or modifying effect on the growth of plants. Controlling or modifying effects include all deviation from natural development, for example killing, retardation, leaf burn, albinism, dwarfing and the like. [0166] Liquid formulations include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions, oil-in -water emulsions, flowable 62 ny-2699290 Attorney Docket No.26327-20012.40 concentrates and/or suspoemulsions), and the like, which optionally can be thickened into gels. The general types of aqueous liquid formulations are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion, oil-in-water emulsion, flowable concentrate, and suspoemulsion. The general types of nonaqueous liquid formulations are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate, and oil dispersion. [0167] The general types of solid formulations are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings), and the like, which can be water- dispersible ("wettable") or water-soluble. Films and coatings formed from film-forming solutions or flowable suspensions are particularly useful for seed treatment. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation. Alternatively, the entire formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength formulations are primarily used as intermediates for further formulation. [0168] Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water, but occasionally another suitable medium like an aromatic or paraffinic hydrocarbon or vegetable oil. Spray volumes can range from about from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. [0169] Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting. [0170] The formulations will typically contain effective amounts of active ingredient, diluent, and surfactant within the following approximate ranges, shown in Table 2, which add up to 100 percent by weight. 63 ny-2699290 Attorney Docket No.26327-20012.40 Table 2. Formulation Ratios
Figure imgf000066_0001
[0171] Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. [0172] Liquid diluents include, for example, water; N,N-dimethylalkanamides (e.g., N,N- dimethylformamide); limonene; dimethyl sulfoxide; N-alkylpyrrolidones (e.g., N- methylpyrrolidinone); alkyl phosphates (e.g., triethyl phosphate); ethylene glycol; triethylene glycol; propylene glycol; dipropylene glycol; polypropylene glycol; propylene carbonate; butylene carbonate; paraffins (e.g., white mineral oils, normal paraffins, isoparaffins); alkylbenzenes; alkylnaphthalenes; glycerine; glycerol triacetate; sorbitol; aromatic hydrocarbons; dearomatized aliphatics; alkylbenzenes; alkylnaphthalenes; ketones such as cyclohexanone, 2-heptanone, isophorone, and 4-hydroxy-4-methyl-2-pentanone; acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate, and isobornyl acetate; other esters such as alkylated lactate esters, dibasic esters, DON\O^DQG^DU\O^EHQ]RDWHV^^DQG^Ȗ-butyrolactone; and alcohols, which can be linear, branched, saturated or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 64 ny-2699290 Attorney Docket No.26327-20012.40 isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol, cresol, and benzyl alcohol. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22) such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut, and palm kernel), animal- sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof. Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources and can be purified by distillation. Typical liquid diluents are described in C. Marsden & S. Mann, Solvents Guide, Cleaver-Hume Press, London, 1963. [0173] Surfactants can be classified as nonionic, anionic, or cationic. Nonionic surfactants useful for the present formulations include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides, and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor, and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates, and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenol (including those prepared from ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylate esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters, and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyd PEG (polyethylene glycol) resins, graft or comb polymers and star polymers; polyethylene glycols (PEGs); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar-derivatives such as sucrose esters, alkyl polyglycosides, and alkyl polysaccharides. 65 ny-2699290 Attorney Docket No.26327-20012.40 [0174] Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; sulfonates of amines and amides such as N,N-alkyltaurates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzenes; sulfonates of condensed naphthalenes; sulfonates of naphthalene and alkyl naphthalene; sulfonates of fractionated petroleum; sulfosuccinamates; and sulfosuccinates and their derivatives such as dialkyl sulfosuccinate salts. [0175] Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines, and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts, and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides. [0176] Also useful for the present formulations are mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic, and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon' s Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987. [0177] Formulations of the present invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents, or surfactants). Such formulation auxiliaries and additives may control the following: pH (buffers), foaming during processing 66 ny-2699290 Attorney Docket No.26327-20012.40 (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone- vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers, and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222. [0178] The compounds of the invention and any other active ingredients are typically incorporated into the present formulations by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid formulations intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2,000 microns can be wet milled using media mills to obtain particles with average diameters below 3 microns. Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. Pat. No.3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 micron to 10 micron range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, “Agglomeration,” Chemical Engineering, December 4, 1967, pp 147-48, Perry 's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and PCT Publication WO 91/13546. Pellets can be prepared as described in U.S. Pat. No. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. Pat. Nos.4,144,050 and 3,920,442 and German Pat. No.3,246,493. Tablets can be prepared as taught in U.S. Pat. Nos.5,180,587, 5,232,701, and 5,208,030. Films can be prepared as taught in Great Britain Pat. No.2,095,558 and U.S. Pat. No.3,299,566. 67 ny-2699290 Attorney Docket No.26327-20012.40 [0179] For further information regarding the art of formulation, see T. S. Woods, “The Formulator's Toolbox - Product Forms for Modern Agriculture” in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp.120-133. See also U.S. Pat. No.3,235,361, Col.6, line 16 through Col.7, line 19 and Examples 10-41; U.S. Pat. No.3,309,192, Col.5, line 43 through Col.7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. Pat. No.2,891,855, Col.3, line 66 through Col.5, line 17 and Examples 1- 4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81- 96; Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in formulation technology, PJB Publications, Richmond, UK, 2000. Biological Activity [0180] Test results indicate that the compounds of the present invention are highly active preemergent and/or postemergent herbicides and/or plant growth regulants. The compounds of the invention generally show highest activity for postemergence weed control (e.g., applied after weed seedlings emerge from the soil) and preemergence weed control (e.g., applied before weed seedlings emerge from the soil). Many of them have utility for broad- spectrum pre- and/or postemergence weed control in areas where complete control of all vegetation is desired such as around fuel storage tanks, industrial storage areas, parking lots, drive-in theaters, airfields, riverbanks, irrigation, and other waterways, around billboards and highway and railroad structures. Many of the compounds of this disclosure, by virtue of selective metabolism in crops versus weeds, or by selective activity at the locus of physiological inhibition in crops and weeds, or by selective placement on or within the environment of a mixture of crops and weeds, are useful for the selective control of grass and broadleaf weeds within a crop/weed mixture. One skilled in the art will recognize that the preferred combination of these selectivity factors within a compound or group of compounds can readily be determined by performing routine biological and/or biochemical assays. [0181] In some variations, provided herein is a method of controlling undesired vegetation, comprising applying a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V), or a salt thereof (including an agriculturally suitable salt thereof). In some variations, 68 ny-2699290 Attorney Docket No.26327-20012.40 the compound is applied at low application rates. In certain variations, the compound is applied at a rate of 1 to 10,000 g per 10,000 m2, 2 to 5,000 g per 10,000 m2, 5 to 2,000 g per 10,000 m2, 1 to 1000 g per 10,000 m2, 1 to 500 g per 10,000 m2, 1 to 100 g per 10,000 m2, 1 to 75 g per 10,000 m2, 15 to 1000 g per 10,000 m2, 15 to 100 g per 10,000 m2, 15 to 75 g per 10,000 m2, or 15 to 60 g per 10,000 m2. In certain variations of the foregoing, the application of the compound at the aforementioned application rates leads to postemergence control of the undesired vegetation and/or preemergence control of the undesired vegetation. [0182] In certain variations, the application of the compound, including at the aforementioned application rate, leads to burndown. In one variation, burndown refers to when an herbicide is used to reduce weed presence at the time of treatment. Burndown is often used in minimum or no-till fields because the weeds cannot be managed by tilling the soil. The burndown application may be used post-harvest and/or prior to crop emergence. Burndown may be useful against weeds that emerge between growing seasons. [0183] In certain variations, the application of the compound, including at the aforementioned application rate, imparts residual control. The compounds described herein may be used as pre-emergence herbicides, which may be applied after crop planting, but prior to crop and/or weed emergence. Herbicides considered pre-emergence also may be referred to as those imparting “residual control,” and provide extended control of germinating or newly emerged weeds. [0184] In one variation, the undesired vegetation is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% controlled. In some variations of the foregoing, the undesired vegetation is a weed. In one variation, the undesired vegetation is a PPO inhibitor-resistant weed. [0185] Examples of crop fields treated by the compounds in the present invention include edible crop fields such as peanut fields, soybean fields, corn fields, and wheat fields, feed crop fields such as sorghum fields and oat fields, industrial crop fields such as cotton fields and rape fields, and sugar crop fields such as sugarcane fields and sugar beet fields. In one variation, crop fields treated by the compounds herein include corn, soybean, wheat, and cotton fields. 69 ny-2699290 Attorney Docket No.26327-20012.40 [0186] Examples of vegetable fields treated by the compounds in the present invention include fields for cultivation of solanaceous vegetables (eggplants, tomatoes, bell peppers, capsicums, potatoes, and the like), fields for cultivation of cucurbitaceous vegetables (cucumbers, pumpkins, zucchini, watermelons, melons, and the like), fields for cultivation of cruciferous vegetables (radishes, turnips, horseradishes, kohlrabies, Chinese cabbages, cabbages, mustard, broccolis, cauliflowers, and the like), fields for cultivation of asteraceous vegetables (burdocks, garland chrysanthemums, artichokes, lettuces, and the like), fields for cultivation of liliaceous vegetables (leeks, onions, garlics, and asparagus), fields for cultivation of apiaceous vegetables (carrots, parsley, celery, parsnips, and the like), fields for cultivation of chenopodiaceous vegetables (spinach, chards, and the like), fields for cultivation of lamiaceous vegetables (perilla, mint, basil, and lavender), strawberry fields, sweet potato fields, yam fields, and taro fields. [0187] Examples of the land under perennial crops in the present invention include orchards, tea fields, mulberry fields, coffee fields, banana fields, palm fields, flowering tree firms, flowering tree fields, planting stock fields, nursery fields, forest lands, and gardens. Examples of the orchard trees in the present invention include pomaceous fruits (apples, pears, Japanese pears, Chinese quinces, quinces, and the like), stone fruits (peaches, plums, nectarines, Japanese apricots, cherries, apricots, prunes, and the like), citrus fruits (Citrus unshiu, oranges, lemons, limes, grapefruits, and the like), nut trees (chestnuts, walnuts, hazelnut trees, almonds, pistachios, cashew nut trees, macadamia nut trees, and the like), berry fruits (grapes, blueberries, cranberries, blackberries, raspberries, and the like), Japanese persimmons, olives, and loquats. [0188] Examples of the non-crop land in the present invention include athletic fields, empty lots, railroad edges, parks, parking lots, road edges, dry riverbeds, lands under a power line, residential lands, and factory sites. [0189] The crop cultivated in the crop field in the present invention is not limited as long as the crop is a variety generally cultivated as a crop. [0190] The plant of the above-mentioned variety may be a plant that can be produced by natural crossing, a plant that can be generated by mutation, an F1 hybrid plant, or a transgenic plant (also referred to as a genetically-modified plant). The plant generally has properties such as obtaining of the tolerance to an herbicide, accumulation of a toxic substance against a 70 ny-2699290 Attorney Docket No.26327-20012.40 pest, suppression of the susceptibility to a disease, increase in the yield potential, improvement in the tolerance to a biotic and an abiotic stressors, accumulation of a substance, and improvement in the preservability and the processability. [0191] An F1 hybrid plant is a first-generation hybrid obtained by crossing varieties of two different strains, and generally has a heterotic property with a trait superior to that of either of the parents. A transgenic plant has a foreign gene introduced from another organism or the like such as a microorganism and has a property that cannot be easily obtained by cross breeding, mutagenesis, or natural recombination in a natural environment. [0192] Examples of the techniques for producing the above-mentioned plants include conventional breeding techniques; genetic engineering techniques; genome breeding techniques; new breeding techniques; and genome editing techniques. Conventional breeding techniques are for obtaining a plant having a desirable property by mutation or crossing. Genetic engineering techniques include techniques for imparting a new property to a target organism by extracting a target gene (DNA) from another organism (for example, a microorganism) and introducing the target gene into the genome of the target organism. Genetic engineering techniques also include antisense techniques or RNA interference techniques for imparting a new or improved property by silencing another gene present in the plant. Genome breeding techniques are for improving breeding efficiency using genomic information, and examples of the genome breeding techniques include DNA marker (also called genomic marker or genetic marker) breeding techniques and genomic selection. For example, DNA marker breeding is a method in which a progeny having a target useful trait gene is selected from a large number of crossed progenies using a DNA marker that is a DNA sequence that serves as a marker of the location of the specific useful trait gene on the genome. In the method, the crossed progeny is analyzed when it is an infant plant using a DNA marker to effectively shorten the time required for the breeding. [0193] Genomic selection is a technique in which a prediction formula is created from a phenotype and genomic information obtained in advance to predict the property from the prediction formula and the genomic information without evaluating the phenotype and is a technique that can contribute to improving breeding efficiency. The term "new breeding techniques" is a general term for breed improvement (breeding) techniques that combine molecular biological techniques. Examples of the new breeding techniques include cisgenesis/intragenesis, oligonucleotide-directed mutagenesis, RNA-dependent DNA 71 ny-2699290 Attorney Docket No.26327-20012.40 methylation, genome editing, grafting on a GM rootstock or a scion, reverse breeding, agroinfiltration, and seed production technology (SPT). The genome editing technique is for converting genetic information in a sequence-specific manner, and it is possible to delete a base sequence, substitute an amino acid sequence, introduce a foreign gene, and the like using the technique. Examples of the tool include sequence-specific genome modification techniques such as a zinc finger nuclease capable of sequence-specific DNA cleavage (Zinc- Finger, ZFN), TALEN, CRISPR-Cas9, CRISPER-Cpf1, Meganuclease, and CAS9 Nickase and Target-AID created by modifying the aforementioned tools. [0194] Examples of the above-mentioned plants include plants listed in the database of the registered genetically-modified crops (GM Approval Database) in the electronic information site of International Service for the Acquisition of Agri-biotech Applications (ISAAA) (http://www.isaaa.org/). More specific examples are herbicide-tolerant plants, pest-resistant plants, disease-resistant plants, plants modified in the quality (for example, with increase or decrease in the content or change in the composition) of the products (for example, starch, amino acids, and fatty acids), fertility trait-modified plants, abiotic stress-tolerant plants, and plants modified in the trait related to the growth or the yield. [0195] Mechanisms of obtaining herbicide tolerance include reduction in the affinity between the agent and its target, rapid metabolism (decomposition, modification, and the like) of the agent by an expressed enzyme that inactivates the agent, or inhibition of incorporation or translocation of the agent in the plant body. Examples of the plants to which herbicide tolerance has been imparted by genetic engineering technique include plants to which tolerance has been imparted to 4-hydroxyphenylpyruvate dioxygenase (hereinafter abbreviated as HPPD) inhibitors such as isoxaflutole and mesotrione, acetolactate synthase (hereinafter abbreviated as ALS) inhibitors such as imidazolinone herbicides containing imazethapyr and sulfonylurea herbicides containing thifensulfuron-methyl, 5- enolpyruvylshikimate-3-phosphate synthase (hereinafter abbreviated as EPSP) inhibitors such as glyphosate, glutamine synthase inhibitors such as glufosinate, auxin herbicides such as 2,4-D and dicamba, and oxynyl herbicides containing bromoxynil. Preferable herbicide- tolerant transgenic plants treated by the combinations of the invention are cereals such as wheat, barley, rye, and oats, canola, sorghum, soybeans, rice, rape, sugar beet, sugar cane, grapes, lentils, sunflowers, alfalfa, pomaceous fruits, drupes, coffee, tea, strawberries, lawn grass, tomatoes, potatoes, cucumbers, and vegetables such as lettuces, and more preferable 72 ny-2699290 Attorney Docket No.26327-20012.40 herbicide-tolerant transgenic plants are cereals such as wheat, barley, rye, and oats, soybeans, rice, vines, tomatoes, potatoes, and pomaceous fruits. [0196] In one example, in order to obtain the glyphosate herbicide-tolerant plants one or more genes are introduced from: a glyphosate-tolerant EPSPS gene (CP4 epsps) from Agrobacterium tumefaciens strain CP4; a glyphosate metabolizing enzyme gene (gat4601, gat4621) in which the metabolic activity of the glyphosate metabolizing enzyme (glyphosate N-acetyltransferase) gene from Bacillus licheniformis is enhanced by a shuffling technique; a glyphosate metabolizing enzyme (glyphosate oxidase gene, goxv247) from Ochrobacterum anthropi strain LBAA; and EPSPS genes from maize having a glyphosate-tolerant mutation (mepsps, 2mepsps). Main examples of the plants are alfalfa (Medicago sativa), Argentine canola (Brassica napus), cotton (Gossypium hirsutum L.), creeping bentgrass (Agrostis stolonifera), maize (Zea mays L.), polish canola (Brassica rapa), potato (Solanum tuberosum L.), soybean (Glycine max L.), sugar beet (Beta vulgaris), and wheat (Triticum aestivum). Some glyphosate-tolerant transgenic plants are commercially available. For example, the genetically-modified plant in which the glyphosate-tolerant EPSPS from the Agrobacterium is expressed is commercially available with a trade name such as “Roundup Ready®” the genetically-modified plant in which the glyphosate metabolizing enzyme that is from Bacillus and has the metabolic activity enhanced by a shuffling technique is expressed is commercially available with a trade name such as “Optimum® GAT®, or “Optimum® Gly canola”, and the genetically-modified plant in which the EPSPS that is from maize and has glyphosate-tolerant mutation is expressed is commercially available with the trade name “GlyTol®”. [0197] In another example, in order to obtain the glufosinate herbicide-tolerant plants one or more genes are introduced from: a phosphinothricin N-acetyltransferase (PAT) gene (bar) that is a glufosinate metabolizing enzyme from Streptomyces hygroscopicus; a phosphinothricin N-acetyltransferase (PAT) enzyme gene (pat) that is a glufosinate metabolizing enzyme from Streptomyces viridochromogenes; and a synthesized pat gene (pat syn) from Streptomyces viridochromogenes strain Tu494. Main examples of the plants include Argentine canola (Brassica napus), chicory (Cichorium intybus), cotton (Gossypium hirsutum L.), maize (Zea mays L.), polish canola (Brassica rapa), rice (Oryza sativa L.), soybean (Glycine max L.), and sugar beet (Beta vulgaris). Some glufosinate-tolerant genetically-modified plants are commercially available. For example, a genetically-modified 73 ny-2699290 Attorney Docket No.26327-20012.40 plant from a glufosinate metabolizing enzyme (bar) from Streptomyces hygroscopicus and from Streptomyces viridochromogenes is commercially available with trade names such as “LibertyLink®”, “InVigor®”, or “WideStrike®”. [0198] In another example, oxynil herbicide-tolerant plants are known. For example, bromoxynil-tolerant transgenic plants into which a nitrilase gene (bxn) is introduced from an oxynil herbicide metabolizing enzyme from Klebsiella pneumoniae subsp. ozaenae. Main examples of the plants are Argentine canola (Brassica napus), cotton (Gossypium hirsutum L.), and tobacco (Nicotiana tabacum L.). The plants are commercially available with a trade name such as “Navigator® canola” or “BXN®”. [0199] ALS herbicide-tolerant plants are also known. Examples include carnations (Dianthus caryophyllus), which are obtained by introduction of an ALS herbicide-tolerant ALS gene (surB) as a selection marker from tobacco (Nicotiana tabacum) and are commercially available with the trade names “Moondust®”, “Moonshadow®”, "Moonshade®”, "Moonlite®”, "Moonaqua®”, “Moonvista®”, “Moonique®”, “Moonpearl®”, “Moonberry®”, and “Moonvelvet®”; flax (Linum usitatissumum L.), into which an ALS herbicide-tolerant ALS gene (als) from Arabidopsis thaliana is introduced is commercially available with the trade name “CDC Triffid Flax”; sulfonylurea herbicide- tolerant and an imidazolinone herbicide-tolerant maize (Zea mays L.) into which an ALS herbicide-tolerant ALS gene (zm-hra) from maize is introduced is commercially available with the trade name “Optimum® GAT™”; an imidazolinone herbicide-tolerant soybean into which an ALS herbicide-tolerant ALS gene (csr1-2) from Arabidopsis thaliana is introduced is commercially available with the trade name “Cultivance®”; and sulfonylurea herbicide- tolerant soybeans into which an ALS herbicide-tolerant ALS gene (gm-hra) from a soybean (Glycine max) is introduced are commercially available with the trade names “Treus®”, “Plenish®”, and "Optimum® GAT™”. There is also cotton into which an ALS herbicide- tolerant ALS gene (S4-HrA) from tobacco (Nicotiana tabacum cv. Xanthi) is introduced. [0200] HPPD herbicide-tolerant plants are also known. In one example, a soybean into which a mesotrione-tolerant HPPD gene (avhppd-03) from an oat (Avena sativa) and a phinothricin N-acetyltransferase (PAT) enzyme gene (pat) are simultaneously introduced. In another example, a soybean tolerant to mesotrione into which a glufosinate metabolizing enzyme from Streptomyces viridochromogenes is introduced is commercially available. 74 ny-2699290 Attorney Docket No.26327-20012.40 [0201] In another example, 2,4-D-tolerant plants include: maize into which an aryloxyalkanoate dioxygenase gene (aad-1) for a 2,4-D metabolizing enzyme from Sphingobium herbicidovorans is introduced is commercially available with the trade name “Enlist® Maize”; and soybean and cotton into which an aryloxyalkanoate dioxygenase gene (aad-12) for a 2,4-D metabolizing enzyme from Delftia acidovorans is introduced is commercially available with the trade name “Enlist® Soybean”. [0202] In another example, Dicamba-tolerant plants include: soybean and cotton into which a dicamba monooxygenase gene (dmo) having a dicamba metabolizing enzyme from Stenotrophomonas maltophilia strain DI-6 is introduced; and a soybean (Glycine max L.) into which a glyphosate-tolerant EPSPS gene (CP4 epsps) from Agrobacterium tumefaciens strain CP4 is introduced simultaneously with the above-mentioned gene is commercially available with the trade name “Genuity® Roundup Ready™ 2 Xtend®”. [0203] Further examples of the commercially available transgenic plants to which herbicide tolerance has been imparted include: the glyphosate-tolerant maize “Roundup Ready® Corn”, “Roundup Ready® 2”, “Agrisure® GT”, “Agrisure® GT/CB/LL”, “Agrisure® GT/RW”, “Agrisure® 3000GT”, “YieldGard™ VT™ Rootworm/RR2”, and “YieldGard™ VT™ Triple”; the glyphosate-tolerant soybeans “Roundup Ready® Soybean” and “Optimum® GAT”; the glyphosate-tolerant cotton “Roundup Ready® Cotton” and “Roundup Ready® Flex”; the glyphosate-tolerant canola “Roundup Ready® Canola”; the glyphosate-tolerant alfalfa “Roundup Ready® Alfalfa”, the glyphosate-tolerant rice “Roundup Ready® Rice”; the glufosinate-tolerant maize “Roundup Ready® 2”, “LibertyLink®”, “Herculex® 1”, “Herculex® RW”, “Herculex® Xtra”, “Agrisure® GT/CB/LL”, “Agrisure® CB/LL/RW”, and “Bt10”; the glufosinate-tolerant cotton “FiberMax™ LibertyLink™”; the glufosinate-tolerant canola “InVigor®”; the glufosinate- tolerant rice “LibertyLink™ Rice” (manufactured by Bayer AG); the bromoxynil-tolerant cotton “BXN”; the bromoxynil-tolerant canola “Navigator®” and “Compass®”; and the glufosinate-tolerant canola “InVigor®”. Additional plants modified with respect to a herbicide are widely known, and the examples of the plants include alfalfa, apples, barley, eucalyptuses, flax, grapes, lentils, rape, peas, potatoes, rice, sugar beet, sunflowers, tobacco, tomato, turfgrass, and wheat that are tolerant to glyphosate (see, for example, U.S. Pat. Nos. 5,188,642, 4,940,835, 5,633,435, 5,804,425, and 5,627,061); beans, cotton, soybeans, peas, potatoes, sunflowers, tomatoes, tobacco, maize, sorghum, and sugar cane that are tolerant to 75 ny-2699290 Attorney Docket No.26327-20012.40 dicamba (see, for example, WO2008051633, U.S. Pat. Nos.7,105,724, and 5,670,454); soybeans, sugar beet, potatoes, tomatoes, and tobacco that are tolerant to glufosinate (see, for example, U.S. Pat. Nos.6,376,754, 5,646,024, and 5,561,236); cotton, peppers, apples, tomatoes, sunflowers, tobacco, potatoes, maize, cucumbers, wheat, soybeans, sorghum, and cereals that are tolerant to 2,4-D (see, for example, U.S. Pat. Nos.6,153,401, 6,100,446, WO2005107437, U.S. Pat. Nos.5,608,147, and 5,670,454); and canola, maize, millet, barley, cotton, mustard, lettuces, lentils, melons, millet, oats, sword beans, potatoes, rice, rye, sorghum, soybeans, sugar beet, sunflowers, tobacco, tomatoes, and wheat that are tolerant to acetolactate synthase (ALS) inhibitor herbicide (for example, a sulfonylurea herbicide and an imidazolinone herbicide) (see, for example, U.S. Pat. No.5,013,659, WO2006060634, U.S. Pat. Nos.4,761,373, 5,304,732, 6,211,438, 6,211,439, and 6,222,100). The rice tolerant to an imidazolinone herbicide is especially known, and examples of the rice include rice having specific mutation (for example, S653N, S654K, A122T, S653(At)N, S654(At)K, and A122(At)T) in the acetolactate synthase gene (acetohydroxyacid synthase gene) (see, for example, US 2003/0217381, and WO200520673); and the examples include barley, sugar cane, rice, maize, tobacco, soybeans, cotton, rape, sugar beet, wheat, and potatoes that are tolerant to an HPPD inhibitor herbicide (for example, an isoxazole herbicide such as isoxaflutole, a triketone herbicide such as sulcotrione or mesotrione, a pyrazole herbicide such as pyrazolynate, or diketonitrile that is a decomposition product of isoxaflutole) (see, for example, WO2004/055191, WO199638567, WO1997049816, and U.S. Pat. No.6,791,014). [0204] Examples of the plants to which herbicide tolerance has been imparted by a classical technique or a genome breeding technique include the rice “Clearfield® Rice”, the wheat “Clearfield® Wheat”, the sunflower “Clearfield® Sunflower”, the lentil “Clearfield® lentils”, and the canola “Clearfield® canola” (manufactured by BASF SE) that are tolerant to an imidazolinone-based ALS inhibitor herbicide such as imazethapyr or imazamox; the soybean “STS® soybean” that is tolerant to a sulfonyl-based ALS inhibitor herbicide such as thifensulfuron-methyl; the sethoxydim-tolerant maize “SR® corn” and ‘Poast Protected® corn” that are tolerant to an acetyl-CoA carboxylase inhibitor such as a trionoxime herbicide or an aryloxy phenoxypropionic acid herbicide; the sunflower “ExpressSun®” that is tolerant to a sulfonylurea herbicide such as tribenuron; the rice “Provisia™ Rice” that is tolerant to an acetyl-CoA carboxylase inhibitor such as quizalofop; and the canola “Triazine Tolerant Canola” that is tolerant to a PSII inhibitor. 76 ny-2699290 Attorney Docket No.26327-20012.40 [0205] Examples of the plants to which herbicide tolerance has been imparted by a genome editing technique include the canola “SU Canola®” tolerant to a sulfonylurea herbicide in which a rapid variety development technique (Rapid Trait Development System, RTDS®) is used. RTDS® corresponds to oligonucleotide-directed mutagenesis of the genome editing technique, and by RTDS, it is possible to introduce mutation in a DNA in a plant via Gene Repair Oligonucleotide (GRON), that is, a chimeric oligonucleotide of the DNA and the RNA without cutting the DNA. In addition, examples of the plants include maize in which herbicide tolerance and phytic acid content have been reduced by deleting the endogenous gene IPK1 using zinc finger nuclease (see, for example, Nature 459, 437-441 2009); and rice to which herbicide tolerance has been imparted using CRISPR-Cas9 (see, for example, Rice, 7, 52014). [0206] In the present invention, examples of the crop tolerant to a specific PPO inhibitor include crops to which PPO having a reduced affinity for the inhibitor is imparted by a genetic engineering technique. Alternatively, the crop may have a substance that detoxifies and decomposes the PPO inhibitor by cytochrome P450 monooxygenase alone or in combination with the above-mentioned PPO. The tolerant crops are described in, for example, patent documents such as WO2011085221, WO2012080975, WO2014030090, WO2015022640, WO2015022636, WO2015022639, WO2015092706, WO2016203377, WO2017198859, WO2018019860, WO2018022777, WO2017112589, WO2017087672, WO2017039969, and WO2017023778, and non-patent document Li & Nicholl in Pest Management Science (2005), Vol.61, pgs.277-285. [0207] Examples of the plants to which herbicide tolerance has been imparted by a new breeding technique in which the property of a GM rootstock is imparted to a scion by a breeding technique in which grafting is used include the non-transgenic soybean scion to which glyphosate tolerance is imparted using the glyphosate-tolerant soybean Roundup Ready® as a rootstock (see Jiang, et al., in Weed Technology (2013) Vol.27, pgs.412-416). [0208] The above-mentioned plants include strains to which two or more traits are imparted among abiotic stress tolerance, disease resistance, herbicide tolerance, pest resistance, a growth trait, a yield trait, nutrient uptake, product quality, a fertility trait, and the like as described above using a genetic engineering technique, a classical breeding technique, a genome breeding technique, a new breeding technique, a genome editing technique, or the 77 ny-2699290 Attorney Docket No.26327-20012.40 like, and strains to which two or more of the properties of the parent strains are imparted by crossing plants having the same or different properties. [0209] Examples of the commercially available plants to which tolerance to two or more herbicides are imparted include the cotton “GlyTol™ LibertyLink™” and “GlyTol™ LibertyLink™” that are tolerant to glyphosate and glufosinate; the maize “Roundup Ready™ LibertyLink™ Maize” that is tolerant to glyphosate and glufosinate; the soybean “Enlist™ Soybean” that is tolerant to glufosinate and 2,4-D; the soybean “Genuity® Roundup Ready (trademark) 2 Xtend (trademark)” that is tolerant to glyphosate and dicamba; the maize and the soybean “OptimumGAT™” that are tolerant to glyphosate and an ALS inhibitor; the genetically modified soybeans “Enlist E3™” and “Enlist™ Roundup Ready® 2 Yield” that are tolerant to three herbicides of glyphosate, glufosinate, and 2,4-D; the genetically modified maize “Enlist™ Roundup Ready® Corn 2” that is tolerant to glyphosate, 2,4-D, and an aryloxyphenoxypropionate (FOPs) herbicide; the genetically modified maize “Enlist™ Roundup Ready® Corn 2” that is tolerant to glyphosate, 2,4-D, and an aryloxyphenoxypropionate (FOPs) herbicide; the genetically modified cotton “Bollgard II® XtendFlex™ Cotton” that is tolerant to dicamba, glyphosate, and glufosinate; and the genetically modified cotton “Enlist™ Cotton” that is tolerant to three herbicides of glyphosate, glufosinate, and 2,4-D. In addition, the cotton tolerant to glufosinate and 2,4-D, the cotton tolerant to both glufosinate and dicamba, the maize tolerant to both glyphosate and 2,4-D, the soybean tolerant to both glyphosate and an HPPD herbicide, and the genetically modified maize tolerant to glyphosate, glufosinate, 2,4-D, an aryloxyphenoxypropionate (FOPs) herbicide, and a cyclohexanedione (DIMs) herbicide have been also developed. [0210] Examples of the commercially available plants to which herbicide tolerance and pest resistance are imparted include the maize “YieldGard Roundup Ready®” and “YieldGard Roundup Ready® 2” that are tolerant to glyphosate and resistant to a corn borer; the maize “Agrisure® CB/LL” that is tolerant to glufosinate and resistant to a corn borer; the maize “Yield Gard® VT Root worm/RR2” that is tolerant to glyphosate and resistant to a corn rootworm; the maize “Yield Gard® VT Triple” that is tolerant to glyphosate and resistant to a corn rootworm and a corn borer; the maize “Herculex® I” that is tolerant to glufosinate and resistant to a lepidopteran maize pest (Cry1F) (for example, resistance to a western bean cutworm, a corn borer, a black cutworm, and a fall armyworm); the maize “YieldGard® Corn Rootworm/Roundup Ready® 2” that is tolerant to glyphosate and 78 ny-2699290 Attorney Docket No.26327-20012.40 resistant to a corn rootworm; the maize “Agrisure® GT/RW” that is tolerant to glufosinate and resistant to a Coleoptera maize pest (Cry3A) (for example, resistant to a western corn rootworm, a northern corn rootworm, and a Mexican corn rootworm); the maize “Herculex® RW” that is tolerant to glufosinate and resistant to a Coleoptera maize pest (Cry34/35Abl) (for example, resistant to a western corn rootworm, a northern corn rootworm, and a Mexican corn rootworm); the maize “Yield Gard® VT Root worm/RR2” that is tolerant to glyphosate and resistant to a corn rootworm; and the cotton “Bollgard 3® XtendFlex®” that is tolerant to dicamba, glyphosate, and glufosinate and resistant to a lepidopteran cotton pest (for example, resistant to bollworms, a tobacco budworm, and armyworms). [0211] In the present invention, a composition of the invention is applied to a place where weeds are growing or likely to grow. Examples of the method of applying the present composition include a method of spraying the present composition on soil and a method of spraying the present composition on weeds. [0212] In some variations, the application rate of a composition of the invention is generally 1 to 10,000 g per 10,000 m2, 2 to 5,000 g per 10,000 m2, 5 to 2,000 g per 10,000 m2, 1 to 1000 g per 10,000 m2, 1 to 500 g per 10,000 m2, 1 to 100 g per 10,000 m2, 1 to 75 g per 10,000 m2, 15 to 1000 g per 10,000 m2, 15 to 100 g per 10,000 m2, 15 to 75 g per 10,000 m2, or 15 to 60 g per 10,000 m2, in terms of the total amount of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V), or a salt thereof (including an agriculturally suitable salt thereof). [0213] In one variation, the application rate of a composition of the invention is generally 1 to 10,000 g per 10,000 m2, 2 to 5,000 g per 10,000 m2, 5 to 2,000 g per 10,000 m2, 1 to 1000 g per 10,000 m2, 1 to 500 g per 10,000 m2, 1 to 100 g per 10,000 m2, 1 to 75 g per 10,000 m2, 15 to 1000 g per 10,000 m2, 15 to 100 g per 10,000 m2, 15 to 75 g per 10,000 m2, or 15 to 60 g per 10,000 m2, in terms of the total amount of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C. [0214] In the present method, an adjuvant may be mixed in a composition of the invention, followed by application. The type of the adjuvant is not particularly limited, and 79 ny-2699290 Attorney Docket No.26327-20012.40 examples of the adjuvant include oil-based adjuvants such as Agri-Dex® and methylated seed oil (MSO), non-ions (esters or ethers of polyoxyethylene) such as Induce, anions (substituted sulfonates) such as Gramine S, cations (polyoxyethylene amines) such as Genamin® T 200BM, and organic silicons such as Silwet® L77. [0215] The pH and the hardness of the spray liquid prepared when a composition of the invention is applied are not particularly limited, and the pH is usually in the range of 5 to 9, and the hardness is usually in the range of 0 to 500. [0216] The time period for applying a composition of the invention is not particularly limited, and is usually in the range of 5:00 AM to 9:00 PM, and the photon flux density is XVXDOO\^^^^WR^^^^^^^^PRO^P2/s. [0217] When a composition of the invention is applied to a crop field, it may be applied before sowing a crop seed, simultaneously with sowing a crop seed, and/or after sowing a crop seed. That is, the frequency of the application of a composition of the invention is once before, simultaneously with, or after sowing a crop seed, twice excluding before the sowing, excluding simultaneously with the sowing, or excluding after the sowing, or three times at all the timing. [0218] When a composition of the invention is applied before sowing a crop seed, it is applied from 50 days before to immediately before the sowing, preferably from 30 days before to immediately before the sowing, more preferably from 20 days before to immediately before the sowing, and still more preferably from 10 days before to immediately before the sowing. [0219] When a composition of the invention is applied after sowing a crop seed, it is usually applied from immediately after the sowing to before flowering. The composition is more preferably applied from immediately after the sowing to before the emergence, or from 1 to 6 leaf stages of the crop. The case where a composition of the invention is applied simultaneously with sowing a crop seed is the case where a sowing machine and a sprayer are integrated with each other. [0220] In the step of applying a composition of the invention in a cultivation area, a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K- II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) or the compound and at least 80 ny-2699290 Attorney Docket No.26327-20012.40 one additional compound selected from the group consisting of the herbicide compound group B and the safener group C are usually mixed with a carrier such as a solid carrier or a liquid carrier, and an auxiliary agent for formulation such as a surfactant is added if necessary to prepare a formulation. Preferable formulation types are aqueous liquid suspension formulations, oil-based suspension formulations, wettable powders, water dispersible granules, granules, water-based emulsions, oil-based emulsions, and emulsifiable concentrates, and more preferable formulation type is emulsifiable concentrates. Furthermore, a formulation containing a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) alone as an active ingredient and a formulation containing the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C as an active ingredient may be used in combination. Furthermore, a formulation containing the present composition as active ingredients and a formulation containing another herbicide as an active ingredient may be used in combination. [0221] Examples of the method of applying a composition of the invention in a cultivation area include a method of spraying it on the soil in the cultivation area and a method of spraying the present composition on a weeds that are growing. The composition is usually diluted with water, followed by spraying. The spray volume is not particularly limited, and is usually 50 to 1,000 L/ha, preferably 100 to 500 L/ha, and more preferably 140 to 300 L/ha. [0222] Specific examples of the weed species to be controlled by the present composition include, but are not limited to, the weed species described below. [0223] Urticaceae weeds to be controlled include Urtica urens. [0224] Polygonaceae weeds to be controlled include Polygonum convolvulus, Polygonum lapathifolium, Polygonum pensylvanicum, Polygonum persicaria, Polygonum longisetum, Polygonum aviculare, Polygonum arenastrum, Polygonum cuspidatum, Rumex japonicus, Rumex crispus, Rumex obtusifolius, and Rumex acetosa. [0225] Portulacaceae weeds to be controlled include Portulaca oleracea. [0226] Caryophyllaceae weeds to be controlled include Stellaria media, Stellaria aquatica, Cerastium holosteoides, Cerastium glomeratum, Spergula arvensis, and Silene gallica. 81 ny-2699290 Attorney Docket No.26327-20012.40 [0227] Molluginaceae weeds to be controlled include Mollugo verticillate. [0228] Chenopodiaceae weeds to be controlled include Chenopodium album, Chenopodium ambrosioides, Kochia scoparia, Salsola kali, and Atriplex spp. [0229] Amaranthaceae weeds to be controlled include Amaranthus retroflexus, Amaranthus viridis, Amaranthus lividus, Amaranthus spinosus, Amaranthus hybridus, Amaranthus palmeri, Amaranthus patulus, Waterhemp (Amaranthus tuberculatus, Amaranthus rudis, or Amaranthus tamariscinus), Amaranthus blitoides, Amaranthus deflexus, Amaranthus quitensis, Alternanthera philoxeroides, Alternanthera sessilis, and Alternanthera tenella. [0230] Papaveraceae weeds to be controlled include Papaver rhoeas, Papaver dubium, and Argemone Mexicana. [0231] Brassicaceae weeds to be controlled include Raphanus raphanistrum, Raphanus sativus, Sinapis arvensis, Capsella bursa-pastoris, Brassica juncea, Brassica napus, Descurainia pinnata, Rorippa islandica, Rorippa sylvestris, Thlaspi arvense, Myagrum rugosum, Lepidium virginicum, and Coronopus didymus. [0232] Capparaceae weeds to be controlled include Cleome affinis. [0233] Fabaceae weeds to be controlled include Aeschynomene indica, Aeschynomene rudis, Sesbania exaltata, Cassia obtusifolia, Cassia occidentalis, Desmodium tortuosum, Desmodium adscendens, Desmodium illinoense, Trifolium repens, Pueraria lobata, Vicia angustifolia, Indigofera hirsuta, Indigofera truxillensis, and Vigna sinensis. [0234] Oxalidaceae weeds to be controlled include Oxalis corniculata, Oxalis strica, and Oxalis oxyptera. [0235] Geraniaceae weeds to be controlled include Geranium carolinense and Erodium cicutarium. [0236] Euphorbiaceae weeds to be controlled include Euphorbia helioscopia, Euphorbia maculata, Euphorbia humistrata, Euphorbia esula, Euphorbia heterophylla, Euphorbia brasiliensis, Acalypha australis, Croton glandulosus, Croton lobatus, Phyllanthus corcovadensis, and Ricinus communis. 82 ny-2699290 Attorney Docket No.26327-20012.40 [0237] Malvaceae weeds to be controlled include Abutilon theophrasti, Sida rhombiforia, Sida cordifolia, Sida spinosa, Sida glaziovii, Sida santaremnensis, Hibiscus trionum, Anoda cristata, and Malvastrum coromandelianum. [0238] Onagraceae weeds to be controlled include Ludwigia epilobioides, Ludwigia octovalvis, Ludwigia decurre, Oenothera biennis, and Oenothera laciniata. [0239] Sterculiaceae weeds to be controlled include Waltheria indica. [0240] Violaceae weeds to be controlled include Viola arvensis and Viola tricolor. [0241] Cucurbitaceae weeds to be controlled include Sicyos angulatus, Echinocystis lobata, and Momordica charantia. [0242] Lythraceae weeds to be controlled include Ammannia multiflora, Ammannia auriculata, Ammannia coccinea, Lythrum salicaria, and Rotala indica. [0243] Elatinaceae weeds to be controlled include Elatine triandra and Elatine californica. [0244] Apiaceae weeds to be controlled include Oenanthe javanica, Daucus carota, and Conium maculatum. [0245] Ceratophyllaceae weeds to be controlled include Ceratophyllum demersum. [0246] Cabombaceae weeds to be controlled include Cabomba caroliniana. [0247] Haloragaceae weeds to be controlled include Myriophyllum aquaticum, Myriophyllum verticillatum, Myriophyllum spicatum, and Myriophyllum heterophyllum. [0248] Sapindaceae weeds to be controlled include Cardiospermum halicacabum. [0249] Primulaceae weeds to be controlled include Anagallis arvensis. [0250] Asclepiadaceae weeds to be controlled include Asclepias syriaca, and Ampelamus albidus. [0251] Rubiaceae weeds to be controlled include Galium aparine, Galium spurium var. echinospermon, Spermacoce latifolia, Richardia brasiliensis, and Borreria alata. 83 ny-2699290 Attorney Docket No.26327-20012.40 [0252] Convolvulaceae weeds to be controlled include Ipomoea nil, Ipomoea hederacea, Ipomoea purpurea, Ipomoea hederacea var. integriuscula, Ipomoea lacunosa, Ipomoea triloba, Ipomoea acuminata, Ipomoea hederifolia, Ipomoea coccinea, Ipomoea quamoclit, Ipomoea grandifolia, Ipomoea aristolochiafolia, Ipomoea cairica, Convolvulus arvensis, Calystegia hederacea, Calystegia japonica, Merremia hedeacea, Merremia aegyptia, Merremia cissoides, and Jacquemontia tamnifolia. [0253] Boraginaceae weeds to be controlled include Myosotis arvensis. [0254] Lamiaceae weeds to be controlled include Lamium purpureum, Lamium amplexicaule, Leonotis nepetaefolia, Hyptis suaveolens, Hyptis lophanta, Leonurus sibiricus, and Stachys arvensis. [0255] Solanaceae weeds to be controlled include Datura stramonium, Solanum nigrum, Solanum americanum, Solanum ptycanthum, Solanum sarrachoides, Solanum rostratum, Solanum aculeatissimum, Solanum sisymbriifolium, Solanum carolinense, Physalis angulata, Physalis subglabrata, and Nicandra physaloides. [0256] Scrophulariaceae weeds to be controlled include Veronica hederaefolia, Veronica persica, Veronica arvensis, Lindernia procumbens, Lindernia dubia, Lindernia angustifolia, Bacopa rotundifolia, Dopatrium junceum, and Gratiola japonica. [0257] Plantaginaceae weeds to be controlled include Plantago asiatica, Plantago lanceolata, Plantago major, and Callitriche palustris. [0258] Asteraceae weeds to be controlled include Xanthium pensylvanicum, Xanthium occidentale, Xanthium italicum, Helianthus annuus, Matricaria chamomilla, Matricaria perforata, Chrysanthemum segetum, Matricaria matricarioides, Artemisia princeps, Artemisia vulgaris, Artemisia verlotorum, Solidago altissima, Taraxacum officinale, Galinsoga ciliata, Galinsoga parviflora, Senecio vulgaris, Senecio brasiliensis, Senecio grisebachii, Conyza bonariensis, Conyza smatrensis, Conyza canadensis, Ambrosia artemisiaefolia, Ambrosia trifida, Bidens tripartita, Bidens pilosa, Bidens frondosa, Bidens subalternans, Cirsium arvense, Cirsium vulgare, Silybum marianum, Carduus nutans, Lactuca serriola, Sonchus oleraceus, Sonchus asper, Wedelia glauca, Melampodium perfoliatum, Emilia sonchifolia, Tagetes minuta, Blainvillea latifolia, Tridax procumbens, Porophyllum ruderale, Acanthospermum australe, Acanthospermum hispidum, 84 ny-2699290 Attorney Docket No.26327-20012.40 Cardiospermum halicacabum, Ageratum conyzoides, Eupatorium perfoliatum, Eclipta alba, Erechtites hieracifolia, Gamochaeta spicata, Gnaphalium spicatum, Jaegeria hirta, Parthenium hysterophorus, Siegesbeckia orientalis, Soliva sessilis, Eclipta prostrata, Eclipta alba, and Centipeda minima. [0259] Alismataceae weeds to be controlled include Sagittaria pygmaea, Sagittaria trifolia, Sagittaria sagittifolia, Sagittaria montevidensis, Sagittaria aginashi, Alisma canaliculatum, and Alisma plantago-aquatica. [0260] Limnocharitaceae weeds to be controlled include Limnocharis flava. [0261] Hydrocharitaceae weeds to be controlled include Limnobium spongia, Hydrilla verticillata, and Najas guadalupensis. [0262] Araceae weeds to be controlled include Pistia stratiotes. [0263] Lemnaceae weeds to be controlled include Lemna aoukikusa, Spirodela polyrhiza, and Wolffia spp. [0264] Potamogetonaceae to be controlled include Potamogeton distinctus, Potamogeton crispus, Potamogeton illinoensis, and Stuckenia pectinata. [0265] Liliaceae weeds to be controlled include Allium canadense, Allium vineale, and Allium macrostemon. [0266] Pontederiaceae weeds to be controlled include Eichhornia crassipes, Heteranthera limosa, Monochoria korsakowii, and Monochoria vaginalis. [0267] Commelinaceae weeds to be controlled include Commelina communis, Commelina bengharensis, Commelina erecta, and Murdannia keisak. [0268] Poaceae weeds to be controlled include Echinochloa crus-galli, Echinochloa oryzicola, Echinochloa crus-galli var formosensis, Echinochloa oryzoides, Echinochloa colona, Echinochloa crus-pavonis, Setaria viridis, Setaria faberi, Setaria glauca, Setaria geniculata, Digitaria ciliaris, Digitaria sanguinalis, Digitaria horizontalis, Digitaria insularis, Eleusine indica, Poa annua, Poa trivialis, Poa pratensis, Alospecurus aequalis, Alopecurus myosuroides, Avena fatua, Sorghum halepense, Sorghum vulgare, Agropyron repens, Lolium multiflorum, Lolium perenne, Lolium rigidum, Bromus catharticus, Bromus 85 ny-2699290 Attorney Docket No.26327-20012.40 sterilis, Bromus japonicus, Bromus secalinus, Bromus tectorum, Hordeum jubatum, Aegilops cylindrica, Phalaris arundinacea, Phalaris minor, Apera spica-venti, Panicum dichotomiflorum, Panicum texanum, Panicum maximum, Brachiaria platyphylla, Brachiaria ruziziensis, Brachiaria plantaginea, Brachiaria decumbens, Brachiaria brizantha, Brachiaria humidicola, Cenchrus echinatus, Cenchrus pauciflorus, Eriochloa villosa, Pennisetum setosum, Chloris gayana, Chlorisvirgata, Eragrostis pilosa, Rhynchelitrum repens, Dactyloctenium aegyptium, Ischaemum rugosum, Isachne globosa, Oryza sativa, Paspalum notatum, Paspalum maritimum, Paspalum distichum, Pennisetum clandestinum, Pennisetum setosum, Rottboellia cochinchinensis, Leptochloa chinensis, Leptochloa fascicularis, Leptochloa filiformis, Leptochloa panicoides, Leersia japonica, Leersia sayanuka, Leersia oryzoides, Glyceria leptorrhiza, Glyceria acutiflora, Glyceria maxima, Agrostis gigantea, Agrostis stolonifera, Cynodon dactylon, Dactylis glomerata, Eremochloa ophiuroides, Festuca arundinacea, Festuca rubra, Imperata cylindrica, Miscanthus sinensis, Panicum virgatum, and Zoysia japonica. [0269] Cyperaceae weeds to be controlled include Cyperus microiria, Cyperus iria, Cyperus compressus, Cyperus difformis, Cyperus flaccidus, Cyperus globosus, Cyperus nipponics, Cyperus odoratus, Cyperus serotinus, Cyperus rotundus, Cyperus esculentus, Kyllinga gracillima, Kyllinga brevifolia, Fimbristylis miliacea, Fimbristylis dichotoma, Eleocharis acicularis, Eleocharis kuroguwai, Schoenoplectiella hotarui, Schoenoplectiella juncoides, Schoenoplectiella wallichii, Schoenoplectiella mucronatus, Schoenoplectiella triangulatus, Schoenoplectiella nipponicus, Schoenoplectiella triqueter, Bolboschoenus koshevnikovii, and Bolboschoenus fluviatilis. [0270] Equisetaceae weeds to be controlled include Equisetum arvense, and Equisetum palustre. [0271] Salviniaceae weeds to be controlled include Salvinia natans. [0272] Azollaceae weeds to be controlled include Azolla japonica and Azolla imbricata. [0273] Marsileaceae weeds to be controlled include Marsilea quadrifolia. [0274] Other weeds to be controlled include Pithophora, Cladophora, Bryophyta, Marchantiophyta, Anthocerotophyta, Cyanobacteria, Pteridophyta, sucker of perennial crops (pomaceous fruits, nut trees, citruses, Humulus lupulus, grapes, and the like). 86 ny-2699290 Attorney Docket No.26327-20012.40 [0275] In the above-mentioned weeds to be controlled, mutations within the species are not particularly limited. That is, the weeds include weeds having reduced sensitivity to a specific herbicide. The reduced sensitivity may be attributed to a mutation at a target site (target site mutation) or may be attributed to any factors other than the target site mutation (non-target site mutation). Examples of the factor of the reduced sensitivity due to a non- target site mutation include increased metabolism, malabsorption, translocation dysfunction, and excretion to out of system. Examples of the factor of the increased metabolism include the enhanced activity of a metabolizing enzyme such as cytochrome P450 monooxygenase, aryl acylamidase, esterase, or glutathione S-transferase. Examples of the excretion to out of system include transport to the vacuole by an ABC transporter. Examples of the weeds having reduced sensitivity due to a target site mutation include weeds having any one of or two or more of the following amino acid substitutions in the ALS gene: Ala122Thr, Ala122Val, Ala122Tyr, Pro197Ser, Pro197His, Pro197Thr, Pro197Arg, Pro197Leu, Pro197Gln, Pro197Ala, Pro197Ile, Ala205Val, Ala205Phe, Asp376Glu, Arg377His, Trp574Leu, Trp574Gly, Trp574Met, Ser653Thr, Ser653Thr, Ser653Asn, Ser635Ile, Gly654Glu, and Gly645Asp. Similarly, examples of the weeds having reduced sensitivity due to a target site mutation include weeds having any one of or two or more of the following amino acid substitutions in the ACCase gene: Ile1781Leu, Ile1781Val, Ile1781Thr, Trp1999Cys, Trp1999Leu, Ala2004Val, Trp2027Cys, Ile2041Asn, Ile2041Val, Asp2078Gly, Cys2088Arg, Gly2096Ala, and Gly2096Ser. [0276] Similarly, as an example of the weeds having reduced sensitivity due to a target site mutation, PPO inhibitor-resistant weeds having one or more mutations selected from an Arg128Leu mutation, an Arg128Met mutation, an Arg128Gly mutation, an Arg128His mutation, a Gly210 deletion mutation, and a Gly399Ala mutation in PPO. The word “PPO” means protoporphyrinogen oxidase. Weeds usually have PPO1 and PPO2 in PPO, and the above-mentioned mutations may be present in either PPO1 or PPO2 or in both. The case where weeds have the mutations in PPO2 is preferable. For example, the word "Arg128Met" means that the mutation is present in the 128th (the number is standardized with PPO2 of Amaranthus palmeri) amino acid. In PPO2 of Ambrosia artemisiaefolia, the mutation corresponds to a mutation in the 98th amino acid (Rousonelos, et al., Weed Science (2012) Vol.60, pgs.335-344) and is known as Arg98Leu. In this case, Arg98 is equivalent to Arg128 according to the present invention. The Arg128Met mutation and the Arg128Gly mutation in the PPO of the weed to be controlled in the present invention are known in 87 ny-2699290 Attorney Docket No.26327-20012.40 Amaranthus palmeri (Giacomini, et al., Pest Management Science (2017) Vol.73, pgs.1559- 1563), the Arg128His mutation is known in Lolium rigidum (Fernandez-Moreno, et al., Weed Science Society of America (WSSA) annual meeting, 2018), and the Gly399Ala mutation is known in Amaranthus palmeri (Rangani, et al., WSSA annual meeting, 2018). In the present invention, the above-mentioned reported resistant weeds are particularly effectively controlled, but particularly effectively controlled weeds are not limited thereto. That is, other weeds having the amino acid mutation are similarly controlled. Not only Amaranthus palmeri having an Arg128Leu mutation, an Arg128Met mutation, an Arg128Gly mutation, an Arg128His mutation, a Gly210 deletion mutation, or a Gly399Ala mutation, but also, for example, waterhemp having the above-mentioned mutation, Ambrosia artemisiaefolia having the above-mentioned mutation, Lolium rigidum having the above-mentioned mutation, Lolium multiflorum having the above-mentioned mutation, and Euphorbia heterophylla having the above-mentioned mutation are effectively controlled. [0277] Similarly, examples of the weeds having reduced sensitivity due to a target site mutation include weeds having an amino acid substitution such as Thr102Ile, Pro106Ser, Pro106Ala, or Pro106Leu in the EPSP gene. In particular, Eleusine indica, Lolium multiflorum, Lolium rigidum, Digitaria insularis, waterhemp, Echinochloa colona, and the like which are resistant to glyphosate and have one or both of the mutations are effectively controlled. Similarly, examples of the weeds having reduced sensitivity due to a target site include weeds having increased copies of the EPSP gene and Amaranthus palmeri, waterhemp, Kochia scoparia, and the like which are resistant to glyphosate and have the mutation are particularly effectively controlled. Conyza canadensis, Conyza smatrensis, and Conyza bonariensis which are resistant to glyphosate in which an ABC transporter is involved are also effectively controlled. [0278] In the cultivation of a crop according to the present invention, plant nutritional management in general cultivation of a crop can be performed. The fertilization system may be based on Precision Agriculture or may be conventionally uniform one. In addition, a nitrogen-fixing bacterium or a mycorrhizal fungus can be inoculated in combination with seed treatment. 88 ny-2699290 Attorney Docket No.26327-20012.40 Combinations [0279] In certain aspects, controlling effect on weeds is exhibited by using a compound of (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M- I), (M-II), (M-III), (M-IV), or (M-V) and a specific compound in combination. [0280] Accordingly, the present invention features – [1] A herbicidal composition including a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of a herbicide compound group B and a safener group C, wherein a weight ratio of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) to the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C is 1:0.1 to 1:50, and the herbicide compound group B is a group consisting of the following B-1 to B-12: B-1 acetolactate synthase inhibitors; B-2 acetyl-CoA carboxylase inhibitors; B-3 protoporphyrinogen IX oxidase inhibitors; B-44-hydrophenylpyruvate dioxygenase inhibitors; B-5 phytoene desaturase inhibitors; B-6 photosystem II inhibitors; B-7 very long chain fatty acid synthesis inhibitors; B-8 microtubule formation inhibitors; B-9 auxin herbicides; B-10 enolpyruvylshikimate 3-phosphate synthase inhibitors; B-11 glutamine synthase inhibitors; and B-12 other herbicides (including agriculturally acceptable salts or derivatives for each of B-1 to B-12) [0281] The present invention also features – [2] the herbicidal composition according to [1], wherein: the B-1 is a group consisting of pyrithiobac, pyrithiobac-sodium salt, pyriminobac, pyriminobac-methyl, bispyribac, bispyribac-sodium salt, pyribenzoxim, pyrimisulfan, pyriftalid, triafamone, amidosulfuron, azimsulfuron, bensulfuron, bensulfuron-methyl, 89 ny-2699290 Attorney Docket No.26327-20012.40 chlorimuron, chlorimuron-ethyl, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, flupyrsulfuron-methyl-sodium, foramsulfuron, halosulfuron, halosulfuron-methyl, imazosulfuron, mesosulfuron, mesosulfuron-methyl, metazosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron, primisulfuron, primisulfuron-methyl, propyrisulfuron, pyrazosulfuron, pyrazosulfuron-ethyl, rimsulfuron, sulfometuron, sulfometuron-methyl, sulfosulfuron, trifloxysulfuron, trifloxysulfuron-sodium salt, chlorsulfuron, cinosulfuron, ethametsulfuron, ethametsulfuron-methyl, iodosulfuron, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, metsulfuron, metsulfuron- methyl, prosulfuron, thifensulfuron, thifensulfuron-methyl, triasulfuron, tribenuron, tribenuron-methyl, triflusulfuron, triflusulfuron-methyl, tritosulfuron, bencarbazone, flucarbazone, flucarbazone-sodium salt, propoxycarbazone, propoxycarbazone-sodium salt, thiencarbazone, thiencarbazone-methyl, cloransulam, cloransulam-methyl, diclosulam, florasulam, flumetsulam, metosulam, penoxsulam, pyroxsulam, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium salt, imazapic, imazapic- ammonium salt, imazapyr, imazapyr-isopropylammonium salt, imazaquin, imazaquin- ammonium, imazethapyr, and imazethapyr-ammonium salt (including agriculturally acceptable salts and derivatives thereof for each); the B-2 is a group consisting of clodinafop, clodinafop-propargyl, cyhalofop, cyhalofop- butyl, diclofop, diclofop-methyl, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P- ethyl, fluazifop, fluazifop-butyl, fluazifop-P, fluazifop-P-butyl, haloxyfop, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-methyl, metamifop, propaquizafop, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, alloxydim, clethodim, sethoxydim, tepraloxydim, tralkoxydim, and pinoxaden (including agriculturally acceptable salts and derivatives thereof for each); the B-3 is a group consisting of azafenidin, oxadiazon, oxadiargyl, carfentrazone, carfentrazone-ethyl, saflufenacil, cinidon, cinidon-ethyl, sulfentrazone, pyraclonil, pyraflufen, pyraflufen-ethyl, butafenacil, fluazolate, fluthiacet, fluthiacet-methyl, flufenpyr, flufenpyr-ethyl, flumiclorac, flumiclorac-pentyl, flumioxazin, pentoxazone, oxyfluorfen, acifluorfen, acifluorfen-sodium salt, aclonifen, chlormethoxynil, chlornitrofen, nitrofen, bifenox, fluoroglycofen, fluoroglycofen-ethyl, fomesafen, fomesafen-sodium salt, lactofen, tiafenacil, and ethyl [3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4- 90 ny-2699290 Attorney Docket No.26327-20012.40 tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetate (including agriculturally acceptable salts and derivatives thereof for each); the B-4 is a group consisting of benzobicyclon, bicyclopyrone, mesotrione, sulcotrione, tefuryltrione, tembotrione, isoxachlortole, isoxaflutole, benzofenap, pyrasulfotole, pyrazolynate, pyrazoxyfen, fenquinotrione, topramezone, tolpyralate, lancotrione, lancotrione-sodium salt, 2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4- (trifluoromethyl)benzamide (CAS Registry Number: 1400904-50-8), 2-chloro-N-(1-methyl- 1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)- benzamide (CAS Registry Number: 1361139-71-0), and 4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexene-1-yl)carbonyl]- 2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (CAS Registry Number: 1353870-34-4) (including agriculturally acceptable salts and derivatives thereof for each); the B-5 is a group consisting of diflufenican, picolinafen, beflubutamid, norflurazon, fluridone, flurochloridone, and flurtamone (including agriculturally acceptable salts and derivatives thereof for each); the B-6 is a group consisting of ioxynil, ioxynil-octanoate, bentazone, pyridate, bromoxynil, bromoxynil-octanoate, chlorotoluron, dimefuron, diuron, linuron, fluometuron, isoproturon, isouron, tebuthiuron, benzthiazuron, methabenzthiazuron, propanil, metobromuron, metoxuron, monolinuron, siduron, simazine, atrazine, propazine, cyanazine, ametryn, simetryn, dimethametryn, prometryn, terbumeton, terbuthylazine, terbutryn, trietazine, hexazinone, metamitron, metribuzin, amicarbazone, bromacil, lenacil, terbacil, chloridazon, desmedipham, and phenmedipham (including agriculturally acceptable salts and derivatives thereof for each); the B-7 is a group consisting of propachlor, metazachlor, alachlor, acetochlor, metolachlor, S- metolachlor, butachlor, pretilachlor, thenylchlor, indanofan, cafenstrole, fentrazamide, dimethenamid, dimethenamid-P, mefenacet, pyroxasulfone, fenoxasulfone, naproanilide, napropamide, anilofos, flufenacet, and ipfencarbazone (including agriculturally acceptable salts and derivatives thereof for each); the B-8 is a group consisting of trifluralin, pendimethalin, ethalfluralin, benfluralin, oryzalin, prodiamine, butamifos, dithiopyr, and thiazopyr (including agriculturally acceptable salts and derivatives thereof for each); 91 ny-2699290 Attorney Docket No.26327-20012.40 the B-9 is a group consisting of 2,4-DB [4-(2,4-dichlorophenoxy)butyric acid] and its salts or esters (dimethylammonium salt, isooctyl ester, and choline salt), MCPA and its salts or esters (dimethylammonium salt, 2-ethylhexyl ester, isooctyl ester, sodium salt, and choline salt), MCPB, mecoprop and its salts or esters (dimethylammonium salt, dioramine salt, ethadyl ester, 2-ethylhexyl ester, isooctyl ester, methyl ester, potassium salt, sodium salt, trolamine salt, and choline salt), mecoprop-P and its salts or esters (dimethylammonium salt, 2- ethylhexyl ester, isobutyl salt, potassium salt, and choline salt), dichlorprop and its salt or ester (butotyl ester, dimethylammonium salt, 2-ethylhexyl ester, isooctyl ester, methyl ester, potassium salt, sodium salt, and choline salt), dichlorprop-P, dichlorprop-P dimethylammonium, triclopyr and its salts or esters (butotyl ester, and triethylammonium salt), fluroxypyr, fluroxypyr-meptyl, picloram and its salts (potassium salt, tris(2- hydroxypropyl)ammonium salt, and choline salt), quinclorac, quinmerac, aminopyralid and its salts (potassium salt, tris(2-hydroxypropyl)ammonium salt, and choline salt), clopyralid and its salts (olamine salt, potassium salt, triethylammonium salt, and choline salt), clomeprop, aminocyclopyrachlor, halauxifen, halauxifen-methyl, florpyrauxifen, and florpyrauxifen-benzyl (including agriculturally acceptable salts and derivatives thereof for each); the B-10 is a group consisting of glyphosate, glyphosate-isopropylammonium salt, glyphosate-trimesium salt, glyphosate-ammonium salt, glyphosate-diammonium salt, glyphosate-dimethylammonium salt, glyphosate-monoethanolamine salt, glyphosate-sodium salt, glyphosate-potassium salt, and glyphosate-guanidine salt (including agriculturally acceptable salts and derivatives thereof for each); B-11 is a group consisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, glufosinate-P-sodium salt, and bialaphos (including agriculturally acceptable salts and derivatives thereof for each); and the B-12 is a group consisting of isoxaben, dichlobenil, methiozolin, diallate, butylate, triallate, chlorpropham, asulam, phenisopham, benthiocarb, molinate, esprocarb, pyributicarb, prosulfocarb, orbencarb, EPTC, dimepiperate, swep, difenoxuron, methyldymron, bromobutide, daimuron, cumyluron, diflufenzopyr, diflufenzopyr-sodium salt, etobenzanid, tridiphane, amitrole, clomazone, 2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3- one (CAS Registry Number: 81777-95-9), (3S,4S)-N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3- (trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8), 92 ny-2699290 Attorney Docket No.26327-20012.40 maleic hydrazide, oxaziclomefone, cinmethylin, benfuresate, ACN, dalapon, chlorthiamid, flupoxam, bensulide, paraquat, paraquat-dichloride, diquat, diquat-dibromide, MSMA, indaziflam, and triaziflam (including agriculturally acceptable salts and derivatives thereof for each). [0282] The present invention also features – [3] the herbicidal composition according to [1] or [2], wherein the safener group C is a group consisting of benoxacor, cloquintocet, cyometrinil, cyprosulfamide, dichlormid, dicyclonone, dietholate, fenchlorazole, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen, mefenpyr, mephenate, naphthalic anhydride, oxabetrinil, 4-(dichloroacetyl)-1-oxa-4-azaspiro[4.5]decane, 2,2,5-trimethyl-3- (dichloroacetyl)-1,3-oxazolidine, and N-(2-methoxybenzoyl)-4- [(methylaminocarbonyl)amino]benzenesulfon-amide. [0283] In one embodiment, the present invention includes – [4] the herbicidal composition according to [1], wherein B-1 is a group consisting of pyrithiobac, pyrithiobac-sodium salt, chlorimuron-ethyl, foramsulfuron, halosulfuron-methyl, nicosulfuron, primisulfuron-methyl, rimsulfuron, trifloxysulfuron-sodium salt, chlorsulfuron, iodosulfuron-methyl-sodium, iofensulfuron sodium, metsulfuron-methyl, prosulfuron, thifensulfuron-methyl, tribenuron- methyl, thiencarbazone-methyl, cloransulam-methyl, flumetsulam, imazamethabenz-methyl, imazamox-ammonium salt, imazapic-ammonium salt, imazapyr-isopropylammonium, imazaquin-ammonium salt, and imazethapyr-ammonium salt (including agriculturally acceptable salts and derivatives thereof for each). [0284] In another embodiment, the present invention includes - [5] the herbicidal composition according to [1], wherein B-2 is a group consisting of fenoxaprop-ethyl, fenoxaprop-P-ethyl, fluazifop-butyl, fluazifop-P-butyl, quizalofop-ethyl, quizalofop-P-ethyl, clethodim, and sethoxydim (including agriculturally acceptable salts and derivatives thereof for each). [0285] In another embodiment, the present invention includes - [6] the herbicidal composition according to [1], wherein B-3 is a group consisting of carfentrazone-ethyl, saflufenacil, sulfentrazone, pyraflufen-ethyl, fluthiacet-methyl, flufenpyr-ethyl, flumiclorac- pentyl, flumioxazin, oxyfluorfen, acifluorfen-sodium salt, fomesafen-sodium salt, lactofen, tiafenacil, and ethyl [(3-{2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo- 93 ny-2699290 Attorney Docket No.26327-20012.40 1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}pyridin-2-yl)oxy]acetate (including agriculturally acceptable salts and derivatives thereof for each). [0286] In another embodiment, the present invention includes - [7] the herbicidal composition according to [1], wherein B-4 is a group consisting of bicyclopyrone, mesotrione, tembotrione, isoxaflutole, fenquinotrione, topramezone, tolpyralate, lancotrione- sodium salt, 2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4- (trifluoromethyl)benzamide (CAS Registry Number 1400904-50-8), 2-chloro-N-(1-methyl- 1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)-benzamide (CAS Registry Number 1361139-71-0), and 4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexene-1-yl)carbonyl]- 2-methyl-1,2,4-triazine-3,5-(2H,4H)-dione (CAS Registry Number 1353870-34-4) (including agriculturally acceptable salts and derivatives thereof for each). [0287] In another embodiment, the present invention includes - [8] the herbicidal composition according to [1], wherein B-5 is a group consisting of norflurazon and fluridone (including agriculturally acceptable salts and derivatives thereof for each). [0288] In another embodiment, the present invention includes - [9] the herbicidal composition according to [1], wherein B-6 is a group consisting of bentazone, bromoxynil octanoate, diuron, linuron, fluometuron, simazine, atrazine, ametryn, prometryn, and metribuzin (including agriculturally acceptable salts and derivatives thereof for each). [0289] In another embodiment, the present invention includes - [10] the herbicidal composition according to [1], wherein B-7 is a group consisting of alachlor, acetochlor, metolachlor, S-metolachlor, dimethenamid, dimethenamid-P, pyroxasulfone, and flufenacet (including agriculturally acceptable salts and derivatives thereof for each). [0290] In another embodiment, the present invention includes - [11] the herbicidal composition according to [1], wherein B-8 is a group consisting of trifluralin, pendimethalin, and ethalfluralin (including agriculturally acceptable salts and derivatives thereof for each). [0291] In another embodiment, the present invention includes - [12] the herbicidal composition according to [1], wherein B-9 is a group consisting of 2,4-DB, fluroxypyr, fluroxypyr-meptyl, clopyralid-olamine salt, clopyralid-potassium salt, clopyralid- triethylammonium salt, halauxifen, halauxifen-methyl, florpyrauxifen, and florpyrauxifen- benzyl (including agriculturally acceptable salts and derivatives thereof for each). 94 ny-2699290 Attorney Docket No.26327-20012.40 [0292] In another embodiment, the present invention includes - [13] the herbicidal composition according to [1], wherein B-10 is a group consisting of a combination of two or more of glyphosate, glyphosate-isopropylammonium salt, glyphosate-ammonium salt, glyphosate-dimethylamine salt, glyphosate-monoethanolamine salt, glyphosate-potassium salt, and glyphosate-guanidine salt (including agriculturally acceptable salts and derivatives thereof for each). [0293] In another embodiment, the present invention includes - [14] the herbicidal composition according to [1], wherein the B-11 is a group consisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, and glufosinate-P-sodium salt (including agriculturally acceptable salts and derivatives thereof for each). [0294] In another embodiment, the present invention includes - [15] the herbicidal composition according to [1], wherein the B-12 is a group consisting of EPTC, diflufenzopyr, diflufenzopyr-sodium salt, clomazone, 2-[(2,4-dichlorophenyl)methyl]-4,4- dimethylisoxazolidin-3-one (CAS Registry Number: 81777-95-9), (3S,4S)-N-(2- fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8), cinmethylin, MSMA, paraquat, paraquat dichloride, diquat, and diquat dibromide (including agriculturally acceptable salts and derivatives thereof for each). [0295] In another embodiment, the present invention includes - [16] The herbicidal composition according to [1], wherein the safener group C is a group consisting of benoxacor, cyprosulfamide, and isoxadifen-ethyl (including agriculturally acceptable salts and derivatives thereof for each). [0296] The present invention also features - [18] A method for controlling weeds, the method including a step of applying a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of the herbicide compound group B and the safener group C simultaneously or sequentially to a place where weeds are growing or to grow. [0297] In one embodiment, the present invention includes - [19] The method according to [18], wherein a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H- IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and the at 95 ny-2699290 Attorney Docket No.26327-20012.40 least one compound selected from the group consisting of the herbicide compound group B and the safener group C are used at a weight ratio of 1:0.1 to 1:50. [0298] In another embodiment, the present invention includes - [20] The method according to [18] or [19], wherein the place where weeds are growing or to grow is a crop field. [0299] The present invention also features - [21] A use of the herbicidal composition according to any one of [1] to [16], for controlling weeds. [0300] Herbicidal compositions according to the present invention also include a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K- II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of an herbicide compound group B and a safener group C. [0301] The method for controlling weeds according to the present invention (hereinafter referred to as “present method”) includes the step of applying the present composition to a place where weeds are growing or likely to grow in a crop field, a vegetable field, a land under perennial crops, a non-crop land, or the like. In a crop field and a vegetable field, the present composition may be applied before, simultaneously with, and/or after sowing a crop seed. [0302] The present method includes the step of applying a compound of formula (I), (G- I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M- II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of the herbicide compound group B and the safener group C simultaneously or sequentially to a place where weeds are growing or likely to grow. In the case of the sequential application, the order of the application is not particularly limited. [0303] The present composition is usually a formulation prepared by mixing a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and at least one compound selected from the group consisting of the herbicide compound group B and the safener group C with a carrier such as a solid carrier or a liquid carrier and adding an auxiliary agent for formulation such as a surfactant if necessary. Preferable formulation types of such a formulation are aqueous liquid suspension concentrates, wettable powders, water dispersible granules, 96 ny-2699290 Attorney Docket No.26327-20012.40 granules, and emulsifiable concentrates. The present composition may be used in combination with a formulation containing another herbicide as an active ingredient. [0304] The total content of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H- II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M- V) and the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present composition is within a range of 0.01 to 90% by weight, preferably 1 to 80% by weight. [0305] Hereinafter, when the at least one compound selected from the group consisting of the herbicide compound group B is a salt (for example, glyphosate-potassium salt), the weight of the at least one compound is represented by the acid equivalent. [0306] A mixing ratio of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) to the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present composition is within a range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50 by weight ratio. [0307] A ratio of application rates of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M- IV), or (M-V) to the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present method is within a range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50 by weight ratio. [0308] In some variations, the mixing ratio of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M- III), (M-IV), or (M-V) to the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C in the present composition include about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.5, about 1:0.7, about 1:1, about 1:2, about 1:3, about 1:5, about 1:7, about 1:10, about 1:15, about 1:20, about 1:30, and about 1:50 by weight ratio. [0309] In some variations, the ratio of application rates of a compound of formula (I), (G- I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M- II), (M-III), (M-IV), or (M-V) to the at least one compound selected from the group 97 ny-2699290 Attorney Docket No.26327-20012.40 consisting of the herbicide compound group B and the safener group C in the present method include about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:1, about 1:1.2, about 1:1.4, about 1:1.6, about 1:1.8, about 1:2, about 1:2.2, about 1:2.4, about 1:2.6, about 1:2.8, about 1:3, about 1:5, about 1:7, about 1:10, about 1:15, about 1:20, about 1:30, and about 1:50 by weight ratio. [0310] The word “about” in the preceding paragraph means that the specified ratio includes the ratio in the range increased or decreased by 10% by weight relative to the specified ratio. For example, a ratio of about 1:2 includes a range of 1:1.8 to 1:2.2. [0311] In the present composition and the present method, particularly preferable examples of the combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H- II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M- V) and the at least one compound selected from the group consisting of the herbicide compound group B and the safener group C and the range of weight ratio thereof include, but are not limited to, the following combinations and the ranges: a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and pyrithiobac (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and pyrithiobac-sodium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and chlorimuron-ethyl (1:0.1 to 1:20); a combination of a compound of formulas formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and foramsulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and halosulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and nicosulfuron (1:0.1 to 1:20); 98 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and primisulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and rimsulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and trifloxysulfuron-sodium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and chlorsulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and iodosulfuron-methyl-sodium (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and iofensulfuron-sodium (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and metsulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and prosulfuron (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and thifensulfuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and tribenuron-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and thiencarbazone-methyl (1:0.1 to 1:20); 99 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and cloransulam-methyl (1:0.1 to 1:20); a combination of a compound of formulas formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and flumetsulam (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and imazamethabenz-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and imazamox-ammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and imazapic-ammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and imazapyr-isopropylammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and imazaquin-ammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and imazethapyr-ammonium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fenoxaprop-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fenoxaprop-P-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fluazifop-butyl (1:0.1 to 1:20); 100 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fluazifop-P-butyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and quizalofop-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and quizalofop-P-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and clethodim (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and sethoxydim (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) carfentrazone-ethyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and saflufenacil (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and sulfentrazone (1:0.1 to 1:30); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and pyraflufen-ethyl (1:0.1 to 1:30); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fluthiacet-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and flufenpyr-ethyl (1:0.1 to 1:20); 101 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and flumiclorac-pentyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and flumioxazin (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and oxyfluorfen (1:0.1 to 1:30); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and acifluorfen-sodium salt (1:0.1 to 1:30); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fomesafen-sodium salt (1:0.1 to 1:30); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and lactofen (1:0.1 to 1:30); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and tiafenacil (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and ethyl [(3-{2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo-1,2,3,6- tetrahydropyrimidine-1-yl]phenoxy}pyridin-2-yl)oxy]acetate (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and bicyclopyrone (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and mesotrione (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and tembotrione (1:0.1 to 1:20); 102 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and isoxaflutole (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fenquinotrione (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and topramezone (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and tolpyralate (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and lancotrione-sodium salt (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V)and 2- methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide (CAS Registry Number: 1400904-50-8) (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and 2- chloro-N-(1-methyl-1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethyl)- benzamide (CAS Registry Number: 1361139-71-0) (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and 4-(4- fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexene-1-yl)carbonyl]-2-met- hyl-1,2,4-triazine- 3,5(2H,4H)-dione (CAS Registry Number: 1353870-34-4) (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and norflurazon (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fluridone (1:0.1 to 1:20); 103 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and bentazone (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and bromoxynil octanoate (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and diuron (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and linuron (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fluometuron (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and simazine (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and atrazine (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and ametryn (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and prometryn (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and metribuzin (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and alachlor (1:1 to 1:50); 104 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and acetochlor (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and metolachlor (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and S- metolachlor (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and dimethenamid (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and dimethenamid-P (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and pyroxasulfone (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and flufenacet (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and trifluralin (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and pendimethalin (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and ethalfluralin (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and 2,4- DB (1:1 to 1:50); 105 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fluroxypyr (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and fluroxypyr-meptyl (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and clopyralid-olamine salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and clopyralid-potassium salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and clopyralid-triethylammonium salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and halauxifen (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and halauxifen-methyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and florpyrauxifen (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and florpyrauxifen-benzyl (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glyphosate (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glyphosate-isopropylammonium salt (1:1 to 1:50); 106 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glyphosate-ammonium salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glyphosate-dimethylamine salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glyphosate-monoethanolamine salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glyphosate-potassium salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glyphosate-guanidine salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glufosinate (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glufosinate-ammonium salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glufosinate-P (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and glufosinate-P-sodium salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and EPTC (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and diflufenzopyr (1:1 to 1:50); 107 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and diflufenzopyr-sodium salt (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and clomazone (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and 2- [(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one (CAS Registry Number: 81777-95-9) (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and (3S,4S)--N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-- 3- pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8) (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and cinmethylin (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and MSMA (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and paraquat (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and paraquat-dichloride (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and diquat (1:1 to 1:50); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and diquat-dibromide (1:1 to 1:50); 108 ny-2699290 Attorney Docket No.26327-20012.40 a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and benoxacor (1:0.1 to 1:20); a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and cyprosulfamide (1:0.1 to 1:20); or a combination of a compound of formula (I), (G-I), (G-II), (G-III), (H-I), (H-II), (H-III), (H-IV), (K-I), (K-II), (K-III), (K-IV), (M-I), (M-II), (M-III), (M-IV), or (M-V) and isoxadifen-ethyl (1:0.1 to 1:20). [0312] Before, simultaneously with, and/or after sowing a crop seed treated with one or more compounds selected from the group consisting of an insecticide compound, a nematicide compound, a fungicide compound, and the like, the present composition may be applied to the field in which the crop seed have been sown or is to be sown. [0313] In some embodiments, the present composition may be used in combination with another pesticidally-active compound. Examples of the insecticide compound, the nematicide compound, and the fungicide compound which may be used in combination with the present composition include neonicotinoid compounds, diamide compounds, carbamate compounds, organophosphorus compounds, biological nematicide compounds, other insecticide compounds and nematicide compounds, azole compounds, strobilurin compounds, metalaxyl compounds, SDHI compounds, and other fungicide compounds and plant growth regulators. ENUMERATED EMBODIMENTS [0314] The following enumerated embodiments are representative of some aspects of the invention. Embodiment A1. A compound of formula (I):
Figure imgf000111_0001
or a salt thereof, wherein: 109 ny-2699290 Attorney Docket No.26327-20012.40 R1 is OR1a or N(R1a)2; each R1a is, independently, H, C1-4alkyl optionally substituted with C(O)OR1b, C1- 4alkyl optionally substituted with C(O)N(R1c)2, C2-4alkenyl, C2-4alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2- 4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is, independently, H, C1-4alkyl, or C3-6cycloalkyl, wherein each C1-4alkyl or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; R1x is H or C1-6alkyl; each of R2 and R3 is, independently, F or Cl; R4 is H or F; and R5 is F or OC1-2alkyl, provided that: (i) when R1 is OH or OCH3, each of R2 and R3 is not H; (ii) when R1 is NH2, each of R2 and R3 is not H; and (iii) when R2 is F, R3 is not F. Embodiment A2. The compound according to embodiment A1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (II):
Figure imgf000112_0001
salt thereof. Embodiment A3. The compound according to embodiment A2, or a salt thereof, wherein R1a is C1-4alkyl optionally substituted with C(O)OR1b or C(O)N(R1c)2. 110 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment A4. The compound according to embodiment A2, or a salt thereof, wherein R1a is pyridyl substituted with OCH2CO2R1x. Embodiment A5. The compound according to embodiment A1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (III):
Figure imgf000113_0001
salt thereof. Embodiment A6. The compound according to embodiment A5, or a salt thereof, wherein each R1a is, independently, H or S(O)2C1-4alkyl. Embodiment A7. The compound according to any one of embodiments A1 to A6, or a salt thereof, wherein R4 is F. Embodiment A8. The compound according to any one of embodiments A1 to A6, or a salt thereof, wherein R4 is H. Embodiment A9. The compound according to any one of embodiments A1 to A8, or a salt thereof, wherein R2 is Cl and R3 is F. Embodiment A10. The compound according to embodiment A1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof. Embodiment A11. An agricultural composition, comprising: a compound of any one of embodiments A1 to A10, or a salt thereof; and at least one additional component that serves as a carrier. Embodiment A12. The composition of embodiment A11, wherein at least one additional component is a surfactant or a diluent. Embodiment A13. The composition of embodiment A11 or 12, wherein the composition is an herbicidal composition. 111 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment A14. A method of controlling undesired vegetation, comprising contacting the undesired vegetation or its environment with a compound of formula (I), or a salt thereof, or an agricultural composition comprising said compound and at least one additional component that serves as a carrier, wherein the compound of formula (I) is:
Figure imgf000114_0001
wherein: R1 is OR1a or N(R1a)2; each R1a is, independently, H, C1-4alkyl optionally substituted with C(O)OR1b, C1- 4alkyl optionally substituted with C(O)N(R1c)2, C2-4alkenyl, C2-4alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2- 4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is, independently, H, C1-4alkyl, or C3-6cycloalkyl, wherein each C1-4alkyl or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; R1x is H or C1-6alkyl; each of R2 and R3 is, independently, F or Cl; R4 is H or F; and 112 ny-2699290 Attorney Docket No.26327-20012.40 R5 is F or OC1-2alkyl. The method according to embodiment A11, wherein the compound of formula (I) is a compound of any one of claims 1 to 10, or a salt thereof. Embodiment B1. A compound of formula (I):
Figure imgf000115_0001
or a salt thereof, wherein R1 is OR1a, NHS(O)2R1b, or NHS(O)2N(R1a)(R1b); R1a is H or C1-6alkyl optionally substituted with C(O)OC1-4alkyl or C(O)OC2-4alkenyl; R1b is C1-6alkyl; R2 is Cl or OCHF2; R3 is H or F; and R4 is H or F. Embodiment B2. The compound according to embodiment B1, or a salt thereof, wherein R4 is F. Embodiment B3. The compound according to embodiment B1, or a salt thereof, wherein R4 is H. Embodiment B4. The compound according to embodiment B1, or a salt thereof, wherein R2 is Cl and R3 is F. Embodiment B5. The compound according to embodiment B1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (II): 113 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000116_0001
salt thereof. Embodiment B6. The compound according to embodiment B1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (III):
Figure imgf000116_0002
salt thereof. Embodiment B7. The compound according to embodiment B1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (IV):
Figure imgf000116_0003
salt thereof. Embodiment B8. The compound according to any one of embodiments B5 to B7, or a salt thereof, wherein R2 is Cl, R3 is F, and R4 is F. Embodiment B9. The compound according to any one of embodiments B5 to B7, or a salt thereof, wherein R2 is Cl, R3 is F, and R4 is H. Embodiment B10. The compound according to embodiment B1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof. Embodiment B11. An agricultural composition, comprising: a compound of any one of embodiments B1 to B10, or a salt thereof; and at least one additional component that serves as a carrier. 114 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment B12. The composition of embodiment B11, wherein at least one additional component is a surfactant or a diluent. Embodiment B13. The composition of embodiment B11 or B12, wherein the composition is an herbicidal composition. Embodiment B14. A method of controlling undesired vegetation, comprising contacting the undesired vegetation or its environment with a compound of any one of embodiments B1 to B10, a salt thereof, or a composition of any one of embodiments B11 to B13. Embodiment C1. A compound of formula (I):
Figure imgf000117_0001
or a salt thereof, wherein: R1 is C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, each substituted with C(O)ORx and optionally substituted with halo; Rx is H or C1-6alkyl; R2 is Cl; R3 is H or F; R4 is H or F; and R5 is OCH3 or F. Embodiment C2. The compound according to embodiment C1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (II): 115 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000118_0001
or a salt thereof, wherein: X is H or halo. Embodiment C3. The compound according to embodiment C1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (III):
Figure imgf000118_0002
or a salt thereof, wherein: X is H or halo. Embodiment C4. The compound according to any one of embodiments C1 to C3, or a salt thereof, wherein R3 is F. Embodiment C5. The compound according to any one of embodiments C1 to C4, or a salt thereof, wherein X is Cl. Embodiment C6. The compound according to any one of embodiments C1 to C5, or a salt thereof, wherein R4 is F. Embodiment C7. The compound according to any one of embodiments C1 to C5, or a salt thereof, wherein R4 is H. Embodiment C8. The compound according to any one of embodiments C1 to C6, or a salt thereof, wherein Rx is H. 116 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment C9. The compound according to any one of embodiments C1 to C6, or a salt thereof, wherein Rx is C1-2alkyl. Embodiment C10. The compound according to embodiment C1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof. Embodiment C11. An agricultural composition, comprising: a compound of any one of embodiments C1 to C10, or a salt thereof; and at least one additional component that serves as a carrier. Embodiment C12. The composition of embodiment C11, wherein at least one additional component is a surfactant or a diluent. Embodiment C13. The composition of embodiment C11 or C12, wherein the composition is an herbicidal composition. Embodiment C14. A method of controlling undesired vegetation, comprising contacting the undesired vegetation or its environment with a compound of any one of embodiments C1 to C10, a salt thereof, or a composition of any one of embodiments C11 to C13. Embodiment D1. A compound of formula (I):
Figure imgf000119_0001
wherein R1 is OR1a, C(O)OR1a, C(O)NHS(O)2R1b, S(O)2NHR1a, or S(O)2NHC(O)R1b; R1a is H, C1-6alkyl optionally substituted with C(O)OC1-2alkyl, or C3-6cycloalkyl; R1b is C1-6alkyl, or C3-6cycloalkyl; R2 is Cl or NO2; R3 is H or F; 117 ny-2699290 Attorney Docket No.26327-20012.40 R4 is H or F; and R5 is F or CF3. Embodiment D2. The compound according to embodiment D1, or a salt thereof, wherein R1 is OR1a. Embodiment D3. The compound according to embodiment D1, or a salt thereof, wherein R1 is C(O)OR1a. Embodiment D4. The compound according to embodiment D1, or a salt thereof, wherein R1 is C(O)NHS(O)2R1b. Embodiment D5. The compound according to embodiment D1, or a salt thereof, wherein R1 is S(O)2NHR1a. Embodiment D6. The compound according to embodiment D1, or a salt thereof, wherein R1 is S(O)2NHC(O)R1b. Embodiment D7. The compound according to embodiment D1, or a salt thereof, wherein R3 is H. Embodiment D8. The compound according to any one of embodiments D1 to D7, or a salt thereof, wherein each of R4 and R5 is F. Embodiment D9. The compound according to any one of embodiments D1 to D7, or a salt thereof, wherein R5 is CF3. Embodiment D10. The compound according to any one of embodiments D1 to D7, or a salt thereof, wherein R5 is F and R4 is H. Embodiment D11. The compound according to any one of embodiments D1 to D10, or a salt thereof, wherein R2 is NO2. Embodiment D12. The compound according to any one of embodiments D1 to D11, or a salt thereof, wherein R1a or R1b is C1-4alkyl. Embodiment D13. The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (II): 118 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000121_0001
salt thereof. Embodiment D14. The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (III):
Figure imgf000121_0002
salt thereof. Embodiment D15. 15. The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (IV):
Figure imgf000121_0003
salt thereof. Embodiment D16. The compound according to embodiment D1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (V):
Figure imgf000121_0004
salt thereof. Embodiment D17. The compound according to embodiment D1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof. Embodiment D18. An agricultural composition, comprising: a compound of any one of embodiments D1 to D17, or a salt thereof; and at least one additional component that serves as a carrier. 119 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment D19. The composition of embodiment D18, wherein at least one additional component is a surfactant or a diluent. Embodiment D20. The composition of embodiment D18 or D19, wherein the composition is an herbicidal composition. Embodiment D21. A method of controlling undesired vegetation, comprising contacting the undesired vegetation or its environment with a compound of any one of embodiments D1 to D17, a salt thereof, or a composition of any one of embodiments D18 to D20. Embodiment E1. A compound of formula (I):
Figure imgf000122_0001
or a salt thereof, wherein: R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with C(O)ORx and optionally substituted with halogen; each R1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR1b, C1- 6alkyl optionally substituted with C(O)N(R1c)2, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2- 4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is , independently, H, C1-6alkyl, or C3-6cycloalkyl, wherein each C1-6alkyl or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; 120 ny-2699290 Attorney Docket No.26327-20012.40 R1x is H or C1-6alkyl; R2 is H, F, Cl, OCHF2, or NO2; R3 is H, F, or Cl; each of R4, R6, and R7 is H or F; R5 is H, F, CF3. or OC1-2alkyl; X is O or a bond, wherein when X is a bond, R1 is not OH, NH2, CH3, S(O)2NHR1a or S(O)2NHC(O)R1b and at least one of R2 or R3 is not H; when X is a bond and R1 is OCH3, CO2CH3, CO2CH2CH3, or CH=CHCO2H, each of R2 and R3 is not H; when X is O, R2 and at least one of R1 or R3 is not H; and when X is O, R1 is not NHCH3; and Ring A contains at least 3 F. Embodiment E2. The compound according to embodiment E1, or a salt thereof, wherein Ring A contains at least 4 F. Embodiment E3. The compound according to embodiment E1, or a salt thereof, wherein R4 is H or F and each of R5, R6, and R7 is F. Embodiment E4. The compound according to embodiment E1, or a salt thereof, wherein Ring A contains 5 F. Embodiment E5. The compound according to any one of embodiments E1 to E4, or a salt thereof, wherein X is a bond. Embodiment E6. The compound according to any one of embodiments E1 to E4, or a salt thereof, wherein X is O. Embodiment E7. The compound according to embodiment E1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (G-I): 121 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000124_0001
(G-I), or a salt thereof, wherein: R1 is ORG1a or N(RG1a)2; each RG1a is, independently, H, C1-4alkyl optionally substituted with C(O)ORG1b, C1- 4alkyl optionally substituted with C(O)N(RG1c)2, C2-4alkenyl, C2-4alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)N(RG1x), C1-4alkyl, C(O)OCH2C2-4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2RG1x, pyridyl optionally substituted with OCH2CO2RG1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each RG1b is , independently, H, C1-4alkyl, or C3-6cycloalkyl, wherein each C1-4alkyl or C3-6cycloalkyl of RG1b is optionally substituted with C(O)ORG1x and up to 4 F atoms; each RG1c is, independently, RG1b, or two RG1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)ORG1x; R1x is H or C1-6alkyl; each of R2 and R3 is, independently, F or Cl; R4 is H or F; and R5 is F or OC1-2alkyl. Embodiment E8. The compound according to embodiment E7, or a salt thereof, wherein said compounds of formula (G-I) is a compound of formula (G-II):
Figure imgf000124_0002
122 ny-2699290 Attorney Docket No.26327-20012.40 or a salt thereof. Embodiment E9. The compound according to embodiment E8, or a salt thereof, wherein RG1a is C1-4alkyl optionally substituted with C(O)ORG1b or C(O)N(RG1c)2. Embodiment E10. The compound according to embodiment E8, or a salt thereof, wherein RG1a is pyridyl substituted with OCH2CO2RG1x. Embodiment E11. The compound according to embodiment E7, or a salt thereof, wherein said compound of formula (G-I) is a compound of formula (G-III):
Figure imgf000125_0001
or a salt thereof. Embodiment E12. The compound according to embodiment E11, or a salt thereof, wherein each RG1a is, independently, H or S(O)2C1-4alkyl. Embodiment E13. The compound according to any one of embodiments E7 to E12, or a salt thereof, wherein R4 is F. Embodiment E14. The compound according to any one of embodiments E7 to E12, or a salt thereof, wherein R4 is H. Embodiment E15. The compound according to any one of embodiments E7 to E14, or a salt thereof, wherein R2 is Cl and R3 is F. Embodiment E16. The compound according to embodiment E7, or a salt thereof, wherein said compound of formula (I) is a compound of formula (H-I):
Figure imgf000125_0002
123 ny-2699290 Attorney Docket No.26327-20012.40 or a salt thereof, wherein: RH1 is ORH1a, NHS(O)2RH1b, or NHS(O)2N(RH1a)(RH1b); RH1a is H or C1-6alkyl optionally substituted with C(O)OC1-4alkyl or C(O)OC2- 4alkenyl; RH1b is C1-6alkyl; R2 is Cl or OCHF2; R3 is H or F; and R4 is H or F. Embodiment E17. The compound according to embodiment E16, or a salt thereof, wherein R4 Embodiment E18. The compound according to embodiment E16, or a salt thereof, wherein R4 Embodiment E19. The compound according to embodiment E16, or a salt thereof, wherein R2 is Cl and R3 is F. Embodiment E20. The compound according to embodiment E16, wherein said compound of formula (H-I) is a compound of formula (H-II):
Figure imgf000126_0001
(H-II), or a salt thereof. Embodiment E21. The compound according to embodiment E16, or a salt thereof, wherein said compound of formula (H-I) is a compound of formula (H-III): 124 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000127_0001
or a salt thereof. Embodiment E22. The compound according to embodiment E16, or a salt thereof, wherein said compound of formula (H-I) is a compound of formula (H-IV):
Figure imgf000127_0002
or a salt thereof. Embodiment E23. The compound according to any one of embodiments E20 to E22, or a salt thereof, wherein R2 is Cl, R3 is F, and R4 is F. Embodiment E24. The compound according to any one of embodiments E20 to E22, or a salt thereof, wherein R2 is Cl, R3 is F, and R4 is H. Embodiment E25. The compound according to embodiment E1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (K-I):
Figure imgf000127_0003
or a salt thereof, wherein: RK1 is C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, each substituted with C(O)ORKx and optionally substituted with halo; 125 ny-2699290 Attorney Docket No.26327-20012.40 R2 is Cl; R3 is H or F; R4 is H or F R5 is OCH3 or F; and RKx is H or C1-6alkyl. Embodiment E26. The compound according to embodiment E25, or a salt thereof, wherein said compound of formula (K-I) is a compound of formula (K-II):
Figure imgf000128_0001
or a salt thereof, wherein: X1 is H or halo. Embodiment E27. The compound according to embodiment E25, or a salt thereof, wherein said compound of formula (K-I) is a compound of formula (K-III):
Figure imgf000128_0002
or a salt thereof, wherein: X1 is H or halo. Embodiment E28. The compound according to any one of embodiments E25 to E27, or a salt thereof, wherein R3 is F. 126 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment E29. The compound according to any one of embodiments E25 to E27, or a salt thereof, wherein X is Cl. Embodiment E30. The compound according to any one of embodiments E25 to E28, or a salt thereof, wherein RKx is H. Embodiment E31. The compound according to any one of embodiments E25 to E30, or a salt thereof, wherein RKx is C1-2alkyl. Embodiment E32. The compound according to embodiment E1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (M-I):
Figure imgf000129_0001
or a salt thereof, wherein: RM1 is ORM1a, C(O)ORM1a, C(O)NHS(O)2RM1b, S(O)2NHRM1a, or S(O)2NHC(O)RM1b; RM1a is H, C1-6alkyl optionally substituted with C(O)OC1-2alkyl, or C3-6cycloalkyl; RM1b is C1-6alkyl, or C3-6cycloalkyl; RM2 is Cl or NO2; R4 is H or F; and R5 is F or CF3. Embodiment E33. The compound according to embodiment E32, or a salt thereof, wherein RM1 is ORM1a. Embodiment E34. The compound according to embodiment E32, or a salt thereof, wherein R1 is C(O)ORM1a. Embodiment E35. The compound according to embodiment E32, or a salt thereof, wherein R1 is C(O)NHS(O)2RM1b. 127 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment E36. The compound according to embodiment E32, or a salt thereof, wherein R1 is S(O)2NHRM1a. Embodiment E37. The compound according to embodiment E32, or a salt thereof, wherein R1 is S(O)2NHC(O)RM1b. Embodiment E38. The compound according to any one of embodiments E32 to E37, or a salt thereof, wherein each of R4 and R5 is F. Embodiment E39. The compound according to any one of embodiments E32 to E37, or a salt thereof, wherein R5 is CF3. Embodiment E40. The compound according to any one of embodiments E32 to E37, or a salt thereof, wherein R5 is F and R4 is H. Embodiment E41. The compound according to any one of embodiments E32 to E40, or a salt thereof, wherein R2 is NO2. Embodiment E42. The compound according to any one of embodiments E32 to E41, or a salt thereof, wherein RM1a or RM1b is C1-4alkyl. Embodiment E43. The compound according to embodiment E32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-II):
Figure imgf000130_0001
or a salt thereof. Embodiment E44. The compound according to embodiment E32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-III): 128 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000131_0001
or a salt thereof. Embodiment E45. The compound according to embodiment E32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-IV):
Figure imgf000131_0002
or a salt thereof. Embodiment E46. The compound according to embodiment E32, wherein said compound of formula (M-I) is a compound of formula (M-V):
Figure imgf000131_0003
or a salt thereof. Embodiment E47. The compound according to embodiment E1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof. Embodiment E48. An agricultural composition, comprising: a compound of any one of embodiments E1 to E47, or a salt thereof; and at least one additional component that serves as a carrier. 129 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment E49. The composition of embodiment E48, wherein at least one additional component is a surfactant or a diluent. Embodiment E50. The composition of embodiment E47 or E48, wherein the composition is an herbicidal composition. Embodiment E51. A method of controlling undesired vegetation, comprising contacting the undesired vegetation or its environment with a compound of formula (I), or a salt thereof, or an agricultural composition comprising said compound and at least one additional component that serves as a carrier, wherein the compound of formula (I) is:
Figure imgf000132_0001
wherein: R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with C(O)ORx and optionally substituted with halogen; each R1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR1b, C1- 6alkyl optionally substituted with C(O)N(R1c)2, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2- 4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is , independently, H, C1-6alkyl, or C3-6cycloalkyl, wherein each C1-6alkyl or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; 130 ny-2699290 Attorney Docket No.26327-20012.40 R1x is H or C1-6alkyl; R2 is H, F, Cl, OCHF2, or NO2; R3 is H, F, or Cl; each of R4, R6, and R7 is H or F; R5 is H, F, CF3. or OC1-2alkyl; X is O or a bond, wherein when X is a bond R1 is not S(O)2NHR1a or S(O)2NHC(O)R1b; and Ring A contains at least 3 F. Embodiment E52. The method according to embodiment E51, wherein the compound of formula (I) is a compound of any one of embodiments 1 to 47, or a salt thereof. Embodiment F1. A method comprising contacting undesired vegetation or its environment with a fluorophenyl analog of a base compound, wherein the base compound (i) inhibits protoporphyrinogen oxidase (PPO) and (ii) comprises a terminal cyclic moiety, wherein the fluorophenyl analog replaces the terminal cyclic moiety of the base compound with a terminal phenyl moiety substituted with 4 or 5 fluoro groups, and wherein the fluorophenyl analog has one or more of the following properties: (i) similar or improved inhibition of wild-type PPO, relative to the base compound; ^LL^^VLPLODU^RU^LPSURYHG^LQKLELWLRQ^RI^ǻ*^^^^PXWDQW^332^^UHODWLYH^WR^WKH^EDVH^ compound; (iii) similar or improved xylem mobility, relative to the base compound; (iv) similar or improved phloem mobility, relative to the base compound; or (v) similar or improved soil mobility, relative to the base compound. 131 ny-2699290 Attorney Docket No.26327-20012.40 Embodiment F2. The method of embodiment F1, wherein the base compound comprises a terminal alkyl ester moiety, and wherein the fluorophenyl analog replaces the terminal alkyl ester moiety with a carboxylic acid moiety. Embodiment F3. The method of embodiment F1 or F2, wherein the method comprises contacting the undesired vegetation or its environment with an herbicidally effective amount of the fluorophenyl analog. Embodiment F4. The method of any one of embodiments F1 to F5, wherein, when the fluorophenyl analog sits in the active site of PPO, the terminal phenyl moiety of the IOXRURSKHQ\O^DQDORJ^H[KLELWV^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ZLWK^WKH^SKHQ\O^ULQJ^RI^D^ phenylalanine residue of the PPO. Embodiment F5. The method of embodiment F4, wherein the phenylalanine residue is Phe392 in Amaranthus palmeri. Embodiment F6. The method of any one of embodiments F1 to F5, wherein the fluorophenyl analog is a compound of formula (I): [A] – [B] (I), wherein: A is a terminal phenyl moiety substituted with 4 or 5 fluoro groups; and B is a core structure optionally substituted with one or more mobility targeting moieties. Embodiment F7. The method of embodiment F6, wherein [B] i) binds in the active site of the PPO; and ii) when binding in the active site of the PPO, positions the terminal phenyl moiety >$@^WR^H[KLELW^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ZLWK^WKH^SKHQ\O^ULQJ^RI^D^SKHQ\ODODQLQH^ residue in the active site of the PPO. Embodiment F8. The method of embodiment F6 or embodiment F7, wherein the core structure of [B] is selected from the group consisting of
Figure imgf000134_0001
, 132 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000135_0001
Embodiment F9. The method of embodiment F8, wherein the core structure of [B] is selected from the group consisting
Figure imgf000135_0002
. Embodiment F10. The method of any one of embodiments F6 to F9, wherein the one or more mobility targeting moieties selectively enhances xylem mobility. Embodiment F11. The method of any one of embodiments F6 to F9, wherein the one or more mobility targeting moieties selectively enhances phloem mobility. Embodiment F12. The method of any one of embodiments F6 to F9, wherein the one or more mobility targeting moieties selectively enhances both xylem and phloem mobility. Embodiment F13. The method of any one of embodiments F6 to F12, wherein the one or more mobility targeting moieties are each independently selected from the group consisting
Figure imgf000135_0003
133 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000136_0001
Embodiment F14. The method of any one of embodiments F1 to F15, wherein the terminal phenyl moiety is substituted with 4 fluoro groups. Embodiment F15. The method of any one of embodiments F1 to F15, wherein the terminal phenyl moiety is substituted with 5 fluoro groups. Embodiment F16. A method comprising contacting undesired vegetation or its environment with a fluorophenyl analog, wherein the fluorophenyl analog comprises a terminal phenyl moiety substituted with 4 or 5 fluoro groups, wherein: when the fluorophenyl analog binds in the active site of PPO, the terminal phenyl PRLHW\^RI^WKH^IOXRURSKHQ\O^DQDORJ^H[KLELWV^D^ʌ- ʌ^VWDFNLQJ^LQWHUDFWLRQ^ZLWK^WKH^SKHQ\O^ULQJ^RI^ a phenylalanine residue of the PPO. Embodiment F17. The method of embodiment F16, wherein the fluorophenyl analog exhibits: (a) inhibition of wild-type PPO; ^E^^LQKLELWLRQ^RI^ǻ*^^^^PXWDQW^332^ (c) xylem mobility; (d) phloem mobility; or (e) soil mobility, or any combination of (a)-(e). EXAMPLES [0315] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation. 134 ny-2699290 Attorney Docket No.26327-20012.40 Compound Synthesis and Characterization [0316] Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a procedure described in other Examples or Steps.1H-NMR spectra are reported in ppm downfield from tetramethylsilane; “s” means singlet, “d” means doublet, “t” means triplet, “q” means quartet, “m” means multiplet, “dd” means doublet of doublets, “dt” means doublet of triplets, and “br s” means broad singlet. Mass spectra (MS) are reported as the molecular weight of the highest isotopic abundance parent ion (M+1) formed by addition of H+ (molecular weight of 1) to the molecule, or (M-1) formed by the loss of H+ (molecular weight of 1) from the molecule, observed by using liquid chromatography coupled to a mass spectrometer (LCMS) using either atmospheric pressure chemical ionization (AP+) where "amu" stands for unified atomic mass units or electrospray ionization (ES+). Example 1. Preparation of 4'-chloro-2,2',3,4,5,6-hexafluoro-5'-methoxy-1,1'-biphenyl (Compound 1) and 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-ol (Compound 2)
Figure imgf000137_0001
Scheme 11 [0317] As shown in Step 1 of Scheme 11, to a degassed mixture of 1-bromo-4-chloro-2- fluoro-5-methoxybenzene (2.5 g, 10.44 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (2.6 g, 10.44 mmol) in dioxane (25 mL) were added potassium acetate (1.5 g, 15.7 mmol) and Pd(dppf)Cl2*CH2Cl2 (764 mg, 1.04 mmol). The mixture was stirred at 80^ for 16 hours under a nitrogen atmosphere, cooled, diluted with water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, 135 ny-2699290 Attorney Docket No.26327-20012.40 and the residue purified by flash chromatography (15% to 50% ethyl acetate/hexane) to afford 2-(4-chloro-2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 1001, 2.2 g, 88% yield) as a white solid. GCMS calculated for C13H17BClFO3 = 286.1, found, 286.1. [0318] As shown in Step 2 of Scheme 11, to a degassed solution of 1,2,3,4,5-pentafluoro- 6-iodobenzene (1.7 g, 5.8 mmol) and 2-(4-chloro-2-fluoro-5-methoxyphenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (2.5 g, 8.7 mmol) in toluene (15 mL) and H2O (5 mL) were added K3PO4 (2.5 g, 11.6 mmol) and [1,^ƍ-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2, 379.1 mg, 0.58 mmol). The resulting mixture was stirred at 90^ for 16 hours under a nitrogen atmosphere, cooled, diluted with water, and the aqueous solution extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (9% to 15% ethyl acetate/hexane) to afford 4'-chloro-2,2',3,4,5,6-hexafluoro-5'-methoxy-1,1'- biphenyl (1.4 g) as a white solid. An aliguot of the crude product (100 mg) was purified by preparative reversed-phase HPLC (80% to 95% acetonitrile/water containing 10 mM NH4HCO3) to afford 4'-chloro-2,2',3,4,5,6-hexafluoro-5'-methoxy-1,1'-biphenyl (Compound 1, 50 mg, 50% yield) as a white solid: GCMS calculated for C13H5ClF6O = 325.9, found,326.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.2 Hz, 1H), 7.38 (d, J = 6.4 Hz, 1H), 3.87 (s, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í122.24, í140.48, í153.66, í162.26. [0319] As shown in Step 3 of Scheme 11, to a solution of 4'-chloro-2,2',3,4,5,6- hexafluoro-5'-methoxy-1,1'-biphenyl (1.3 g, 4.0 mmol) in DCM (13 mL) was added tribromoborane (4.9 g, 20.0 mmol) dropwise at 0^ under nitrogen atmosphere. The resulting mixture was stirred at 25^ for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched by the addition of water at 0^. The aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed- phase flash chromatography with (35% to 40% acetonitrile/water to afford 4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-ol (540 mg) as a white solid with 80% purity. A 100 mg aliquot was further purified by reversed-phase preparative-HPLC (55% to 60% acetonitrile/water containing 0.1% formic acid) to afford 4-chloro-2',3',4',5',6,6'-hexafluoro- [1,1'-biphenyl]-3-ol (Compound 2, 40 mg, 40% yield) as a white solid: MS (ESI) calculated 136 ny-2699290 Attorney Docket No.26327-20012.40 for C12H3ClF6O [Mí1]í = 310.9, found 310.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^ 1H), 7.61 (d, J = 9.4 Hz, 1H), 7.06 (d, J = 6.4 Hz, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^ í124.33, í141.17, í153.88, í162.12. Example 2. Preparation of methyl 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- yl)oxy)acetate (Compound 3) and 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- yl)oxy)acetic acid (Compound 4)
Figure imgf000139_0001
Scheme 12 [0320] As shown in Step 1 of Scheme 12, to a degassed mixture of 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-ol (200 mg, 0.64 mmol) and methyl 2-bromoacetate (117 mg, 0.76 mmol) in DMF (2 mL) was added K2CO3 (265 mg, 1.9 mmol) in portions. The mixture was stirred at 50^ for 16 hours under a nitrogen atmosphere, cooled, diluted with water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (35% to 45% acetonitrile) and further purified by reversed phase preparative-HPLC (55% to 67% acetonitrile/water containing 10 mM NH4HCO3) to afford methyl 2-((4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)oxy)acetate (Compound 3, 26 mg, 51% yield) as a white solid: GCMS calculated for C15H7ClF6O3 = 384.0, found 383.9; 1H-NMR (400 MHz, DMSO- d6^^į^^^^^^^G^^J = 9.2 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 4.96 (s, 2H), 3.70 (s, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í121.22, í140.41, í153.44, í162.13. [0321] As shown in Step 2 of Scheme 12, to a mixture of methyl 2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) acetate (50 mg, 0.13 mmol) in THF (0.9 mL) and H2O (0.3 mL) was added lithium hydroxide (16 mg, 0.39 mmol). The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The aqueous solution was acidified with formic acid to pH 3-4 and then was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed- 137 ny-2699290 Attorney Docket No.26327-20012.40 phase flash chromatography (15% to 50% acetonitrile in water) and further purified by reversed phase preparative-HPLC (50% to 58% acetonitrile in water containing 0.1% formic acid) to afford 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)acetic acid (Compound 4, 15 mg, 38% yield) as a white solid: MS (ESI) calculated for C14H5ClF6O3 [Mí1]í = 368.9, found 368.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 9.2 Hz, 1H), 7.32 (d, J = 6.4 Hz, 1H), 4.81 (s, 2H); 19F-NMR (376 MHz, DMSO-d6^^į^ í121.77, í140.42, í153.57, í162.20. [0322] Using the methyl 2-bromoacetate in a transformation similar to that described in Step 1 of Scheme 12, ethyl 2-({4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- yl}oxy)acetate (Compound 5, 90 mg, 69% yield) was prepared as a white solid: MS (ESI) calculated for C16H9ClF6O3 [M+1]+ = 399.0, found 398.9; 1H-NMR (400 MHz, DMSO-d6) į 7.77 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 4.95 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6) į í121.25, í140.47, í153.40, í162.14. [0323] Sulfonylation of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-ol (Compound 2) with triflic anhydride in DCM at 0^ to room temperature afforded 4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl trifluoromethanesulfonate (Compound 11) as a white solid: GCMS calculated for C13H2ClF9O3S = 443.9, found 443.9; 1H-NMR (400 MHz, chloroform-G^^į^^^^^^^G^^J = 8.4 Hz, 1H), 7.42 (d, J = 6.0 Hz, 1H); 19F-NMR (376 MHz, Chloroform-G^^į^í73.07, í108.68, í139.64, í151.16, í160.62. [0324] Reaction of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-ol (Compound 2) with cyclopentanol, PPh3 (1.5 equiv.) and diisopropyl azodicarboxylate (1.5 equiv.) at 0°C to room temperature afforded 4'-chloro-5'-(cyclopentyloxy)-2,2',3,4,5,6-hexafluoro-1,1'- biphenyl (Compound 12, 31 mg, 31% yield) as a white solid. GCMS calculated for C17H11ClF6O = 380.0, found 380.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.2 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 4.94 – 4.85 (m, 1H), 1.97 – 1.85 (m, 2H), 1.80 – 1.68 (m, 4H), 1.66 – 1.53 (m, 2H); 19F-NMR (377 MHz, DMSO-d6^^į^í122.24, í140.57, í153.83, í162.27. [0325] Reaction of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-ol (Compound 2) with methyl 2-bromo-2-methylpropanoate (2.0 equiv.) and Cs2CO3 (2.0 equiv.) in DMF at 80°C afforded methyl 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy)-2- methylpropanoate (Compound 19, 120 mg, 60% yield) as a white solid: GCMS calculated for C17H11ClF6O3 = 412.0, found 412.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.2 Hz, 138 ny-2699290 Attorney Docket No.26327-20012.40 1H), 7.11 (d, J = 6.4 Hz, 1H), 3.71 (s, 3H), 1.58 (s, 6H); 19F-NMR (376 MHz, DMSO-d6^^į^ í118.90, í141.06, í153.71, í162.22. Subsequent saponification of 2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy)-2-methylpropanoate with LiOH in THF/water at room temperature afforded 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'- biphenyl]-3-yl) oxy)-2-methylpropanoic acid (Compound 20, 40 mg, 51% yield) as a white solid: MS (ESI) calculated for C16H9ClF6O3 [Mí1]í = 397.0, found 396.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 9.2 Hz, 1H), 7.14 (d, J = 6.4 Hz, 1H), 1.56 (s, 6H); 19F-NMR (376 MHz, DMSO-d6) į^í119.48, í141.03, í153.50, í162.09. Example 3. Preparation of 4,6-dichloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-ol (Compound 6) and 2',4'-dichloro-2,3,4,5,6-pentafluoro-5'-(prop-2-yn-1-yloxy)-1,1'-biphenyl (Compound 7)
Figure imgf000141_0001
Scheme 13 [0326] As shown in Step 1 of Scheme 13, to a degassed mixture of 2,4-dichloro-5- methoxyphenylboronic acid (450 mg, 2.03 mmol) and iodopentafluorobenzene (719 mg, 2.44 mmol) in toluene (10 mL) and H2O (2 mL) at room temperature were added K3PO4 (865 mg, 4.1 mmol) and Pd(dtbpf)Cl2 (267 mg, 0.41 mmol). The resulting mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere, cooled, concentrated under reduced pressure, and the residue purified by silica gel chromatography (0% to 20% ethyl acetate/petroleum ether) to afford 2',4'-dichloro-2,3,4,5,6-pentafluoro-5'-methoxy-1,1'-biphenyl solid (Compound 1002, 400 mg, 57% yield) as a light-yellow solid: GCMS calculated for C13H5Cl2F5O = 342.0, found 342.1. 139 ny-2699290 Attorney Docket No.26327-20012.40 [0327] As shown in Step 2 of Scheme 13, to a stirred mixture of 2',4'-dichloro-2,3,4,5,6- pentafluoro-5'-methoxy-1,1'-biphenyl (380 mg, 1.10 mmol) in DCE (4 mL) was added boron tribromide (1387 mg, 5.54 mmol) dropwise at 0°C. The resulting mixture was stirred at 80°C for 4 hours under a nitrogen atmosphere, cooled, quenched with MeOH at 0°C, and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (10% to 60% acetonitrile in water) to afford 4,6-dichloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-ol (Compound 6, 25 mg, 7% yield) as a white solid: MS (ESI) calculated for C12H3Cl2F5O) [Mí1]í = 327.0, found 327.1; 1H-NMR (400 MHz, DMSO-d6^^į^ 7.75 (s, 1H), 7.06 (d, J = 1.4 Hz, 1H); 19F-NMR (377 MHz, DMSO-d6^^į^í140.76, í153.88, í162.21. [0328] As shown in Step 3 of Scheme 13, to a stirred mixture of 4,6-dichloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-ol (100 mg, 0.30 mmol) in DMF (3 mL) were added K2CO3 (126 mg, 0.91 mmol) and propargyl bromide (108 mg, 0.91 mmol). The resulting mixture was stirred at room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed phase flash chromatography (10% to 80% acetonitrile in water) to afford 2',4'-dichloro-2,3,4,5,6- pentafluoro-5'-(prop-2-yn-1-yloxy)-1,1'-biphenyl (Compound 7, 27 mg, 24% yield) as a white solid: GCMS calculated for C15H5Cl2F5O = 366.0, found 366.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^V^^^+^^^^^^^^^V^^^+^^ 4.97 (d, J = 2.4 Hz, 2H), 3.67 (s, 1H); 19F-NMR (377 MHz, DMSO-d6^^į^í140.11, í153.25, í162.08. [0329] Using 2-iodopropane in a transformation similar to that described in Step 3 of Scheme 13, 2',4'-dichloro-2,3,4,5,6-pentafluoro-5'-isopropoxy-1,1'-biphenyl (Compound 8) was also prepared: GCMS calculated for C15H9Cl2F5O = 370.0, found 370.0; 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^– 4.54 (m, 1H), 1.30 (d, J = 6.0 Hz, 6H); 19F NMR (376 MHz, DMSO-d6^^į^í^^^^^^^^í^^^^^^^^í^^^^^^^ Example 4. Preparation of ethyl 2-((3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- yl)oxy)pyridin-2-yl)oxy)acetate (Compound 9) and 2-((3-((4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2-yl)oxy)acetic acid (Compound 10) 140 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000143_0001
Scheme 14 [0330] As shown in Step 1 of Scheme 14, to a stirred solution of 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-ol (Compound 2, 540 mg, 1.73 mmol) in acetonitrile (4 mL) were added 3-fluoro-2-nitropyridine (246 mg, 1.73 mmol) and K2CO3 (287 mg, 2.07 mmol). The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere, cooled, diluted with water, and extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by silica gel chromatography (0% to 25% EtOAc/petroleum ether to afford 3-((4- chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)-2-nitropyridine (Compound 1003, 400 mg, 53% yield) as a yellow solid: MS (ESI) calc’d for C17H5ClF6N2O3 [M+1]+ = 435.0, found 435.0. [0331] As shown in Step 2 of Scheme 14, to a stirred solution of 3-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)-2-nitropyridine (600 mg, 1.38 mmol) in MeOH (7 mL) and water (1.4 mL) were added Fe powder (385 mg, 6.9 mmol) and NH4Cl (738 mg, 13.8 mmol). The resulting mixture was stirred at 80°C for 2 hours, filtered, the filter cake washed with MeOH, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 35% EtOAc/petroleum ether) to afford 3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- 141 ny-2699290 Attorney Docket No.26327-20012.40 yl)oxy)pyridin-2-amine (Compound 1004, 360 mg, 64% yield) as a brown oil: MS (ESI) calc’d for C17H7ClF6N2O [M+1]+ = 405.0, found 405.0. [0332] As shown in Step 3 of Scheme 14, to a stirred solution of 3-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2-amine (350 mg, 0.87 mmol) in H2SO4 (5%, 4 mL) was added NaNO2 (119 mg, 1.73 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was extracted with ethyl acetate, the combined organics dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by silica gel chromatography (0% to 10% MeOH/DCM) to afford 3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- yl)oxy)pyridin-2(1H)-one (Compound 1005, 160 mg, 46% yield) as a colorless oil: MS (ESI) calc’d for C17H6ClF6NO2 [M+1]+ = 406.0, found 406.0. [0333] As shown in Step 4 of Scheme 14, To a stirred solution of 3-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2(1H)-one (50 mg, 0.12 mmol) in DCE (3 mL) were added ethyl diazoacetate (70 mg, 0.62 mmol) and BF3.Et2O (catalytic, 2 drops). The resulting mixture was stirred at 85°C for 3 hours under a nitrogen atmosphere, diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative-TLC (1:10 MeOH/DCM) to afford ethyl 2-((3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2- yl)oxy)acetate (Compound 9, 30 mg, 25% yield) as a colorless oil: MS (ESI) calc’d for C21H12ClF6NO4 [M+1]+ = 492.0, found 492.2; 1H-NMR (400 MHz, DMSO-d6) į 8.03 – 7.94 (m, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.59 – 7.44 (m, 1H), 7.19 (d, J = 6.4 Hz, 1H), 7.14 – 7.01 (m, 1H), 4.95 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6) į í118.15, í140.51, í153.49, í162.20. [0334] As shown in Step 5 of Scheme 15, to a stirred solution of ethyl 2-((3-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)pyridin-2-yl)oxy)acetate (30 mg, 0.06 mmol) in THF (1 mL) and H2O (0.3 mL) was added LiOH (4.4 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 2 hours, acidified to pH 4 with 1M HCl, and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative-TLC (1:1 EtOAc/petroleum ether) to afford 2-((3-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'- biphenyl]-3-yl)oxy)pyridin-2-yl)oxy)acetic acid (Compound 10, 6.0 mg, 21% yield) as 142 ny-2699290 Attorney Docket No.26327-20012.40 a white solid. MS (ESI) calc’d for C19H8ClF6NO4 [M+1]+ = 464.0, found 464.1; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.93 (m, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.56 – 7.42 (m, 1H), 7.25 (d, J = 6.4 Hz, 1H), 7.09 – 6.98 (m, 1H), 4.76 (s, 2H); 19F-NMR (376 MHz, DMSO-d6) į^í118.52, í140.58, í153.66, í162.16. Example 5. Preparation of methyl ((S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]- 3-yl)oxy)propanoyl)-L-prolinate (Compound 13), methyl ((R)-2-((4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)oxy)propanoyl)-L-prolinate (Compound 14), ((S)-2-((4- chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)propanoyl)-L-proline (Compound 15), and ((R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)propanoyl)-L- proline (Compound 16)
Figure imgf000145_0001
Figure imgf000145_0002
Figure imgf000145_0003
Scheme 15 [0335] As shown in Step 1 of Scheme 15, to a stirred mixture of 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-ol (Compound 2, 300 mg, 0.94 mmol) in DMF (3 mL) were added methyl 2-bromopropanoate (193 mg, 1.15 mmol) and K2CO3 (265.2 mg, 1.92 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere, diluted with water, and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by silica gel column chromatography (0% to 20% ethyl acetate/petroleum ether) to afford methyl 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) 143 ny-2699290 Attorney Docket No.26327-20012.40 propanoate (Compound 1006, 310 mg, 80% yield) as a colorless oil: GCMS calculated for C16H9ClF6O3 = 398.0, found 398.0. [0336] As shown in Step 2 of Scheme 15, to a stirred mixture of methyl 2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoate (310 mg, 0.77 mmol) in THF (3 mL) and H2O (1 mL) was added LiOH (56 mg, 2.33 mmol). The resulting mixture was stirred at room temperature for 2 hours, acidified to pH 3 with 2M HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoic acid (Compound 1007, 280 mg, 93% yield) as a white solid: MS (ESI) calculated for C15H7ClF6O3 [Mí1]í = 383.1, found 383.1. [0337] As shown in Step 3 of Scheme 15, to a stirred mixture of 2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoic acid (210 mg, 0.54 mmol) in DMF (2 mL) were added methyl (2S)-pyrrolidine-2-carboxylate (8 mg, 0.06 mmol), HATU (270 mg, 0.71 mmol) and DIEA (212 mg, 1.63 mmol). The resulting mixture was stirred at room temperature for 2 hours, diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by silica gel chromatography (0% to 30% ethyl acetate in petroleum ether to afford a racemic mixture of methyl (2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-prolinate (220 mg, 81% yield) as a colorless oil: MS (ESI) calculated for C21H16ClF6NO4 [M+1] + = 496.1, found 496.3. [0338] As shown in Step 4 of Scheme 15, a racemic mixture of methyl (2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-prolinate (110 mg) was separated by preparative-chiral-HPLC using the following conditions - Column: CHIRALPAK IG, 2 x ^^^FP^^^^^P^^0RELOH^3KDVH^$^^hexane (0.2% formic acid), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Elution: 15% B over 16 minutes; Wave Length: 220/254 nm; RT1: 7.56 minutes; RT213.96 minutes to afford methyl ((S)-2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-prolinate (Compound 13, 24 mg, 21% yield) as a colorless oil with longer retention time on chiral HPLC: MS (ESI) calculated for C21H16ClF6NO4 [M+1]+ = 496.1, found 496.0; 1H-NMR (400 MHz, DMSO-d6) į^^^^^^– 7.71 (m, 1H), 7.28 – 7.18 (m, 1H), 5.27 – 4.92 (m, 1H), 4.71 – 4.27 (m, 1H), 3.82 – 144 ny-2699290 Attorney Docket No.26327-20012.40 3.71 (m, 1H), 3.60 (s, 2H), 3.58 – 3.38 (m, 2H), 2.24 – 2.06 (m, 1H), 2.02 – 1.76 (m, 3H), 1.51 – 1.41 (m, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í121.23, í140.48, í141.29, í153.35, í162.13 and methyl ((R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-prolinate (Compound 14, 34 mg, 30% yield) as a colorless oil with shorter retention time on chiral HPLC: MS (ESI) calculated for C21H16ClF6NO4 [M+1]+ = 496.1, found 496.1; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.74 (m, 1H), 7.20 – 7.02 (m, 1H), 5.15 – 5.10 (m, 1H), 4.36 – 4.33 (m, 1H), 3.77 – 3.71 (m, 1H), 3.55 – 3.51 (m, 1H), 3.44 (s, 3H), 2.16 – 1.78 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^ í121.23, í139.94, í141.15, í153.64, í162.61. [0339] As shown in Step 5 of Scheme 15, to a racemic mixture of methyl (2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-prolinate from Step 3 above (120 mg, 0.24 mmol) in DCE (2 mL) was added Me3SnOH (132 mg, 0.73 mmol). The resulting mixture was stirred at 65°C for 16 hours, cooled, diluted water, and acidified with 1M HCl pH 4. The aqueous solution was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a racemic mixture of (2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)propanoyl)-L-proline (60 mg, 48% yield) as a white solid: MS (ESI) calculated for C20H14ClF6NO4 [M+1]+ = 482.1, found 482.0. [0340] As shown in Step 6 of Scheme 15, a racemic mixture of (2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)propanoyl)-L-proline (85 mg) was separated by preparative-chiral-HPLC using the following conditions - Column: CHIRALPAK IG, 2 x ^^^FP^^^^^P^^Mobile Phase A: hexane (0.2% formic acid), Mobile Phase B: 1:1 EtOH/DCM; Flow rate: 20 mL/min; Elution: 10% B over 21 minutes; Wave Length: 220/254 nm; RT1: 9.88 minutes, RT2: 17.70 minutes; to afford ((S)-2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-proline (Compound 15, 43 mg, 49%) as a white solid with longer retention time on chiral HPLC: MS (ESI) calculated for C20H14ClF6NO4 [M+1]+ = 482.1, found 482.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^ (s, 1H), 7.74 – 7.69 (m, 1H), 7.15 (d, J = 6.0 Hz, 1H), 5.21 – 4.83 (m, 1H), 4.25 – 4.21 (m, 1H), 3.76 – 3.72 (m, 1H), 3.49 – 3.31 (m, 1H), 2.14 – 1.81 (m, 4H), 1.48 (d, J = 6.4 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í121.06, í140.31, í141.30, í153.47, í162.20 and ((R)-2- ((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl) oxy) propanoyl)-L-proline (Compound 16, 32 mg, 36% yield) as a white solid with shorter retention time on chiral 145 ny-2699290 Attorney Docket No.26327-20012.40 HPLC: MS (ESI) calculated for C20H14ClF6NO4 [M+1]+ = 482.1, found 482.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^– 7.75 (m, 1H), 7.08 (d, J = 6.0 Hz, 1H), 5.07 – 5.03 (m, 1H), 4.25 – 4.22 (m, 1H), 3.74 – 3.71 (m, 1H), 3.59 – 3.48 (m, 1H), 2.21 – 2.07 (m, 1H), 2.16 – 1.80 (m, 3H), 1.49 (d, J = 6.4 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í120.90, í139.47, í141.96, í153.87, í162.57. [0341] Reaction of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-ol (Compound 2, 300 mg, 0.94 mmol) in with methyl 2-bromopropanoate (1.2 equiv.) and K2CO3 (2.2 equiv.) in a manner similar to that described for Step 1 of Scheme 15 produced methyl 2-((4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)acetate. Subsequent saponification of methyl 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)acetate with LiOH in a manner similar to that described for Step 2 produced 2-((4-chloro-2',3',4',5',6,6'-hexafluoro- [1,1'-biphenyl]-3-yl)oxy)acetic acid. Reaction of 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'- biphenyl]-3-yl)oxy)acetic acid in a manner similar to that described for Step 3 produced methyl (2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)acetyl)-L-prolinate (Compound 17) as a white solid: MS (ESI) calculated for C20H14ClF6NO4 [M+1]+ = 482.0, found 482.0; 1H-NMR (400 MHz, methanol-d4^^į^^^^^^^P^^^+^^^^^^^^^G^^J = 6.4 Hz, 1H), 4.96 – 4.69 (m, 2H), 4.52 – 4.48 (m, 1H), 3.78 – 3.58 (m, 5H), 2.36 – 1.65 (m, 4H); 19F-NMR (400 MHz, methanol-d4^^į^í122.72, í142.01, í156.88, í165.20. Subsequent saponification of methyl (2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)oxy)acetyl)-L-prolinate with trimethylstannanol in DCE at 80°C produced (2-((4-chloro-2',3',4',5',6,6'-hexafluoro- [1,1'-biphenyl]-3-yl)oxy)acetyl)-L-proline (Compound 18) as a white solid: MS (ESI) calculated for C19H12ClF6NO4 [Mí1]í = 466.0, found 465.9; 1H-NMR (400 MHz, methanol- d4^^į^^^^^^^G^^J = 8.8 Hz, 1H), 7.18 – 7.16 (m, 1H), 4.98 – 4.90 (m, 2H), 4.69 – 4.46 (m, 1H), 3.78 – 3.50 (m, 2H), 2.39 – 1.76 (m, 4H); 19F-NMR (400 MHz, methanol-d4^^į^í122.72, í142.22, í156.85, í165.12. Example 6. Preparation of N-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)-N- (methylsulfonyl)methanesulfonamide (Compound 21) and N-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)methanesulfonamide (Compound 22). 146 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000149_0001
Scheme 16 [0342] As shown in Step 1 of Scheme 16, to a degassed solution of pentafluorobenzene (4.58 g, 27.3 mmol) in isopropyl acetate (30 mL) were added K2CO3 (3.77 g, 0.03 mmol), Sphos (1.12 g, 2.73 mmol), 2-bromo-1-fluoro-4-nitrobenzene (3.00 g, 13.64 mmol), and Pd(OAc)2 (0.31 g, 1.364 mmol). The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere, cooled, filtered, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 40% ethyl acetate in petroleum ether) to afford 2,2',3,4,5,6- hexafluoro-5'-nitro-1,1'-biphenyl (Compound 1008, 3.76 g, 89% yield) as a white solid: GCMS calculated for C12H3F6NO2 = 307.0, found 307.0; 1H-NMR (400 MHz, DMSO- d6^^į^^^^^^– 8.59 (m, 1H), 8.55 – 8.52 (m, 1H), 7.83 – 7.78 (m, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^í103.55, í140.53, í152.79, í161.95. [0343] As shown in Step 2 of Scheme 16, to a stirred solution of 2,2',3,4,5,6-hexafluoro- 5'-nitro-1,1'-biphenyl (5.5 g, 17.9 mmol) in EtOH (20 mL) was added a stirred solution of sodium hyposulfite (15.6 g, 90 mmol) in H2O (20 mL). The resulting mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography with (0% to 5% ethyl acetate in petroleum ether) to afford 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-amine (Compound 1009, 1.4 g, 26%) as a yellow solid: MS (ESI) calculated for C12H5F6N [Mí1]í = 276.0; found, 276.0. 147 ny-2699290 Attorney Docket No.26327-20012.40 [0344] As shown in Step 3 of Scheme 16, to a solution of 2',3',4',5',6,6'-hexafluoro-[1,1'- biphenyl]-3-amine (400 mg, 1.4 mmol) in AcOH (2 mL) and DCE (2 mL) was added isocyanuric chloride (100 mg, 0.43 mmol). The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was quenched with water and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 5% ethyl acetate in petroleum ether) to afford 4- chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-amine (Compound 1010, 60 mg, 10% yield) as a brown solid: MS (ESI) calculated for C12H4ClF6N [Mí1]í = 310.0; found, 309.9. [0345] As shown in Step 4 of Scheme 16, to a solution of 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-amine (40 mg, 0.12 mmol) and TEA (39 mg, 0.38 mmol) in DCM (1 mL) was added MsCl (22 mg, 0.19 mmol) at 0°C. The resulting mixture was stirred at room temperature for 16 hours, cooled, diluted with water, and the aqueous solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (5% to 75% acetonitrile in water) to afford N-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)-N- (methylsulfonyl)methanesulfonamide (Compound 21, 16 mg, 26% yield) as a white solid: GCMS calculated for C14H8ClF6NO4S2 = 466.9, found 466.9; 1H-NMR (400 MHz, DMSO- d6^^į^^^^^^^G^^J = 6.8Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 3.61 (s, 6H); 19F-NMR (376 MHz, DMSO-d6^^į^í107.68, í140.19, í152.70, í161.90. [0346] As shown in Step 5 of Scheme 16, to a solution of N-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)-N-(methylsulfonyl) methanesulfonamide (60 mg, 0.12 mmol) in THF (0.5 mL) was added 2 M NaOH (0.5 mL). The resulting mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography 5% to 85% acetonitrile in water) to afford N-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl) methanesulfonamide (Compound 22, 10.8 mg, 20% yield) as a white solid: MS (ESI) calculated for C13H6ClF6NO2S [Mí1]í = 388.0, found 388.0; 1H- NMR (400 MHz, DMSO-d6^^į^^^^^^^V^^^+^^^^^^^^– 7.86 (m, 1H), 7.69 – 7.64 (m, 1H), 3.09 (s, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í114.00, í140.70, í153.39, í162.04. 148 ny-2699290 Attorney Docket No.26327-20012.40 Example 7. Preparation of N-(4,6-dichloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3- yl)methanesulfonamide (Compound 23) and N-(4,6-dichloro-2',3',5',6'-tetrafluoro-4'- methoxy-[1,1'-biphenyl]-3-yl)methanesulfonamide (Compound 24)
Figure imgf000151_0001
[0347] As shown in Step 1 of Scheme 17, to a degassed solution of 2-bromo-1-chloro-4- nitrobenzene (5.0 g, 21.1 mmol) and pentafluorobenzene (1.4 g, 84.6 mmol) in isopropyl acetate (50 mL) were added K2CO3 (5.8 g, 42.3 mmol), Pd(OAc)2 (475 mg, 2.1 mmol) and SPhos (868 mg, 2.1 mmol) under nitrogen. The resulting solution was then stirred at 80°C for 2 hours under a nitrogen atmosphere, cooled, diluted with water, and the aqueous solution extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (5% to 60% acetonitrile in water) to afford 2'-chloro-2,3,4,5,6-pentafluoro-5'-nitro-1,1'-biphenyl (Compound 1011, 1.0 g, 13% yield) as a white solid: GCMS calculated for C12H3ClF5NO2 = 323.0, found 323.0. [0348] As shown in Step 2 of Scheme 17, to a solution of 2'-chloro-2,3,4,5,6-pentafluoro- 5'-nitro-1,1'-biphenyl (1.0 g, 3.1 mmol) in EtOH (5 mL) were added sodium hydrosulfite (2.7 g, 15.5 mmol) and water (10 mL). The resulting solution was stirred at 100°C for 4 hours, cooled, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 30% ethyl acetate in n-hexane) to 149 ny-2699290 Attorney Docket No.26327-20012.40 afford 6-chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-amine (Compound 1012, 600 mg, 59% yield) as a white solid: MS (ESI) calculated for C12H5ClF5N [Mí1]í = 292.0, found 292.0. [0349] As shown in Step 3 of Scheme 17, to a solution of 6-chloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-amine (200 mg, 0.68 mmol) in acetonitrile (2 mL) was added N-chlorosuccimide (73 mg, 0.54 mmol) at 20°C. The resulting solution was stirred at 80°C for 16 hours, cooled, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative-TLC (1:7 EtOAc/petroleum ether) to afford 4,6-dichloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-amine (Compound 1013, 100 mg, 40% yield) as a yellow oil: MS (ESI) calculated for C12H4Cl2F5N [Mí1]í = 326.0, found 326.0. [0350] As shown in Step 4 of Scheme 17, To a solution of 4,6-dichloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-amine (50 mg, 0.15 mmol) and TEA (46 mg, 0.45 mmol) in DCM (1 mL) was added MsCl (35 mg, 0.30 mmol) at 0°C. The resulting solution was stirred at 0°C for 2 hours, diluted with water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative-TLC with (1:3 EtOAc/petroleum ether) to afford N-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)-N-(methylsulfonyl)methanesulfonamide (Compound 23, 40 mg, 48% yield) as a white solid: MS (ESI) calculated for C14H8Cl2F5NO4S2 [M+1]+ = 484.0; found 484.0. [0351] As shown in Step 5 of Scheme 17, To a solution of N-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)-N-(methylsulfonyl)methanesulfonamide (25 mg, 0.05 mmol) in MeOH (0.5 mL), water (0.5 mL), and THF (0.5 mL) was added NaOH (4.1 mg, 0.10 mmol) at 20°C. The resulting solution was then stirred at 20°C for 2 hours, diluted with water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by achiral prep SFC using the following conditions - Column: DAICEL DCpak P4VP, 4.6 x 50 mm, 3 um; Mobile Phase A: water (1% 2 M NH3); Mobile Phase B: MeOH (1% 2 M NH3-MeOH); Flow rate: 2 mL/min; Elution with isocratic 5% B to afford N-(4,6-dichloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]- 3-yl)methanesulfonamide (Compound 23, 5.2 mg, 23% yield) as a white solid: MS (ESI) 150 ny-2699290 Attorney Docket No.26327-20012.40 calculated for C13H6Cl2F5NO2S [Mí1]í = 403.9, found 403.9; 1H-NMR (400 MHz, methanol-d4^^į^^^^^^^V^^^+^^^^^^^^^V^^1H), 3.08 (s, 3H); 19F-NMR (400 MHz, DMSO-d6^^į^ í142.14, í156.24, í164.79. [0352] Also isolated was N-(4,6-dichloro-2',3',5',6'-tetrafluoro-4'-methoxy-[1,1'-biphenyl]- 3-yl)methanesulfonamide (Compound 24, 2.0 mg, 10% yield) as a white solid: MS (ESI) calculated for C14H9Cl2F4NO3S [Mí1]í = 416.0, found 415.9; 1H-NMR (400 MHz, methanol-d4^^į^^^^^^^V^^1H), 7.60 (s, 1H), 4.16 (s, 3H), 3.05 (s, 3H); 19F-NMR (400 MHz, DMSO-d6^^į^í144.10, í167.21. Example 8. Preparation 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-amine (Compound 25)
Figure imgf000153_0001
Scheme 18 [0353] As shown in Step 1 of Scheme 18, to a stirred solution of 1,2,3,5- tetrafluorobenzene (5.00 g, 33.3 mmol) in THF (50 mL) was added n-BuLi (2.13 g, 33.3 mmol) dropwise at í78^ under nitrogen atmosphere. The resulting mixture was stirred at 25^ for 2 hours and I2 (4.31 g, 17.0 mmol) was added at -78^^^7KH^UHVXOW^VROXWLRQ^ZDV^ stirred at 25°C for additional 2 hour under a nitrogen atmosphere and the reaction quenched by the addition of saturated sodium thiosulfate aqueous solution at 0°C. The resulting mixture was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1,2,3,5-tetrafluoro-4-iodobenzene (Compound 1016, 7.00 g, 76%) as a brown oil: GCMS calc’d for C6HF4I = 275.9, found 276.0. 151 ny-2699290 Attorney Docket No.26327-20012.40 [0354] As shown in Step 2 of Scheme 18, to a stirred solution of (4-chloro-2- fluorophenyl)boronic acid (2.00 g, 10.3 mmol) and K3PO4 (4.37 g, 20.6 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added 1,2,3,5-tetrafluoro-4-iodobenzene (2.85 g, 10.3 mmol), XPhos (983 mg, 2.06 mmol) and XPhos Pd G3 (1.74 g, 2.06 mmol). The resulting mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere, cooled, diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by silica gel chromatography (0% to 5% dichloromethane in petroleum ether) to afford 4'-chloro-2,2',3,4,6-pentafluoro-1,1'-biphenyl (Compound 1017, 1.3 g, 45% yield) as a brown oil: GCMS calc’d for C12H4ClF5 = 278.0, found 278.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.54 (m, 3H), 7.54 – 7.44 (m, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^ í110.99, í115.69, í131.77, í134.11, í165.14. [0355] As shown in Step 3 of Scheme 18, to a stirred solution of 4'-chloro-2,2',3,4,6- pentafluoro-1,1'-biphenyl (480 mg, 1.72 mmol) in H2SO4 (2 mL) was added concentrated HNO3 ^^^^^PJ^^^^^^^PPRO^^^7KH^UHVXOWLQJ^VROXWLRQ^ZDV^VWLUUHG^DW^^^^^IRU^^^^Kours, cooled, diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 25% ethyl acetate in petroleum ether) to afford a mixture of 4'-chloro-2,2',3,4,6-pentafluoro-5'-nitro-1,1'-biphenyl and 4-chloro-2,2',3',4',6'-pentafluoro-3,5-dinitro-1,1'-biphenyl (500 mg) as a brown oil. A 200 mg aliquot was purified by preparative-HPLC using the following conditions - Column: Xselect CSH OBD Column 30 x 150 mm, 5 um; Mobile Phase A: water (0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 60 mL/min; Gradient: stepwise 51%, to 61% to 65% to afford 4'-chloro-2,2',3,4,6-pentafluoro-5'-nitro-1,1'-biphenyl (Compound 1018, 25 mg, 4% yield) as a white solid: GCMS calc’d for C12H3ClF5NO2 = 323.0, found 323.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^– 8.48 (m, 1H), 8.19 – 8.11 (m, 1H), 7.85 – 7.73 (m, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^í103.76, í115.25, í130.19, í133.39, í164.59. [0356] As shown in Step 4 of Scheme 18, to a stirred solution of a mixture of 4'-chloro- 2,2',3,4,6-pentafluoro-5'-nitro-1,1'-biphenyl and 4-chloro-2,2',3',4',6'-pentafluoro-3,5-dinitro- 1,1'-biphenyl (200 mg) in MeOH (2 mL) were added AcOH (0.2 mL) and Zn (101 mg, 1.54 mmol). The resulting solution was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was diluted by the addition of water and extracted with 152 ny-2699290 Attorney Docket No.26327-20012.40 dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative-HPLC with the following conditions: - Column: XBridge Prep OBD &^^^&ROXPQ^^^^^[^^^^^PP^^^^P^^0RELOH^3KDVH^$^^ZDWHU^^^^^PPRO^/^1+4HCO3), Mobile Phase B: acetonitrile; flow rate: 60 mL/min; Gradient: 45% B to 55% B in 10 min; to afford 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-amine (Compound 25, 45.1 mg, 49% yield) as a white solid: MS (ESI) calc’d for C12H5ClF5N >0í^@í = 292.0, found 291.8; 1H- NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.63 (m, 1H), 7.41 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 6.8 Hz, 1H), 5.46 (s, 2H); 19F-NMR (376 MHz, DMSO-d6^^į^í115.76, í129.11, í132.18, í134.23, í164.97. Example 9. Preparation of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-carboxylic acid (Compound 26)
Figure imgf000155_0001
Scheme 19 [0357] As shown in Step 1 of Scheme 19, to a degassed mixture of methyl 5-bromo-2- chloro-4-fluorobenzoate (860 mg, 3.22 mmol) in dioxane (10 mL) were added Pd(dppf)Cl2 (235 mg, 0.32 mmol), KOAc (473 mg, 4.82 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (1.2 g, 4.82 mmol). The resulting mixture was stirred at 80°C for 16 hours under an atmosphere of nitrogen, cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to afford methyl 2-chloro-4- fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Compound 1019, 1.0 g, 98% 153 ny-2699290 Attorney Docket No.26327-20012.40 yield) as a white solid: 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 6.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 1.32 (s, 12H). [0358] As shown in Step 2 of Scheme 19, to a degassed mixture of methyl 2-chloro-4- fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (1.0 g, 3.18 mmol) in dioxane (10 ml) and water (4 ml) were added K3PO4 (1.3 g, 6.36 mmol), APhos (150 mg, 0.35 mmol) and APhos Pd G3 (350 mg, 0.55 mmol) at room temperature under and atmosphere of nitrogen, followed by the addition of 1,2,3,4,5-pentafluoro-6-iodobenzene (1.4 g, 4.77 mmol). The resulting mixture was stirred at 100°C for 16 hours under nitrogen, cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (5% to 70% acetonitrile in water) to afford methyl 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]- 3-carboxylate (Compound 1020, 100 mg, 8% yield) as a yellow oil: 1H NMR (400 MHz, DMSO-d6^^į^^^^^^– 8.00 (m, 1H), 7.97 – 7.76 (m, 1H), 3.88 (d, J = 2.8 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í106.17, í140.70, í153.00, í161.89. [0359] As shown in Step 3 of Scheme 19, to a mixture of methyl 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-carboxylate (100 mg, 0.28 mmol) in tetrahydrofuran (0.9 ml) and water (0.3 ml) was added lithium hydroxide (20 mg, 0.85 mmol). The resulting mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure to remove tetrahydrofuran, acidified to pH 3 - 4 with citric acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (20% to 60% acetonitrile in water) to afford 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-carboxylic acid (Compound 26, 28 mg, 29% yield): MS (ESI) calculated for C13H3ClF6O2 [Mí1]í = 339.0; found, 338.9; 1H-NMR (400 MHz, DMSO-d6^^į^ 13.72 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^í107.26, í140.75, í153.21, í162.10. Example 10. Preparation of isopropyl 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- carboxylate (Compound 2) 154 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000157_0001
Scheme 20 [0360] As shown in Step 1 of Scheme 20, to a mixture of methyl 5-bromo-2-chloro-4- fluorobenzoate (1.0 g, 3.74 mmol) in tetrahydrofuran (10 mL) were added lithium hydroxide (269 mg, 11.22 mmol) and water (3 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure to remove tetrahydrofuran, acidified to pH 3 to 4 with formic acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced to afford 5-bromo-2-chloro-4-fluorobenzoic acid (Compound 1021, 900 mg) as a white solid: MS (ESI) calculated for C7H3BrClFO2 [Mí1]í = 252.9, found 252.7. This material was used in subsequent reactions without further purification. [0361] As shown in Step 2 of Scheme 20, to a solution of 5-bromo-2-chloro-4- fluorobenzoic acid (930 mg, 3.67 mmol) in DMF (10 mL) were added K2CO3 (1.01 g, 7.34 mmol) and 2-iodopropane (936 mg, 5.50 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to afford isopropyl 5-bromo-2-chloro-4-fluorobenzoate (Compound 1022, 830 mg, 76% yield) as a yellow oil: 1H-NMR (400 MHz, DMSO-d6^^į^ 8.13 – 8.10 (m, 1H), 7.79 – 7.76 (m, 1H), 5.20 – 5.10 (m, 1H), 1.36 – 1.31 (m, 6H). [0362] As shown in Step 3 of Scheme 20, to a degassed mixture of isopropyl 5-bromo-2- chloro-4-fluorobenzoate (550 mg, 1.86 mmol) in acetonitrile (6 mL) and water (1.2 mL) were 155 ny-2699290 Attorney Docket No.26327-20012.40 added K2CO3 (514 mg, 3.72 mmol), (perfluorophenyl)boronic acid (592 mg, 2.79 mmol) and Pd(dtbpf)Cl2 (243 mg, 0.37 mmol). The resulting mixture was stirred at 80°C for 16 hours under an atmosphere of nitrogen, cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (5% to 80% acetonitrile in water) to afford isopropyl 4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-carboxylate (Compound 27, 77 mg, 10% yield) as a reddish brown solid: GCMS calculated for C6H9ClF6O2 = 382.0, found 382.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 7.2 Hz, 1H), 7.92 (d, J = 9.6 Hz, 1H), 5.21 – 5.13 (m, 1H), 1.33 (d, J = 6.4 Hz, 6H); 19F-NMR (376 MHz, DMSO-d6^^į^í106.63, í140.64, í153.05, í161.97. Example 11. Preparation of 4-chloro-2',3',4',5',6,6'-hexafluoro-N- [isopropyl(methyl)sulfamoyl]-[1,1'-biphenyl]-3-carboxamide (Compound 28)
Figure imgf000158_0001
Scheme 21 [0363] As shown in Scheme 21, to a stirred solution of 4-chloro-2',3',4',5',6,6'-hexafluoro- [1,1'-biphenyl]-3-carboxylic acid (70 mg, 0.20 mmol) in DCM (1 mL) was added oxalyl chloride (130 mg, 1.03 mmol) and DMF (1 drop) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) and the solution added to a mixture of isopropyl(methyl)sulfamoylamine (47 mg, 0.30 mmol), TEA (104 mg, 1.03 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (1 mL) at 0°C. The resulting mixture was stirred at room temperature for additional 16 hours, cooled, diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative-HPLC [Column: Xselect CSH C18 OBD Column 30 x 150 mm, 5 micron; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: acetonitrile; 156 ny-2699290 Attorney Docket No.26327-20012.40 Flow rate: 60 mL/min; Gradient: 55% B to 70% B in 8 min, then 70% B] to afford 4-chloro- 2',3',4',5',6,6'-hexafluoro-N-[isopropyl(methyl)sulfamoyl]-[1,1'-biphenyl]-3-carboxamide (Compound 3, 20 mg, 20% yield) as a white solid: MS (ESI) calculated for C17H13ClF6N2O3S [Mí1]í = 473.0, found 472.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 9.6 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 4.17 – 4.07 (m, 1H), 2.83 (s, 3H), 1.15 (d, J = 6.8 Hz, 6H); 19F-NMR (400 MHz, DMSO-d6^^į í108.14, í140.38, í153.07, í162.01. [0364] Using the requisite sulfonamides in a procedure analogous to that described for the conversion of Compound 26 to Compound 28 in Scheme 21, the following compounds were also prepared: 4-chloro-N-(N,N-dimethylsulfamoyl)-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-carboxamide (Compound 29): MS (ESI) calculated for C15H9ClF6N2O3S [Mí1]í = 445.0, found 444.9; 1H- NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^– 7.85 (m, 2H), 2.89 (s, 6H); 19F-NMR (400 MHz, DMSO-d6^^į í108.68, í140.42, í153.07, í162.01; and 4-chloro-2',3',4',5',6,6'-hexafluoro-N-(isopropylsulfonyl)-[1,1'-biphenyl]-3-carboxamide (Compound 30): MS (ESI) calculated for C16H10ClF6NO3S [Mí1]í = 444.0; found 444.0; 1H- NMR (400 MHz, methanol-d4) į 7.75 (d, J = 7.2 Hz, 1H), 7.63 – 7.30 (m, 1H), 3.90 – 3.74 (m, 1H), 1.56 – 1.35 (m, 6H); 19F-NMR (376 MHz, methanol-d4) į í110.27, í142.45, í156.06, í164.72. Example 12. Preparation of methyl 4-chloro-2',3',5',6'-tetrafluoro-4'-methoxy-[1,1'-biphenyl]- 3-carboxylate (Compound 31), 4-chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-carboxylic acid (Compound 32), and 1-(allyloxy)-2-methyl-1-oxopropan-2-yl 4-chloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-carboxylate (Compound 33) 157 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000160_0001
Scheme 22 [0365] As shown in Step 1 of Scheme 22, to a degassed mixture of (4-chloro-3- (methoxycarbonyl)phenyl)boronic acid (1.0 g, 4.66 mmol) in dioxane (10 mL) and H2O (2 mL) were added 1,2,3,4,5-pentafluoro-6-iodobenzene (2.1 g, 6.99 mmol), Pd(dtbpf)Cl2 (0.3 g, 0.47 mmol) and K3PO4 (1.9 g, 9.33 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere. The solvents were removed under reduced pressure and the residue purified by silica gel chromatography (0% to 20% ethyl acetate in petroleum ether) to afford methyl 4-chloro-2',3',4',5',6'-pentafluoro-[1,1'- biphenyl]-3-carboxylate (Compound 31, 540 mg, 34% yield) as a yellow solid: GCMS calculated for C14H6ClF5O2 = 336.0, found 336.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í143.14, í155.03, í162.48. [0366] As shown in Step 2 of Scheme 22, to a stirred mixture of methyl 4-chloro- 2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-carboxylate (400 mg, 1.19 mmol) in THF (3 mL) and H2O (1 mL) was added lithium hydroxide (85 mg, 3.56 mmol). The resulting mixture was stirred at room temperature for 2 hours, diluted with water, acidified to pH 4 with 1M HCl, and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash - chromatography (35% to 70% acetonitrile in water) to afford 4-chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-carboxylic acid (Compound 32, 231 mg, 60% yield) as a white solid: MS (ESI) calculated for C13H4ClF5O2 [Mí1]í = 321.0, found 320.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^G^^J = 8.4 158 ny-2699290 Attorney Docket No.26327-20012.40 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^í143.20, í155.37, í162.54 [0367] As shown in Step 3 of Scheme 22, to a stirred mixture of 4-chloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-carboxylic acid (50 mg, 0.15 mmol) in acetonitrile (1 mL) were added allyl 2-hydroxy-2-methylpropanoate (22 mg, 0.15 mmol), dicyclohexylcarbodiimide (47.9 mg, 0.22 mmol) and DMAP (1.89 mg, 0.05 mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 hour under a nitrogen atmosphere, diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (5% to 60% acetonitrile in water) to afford 1-(allyloxy)-2-methyl-1-oxopropan-2-yl 4-chloro- 2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-carboxylate (Compound 33, 29 mg, 41% yield) as a white solid: MS (ESI) calculated for C20H14ClF5O4 [M+1]+ = 449.0, found 449.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^V^^^+^^^^^^^^– 7.75 (m, 2H), 5.93 – 5.78 (m, 1H), 5.36 – 5.21 (m, 2H), 4.65 (s, 2H), 1.66 (s, 6H); 19F-NMR (376 MHz, DMSO-d6^^į^-143.10, -155.07, - 162.45. Example 13. Preparation of 4-(difluoromethoxy)-N-(N,N-dimethylsulfamoyl)-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-carboxamide (Compound 34)
Figure imgf000161_0001
Figure imgf000161_0002
Scheme 23 159 ny-2699290 Attorney Docket No.26327-20012.40 [0368] As shown in Step 1 of Scheme 23, to a degassed mixture of methyl 5-bromo-4- fluoro-2-methoxybenzoate (2.0 g, 7.60 mmol) in isopropyl acetate (30 mL) were added pentafluorobenzene (2.6 g, 15.21 mmol), Pd(OAc)2 (0.2 g, 0.76 mmol) and SPhos (0.6 g, 1.52 mmol). The resulting mixture was stirred at 90°C for overnight under a nitrogen atmosphere, cooled, diluted with water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 15% ethyl acetate in petroleum ether) to afford methyl 2',3',4',5',6,6'- hexafluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylate (Compound 1023, 2.0 g, 75% yield) as a white solid: GCMS calculated for C15H8F6O3 = 350.0, found 350.0. [0369] As shown in Step 2 of Scheme 23, To a stirred mixture of methyl 2',3',4',5',6,6'- hexafluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylate (2.0 g, 5.71 mmol) in DCM (100 mL) was added boron tribromide (7.2 g, 28.56 mmol) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours, diluted with water at 0°C, and the aqueous solution extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by flash chromatography (0% to 15% ethyl acetate in petroleum ether) to afford methyl 2',3',4',5',6,6'-hexafluoro-4-hydroxy-[1,1'- biphenyl]-3-carboxylate (Compound 1024, 400 mg, 21% yield) as a yellow solid: GCMS calculated for C14H6F6O3 = 336.0, found 336.0. [0370] As shown in Step 3 of Scheme 23, to a degassed mixture of methyl 2',3',4',5',6,6'- hexafluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate (350 mg, 1.04 mmol) in acetonitrile (7 mL) and H2O (7 mL) were added difluoromethyl trifluoromethanesulfonate (625 mg, 3.12 mmol) and KOH (701 mg, 12.49 mmol). The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere, diluted with water, and the aqueous solution extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue purified by reversed-phase flash column chromatography (5% to 70% acetonitrile in water) to afford 4-(difluoromethoxy)-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-carboxylic acid (Compound 1025, 210 mg, 52% yield) as a white solid: MS (ESI) calculated for C14H4F8O3 [Mí1]í = 371.0, found 371.0. 160 ny-2699290 Attorney Docket No.26327-20012.40 [0371] As shown in Step 4 of Scheme 23, to a stirred solution of 4-(difluoromethoxy)- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-carboxylic acid (180 mg, 0.48 mmol) in DCM (5 mL) was added oxalyl chloride (92 mg, 0.73 mmol) and DMF (0.1 mL). The mixture was stirred at room temperature for 30 minutes under nitrogen then concentrated under reduced pressure to afford crude 4-(difluoromethoxy)-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- carbonyl chloride (200 mg). This material was taken up in DCM (5 mL) followed by the addition of DMAP (6 mg, 0.05 mmol) and TEA (244.7 mg, 2.42 mmol). The resulting mixture was stirred at room temperature for 2 hours, diluted with water, and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (5% to 50% acetonitrile in water) to afford 4-(difluoromethoxy)-N-(N,N-dimethylsulfamoyl)-2',3',4',5',6,6'-hexafluoro- [1,1'-biphenyl]-3-carboxamide (Compound 34, 80 mg, 35% yield) as a white solid: MS (ESI) calculated for C16H10F8N2O4S [Mí1]í = 477.0, found 476.9; 1H-NMR (400 MHz, DMSO-d6) į^^^^^^^^^V^^^+^^^^^^^^^G^^J = 7.6 Hz, 1H), 7.58 – 7.49 (d, J = 10.8 Hz, 1H), 7.40 (t, J = 72.4 Hz, 1H), 2.90 (s, 6H); 19F-NMR (377 MHz, DMSO-d6^^į^í83.19, í105.92, í140.59, í153.30, í162.09. Example 14. Preparation of isopropyl 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3- carboxylate (Compound 35), 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-carboxylic acid (Compound 36), and 4-chloro-N-(N,N-dimethylsulfamoyl)-2',3',4',6,6'-pentafluoro-[1,1'- biphenyl]-3-carboxamide (Compound 37)
Figure imgf000163_0001
Scheme 23 161 ny-2699290 Attorney Docket No.26327-20012.40 [0372] As shown in Step 1 of Scheme 23, to a solution of 2-chloro-4-fluorobenzoic acid (5.0 g, 28.6 mmol) in concentrated H2SO4 (50 mL) was added 1-iodopyrrolidine-2,5-dione (7.09 g, 31.5 mmol) in portions at 0°C. The resulting mixture was stirred at 25°C for 16 hours, filtered, and the filter cake was collected and dried under vacuum to afford 2-chloro-4- fluoro-5-iodobenzoic acid (Compound 1026, 7.00 g, 81% yield) as a white solid: MS (ESI) calculated for C7H3ClFIO2 [Mí1]í = 299.0, found 299.0. [0373] As shown in Step 2 of Scheme 23, to a solution of 2-chloro-4-fluoro-5-iodobenzoic acid (7.00 g, 23.3 mmol) in DMF (70 mL) were added 2-iodopropane (6.34 g, 37.3 mmol) and K2CO3 (6.44 g, 46.6 mmol) at 25°C. The resulting mixture was stirred at 25°C for 16 hours, diluted with water, and extracted with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (10% to 100% acetonitrile in water) to afford isopropyl 2-chloro-4-fluoro-5-iodobenzoate (Compound 1027, 5.40 g, 67% yield) as a yellow solid: GCMS calculated for C10H9ClFIO2 = 342.0, found 342.0. [0374] As shown in Step 3 of Scheme 23, to a degassed solution of isopropyl 2-chloro-4- fluoro-5-iodobenzoate (1.00 g, 2.92 mmol) in toluene (10 mL) and H2O (2 mL) were added 4,4,5,5-tetramethyl-2-(2,3,4,6-tetrafluorophenyl)-1,3,2-dioxaborolane (967 mg, 3.50 mmol), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II); tri-tert- butylphosphonium tetrafluoroborate (84 mg, 0.29 mmol) and K3PO4 (1239 mg, 5.84 mmol) at 25°C. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere, cooled, and the volatiles removed under reduced pressure. The residue was purified by preparative-HPLC using the following conditions: (Column: XBridge Prep C18 Column, 19 x ^^^^PP^^^^P^^mobile phase A: water (0.1% formic acid); mobile phase B: acetonitrile; flow rate: 25 mL/min; gradient: 65% B to 75% B) to afford isopropyl 4-chloro-2',3',4',6,6'- pentafluoro-[1,1'-biphenyl]-3-carboxylate (Compound 35, 400 mg, 37% yield) as a white solid: MS (ESI) calculated for C16H10ClF5O2 [M+1]+ = 365.0, found 365.0; 1H-NMR (400 MHz, DMSO-d6) į 8.03 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.77 – 7.69 (m, 1H), 5.23 – 5.13 (m, 1H), 1.34 (d, J = 6.0 Hz, 6H); 19F-NMR (377 MHz, DMSO-d6) į í106.79, í115.58, í131.03, í133.74, í164.79. [0375] As shown in Step 4 of Scheme 23, to a solution of isopropyl 4-chloro-2',3',4',6,6'- pentafluoro-[1,1'-biphenyl]-3-carboxylate (400 mg, 1.10 mmol) in THF (8 mL) and H2O (2 mL) was added lithium hydroxide (78 mg, 3.29 mmol). The resulting solution was stirred at 162 ny-2699290 Attorney Docket No.26327-20012.40 25°C for 16 hours, diluted with water, acidified to pH 4 with 1 M HCl, and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash column chromatography (0% to 50% acetonitrile/water) to afford 4-chloro-2',4',6,6'-tetrafluoro-[1,1'- biphenyl]-3-carboxylic acid (Compound 36, 120 mg, 35% yield) as a white solid: MS (ESI) calculated for C13H5ClF4O2 [Mí1]í = 321.0, found 321.0; 1H-NMR (400 MHz, DMSO-d6) į^ 13.69 (s, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.74 – 7.72 (m, 1H); 19F- NMR (377 MHz, DMSO-d6^^į^í115.57, í131.26, í133.78, í164.85. [0376] As shown in Step 5 of Scheme 23, to a solution of 4-chloro-2',3',4',6,6'- pentafluoro-[1,1'-biphenyl]-3-carboxylic acid (90 mg, 0.28 mmol) and DIEA (103 mg, 0.84 mmol) in DMF (2 mL) were added dimethyl(sulfamoyl)amine (69 mg, 0.56 mmol) and PyBOP (145 mg, 0.28 mmol). The resulting solution was stirred at 25°C for 2 hours, diluted with water, and extracted with CH2Cl2. The organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative- HPLC using the following conditions: (Column: Xselect CSH OBD Column 30 x 150 mm, 5 um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; Gradient: 56% B to 66% B in 10 min) to afford 4-chloro-N-(dimethylsulfamoyl)- 2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-carboxamide (Compound 37, 41 mg, 34% yield) as a white solid: MS (ESI) calculated for C15H10ClF5N2O3S >0í^@í = 427.0, found 427.0; 1H- NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^– 7.79 (m, 2H), 7.77 – 7.67 (m, 1H), 2.92 (s, 6H); 19F-NMR (377 MHz, DMSO-d6^^į^í108.45, í115.24, í131.12, í133.48, í164.88. Example 15. Preparation of ethyl (R)-2-chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'- biphenyl]-3-yl)propanoate (Compound 38), ethyl (S)-2-chloro-3-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (Compound 39), (R)-2-chloro-3-(4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (Compound 40), and (S)-2- chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (Compound 41) 163 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000166_0002
Figure imgf000166_0001
Scheme 24 [0377] As shown in Step 1 of Scheme 24, a mixture of 4-chloro-2-fluorophenylboronic acid (1.0 g, 5.73 mmol), iodopentafluorobenzene (2.0 g, 6.88 mmol), 1,1'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (0.37 g, 0.57 mmol) and K3PO4 (2.4 g, 11.47 mmol) in Toluene (10 mL) and H2O (2 mL) was stirred at 90°C for overnight under a nitrogen atmosphere, cooled, the volatiles removed under reduced pressure, and the residue purified by flash chromatography (0% to 10% ethyl acetate in petroleum ether) to afford 4'- chloro-2,2',3,4,5,6-hexafluoro-1,1'-biphenyl (Compound 1028, 800 mg, 47% yield) as a yellow oil: GCMS (ESI) calculated for C12H3ClF6 = 296.0, found 296.0. [0378] As shown in Step 2 of Scheme 24, to a solution of 4'-chloro-2,2',3,4,5,6- hexafluoro-1,1'-biphenyl (800 mg, 2.70 mmol) in H2SO4 (4 mL) was added HNO3 (510 mg, 8.08 mmol). The resulting mixture was stirred at room temperature for 3 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by flash chromatography (0% to 10% ethyl acetate in petroleum ether) to afford 4'-chloro-2,2',3,4,5,6-hexafluoro-5'-nitro-1,1'-biphenyl (Compound 1029, 670 mg, 73% yield) as a yellow solid: GCMS (ESI) calculated for C12H2F6ClNO2 = 341.0, found 341.0. 164 ny-2699290 Attorney Docket No.26327-20012.40 [0379] As shown in Step 3 of Scheme 24, to a solution of 4'-chloro-2,2',3,4,5,6- hexafluoro-5'-nitro-1,1'-biphenyl (670 mg, 2.20 mmol) in MeOH (10 mL) and AcOH (1 mL) was added and Zn dust (1.4 g, 22.0 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for overnight, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to afford 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-amine (Compound 1030, 400 mg, 65% yield) as a white solid: MS (ESI) calculated for C12H4ClF6N [M+1]+ = 312.0, found 312.0. [0380] As shown in Step 4 of Scheme 24, to a mixture of 4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-amine (400 mg, 1.28 mmol) and ethyl acrylate (218 mg, 2.18 mmol) in acetonitrile (5 mL) were added CuCl2 (207 mg, 1.54 mmol) and t-BuONO (172 mg, 1.66 mmol). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to afford a racemic mixture of ethyl 2-chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (260 mg, 47% yield) as a yellow oil: GCMS (ESI) calculated for C17H10Cl2F6O2 = 430.1, found 430.1. [0381] As shown in Step 5 of Scheme 24, the racemic mixture of ethyl 2-chloro-3-(4- chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (100 mg) was separated by preparative CHIRAL-HPLC using the following conditions: [Column: CHIRALPAK AD-3, 4.6 x ^^^^PP^^^^P^^mobile phase: hexane/EtOH = 95: 5; flow rate: 1 mL/min] to afford ethyl (S)-2-chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (Compound 39, 30 mg, 30% yield) as a yellow oil with shorter retention time: GCMS (ESI) calculated for C17H10Cl2F6O2 = 430.0, found 430.0; 1H-NMR (400 MHz, methanol-d4^^į^^^53 – 7.51 (m, 2H), 4.71 (t, J = 7.6 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.56 (dd, J = 14.0, 7.2 Hz, 1H), 3.39 (dd, J = 14.4, 8.0 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H); 19F-NMR (377 MHz, methanol- d4^^į^í114.31, í142.67, í156.41, í164.85; and ethyl (R)-2-chloro-3-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (Compound 38, 30 mg, 30% yield) as a yellow oil with longer retention time on chiral HPLC: GCMS (ESI) calculated for C17H10Cl2F6O2 = 430.0, found 430.0; 1H-NMR (400 MHz, methanol-d4^^į^^^^^^– 7.51 (m, 2H), 4.71 (t, J = 7.6 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.56 (dd, J = 14.0, 7.2 Hz, 1H), 3.39 (dd, J = 14.4, 8.0 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H); 19F-NMR (377 MHz, methanol-d4^^į^í114.32, í142.67, í156.42, í164.85. 165 ny-2699290 Attorney Docket No.26327-20012.40 [0382] As shown in Step 6 of Scheme 24, the racemic mixture of ethyl 2-chloro-3-(4- chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (100 mg, 0.24 mmol), produced as indicated in Step 4, and LiOH*H2O (20 mg, 0.48 mmol) in THF (1.5 mL) and H2O (1.5 mL) was stirred at room temperature for 2 hour under a nitrogen atmosphere, diluted with water, and acidified with 1M HCl to pH 4, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 50% ethyl acetate in petroleum ether) to afford a racemic mixture of 2-chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (80 mg, 86% yield) as a yellow solid: MS (ESI) calculated for C15H6Cl2F6O2 [Mí1]í = 401.0, found 401.0. [0383] As shown in Step 7 of Scheme 24, the racemic mixture of 2-chloro-3-(4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (80 mg) was separated by prep chiral-HPLC with the following conditions: [Column: CHIRALPAK IG-3, 4.6 x 50mm, 3.0 μm; mobile phase: hexane (0.2% FA ) : (1:1 MeOH/EtOH) = 95: 5; flow rate: 1 mL/min) to afford (S)-2-chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (Compound 41, 15 mg, 38% yield) as a yellow solid with shorter retention time: MS (ESI) calculated for C15H6Cl2F6O2 [Mí1]í = 401.0, found 400.8; 1H-NMR (400 MHz, DMSO-d6^^į^ 13.58 (br, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 4.73 (dd, J = 9.2, 5.6 Hz, 1H), 3.52 (dd, J = 14.6, 5.6 Hz, 1H), 3.29 – 3.27 (m, 1H); 19F-NMR (377 MHz, DMSO-d6^^į^ í113.29, í140.75, í153.25, í161.98; and (R)-2-chloro-3-(4-chloro-2',3',4',5',6,6'-hexafluoro- [1,1'-biphenyl]-3-yl)propanoic acid (Compound 40, 14 mg, 35.7%) as a yellow solid with longer retention time: MS (ESI) calculated for C15H6Cl2F6O2 [Mí1]í = 401.0, found 400.8; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^EU^^^+^^^^^^^^^G^^J = 9.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 4.74 (dd, J = 9.2, 5.6 Hz, 1H), 3.52 (d, J = 14.6, 5.6 Hz, 1H), 3.29 – 3.27 (m, 1H); 19F-NMR (377 MHz, DMSO-d6^^į^í113.28, í140.75, í153.25, í161.98. Example 16. Preparation of ethyl (Z)-2-chloro-3-(4-chloro-2',3',4',5',6'-pentafluoro-[1,1'- biphenyl]-3-yl)acrylate (Compound 42), (Z)-2-chloro-3-(4-chloro-2',3',4',5',6'-pentafluoro- [1,1'-biphenyl]-3-yl)acrylic acid (Compound 43), and (Z)-2-chloro-3-(4-chloro-2',3',5',6'- tetrafluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)acrylic acid (Compound 44) 166 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000169_0001
Scheme 25 [0384] As shown in Step 1 of Scheme 25, to a stirred mixture of 5-bromo-2- chlorobenzaldehyde (3.0 g, 14.2 mmol) in dioxane (40 mL) were added 4,4,5,5-tetramethyl- 2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.2 g, 41.01 mmol), KOAc (2.7 g, 27.34 mmol) and Pd(dppf)Cl2 (1.0 g, 1.36 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere, cooled, the volatiles removed under reduced pressure, and the residue purified by flash chromatography (0% to 10% ethyl acetate in petroleum ether) to afford 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzaldehyde (Compound 1031, 1.0 g, 80% purity) as a yellow solid: GCMS calculated for C13H16BClO3 = 266.1, found 266.0. This material was used as in subsequent reactions without further purification. [0385] As shown in Step 2 of Scheme 25, to a stirred mixture of 2-chloro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.0 g, 3.60 mmol) in toluene (20 mL) and H2O (4 mL) were added iodopentafluorobenzene (1.3 g, 4.32 mmol), K3PO4 (1.5 g, 7.20 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.5 g, 0.72 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at 90°C overnight under nitrogen, cooled, the volatiles removed under reduced pressure, and the residue purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to afford 4-chloro- 167 ny-2699290 Attorney Docket No.26327-20012.40 2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-carbaldehyde (Compound 1032, 500 mg, 43% yield) as a light-yellow solid: GCMS calculated for C13H4ClF5O = 306.0, found 306.0. [0386] As shown in Step 3 of Scheme 25, to a stirred mixture of 4-chloro-2',3',4',5',6'- pentafluoro-[1,1'-biphenyl]-3-carbaldehyde (200 mg, 0.65 mmol) and methyl chloroacetate (92 mg, 0.84 mmol) in DCM (4 mL) was added triethylamine (330 mg, 3.26 mmol). The resulting mixture was stirred at room temperature overnight under an atmosphere of nitrogen atmosphere, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (10% to 80% acetonitrile in water) to afford ethyl (Z)-2-chloro-3-(4- chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-yl)acrylate (Compound 42, 26 mg, 9.3% yield) as a white solid: MS (ESI) calculated for C17H9Cl2F5O2 [M+1]+ = 411.0, found 410.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^V^^^+^^^^^^^^^G^^J = 2.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.0, 2.0 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 19F- NMR (377 MHz, DMSO-d6^^į^í143.30, í155.18, í162.37. [0387] As shown in Step 4 of Scheme 25, to a stirred solution of ethyl (Z)-2-chloro-3-(4- chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-yl)acrylate (25 mg, 0.06 mmol) in THF (1 mL) and H2O (1 mL) was added LiOH (5 mg, 0.12 mmol). The resulting mixture was stirred at room temperature overnight under an atmosphere of nitrogen atmosphere, acidified to pH 4 with citric acid, concentrated under reduced pressure, and the residue purified by reversed- phase flash chromatography (10% to 80% acetonitrile in water) to afford (Z)-2-chloro-3-(4- chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-yl)acrylic acid (Compound 43, 6 mg, 24% yield) as a white solid: MS (ESI) calculated for C15H5Cl2F5O2 [Mí1]í = 381.0, found 380.8; 1H-NMR (400 MHz, methanol-d4^^į^^^^^^– 7.93 (m, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H); 19F-NMR (377 MHz, methanol-d4^^į^í145.32, í158.31, í165.17. [0388] As shown in Step 5 of Scheme 25, To a stirred mixture of ethyl (Z)-2-chloro-3-(4- chloro-2',3',4',5',6'-pentafluoro-[1,1'-biphenyl]-3-yl)acrylate (45 mg, 0.10 mmol) in THF (1.5 mL) and MeOH (1.5 mL) was added LiOH (9.1mg, 0.21 mmol). The resulting mixture was stirred at room temperature overnight under an atmosphere of nitrogen atmosphere, was acidified to pH ~4 with citric acid, concentrated under reduced pressure, and the residue purified by purified by reversed-phase flash chromatography (10% to 50% methanol in water) to afford (Z)-2-chloro-3-(4-chloro-2',3',5',6'-tetrafluoro-4'-methoxy-[1,1'-biphenyl]-3- yl)acrylic acid (Compound 44, 7 mg, 15% yield) as a white solid: MS (ESI) calculated for C16H8Cl2F4O3 [Mí1]í = 393.0, found 392.9; 1H-NMR (400 MHz, methanol-d4^^į^^^^^^– 7.99 168 ny-2699290 Attorney Docket No.26327-20012.40 (m, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.48 – 7.46 (m, 1H), 4.14 (s, 3H); 19F-NMR (377 MHz, methanol-d4^^į^í147.29, í160.20. Example 17. Preparation of methyl (E)-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]- 3-yl)acrylate (Compound 45), (E)-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- yl)acrylic acid (Compound 46), methyl 3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]- 3-yl)propanoate (Compound 47), and 3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3- yl)propanoic acid (Compound 48),
Figure imgf000171_0001
Scheme 26 [0389] As shown in Step 1 of Scheme 26, to a solution of 4'-chloro-2,2',3,4,5,6- hexafluoro-1,1'-biphenyl (200 mg, 0.67 mmol) in CF3SO3H (4 mL) was added N- bromosuccinimide (120 mg, 0.67 mmol) in portions at 0°C. The resulting mixture was stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase flash chromatography (5% to 75% acetonitrile in water) to afford 5'-bromo-4'-chloro-2,2',3,4,5,6- hexafluoro-1,1'-biphenyl (Compound 1033, 110 mg, 42% yield) as a white solid: GCMS calculated for C12H2BrClF6 = 373.9/375.9, found 373.9/375.9; 1H-NMR (400 MHz, DMSO- d6^^į^^^^^^^G^^J = 7.2 Hz, 1H), 8.00 (d, J = 9.6 Hz,1H); 19F-NMR (377 MHz, DMSO-d6^^į^ í112.35, í140.47, í152.84, í161.96. [0390] As shown in Step 2 of Scheme 26, to a solution of 5'-bromo-4'-chloro-2,2',3,4,5,6- hexafluoro-1,1'-biphenyl (200 mg, 0.53 mmol), methyl acrylate (138 mg, 1.60 mmol) and TEA (270 mg, 2.67 mmol) in DMF (3 mL) were added 1,3- 169 ny-2699290 Attorney Docket No.26327-20012.40 bis(diphenylphosphino)propane (dppp, 33 mg, 0.08 mmol) and Pd(AcO)2 (12 mg, 0.05 mmol) under an atmosphere of nitrogen. The mixture was stirred at 110°C for 16 hours under nitrogen, cooled, diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to afford methyl (E)-3-(4- chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)acrylate (Compound 45, 27 mg, 13% yield) as a white solid: GCMS calc’d for C16H7ClF6O2 = 380.0; found 380.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 7.6 Hz, 1H), 7.95 – 7.81 (m, 2H), 6.78 (d, J = 16.0 Hz, 1H), 3.76 (s, 3H); 19F-NMR (377 MHz, DMSO-d6^^į^í108.83, í140.28, í152.85, í162.00. [0391] As shown in Step 3 of Scheme 26, to a mixture of methyl (E)-3-(4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)acrylate (150 mg, 0.39 mmol) in THF (2 mL) and H2O (0.5 mL) was added and lithium hydroxide (38 mg, 1.58 mmol). The resulting mixture was stirred at room temperature for 16 hours, diluted with water, acidified with 1M HCl to pH 4, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 20% ethyl acetate in n- hexane) to afford (E)-3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)acrylic acid (Compound 46, 30 mg, 21% yield) as a white solid: MS (ESI) calc’d for C15H5ClF6O2 [Mí1]í = 365.0, found 364.9; 1H-NMR (400 MHz, DMSO-d6) į 12.61 (s, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.00 – 7.70 (m, 2H), 6.75 – 6.46 (m, 1H); 19F-NMR (377 MHz, DMSO-d6) į í109.30, í140.32, í153.10, í162.05. [0392] As shown in Step 4 of Scheme 26, to a solution of methyl (E)-3-(4-chloro- 2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)acrylate (100 mg, 0.26 mmol) in MeOH (2 mL) was added dry Pd/C (10 mg) under an atmosphere of nitrogen. The atmosphere was replaced with hydrogen and the mixture = stirred at room temperature for 16 hours under hydrogen (2 atm), filtered, the filtrate collected and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (30% to 90% acetonitrile in water) to afford methyl 3-(4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (Compound 47, 17 mg, 12% yield) as a colorless oil: GCMS calc’d for C16H9ClF6O2 = 382.0, found 382.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.66 (m, 1H), 7.59 (d, J = 7.6 170 ny-2699290 Attorney Docket No.26327-20012.40 Hz, 1H), 3.59 (s, 3H), 3.08 – 2.94 (m, 2H), 2.79 – 2.59 (m, 2H); 19F-NMR (377 MHz, DMSO-d6^^į^í114.52, í140.91, í153.48, í162.08. [0393] As shown in Step 5 of Scheme 26, A mixture of methyl 3-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)propanoate (60 mg, 0.15 mmol) and lithium hydroxide (15 mg, 0.63 mmol) in THF (3 mL) and H2O (0.75 mL) was stirred at room temperature for 16 hours, acidified with 1M HCl to pH ~ 5, diluted by water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (10% to 90% acetonitrile in water) to afford 3-(4-chloro-2',3',4',5',6,6'- hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (Compound 48, 30 mg, 51% yield) as a white solid: MS (ESI) calc’d for C15H7ClF6O2 >0í^@í = 367.0, found 367.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 9.6 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 3.02 – 2.87 (m, 2H), 2.68 – 2.55 (m, 2H); 19F-NMR (377 MHz, DMSO-d6^^į^í^^^^^^^^í^^^^^^^^í^^^^^^^ í^^^^^^. Example 18. Preparation of 2-nitro-5-(perfluorophenoxy)benzoic acid (Compound 49)
Figure imgf000173_0001
Scheme 27 [0394] As shown in Step 1 of Scheme 27, to a mixture of pentafluorophenol (924 mg, 5.0 mmol) in DMF (10 mL) was added NaH (301 mg- 60% by weight in mineral oil, 7.5 mmol) in portions at 0°C under nitrogen. The resulting mixture was stirred at 0°C for 20 min, followed by the dropwise addition of a solution of methyl 5-fluoro-2-nitrobenzoate (1.00 g, 5.02 mmol) in DMF (2 mL) at 0°C. The resulting mixture was allowed to warm to 80°C and stirred for additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0-5% ethyl acetate in petroleum ether) to afford methyl 2- 171 ny-2699290 Attorney Docket No.26327-20012.40 nitro-5-(2,3,4,5,6-pentafluorophenoxy)benzoate (Compound 1034, 500 mg, 25% yield) as a yellow solid: GCMS calculated for C14H6F5NO5 = 363.0, found 363.0. [0395] As shown in Step 2 of Scheme 27, to a mixture of methyl 2-nitro-5- (perfluorophenoxy) benzoate (500 mg, 1.38 mmol) in THF (4.5 mL) and water (1.5 mL) was added LiOH (174 mg, 4.15 mmol). The resulting mixture was stirred at room temperature for 16 hours, diluted by the addition of water, and acidified to pH 5 with formic acid. The aqueous solution was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography (10 to 42% acetonitrile in water) to afford 2-nitro-5-(perfluorophenoxy)benzoic acid (Compound 49, 250 mg, 52% yield) as a white solid: 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^ 8.13 (d, J = 9.0 Hz, 1H), 7.75 – 7.28 (m, 2H); 19F-NMR (376 MHz, DMSO-d6^^į^í154.75, í159.50, í161.84. Example 19. Preparation of N-(methylsulfonyl)-2-nitro-5-(perfluorophenoxy)benzamide (Compound 50)
Figure imgf000174_0001
Scheme 28 [0396] As shown in Scheme 28, to a stirred solution of 2-nitro-5-(2,3,4,5,6- pentafluorophenoxy)benzoic acid (100 mg, 0.28 mmol) in DCM (2 mL) were added oxalyl chloride (55 mg, 0.42 mmol) and DMF (2 drops) and the reaction mixture was stirred for 10 minutes at room temperature under a nitrogen atmosphere. To the mixture was added a solution of methanesulfonamide (54 mg, 0.57 mmol) and triethylamine (144 mg, 1.43 mmol) in DCM (2 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour, diluted with water, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (5 to 60% acetonitrile in water, 0.1% FA) to afford N-(methylsulfonyl)-2- nitro-5-(perfluorophenoxy)benzamide (Compound 50, 40 mg, 32% yield) as a white solid: 172 ny-2699290 Attorney Docket No.26327-20012.40 MS (ESI) calculated for C14H7F5N2O6S [Mí1]í = 425.0 found, 425.1; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+), 8.26 (d, J = 9.2 Hz, 1H), 7.58 – 7.52 (m, 2H); 19F-NMR (400 MHz, DMSO-d6^^į^í154.65, í159.38, í161.84. [0397] Reacting the appropriate amine or alcohol to the intermediary acyl chloride in a transformation similar to that described in Scheme 28, the following compounds were also prepared: N-(ethylsulfonyl)-2-nitro-5-(perfluorophenoxy)benzamide (Compound 53): MS (ESI) calculated for C15H9F5N2O6S [Mí1]í = 439.0, found 439.3; 1H-NMR (400 MHz, DMSO-d6) į^^^^^^^^V^^^+^^^^^^^^^G^^J = 9.0 Hz, 1H), 7.64 – 7.36 (m, 2H), 3.46 (d, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í154.65, í159.40, í161.87; and 2-ethoxy-2-oxoethyl 2-nitro-5-(perfluorophenoxy)benzoate (Compound 54): GCMS (ESI) calculated for C17H10F5NO7 = 435.0, found 435.0; 1H-NMR (400 MHz, chloroform-G^^į^^^^^^ (d, J = 9.2 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.21 – 7.14 (m, 1H), 4.87 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í152.82, í156.65, í160.14. Example 20. Preparation of 1-ethoxy-1-oxopropan-2-yl 2-chloro-5- (perfluorophenoxy)benzoate (Compound 51)
Figure imgf000175_0001
Scheme 29 [0398] As shown in Step 1 of Scheme 29, to a stirred solution of methyl 2-chloro-5- hydroxybenzoate (500 mg, 2.65 mmol) in DMF (5 mL) was added NaH (159.2 mg - 60% by weight in mineral oil 3.98 mmol) in portions at 0°C under a nitrogen atmosphere. The 173 ny-2699290 Attorney Docket No.26327-20012.40 resulting mixture was stirred at 0°C for 30 minutes, followed by the addition of hexafluorobenzene (987 mg, 5.30 mmol) at 0°C. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (5% to 70% acetonitrile in water) to afford methyl 2-chloro-5-(perfluorophenoxy)benzoate (Compound 1035, 360 mg, 40% yield) as a white solid: GCMS calculated for C14H6ClF5O3 = 352.0, found 352.0. [0399] As shown in Step 2 of Scheme 29, to a solution of methyl 2-chloro-5- (perfluorophenoxy)benzoate (310 mg, 0.88 mmol) in THF (3 mL) and H2O (1 mL) was added LiOH (111 mg, 2.64 mmol) at 25°C. The resulting mixture was stirred at 25°C for 3 hours, diluted with water, and acidified to pH 3 with citric acid. The aqueous solution was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-chloro-5- (perfluorophenoxy)benzoic acid (Compound 1036, 300 mg, crude) as a yellow solid. MS (ESI) calculated for C13H4ClF5O3 [Mí1]í = 337.0, found 337.1. This material was used in subsequent reactions as is. [0400] As shown in Step 3 of Scheme 29, to a stirred mixture of 2-chloro-5- (perfluorophenoxy)benzoic acid (50 mg, 0.15 mmol), ethyl 2-hydroxypropanoate (26 mg, 0.22 mmol) and PPh3 (58 mg, 0.22 mmol) in THF (1 mL) was added diisopropylazodicarboxylate (45 mg, 0.22 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for additional 3 hours under nitrogen. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative-TLC (1:5 EtOAc/petroleum ether) to afford 1-ethoxy-1-oxopropan-2-yl 2-chloro-5-(perfluorophenoxy)benzoate (Compound 51, 35.0 mg, 61%) as a colorless oil. MS (ESI) calculated for C18H12ClF5O5 [M+1]+ = 439.0. found 438.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.60 (m, 2H), 7.43 – 7.38 (m, 1H), 5.27 (q, J = 6.8 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 19F-NMR (376 MHz, DMSO-G^^^į^í154.97, í160.09, í162.13. Example 21. Preparation of 1,2,3,4,5-pentafluoro-6-(3-methoxy-4-nitrophenoxy)benzene (Compound 4) 174 ny-2699290 Attorney Docket No.26327-20012.40 Scheme 30 [0401] As shown in Scheme 30, to a mixture of methyl 3-methoxy-4-nitrophenol (500 mg, 2.96 mmol) in DMF (4 mL) was added NaH (236 mg - 60% by weight in mineral oil, 5.91 mmol) in portions under nitrogen. The resulting mixture was stirred at 0°C for 30 minutes, followed by the addition of hexafluorobenzene (2.2 g, 11.8 mmol) dropwise at 0°C under nitrogen. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The mixture was quenched by the addition of water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (0 to 60% ethyl acetate in petroleum ether) to afford 1,2,3,4,5-pentafluoro-6- (3-methoxy-4-nitrophenoxy)benzene (Compound 52, 700 mg, 71% yield) as a white solid: MS (ESI) calculated for C13H6F5NO4 [M+1]+ = 336.0; found, 336.1; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.2 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.83 – 6.80 (m, 1H), 3.94 (s, 3H); 19F-NMR (400 MHz, DMSO-d6^^į^í154.86, í159.76, í162.10. Example 22. Preparation of 2-nitro-5-(2,3,4,5,6-pentafluorophenoxy)phenol (Compound 55) and 1-(3-ethoxy-4-nitrophenoxy)-2,3,4,5,6-pentafluorobenzene (Compound 56)
Figure imgf000177_0001
Scheme 31 [0402] As shown in Step 1 of Scheme 31, to a stirred mixture of 1,2,3,4,5-pentafluoro-6- (3-methoxy-4-nitrophenoxy)benzene (350 mg, 1.044 mmol) in DCM (5 mL) was added BBr3 (2616 mg, 10.44 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers 175 ny-2699290 Attorney Docket No.26327-20012.40 were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by silica gel chromatography (0 to 10% ethyl acetate in petroleum ether to afford 2-nitro-5-(2,3,4,5,6-pentafluorophenoxy)phenol (Compound 55, 270 mg, 80.5% yield) as a yellow solid: MS (ESI) calculated for C12H4F5NO4 [Mí1]í = 320.0, found, 320.2; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.88 (m, 1H), 6.47 – 6.40 (m, 2H); 19F NMR (377 MHz, DMSO-d6^^į^í155.15, í159.88, í162.33. [0403] As shown in Step 2 of Scheme 31, to a stirred mixture of 2-nitro-5-(2,3,4,5,6- pentafluorophenoxy)phenol (150 mg, 0.46 mmol) in DMF (5 mL) were added K2CO3 (127 mg, 0.92 mmol) and ethyl iodide (109 mg, 0.70 mmol). The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash chromatography (10% to 80% acetonitrile in water) to afford 1-(3-ethoxy-4-nitrophenoxy)-2,3,4,5,6-pentafluorobenzene (Compound 56, 84 mg, 51% yield) as a white solid: MS (ESI) calculated for C14H8F5NO4 [M+1]+ = 350.0, found, 350.1; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.2 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 9.2, 2.4 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 19F-NMR (377 MHz, DMSO-d6^^į^í154.93, í159.86, í162.09. Example 23. Preparation of 2-nitro-5-(perfluorophenoxy)benzenesulfonamide (Compound 57)
Figure imgf000178_0001
Scheme 32 176 ny-2699290 Attorney Docket No.26327-20012.40 [0404] As shown in Step 1 of Scheme 32, to a solution of 3-bromo-4-nitrophenol (8.00 g, 36.7 mmol) in DMF (80 mL) was added K2CO3 (10.14 g, 73.4 mmol) followed by stirring the mixture at 10^^^for 1 hour. After cooling to room temperature, hexafluorobenzene (68.3 g, 367 mmol) was added dropwise at 25^, followed by stirring the mixture for 3 days at 100^. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue purified by reversed-phase flash column chromatography (5% to 100% acetonitrile/water, 0.1% formic acid) to afford 1-(3-bromo-4- nitrophenoxy)-2,3,4,5,6-pentafluorobenzene (Compound 1037, 1.9 g, 13% yield) as a brown oil: GCMS calculated for C12H3BrF5NO3 = 382.9, found 382.9. [0405] As shown in Step 2 of Scheme 32, to a degassed solution of benzyl mercaptan (582 mg, 4.68 mmol) and 1-(3-bromo-4-nitrophenoxy)-2,3,4,5,6-pentafluorobenzene (1.80 g, 4.68 mmol) in 1,4-dioxane (20 mL) were added XantPhos (271 mg, 0.46 mmol) and DIEA (1.21 J^^^^^^^PPRO^^^7KH^UHVXOWLQJ^PL[WXUH^ZDV^VWLUUHG^DW^^^^^IRU^^^^Kours under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate, and the combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (5% to 100% acetonitrile/water, 0.1% formic acid) to afford 1-[3- (benzylsulfanyl)-4-nitrophenoxy]-2,3,4,5,6-pentafluorobenzene (Compound 1038, 1.2 g, 59% yield) as a yellow oil: GCMS calculated for C19H10F5NO3S = 427.0; found 427.0. [0406] As shown in Step 3 of Scheme 32, to a stirred mixture of 1,3-dichloro-5,5- dimethylimidazolidine-2,4-dione (691 mg, 3.51 mmol) in AcOH (3 mL) and H2O (3 mL) was added 1-[3-(benzylsulfanyl)-4-nitrophenoxy]-2,3,4,5,6-pentafluorobenzene (600 mg, 1.40 mmol) in portions at 0^^^The resulting mixture was stirred at 0^^for 2 hours to produce 2- nitro-5-(perfluorophenoxy)benzenesulfonyl chloride (Compound 1039), which was used in subsequent steps directly as is. [0407] As shown in Step 4 of Scheme 32, to 2-nitro-5-(perfluorophenoxy)benzenesulfonyl chloride was added saturated NH3(aq.) (2 mL, 51.4 PPRO^^GURSZLVH^DW^^^^^7KH^UHVXOWLQJ^ PL[WXUH^ZDV^VWLUUHG^DW^^^^IRU^^^Kours, concentrated under reduced pressure, and the residue purified by flash chromatography (0 to 100% ethyl acetate in petroleum ether) and further purified by preparative reversed-phase HPLC (40% to 50% acetonitrile/water containing 0.1% formic acid) to afford 2-nitro-5-(2,3,4,5,6-pentafluorophenoxy)benzenesulfonamide 177 ny-2699290 Attorney Docket No.26327-20012.40 (Compound 57, 360 mg, 66%) as a white solid: MS (ESI) calculated for C12H5F5N2O5S) [MíH]í = 383.0; found, 382.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^-^ ^^^^^+]^^^+^^^ 7.73 (d, J = 2.8 Hz, 1H), 7.62 – 7.54 (m, 1H), 4.97 (s, 2H); 19F-NMR (376 MHz, DMSO-d6) į^í154.50, í159.14, í161.65. Example 24. Preparation of N-((2-nitro-5-(perfluorophenoxy)phenyl)sulfonyl)acetamide (Compound 58)
Figure imgf000180_0001
Scheme 33 [0408] As shown in Scheme 33, to a stirred solution of 2-nitro-5-(2,3,4,5,6- pentafluorophenoxy)benzenesulfonamide (100 mg, 0.26 mmol) in MeCN (1 mL) were added TEA (52 mg, 0.52 mmol), acetyl chloride (24 mg, 0.312 mmol), and DMAP (3 mg, 0.03 mmol). The resulting mixture was stirred at 25^^for 3 hours, followed by purification by reversed-phase preparative HPLC (45% to 55% acetonitrile/water containing 0.1% formic acid) to afford N-[2-nitro-5-(2,3,4,5,6-pentafluorophenoxy)benzenesulfonyl]acetamide (Compound 59, 47 mg, 42% yield) as a white solid: MS (ESI) calculated for C14H7F5N2O6S [MíH]í = 425.0; found, 424.8; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 8.8 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.73 – 7.65 (m, 1H), 2.02 (s, 3H); 19F-NMR (376 MHz, DMSO-d6^^į^í154.24, í159.01, í161.68. [0409] Using propionyl chloride in a transformation similar to that described in Scheme 33, the following compound was also prepared: N-((2-nitro-5-(perfluorophenoxy)phenyl)sulfonyl)propionamide (Compound 60): MS (ESI) calculated for (C15H9F5N2O6S) [MíH]í = 439.0, found, 438.9; 1H-NMR (400 MHz, DMSO- d6^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 8.8 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.73 – 7.66 (m, 1H), 2.33 (q, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, DMSO-d6^^į^í154.23, í159.04, í161.68. Example 25. Preparation of N-((2-nitro-5-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy)phenyl)sulfonyl)acetamide (Compound 60) 178 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000181_0001
Scheme 34 [0410] As shown in Step 1 of Scheme 34, to a solution of 3-bromo-4-nitrophenol (5.00 g, 22.94 mmol) in DMF (50 mL) was added NaH (1.76 g - 60% by weight in mineral oil, 45.9 mmol) in portions at 0^. The resulting mixture was stirred at 0^ for 1 hour, followed by the addition of perfluorotoluene (32.5 g, 138 mmol) dropwise at 25^ under nitrogen. The mixture was heated at 80^ for 16 hours with stirring, cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 25% ethyl acetate in petroleum ether) to afford 1-(3- bromo-4-nitrophenoxy)-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene (Compound 1040, 6.00 g, 60% yield) as a brown oil: GCMS (ESI) calculated for C13H3BrF7NO3 = 432.9 & 434.9, found 432.9 & 434.9; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.0 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.54 (dd, J = 9.0, 2.8 Hz, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^í55.25, í139.59, í150.39. [0411] As shown in Step 2 of Scheme 34, to a stirred solution of 1-(3-bromo-4- nitrophenoxy)-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene (8.00 g, 18.43 mmol) in toluene (80 mL) were sequentially added Pd2(dba)3 (1.69 g, 1.84 mmol), XantPhos (1.07 g, 1.84 mmol), DIEA (4.76 g, 36.86 mmol) and phenylmethanethiol (2.52 g, 20.27 mmol) under a 179 ny-2699290 Attorney Docket No.26327-20012.40 nitrogen atmosphere. The resulting solution was stirred at 110^ for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reversed-phase flash chromatography (10% to 90% acetonitrile in water) to afford 1-[3-(benzylsulfanyl)-4- nitrophenoxy]-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene (Compound 1041, 3.00 g, 34% yield) as a yellow solid: GCMS (ESI) calculated for C20H10F7NO3S = 477.0, found, 477.0. [0412] As shown in Step 3 of Scheme 34, to a stirred solution of 1-[3-(benzylsulfanyl)-4- nitrophenoxy]-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene (1.00 g, 2.09 mmol) in MeCN (20 mL) and H2O (2 mL) were added AcOH (2 mL) and 1,3-dichloro-5,5- dimethylimidazolidine-2,4-dione (1.03 g, 5.24 mmol) at 0^. The resulting mixture was stirred at 0^ for 16 hours, concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-nitro- 5-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)benzenesulfonyl chloride (Compound 1042), which was used in subsequent reactions directly as is. [0413] As shown in Step 4 of Scheme 34, 2-nitro-5-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy)benzenesulfonyl chloride was dissolved in MeCN (20 mL) and added a solution of concentrated NH3(aq.) ^^^P/^^^7KH^UHVXOWLQJ^VROXWLRQ^ZDV^VWLUUHG^DW^^^^^ for 2 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography (0% to 50% ethyl acetate in petroleum ether) to afford 2-nitro-5-[2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy]benzenesulfonamide (Compound 1043, 500 mg, 55% yield) as a white solid: MS (ESI) calculated for C13H5F7N2O5S [MíH]í = 433.0; found, 433.0; 1H-NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.2 Hz, 1H), 7.96 (s, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.73 – 7.66 (m, 1H); 19F-NMR (376 MHz, DMSO-d6^^į^í55.23, í140.89, í152.04. [0414] As shown in Step 5 of Scheme 34, to a stirred solution of 2-nitro-5-[2,3,5,6- tetrafluoro-4-(trifluoromethyl)phenoxy]benzenesulfonamide (100 mg, 0.23 mmol) and TEA (70 mg, 0.69 mmol) in DCM (2 mL) were added acetyl chloride (18 mg, 0.23 mmol) and '0$3^^^^^^PJ^^^^^^^^PPRO^^DW^^^^^^7KH^UHVXOWLQJ^VROXWLRQ^ZDV^VWLUUHG^DW^^^^^IRU^^^^ hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were 180 ny-2699290 Attorney Docket No.26327-20012.40 washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by preparative reversed-phase HPLC (48% to 56% acetonitrile/water containing 0.1% formic acid) to afford N-((2-nitro-5-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenoxy)phenyl)sulfonyl)acetamide (Compound 60, 42.6 mg, 38% yield) as a white solid: MS (ESI) calculated for C15H7F7N2O6S) [MíH]í = 475.0, found 475.0; 1H- NMR (400 MHz, DMSO-d6^^į^^^^^^^^EU^^^+^^^^^^^^^d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.81 – 7.74 (m, 1H), 2.06 (s, 3H); 19F-NMR (377 MHz, DMSO-d6^^į^í55.26, í141.04, í151.85. [0415] Using propionyl chloride in a transformation similar to that described for step 5 in Scheme 34, the following compound was also prepared: N-((2-nitro-5-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)sulfonyl)propionamide (Compound 61): MS (ESI) calculated for C16H9F7N2O6S [M+1]+ = 489.0, found 489.0; 1H- NMR (400 MHz, DMSO-d6) į^^^^^^^^V^^^+^^^^^^^^^G^^J = 8.8 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.81 – 7.74 (m, 1H), 2.27 (q, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H); 19F-NMR (377 MHz, DMSO-d6^^į^í55.24, í141.00, í151.85. Example 26. Amaranthus tuberculatum Protoporphyrinogen Oxidase (AmPPO) Expression and Purification [0416] The coding sequence of AmPPO was optimized for E. coli expression and assembled from synthetic oligonucleotides. Synthetic fragments were introduced into a pET28b vector (Novagen) using restriction-less “Hot Fusion” cloning process (Fu C., et al., ‘Hot Fusion: An Efficient Method to Clone Multiple DNA Fragments as Well as Inverted Repeats without Ligase,’ PLoS One (2014) Vol.9(12), page e115318). The resulting DNA was sequence-YHULILHG^^&RQVWUXFW^HQFRGLQJ^PXWDQW^YHUVLRQ^^ǻ*^^^-AmPPO) of the enzyme was produced via PCR-based mutagenesis using Q5 mutagenesis kit (NEB). [0417] Lysogeny broth (LB media, 10 mL) supplemented with 100 μg/mL kanamyci was inoculated with a single colony of BL21(DE3) competent E. coli transformed with pET28b_PPO_CHis. [Is pET28b_PPO_CHis. The culture was grown at 37°C with shaking at 230 rpm overnight. This culture was then used to inoculate 1 L of autoinduction media (AIM) prepared by the method of Fox, B. G., & Blommel, P. G. (2009), Autoinduction of protein expression, ‘Current Protocols in Protein Science,’ Chapter 5, Unit–5.23. The resulting culture was grown at 37°C with shaking at 230 rpm for 4 to 6 hours and an additional 40 to 181 ny-2699290 Attorney Docket No.26327-20012.40 48 hours at 18°C. The culture was collected and centrifuged. The resulting AmPPO enzyme- containing cell pellets were frozen and stored at -80°C for future use. [0418] 7KH^VDPH^SURFHGXUH^XVHG^WR^SURGXFH^$P332^ZDV^XVHG^WR^SURGXFH^PXWDQW^ǻ*^^^- AmPPO (a PPO mutant in which the glycine at position 210 is absent), except E. coli used ZDV^WUDQVIRUPHG^ZLWK^S(7^^EB^ǻ*^^^^332B&KLV. [0419] A detergent solution was prepared by mixing together the following: 175 mL of B- PER Thermo Scientific); 75 mL of Y-PER (Thermo Scientific); 15 mL of 1M TRIS buffer, pH 9.0, 15 mL of 5M NaCl; 50 mL of glycerol; 2.5 mL of Triton-X100; and 1 mg of Flavin Adenine Dinucleotide (FAD). A portion of this solution (about 80 mL -100 mL) is set aside and supplemented with imidazole to a final concentration of 10 mM and a pH of pH 8.0. The remainder of detergent solution was supplemented with Hen Egg White Lysozyme (Gold Bio, 1 mg/mL) and Serratia endonuclease (produced in house) and added to about 45 g of frozen enzyme-containing cell pellets, which were allowed to thaw in the lysis solution with vigorous stirring for 30 minutes at room temperature, then briefly sonicated (30 seconds on 50% power using a VWR brand sonic disruptor). Incubation was continued with stirring for additional 15-30 minutes at 4°C. The lysate was clarified for 35 minutes by centrifugation at 14,000 RPM. The resulting clarified lysate was incubated for 1 hour at 4°C with gentle stirring with His-SELECT® resin (Sigma, 20 mL of 50% slurry in 20% ethanol, washed 2x with 30 mM TRIS pH 8.1, 10 % glycerol, 220 mM NaCl). The resin slurry was transferred to a disposable plastic column and washed with 10 mM Imidazole, 250 mM NaCl, 30 mM TRIS pH 8.5, 10 % glycerol until the bound protein was deemed sufficiently washed away from lysate components (about 6-8 column volumes). The resin was then washed thoroughly (about 3 column volumes) with the previously set-aside detergent I-10 final buffer, followed by elution with the same buffer supplemented with 250 mM imidazole, pH 8.1. Enzyme- containing fractions were collected and pooled based on SDS-PAGE analysis. Pooled fractions were diluted with pure glycerol to final concentration of 50% and the AmPPO HQ]\PH^RU^PXWDQW^ǻ*^^^-AmPPO was stored at -20°C in liquid form. Example 27. PPO in vitro assay. [0420] Protoporphyrinogen IX (PPGIX) is prepared by reduction of protoporphyrin IX (PPIX) with a sodium amalgam as described by Jacobs and Jacobs, Enyzme 28: 206 (1982). 182 ny-2699290 Attorney Docket No.26327-20012.40 Once prepared, the PPGIX solution is kept in the dark and all subsequent manipulations of it are performed in the dark. [0421] The Base Buffer for the assay was 50 mM TRIS pH 8.5, 160 mM NaCl, 2 mM DTT, 0.01% Triton X-100. An antifoam solution was prepared by two serial 1 to 10 dilutions of Antifoam B Emulsion (SigmaAldrich) with Milli-Q water. Buffer A was freshly prepared E\^GLOXWLQJ^$P332^RU^PXWDQW^ǻ*^^^-AmPPO in Base Buffer to 3-8 ug/ml concentration of enzyme. Buffer B was prepared by adding 2 ml of reduced 2 mM PPIX to 60 ml of Base Buffer and adjusting the pH back to 8.5 using glacial acetic acid. Finally, antifoam B (Sigma) was added to 0.01% final concentration. Buffer B was protected from light and used within 3 hours of its preparation. [0422] A 384 well, clear bottom plate was used for the assay. Each test compound was dissolved in DMSO to a concentration of 30 mM. The test compounds, tested in triplicate, a butafenacil control, and a DMSO control were dispensed as 1.2 μL drops into a well of the plate. The wells were diluted with 60 μL of Buffer A and serially diluted 1 volume to 3 volumes over 7 dilutions by removing 20 μL from the first well, mixing well with 40 μL of Buffer A in a second well, removing 20 μL from the second well, and continuing the dilutions in this manner until there were 8 test wells. To initiate the reaction, 40 μL of Buffer B was added to each well and the wells gently mixed at least 2 times. The plate was centrifuged at 2000 rpm for 1 minute and the absorbance or fluorescence were read at ambient temperature using a plate reader. IC50’s were calculated using a nonlinear regression Sigmoidal dose-response model (GraphPad Prism, variable slope) with curve bottoms constrained to zero and curve tops constrained to plate-specific Vaverage. [0423] Compounds 1 to 3, 5, 7, 9 to 10, 12 to 14, 16 to 19, 22, 25, 27 to 28, 30 to 31, 33 to 35, 37 to 41, 43 to 48, 51 to 52, 54, and 56 to 61 had an IC50 of less than 100 nM in the PPO in vitro assay. Compounds 4, 6, 8, 11, 15, 20 to 21, 23 to 24, 26, 29, 36, 42, 50, 53, and 55 had an IC50 of less than 1 μM in this assay. [0424] Compounds 10, 14, 19, 27, 35, 45 to 46, and 61 had an IC50 of less than 100 nM in WKH^ǻ*^^^^332^in vitro assay. Compounds 5 to 7, 9, 12 to 13, 16 to 17, 23, 25, 28 to 31, 33, 37 to 44, 47 to 48, 52, 56, and 58 to 60 had an IC50 of less than 1 μM in this assay. Example 28. Testing the post-emergence herbicidal activity of compounds of the invention. 183 ny-2699290 Attorney Docket No.26327-20012.40 [0425] Selected compounds of the invention were screened at 100 PPM against Amaranthus retroflexus (AMARE), Echinochloa crus-galli (ECHCG), Kochia scoparia (KCHSC), and/or Setaria italica (SETIT). [0426] Accordingly, PPO susceptible weed seeds were sown in 5” x 5” pots by quadrant containing Miracle-Gro potting mix (Scotts Miracle-Gro Company, Marysville, OH, USA) and grown in a Conviron growth chamber with appropriate growth conditions (temperature of 26/22°C with photoperiod 16/8 h light day/night and light intensity of 300 μmol m-2 s-1 supplemented by LED lamps). Relative humidity in the growth chamber was maintained at around 65%. Plants were grown until 2-4 leaf stage and thinned to 5-8 plants per quadrant per species. [0427] Compounds were formulated in 25% Acetone, 1% Crop oil concentrate (COC- Agridex), 0.1% Tween-20, and 2.5% Ammonium sulphate (AMS). Three replicate pots were treated with each compound. Treatment consisting of the above formulation excluding active compound was applied as a treatment control (TC). Plants were treated with the test compound solution in a laboratory spray chamber fitted with 8003 flat fan nozzles calibrated to deliver 187-200 L ha-1 at 269 kPa. Plants were placed back in the growth chamber and evaluated for % visual injury compared to TC 7 days after treatment (DAT). The data presented in Table 3 indicate a percentage control, where 100% control indicates complete inhibition of growth. Table 3. Post-emergence herbicidal activity of selected compounds of the invention 7 days after the compound application (Entries labeled “--” were not tested)
Figure imgf000186_0001
184 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000187_0001
Example 29. Testing the pre-emergence herbicidal activity of compounds of the invention. [0428] Selected compounds of the invention were screened at 200 PPM against Amaranthus retroflexus (AMARE). [0429] Accordingly, PPO susceptible weed seeds were planted in 5” x 5” pots by quadrant containing custom field soil mix (Sandy loam with 4.7% OM, pH 7.0) and covered with a fine layer of the same soil. Compounds were formulated in 25% Acetone, 1% Crop oil concentrate (COC-Agridex), 0.1% Tween-20, and 2.5% Ammonium sulphate (AMS). Three replicate pots were treated with each compound. Treatment consisting of the above formulation excluding active compound was applied as a treatment control (TC). Pots were treated with the test compound solution in a laboratory spray chamber fitted with 8003 flat fan nozzles calibrated to deliver 187-200 L ha-1 at 269 kPa. Compound was incorporated into the soil by simulating rainfall equivalent to 0.2 mm using the same track sprayer. Subsequently, pots were irrigated from the bottom until assessed for % growth and germination inhibition. Pots were placed back in the growth chamber and evaluated for % growth and germination inhibition compared to TC 7 days after treatment (DAT). Growth conditions are similar to the ones mentioned in POST emergence assay. [0430] The data presented in Table 4 indicate a percentage control, where 100% control indicates complete inhibition of growth and germination. Table 4. Pre-emergence herbicidal activity of selected compounds of the invention 7 days after the compound application
Figure imgf000187_0002
Example 30. Preparation of Fluorophenyl Analogs. 185 ny-2699290 Attorney Docket No.26327-20012.40 [0431] Fluorophenyl analogs of several commercially available PPO inhibitors were synthesized. The fluorophenyl analogs prepared are listed in Table 5, below, along with the commercial PPO inhibitors from which they were derived. Analogs that also appear in Table 1 are identified by their corresponding compound number. Table 5. Fluorophenyl Analogs and Corresponding Base Compounds
Figure imgf000188_0001
186 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000189_0001
187 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000190_0001
188 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000191_0002
[0432] Fluorophenyl analogs A1, A2, A5-A12, A15-A19, and A21 listed in Table 5, above, were prepared according to the synthetic procedures described in Examples 1-25. Characterization data for these analogs is also provided in Examples 1-25. [0433] The remaining fluorophenyl analogs listed in Table 5 were prepared according to general synthetic schemes A and B, as shown below. Information related to the synthesis and characterization of these fluorophenyl analogs is summarized in Table 6, below.
Figure imgf000191_0001
General Synthetic Scheme A 189 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000192_0001
General Synthetic Scheme B Table 6. Characterization Data for Certain Fluorophenyl Analogs
Figure imgf000192_0002
190 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000193_0001
Example 31. Assessment of in vitro Inhibition of PPO Activity by Fluorophenyl Analogs [0434] The inhibition of wild-W\SH^DQG^PXWDQW^^ǻ*^^^^^332 by the fluorophenyl analogs of Table 5 was assessed using the assays described in Examples 26 and 27. [0435] IC50 vaOXHV^IRU^ERWK^ZLOG^W\SH^^:7^^DQG^PXWDQW^^ǻ*^^^^^332^IRU^HDFK^ fluorophenyl analog are provided in Table 7, below. Entries in Table 7 marked as “A” have IC50 values of less than or equal to 100 nM; entries marked as “B” have IC50 values greater than 100 nM, but less than or equal to 1μM; and entries marked as “C” have IC50 values greater than 1μM. Table 7. Inhibition of WT PPO and ǻ*^^^ PPO by Fluorophenyl Analogs 191 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000194_0001
Example 32. Computational Modeling of Fluorophenyl Analog-PPO Binding [0436] The binding of fluorophenyl analogs A5 and A21 was modeled using Schrodinger Maestro. The PPO model was based upon 1SEZ structure of the Nicotiana tabacum PPO in the protein databank found at https://www.ebi.ac.uk/pdbe/entry/pdb/1sez. An image of the predicted binding configuration for fluorophenyl analog A5 is shown in Fig.1. An image of the predicted binding configuration for fluorophenyl analog A21 is shown in Fig.2. As shown in Figs.1 and 2, in the binding configuration for both of compounds X and Y, the fluorophenyl moiety is in close proximity and oriented parallel to the phenyl ring of the SKHQ\ODODQLQH^PRLHW\^^3KH^^^^^RI^WKH^332^PRGHO^^LQGLFDWLYH^RI^DQ^DWWUDFWLYH^ʌ- ʌ^VWDFNLQJ^ interaction between the fluorophenyl moiety and the phenylalanine residue. Example 33. Xylem and phloem mobility assay [0437] Compounds are tested for leaf penetration, translocation, and herbicidal activity in a grass weed species when applied with or without an adjuvant to increase the compound 192 ny-2699290 Attorney Docket No.26327-20012.40 cuticle penetration. Four to five PPO susceptible Setaria Italica (Foxtail millet) seed (Ernst Conservation Seeds, Meadville, PA) are sown in each of the 1.5 x 1.5-inch 6 cell plug inserts containing Miracle-Gro™ potting mix (Scotts Miracle-Gro Company, Marysville, OH, USA) and grown in a Conviron growth chamber with appropriate growth conditions (temperature of 26/22oC with photoperiod 16/8 h light day/night and light intensity of 300 μmol m-2 s-1 supplemented by LED lamps). Relative humidity in the growth chamber is maintained at around 65%. Plants are grown until 1-2 leaf stage (one expanded leaf and one emerging leaf) and thinned to single plant per cell. [0438] Test compounds are formulated to a final concentration of 1.5 mM in 25% Acetone, 0.1% Tween-20 and 2.5% Ammonium sulphate (AMS) with or without the addition of 1% v/v Crop oil concentrate (COC, Agridex). A total of 6 μL are applied as 3 x 2 μL droplets on the adaxial surface of an emerged Setaria Italica leaf for each of the two compound solutions (with and without COC). Six replicate plants are treated with each compound. Treatment consisting of the above formulation excluding active compound are applied as a treatment control (TC). Plants are placed back in the growth chamber and, seven days after treatment, are evaluated for overall % visual injury compared to TC. Plants are also evaluated for rapid necrosis representative of PPO inhibition at the site of, acropetal to, and basipetal to the droplet application site to estimate the general, xylem, and phloem compound mobility, respectively. In general, compounds with necrosis only at the site of action are considered to be poorly mobile whereas necrosis in the emerging leaf indicates symplastic phloem movement and necrosis from leaf base to tip only on the applied leaf indicates apoplastic xylem movement. [0439] The data can be presented relative to the TC treatment for which the plant and leaf injury percent is considered 0%. “A” represents a percentage leaf or plant injury between 80 and 100%; “B” represents a percentage leaf or plant injury of 20-80%; “C” represents a percentage control below 20%. Example 34. Soil Mobility Assay [0440] PPO susceptible weed and crop seeds are planted in 3-inch pots at three different depths (0.5, 1 and 2-inch) containing custom field soil mix (sandy loam with 4.7% OM, pH 7.0) and covered with a fine layer of the same soil. Three replicate pots are treated with each of the compounds. Treatment consisting of the above formulation excluding active compound 193 ny-2699290 Attorney Docket No.26327-20012.40 is applied as a treatment control (TC). Pots are treated with the test compound solution in a laboratory spray chamber fitted with 8003 even fan nozzles calibrated to deliver 187-200 L ha-1 at 269 kPa. All treatments include the following inert ingredients in the final formulation; 1% Agridex (v/v) (crop oil concentrate) and 2.5% Ammonium sulphate (w/v). Compound is incorporated into the soil by simulating rainfall equivalent to 0.2 mm using the same track sprayer. Subsequently, pots are irrigated from the bottom until assessed for % growth and germination inhibition of both the crop and weed species tested. Pots are placed back in the growth chamber and evaluated for % visual growth and germination inhibition compared to TC 17-21 days after treatment (DAT). 194 ny-2699290

Claims

Attorney Docket No.26327-20012.40 CLAIMS What is claimed is: 1. A compound of formula (I):
Figure imgf000197_0001
or a salt thereof, wherein: R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with C(O)ORw and optionally substituted with halogen; each R1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR1b, C1- 6alkyl optionally substituted with C(O)N(R1c)2, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2- 4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is , independently, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; R1x is H or C1-6alkyl; Rw is H or C1-6alkyl; R2 is H, F, Cl, OCHF2, or NO2; R3 is H, F, or Cl; 195 ny-2699290 Attorney Docket No.26327-20012.40 each of R4, R6, and R7 is H or F; R5 is H, F, CF3. or OC1-2alkyl; X is O or a bond, provided that: (1) when X is a bond, then R1 is not CH3, S(O)2NHR1a or S(O)2NHC(O)R1b, and at least one of R2 or R3 is not H; (2) when X is a bond and R1 is OH, OCH3, CO2CH3, CO2CH2CH3, or CH=CHCO2H, then each of R2 and R3 is not H; (3) when X is a bond and R1 is NH2, then each of R2 and R3 is not H, and at least one of R2 and R3 is not F; (4) when X is O, then R2 and at least one of R1 or R3 is not H; and (5) when X is O, then R1 is not NHCH3; and Ring A contains at least 3 F. 2. The compound according to claim 1, or a salt thereof, wherein Ring A contains at least 4 F. 3. The compound according to claim 1, or a salt thereof, wherein R4 is H or F and each of R5, R6, and R7 is F. 4. The compound according to claim 1, or a salt thereof, wherein Ring A contains 5 F. 5. The compound according to any one of claims 1 to 4, or a salt thereof, wherein X is a bond. 6. The compound according to any one of claims 1 to 4, or a salt thereof, wherein X is O. 7. The compound according to claim 1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (G-I):
Figure imgf000198_0001
(G-I), 196 ny-2699290 Attorney Docket No.26327-20012.40 or a salt thereof, wherein: R1 is ORG1a or N(RG1a)2; each RG1a is, independently, H, C1-4alkyl optionally substituted with C(O)ORG1b, C1- 4alkyl optionally substituted with C(O)N(RG1c)2, C2-4alkenyl, C2-4alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)N(RG1x), C1-4alkyl, C(O)OCH2C2-4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2RG1x, pyridyl optionally substituted with OCH2CO2RG1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each RG1b is , independently, H, C1-4alkyl, or C3-6cycloalkyl, wherein each C1-4alkyl or C3-6cycloalkyl of RG1b is optionally substituted with C(O)ORG1x and up to 4 F atoms; each RG1c is, independently, RG1b, or two RG1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)ORG1x; R1x is H or C1-6alkyl; each of R2 and R3 is, independently, F or Cl; R4 is H or F; and R5 is F or OC1-2alkyl. 8. The compound according to claim 7, or a salt thereof, wherein said compounds of formula (G-I) is a compound of formula (G-II):
Figure imgf000199_0001
or a salt thereof. 9. The compound according to claim 8, or a salt thereof, wherein RG1a is C1-4alkyl optionally substituted with C(O)ORG1b or C(O)N(RG1c)2. 197 ny-2699290 Attorney Docket No.26327-20012.40 10. The compound according to claim 8, or a salt thereof, wherein RG1a is pyridyl substituted with OCH2CO2RG1x. 11. The compound according to claim 7, or a salt thereof, wherein said compound of formula (G-I) is a compound of formula (G-III):
Figure imgf000200_0001
or a salt thereof. 12. The compound according to claim 11, or a salt thereof, wherein each RG1a is, independently, H or S(O)2C1-4alkyl. 13. The compound according to any one of claims 7 to 12, or a salt thereof, wherein R4 is F. 14. The compound according to any one of claims 7 to 12, or a salt thereof, wherein R4 is H. 15. The compound according to any one of claims 7 to 14, or a salt thereof, wherein R2 is Cl and R3 is F. 16. The compound according to claim 7, or a salt thereof, wherein said compound of formula (I) is a compound of formula (H-I):
Figure imgf000200_0002
or a salt thereof, wherein: RH1 is ORH1a, NHS(O)2RH1b, or NHS(O)2N(RH1a)(RH1b); RH1a is H or C1-6alkyl optionally substituted with C(O)OC1-4alkyl or C(O)OC2- 4alkenyl; 198 ny-2699290 Attorney Docket No.26327-20012.40 RH1b is C1-6alkyl; R2 is Cl or OCHF2; R3 is H or F; and R4 is H or F. 17. The compound according to claim 16, or a salt thereof, wherein R4 is F. 18. The compound according to claim 16, or a salt thereof, wherein R4 is H. 19. The compound according to claim 16, or a salt thereof, wherein R2 is Cl and R3 is F. 20. The compound according to claim 16, wherein said compound of formula (H-I) is a compound of formula (H-II):
Figure imgf000201_0001
(H-II), or a salt thereof. 21. The compound according to claim 16, or a salt thereof, wherein said compound of formula (H-I) is a compound of formula (H-III):
Figure imgf000201_0002
or a salt thereof. 22. The compound according to claim 16, or a salt thereof, wherein said compound of formula (H-I) is a compound of formula (H-IV): 199 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000202_0001
or a salt thereof. 23. The compound according to any one of claims 20 to 22, or a salt thereof, wherein R2 is Cl, R3 is F, and R4 is F. 24. The compound according to any one of claims 20 to 22, or a salt thereof, wherein R2 is Cl, R3 is F, and R4 is H. 25. The compound according to claim 1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (K-I):
Figure imgf000202_0002
or a salt thereof, wherein: RK1 is C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, each substituted with C(O)ORKx and optionally substituted with halo; R2 is Cl; R3 is H or F; R4 is H or F R5 is OCH3 or F; and RKx is H or C1-6alkyl. 200 ny-2699290 Attorney Docket No.26327-20012.40 26. The compound according to claim 25, or a salt thereof, wherein said compound of formula (K-I) is a compound of formula (K-II):
Figure imgf000203_0001
or a salt thereof, wherein: X1 is H or halo. 27. The compound according to claim 25, or a salt thereof, wherein said compound of formula (K-I) is a compound of formula (K-III):
Figure imgf000203_0002
(K-III), or a salt thereof, wherein: X1 is H or halo. 28. The compound according to any one of claims 25 to 27, or a salt thereof, wherein R3 is F. 29. The compound according to any one of claims 25 to 27, or a salt thereof, wherein X is Cl. 30. The compound according to any one of claims 25 to 28, or a salt thereof, wherein RKx is H. 31. The compound according to any one of claims 25 to 30, or a salt thereof, wherein RKx is C1-2alkyl. 201 ny-2699290 Attorney Docket No.26327-20012.40 32. The compound according to claim 1, or a salt thereof, wherein said compound of formula (I) is a compound of formula (M-I):
Figure imgf000204_0001
or a salt thereof, wherein: RM1 is ORM1a, C(O)ORM1a, C(O)NHS(O)2RM1b, S(O)2NHRM1a, or S(O)2NHC(O)RM1b; RM1a is H, C1-6alkyl optionally substituted with C(O)OC1-2alkyl, or C3-6cycloalkyl; RM1b is C1-6alkyl, or C3-6cycloalkyl; RM2 is Cl or NO2; R4 is H or F; and R5 is F or CF3. 33. The compound according to claim 32, or a salt thereof, wherein RM1 is ORM1a. 34. The compound according to claim 32, or a salt thereof, wherein R1 is C(O)ORM1a. 35. The compound according to claim 32, or a salt thereof, wherein R1 is C(O)NHS(O)2RM1b. 36. The compound according to claim 32, or a salt thereof, wherein R1 is S(O)2NHRM1a. 37. The compound according to claim 32, or a salt thereof, wherein R1 is S(O)2NHC(O)RM1b. 38. The compound according to any one of claims 32 to 37, or a salt thereof, wherein each of R4 and R5 is F. 39. The compound according to any one of claims 32 to 37, or a salt thereof, wherein R5 is CF3. 202 ny-2699290 Attorney Docket No.26327-20012.40 40. The compound according to any one of claims 32 to 37, or a salt thereof, wherein R5 is F and R4 is H. 41. The compound according to any one of claims 32 to 40, or a salt thereof, wherein R2 is NO2. 42. The compound according to any one of claims 32 to 41, or a salt thereof, wherein RM1a or RM1b is C1-4alkyl. 43. The compound according to claim 32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-II):
Figure imgf000205_0001
or a salt thereof. 44. The compound according to claim 32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-III):
Figure imgf000205_0002
or a salt thereof. 45. The compound according to claim 32, or a salt thereof, wherein said compound of formula (M-I) is a compound of formula (M-IV): 203 ny-2699290 Attorney Docket No.26327-20012.40
Figure imgf000206_0001
or a salt thereof. 46. The compound according to claim 32, wherein said compound of formula (M-I) is a compound of formula (M-V):
Figure imgf000206_0002
or a salt thereof. 47. The compound according to claim 1, or a salt thereof, wherein the compound of formula (I) is selected from a compound in Table 1, or a salt thereof. 48. An agricultural composition, comprising: a compound of any one of claims 1 to 47, or a salt thereof; and at least one additional component that serves as a carrier. 49. The composition of claim 48, wherein at least one additional component is a surfactant or a diluent. 50. The composition of claim 47 or 48, wherein the composition is an herbicidal composition. 51. A method of controlling undesired vegetation, comprising contacting the undesired vegetation or its environment with a compound of formula (I), or a salt thereof, or an 204 ny-2699290 Attorney Docket No.26327-20012.40 agricultural composition comprising said compound and at least one additional component that serves as a carrier, wherein the compound of formula (I) is:
Figure imgf000207_0001
wherein: R1 is OR1a, N(R1a)2, C(O)OR1a, C(O)NHS(O)2R1b, C(O)NHS(O)2N(R1a)(R1b), S(O)2NHR1a, S(O)2NHC(O)R1b, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl, wherein each C1-4alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with C(O)ORw and optionally substituted with halogen; each R1a is, independently, H, C1-6alkyl optionally substituted with C(O)OR1b, C1- 6alkyl optionally substituted with C(O)N(R1c)2, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C(O)C1-4alkyl, C(O)C3-6cycloalkyl, C(O)NH(R1x), C(O)OCH2C2- 4alkenyl, C(O)OCH2C2-4alkynyl, phenyl optionally substituted with OCH2CO2R1x, pyridyl optionally substituted with OCH2CO2R1x, or S(O)2C1-4alkyl optionally substituted with up to 3 F atoms; each R1b is , independently, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl of R1b is optionally substituted with C(O)OR1x and up to 4 F atoms; each R1c is, independently, R1b, or two R1c connected to an intervening nitrogen atom form a 5-6 membered ring optionally substituted with C(O)OR1x; R1x is H or C1-6alkyl; Rw is H or C1-6alkyl; R2 is H, F, Cl, OCHF2, or NO2; R3 is H, F, or Cl; each of R4, R6, and R7 is H or F; 205 ny-2699290 Attorney Docket No.26327-20012.40 R5 is H, F, CF3. or OC1-2alkyl; X is O or a bond, wherein when X is a bond R1 is not S(O)2NHR1a or S(O)2NHC(O)R1b; and Ring A contains at least 3 F. 52. The method according to claim 51, wherein the compound of formula (I) is a compound of any one of claims 1 to 47, or a salt thereof. 206 ny-2699290
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