Protoporphyrinogen oxidase inhibitors

Abstract

The present invention relates to protoporphyrinogen IX oxidase (PPO) inhibitors of general formula (I), the variables of which are defined herein. The present invention features processes and intermediates for preparing the compounds of formula (I), compositions containing them, and their use as herbicides (e.g., for controlling harmful plants). The present invention also features a method for controlling undesirable vegetation, comprising applying a herbicidally effective amount of at least one PPO inhibitor of formula (I) to a plant, its seeds, and / or its habitat. [Formula 1] JPEG2025503677000056.jpg31169

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 299,866, filed January 14, 2022, which is incorporated by reference in its entirety.

[0002] The present invention relates to protoporphyrinogen IX oxidase (PPO) inhibitors that are useful as herbicides. In particular, the present invention relates to certain fluorinated phenyl compounds, compositions containing such compounds, processes for making such compounds and compositions, and methods for using such compounds for crop protection and controlling undesirable vegetation. [Background technology]

[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 leads to the accumulation of protoporphyrinogen IX in chloroplasts and mitochondria, which is thought to leak into the cytosol where it is oxidized by peroxidase. When exposed to light, protoporphyrin IX can cause the formation of singlet oxygen and other reactive oxygen species in the cytoplasm, leading to lipid peroxidation and membrane destruction, resulting in rapid cell death [Lee HJ et al., Cellular localization of protoporphyrinogen-oxidizing activities of etiolated barley leaves, Plant Physiology (1993) 102: 881].

[0004] To date, thousands of PPO inhibitors have been reported in the literature, and currently, about 30 species are used as herbicides to control weeds in fields [Hao, GF, et al., Protoporphyrinogen oxidase inhibitor: an ideal target for herbicide discovery, Chimia (2011) 65, 961-969]. PPO-inhibiting herbicides include 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, chlorophthalimide, N-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide)]; phenylpyrazoles (e.g., TNPP-ethyl, 2-[1-(2,3,4-trichlorophenyl)-4-nitropyrazolyl-5-oxy]ethyl propionate, M&B 39279); pyridine derivatives (e.g., LS82-556); and fenopyrus acid salts and their O-phenylpyrrolidino and piperidino carbamate analogs (Kramer W., ed., Modern Crop Protection Compounds, 2 nd Ed., Vol 1: Herbicides, (2012) Wiley-VCH, Weinheim, Germany) are molecules of many different structural classes. Many of these compounds competitively inhibit normal reactions catalyzed by enzymes and apparently act as substrate analogues.

[0005] However, the herbicidal properties of these known compounds against harmful plants are not always completely satisfactory.Herbicide-resistant weeds present a serious problem for efficient weed control, because such resistant weeds are becoming more and more widespread, and therefore weed control by applying herbicides is no longer effective, causing great problems for farmers. Resistance to PPO herbicides has evolved slowly (about 40 years since their first commercialization) and has been identified in 13 weed species to date [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 Amaranthus tuberculatus in 2001 [Shoup DE, et al., Common waterhemp (Amaranthus rudis) resistance to protoporphyrinogen oxidase-inhibiting herbicides Weed Sci. (2003) 51: 145-150]. Resistance to PPO herbicides in weed species is thought to result from target site mutations in the PPX2 gene. For example, a unique target site amino acid deletion (Gly 210 ) and Arg 98 Leu substitutions confer PPO resistance in water hyacinth [Patzoldt WL, 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) population resistant to ALS- and PPO-inhibiting herbicides, Weed Sci. (2012) 60:335-344], respectively.

[0006] Thus, there is a need for new methods of effectively controlling weeds, including herbicide-resistant weeds, particularly PPO-resistant weeds, that are simultaneously tolerated by the useful plants (crops) in question. Summary of the Invention

[0007] Thus, in one embodiment, a compound of formula (I): [ka] or a salt thereof, wherein ring A contains at least four F atom substituents, and X and R 1 ~R 6 is as defined herein.

[0008] In certain embodiments, the compound of formula (II): [ka] or a salt thereof, wherein X and R 2 ~R 6 and R 1a is as defined elsewhere herein.

[0009] In certain embodiments, the compound of formula (III): [ka] or a salt thereof, wherein X and R 2 ~R 6 and R 1g is as defined elsewhere herein.

[0010] In another aspect, agricultural compositions (including, in some variations, herbicide compositions) are also provided that include a herbicidally effective amount of a compound of formula (I), (II), or (III), or a salt thereof, and at least one component selected from the group consisting of a surfactant, a solid diluent, and a liquid diluent (e.g., a formulation). 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 can be a herbicide and / or a herbicide safener.

[0011] In yet another aspect, processes for producing the above-identified compounds, salts, and compositions are also provided.

[0012] In certain embodiments, compounds are provided that are intermediates for making one or more compounds of the invention, including one or more compounds in Table 1, or a salt thereof.

[0013] In yet another aspect, there is provided a method for controlling undesirable vegetation growth comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of the invention, a salt thereof, or a composition comprising a compound of the invention as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In one embodiment, the compound of formula (I): [ka] or a suitable salt thereof, wherein X is CH or N; R 1 -SR 1a or -S(O)2R 1b and R 1a is optionally phenyl, C(O)OR 1c , or C(O)N(R 1c )2 replaced by C 1~4 is alkyl, Each R 1c are independently H, CH2CH2OC(O)R 1d , or optionally replaced by C 1~4 alkyl, and the optional substituents are 3~6 Cycloalkyl, C(O)OC 1~4 Alkyl, or up to three F atoms, or two R with an intervening nitrogen atom 1c but optionally C(O)OH or C(O)OC 1~4 Forming a 5-6 membered ring substituted with alkyl, R 1d is C 1~4 Alkyl or C 1~4 alkenyl, R 1b is CH2C(O)C 1~4 Alkyl or N(R 1e )R 1f and R 1e , H, C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, C(O)C 1~2 Alkyl, or OC 1~4 is alkyl, R 1f , H, C 1~6 Alkyl, C(O)C(O)C 1~4 Alkyl, C(O)R 1g , or S(O)2R 1g or R 1e and R 1f together with the intervening nitrogen atom form a 5-6 membered ring optionally containing up to two C(O) ring members; R 1g is C 1~14 Alkyl, C 1~4 Alkenyl, Phenyl, Het, N(R h )2, O.C. 1~4 Alkyl, C 3~6 cycloalkyl, or CH2(OCH2CH2)4CH3, each alkyl group optionally containing up to three F atoms, phenyl, C 3~6 Cycloalkyl, OH, OC 1~4each cycloalkyl group is optionally substituted with OH or OC 1~4 each phenyl group is optionally substituted with up to three Cl or F atoms; Het is a 5-6 membered heterocyclic ring containing up to two ring members selected from O, N, S, or S(O)2, and optionally OH or OC 1~4 is substituted with alkyl, Each R h are independently H, C 1~4 alkyl, benzyl, or phenyl; R 2 and R 3 each of is Cl or F; R 4 , R 5 , and R 6 is F or H, and ring A contains at least four F atoms.

[0015] In one embodiment, R 1 Ha-SR 1a and R 1a is phenyl, C(O)OR 1c , or C(O)N(R 1c )2 replaced by C 1~4 In another embodiment, R 1 is -S(O)2R 1b and R 1b is CH2C(O)C 1~4 In a further embodiment, R 1 is -S(O)2R 1b and R 1b is N(R 1e )R 1f It is.

[0016] In one embodiment, the present invention provides a compound of formula (II): [ka] or a salt thereof.

[0017] In a further embodiment, R 4, R 5 , and R 6 Each of is F. In another further embodiment, R 4 and R 6 Each of is F. In yet another further embodiment, R 4 and R 5 Each of is F.

[0018] In another further embodiment, R 1a is CH(CH3)CONHCH2CH2CO2C 1~4 It is an alkyl.

[0019] In one embodiment, the present invention provides a compound of formula (III): [ka] or a salt thereof.

[0020] In a further embodiment, R 4 , R 5 , and R 6 Each of is F. In another further embodiment, R 4 and R 6 Each of is F. In yet another further embodiment, R 4 and R 5 Each of is F.

[0021] In another embodiment, R 1g is C(O)C 1~6 Alkyl, C(O)C 3-6 Cycloalkyl, C(O)OC 1~6 Alkyl, or C(O)OC 3-6 It is cycloalkyl.

[0022] In one embodiment, a compound of formula (IV): [ka] or a salt thereof (including agriculturally suitable salts thereof), wherein R 1ais defined herein for formula (I).

[0023] In another embodiment, the compound of formula (V): [ka] or a salt thereof (including agriculturally suitable salts thereof), wherein R 1b is defined herein for formula (I).

[0024] In yet another embodiment, a compound of formula (VI): [ka] or a salt thereof (including agriculturally suitable salts thereof), wherein R 2 , R 3 , R 4 , and R 6 Each of A, X, R is independently Cl or F. With respect to formula (I), 1b , and R 5 Each of these is defined herein.

[0025] In another embodiment, the compound of formula (VII): [ka] or a salt thereof (including agriculturally suitable salts thereof), R 1 -SR 7a or -S(O)2NHR 7b and R 7a , H, C 1~6 Alkyl, C(O)C 1~6 Alkyl, or C(O)OC 1~6 alkyl, each C 1~6 Alkyl is optionally phenyl, COR 7b , or C(O)N(R 7b )2, Each R 7bare independently H, phenyl, C 3~6 Cycloalkyl, or C 1~6 Alkyl, optionally containing up to three F atoms, phenyl, C 2~4 Alkenyl, C 2~4 Alkynyl, or C 3~6 cycloalkyl substituted; R 4 , R 5 , and R 6 each of is F or H; Ring A contains at least four F atoms.

[0026] In one embodiment, R 4 , R 5 , and R 6 Each of is F.

[0027] In another embodiment, R 7 SR 7a and R 4 and R 6 Each of R is F. In another embodiment, R 7a CO2R 7b or C(O)N(R 7b )2 replaced by C 1~6 In a further embodiment, two R 7b The group and the intervening nitrogen atom are COR x In another embodiment, R 4 , R 5 , and R 6 Each of is F.

[0028] In another embodiment, R 7 is SO2-NH-R 7a and R 4 and R 6 Each of is F. In one embodiment, R 7a is -C(O)N(R 7b In another embodiment, R 7a is -C(O)C 1~6 Alkyl or -C(O)OC 1~6 In a further embodiment, R4 , R 5 , and R 6 Each of is F.

[0029] In some variations of the foregoing, the salts may be agriculturally suitable salts. In certain variations, the agriculturally suitable salts are salts that exhibit herbicidal activity or that are or can be converted in plants, water, or soil to compounds or salts that have herbicidal activity.

[0030] In some embodiments, a compound selected from the compounds listed in Table 1 below, or a salt thereof (an agriculturally suitable salt thereof) is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0031] In some variations, compounds 1-14 or 67, or salts thereof (including agriculturally suitable salts thereof) are provided. In some variations, compounds 1-14 or 67, or salts thereof (including agriculturally suitable salts thereof) comprise formula (IV) as defined herein. In some variations, compounds 15-24, or salts thereof (including agriculturally suitable salts thereof) are provided. In some variations, compounds 15-24, or salts thereof (including agriculturally suitable salts thereof) comprise formula (V) as defined herein. In one variation, compound 18, or salts thereof (including agriculturally suitable salts thereof) are provided. In some variations, compounds 25-66 or 68-79, or salts thereof (including agriculturally suitable salts thereof) are provided. In some variations, each of compounds 25-66 or 68-79, or salts thereof (including agriculturally suitable salts thereof) comprise formula (VI) as defined herein. In one variation, compound 26, or salts thereof (including agriculturally suitable salts thereof) are provided. In another variation, compound 50, or a salt thereof, including an agriculturally suitable salt thereof, is provided. In yet another variation, compound 51, or a salt thereof, including an agriculturally suitable salt thereof, is provided. In some variations, compounds 52-53, or a salt thereof, including an agriculturally suitable salt thereof, are provided. In some variations, each of compounds 52-53, or a salt thereof, including an agriculturally suitable salt thereof, comprises formula (VI), as defined herein.

[0032] In another aspect, the invention features an agricultural composition that includes a compound of the invention, or a salt thereof, and at least one additional ingredient that functions as a carrier.

[0033] In one embodiment, at least one additional component of the agricultural composition is a surfactant or a diluent.

[0034] In another embodiment, the composition is a herbicide composition.

[0035] In another aspect, the invention features a method for controlling undesirable vegetation, the method comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of the invention, or an agriculturally acceptable salt thereof.

[0036] In one embodiment, the undesirable vegetation includes weeds. In a further embodiment, the undesirable vegetation includes protoporphyrinogen IX oxidase (PPO) inhibitor resistant weeds. In yet another embodiment, the PPO inhibitor resistant weeds have a dG210 mutation.

[0037] In one embodiment, the compound or composition of the present invention is 2 It is applied at a rate of 1 to 100 g per dose.

[0038] In one embodiment, contacting the undesirable vegetation or its environment with a compound or composition of the present invention results in post-emergence control of the undesirable vegetation. In a further embodiment, the undesirable vegetation is controlled by at least 60%. In another embodiment, the undesirable vegetation is controlled by at least 80%. In yet another embodiment, the undesirable vegetation is controlled by at least 90%.

[0039] In one embodiment, contacting the undesirable vegetation or its environment with a compound or composition of the present invention results in pre-emergence control of the undesirable vegetation. In a further embodiment, the undesirable vegetation is controlled by at least 60%. In another embodiment, the undesirable vegetation is controlled by at least 80%. In yet another embodiment, the undesirable vegetation is controlled by at least 90%.

[0040] definition As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition, mixture, process, or method that includes or comprises a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent in such composition, mixture, process, or method.

[0041] The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. When such is recited in a claim, it excludes a claim for the inclusion of materials other than those recited, except for impurities ordinarily associated therewith. When the phrase "consisting of" appears in a phrase in the body of a claim rather than immediately following a preamble, it limits only the elements recited in that phrase and does not exclude other elements from the claim as a whole.

[0042] Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not an exclusive "or." For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), or both A and B are true (or exist).

[0043] Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be open-ended with regard to the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural, unless the number is clearly meant to be singular.

[0044] As referred to herein, the term "seedling", used alone or in combination with words, means a young plant that develops from the embryo of a seed.

[0045] As referred to herein, the term "broadleaf" used alone or in terms such as "broadleaf weed" means a dicotyledon or dicotyledonous plant, a term used to describe a group of angiosperms characterized by an embryo with two cotyledons.

[0046] In the above description, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl", includes straight-chain or branched alkyl, for example, methyl, ethyl, n-propyl, i-propyl, or the various butyl, pentyl, or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the various 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 various butynyl, pentynyl, and hexynyl isomers. "Alkynyl" can also include moieties consisting of multiple triple bonds, such as 2,5-hexadinyl.

[0047] "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the different butoxy, pentoxy and hexyloxy isomers.

[0048] "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0049] The terms "halogen" or "halo", whether used alone or in compound words such as "haloalkyl", or in descriptions such as "alkyl substituted with halogen", include fluorine, chlorine, bromine, or iodine.

[0050] The total number of carbon atoms in the substituent group is "C i~ C j " or "C i ~ j " prefix, where i and j are numbers from 1 to 10. For example, C 1~4 Alkylsulfonyl represents methylsulfonyl to butylsulfonyl, C2alkoxyalkyl represents CH3OCH2-, C3alkoxyalkyl represents, for example, CH3CH(OCH3)-, CH3OCH2CH2-, or CH3CHOCH2-, and C4alkoxyalkyl represents the various isomers of an alkyl group substituted with an alkoxy group containing a total of 4 carbon atoms, including, for example, CH3CH2CH2OCH2- and CH3CHOCH2CH2-.

[0051] When a compound is substituted with a substituent having a subscript indicating that the number of such substituents can be more than one, the substituents (if they are more than one) can be independently selected from the defined substituents, e.g., (R 1 ) m where m is 0, 1, 2, or 3. Additionally, the subscripts may represent ranges, e.g., (R) i~jWhen a variable is designated "i" or "j", the number of substituents may be selected from the integers between "i" and "j", inclusive. When a group contains a substituent which may be, for example, hydrogen (H), it is recognized that when this substituent is designated as hydrogen, this is equivalent to the group being unsubstituted. When a variable is designated as being optionally attached to a position, the hydrogen may be at that position even if it is not listed in the definition of the variable. When one or more positions on a group are referred to as "unsubstituted" or "unsubstituted", a hydrogen atom is attached in a manner that takes up any free valence.

[0052] "Aromatic" indicates that each of the ring atoms is essentially in the same plane, has p-orbitals perpendicular to the plane of the ring, and has (4n+2) pi electrons associated with the ring according to Hückel's rule, where n is a positive integer. The term "aromatic ring system" denotes a carbocyclic or heterocyclic ring system in which at least one ring of the ring system is aromatic.

[0053] The term "non-aromatic ring system" denotes a carbocyclic or heterocyclic ring system which may be fully saturated or slightly or fully unsaturated, provided that none of the rings in the ring system are aromatic.

[0054] The term "optionally substituted" in relation to a heterocyclic ring refers to a group that is unsubstituted or has at least one non-hydrogen substituent that does not abolish the biological activity of the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated. The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted" or the phrase "(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 substitutions.

[0055] The term "acceptable salts" or "salts" in relation to the compounds of the invention includes cations or anions. Preferred cations are the ions of alkali metals, preferably lithium, sodium and potassium, the ions of alkaline earth metals, preferably calcium and magnesium, as well as the ions of transition metals, preferably 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 salts), 2-(2-hydroxyeth-1-oxy)eth-1-ylammonium (diglycolamine salts), di(2-hydroxyeth-1-yl)ammonium (diolamine salts), tris(2-hydroxyethyl)ammonium (trolamine salts), tris(2-hydroxypropyl)ammonium, benzyltomethylammonium, benzyltriethylammonium, N,N,N-trimethylethanolammonium (choline salts), further 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.

[0056] Useful anions of acid addition salts are primarily chloride, bromide, fluoride, iodide, hydrogensulfate, methylsulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, hydrogencarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate and also anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate.

[0057] As used herein, the terms "undesirable vegetation" and "harmful plants" are synonymous.

[0058] Preparation of the Compounds of the Invention A wide variety of synthetic methods are known in the art that allow for the preparation of aromatic and non-aromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, ARKatritzky and CWRees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve-volume set of Comprehensive Heterocyclic Chemistry II, ARKatritzky, CWRees and EFV Scriven editors-in-chief, Pergamon Press, Oxford, 1996.

[0059] The compounds of the present invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Stereoisomers are isomers that have the same constitution but differ 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 around a single bond, where the rotation barrier is high enough to allow the isolation of the isomeric species. Those skilled in the art will understand that one stereoisomer may be more active and / or may show beneficial effects when enriched relative to other stereoisomer(s) or separated from other stereoisomer(s). In addition, those skilled in the art will know how to separate, enrich, and / or selectively prepare the stereoisomers. The compounds of the present invention may exist as a mixture of stereoisomers, as individual stereoisomers, or as optically active forms. For a comprehensive discussion of all aspects of stereoisomerization, see Ernest L. Eliel and Samuel H. Stereochemistry of Organic Compounds, John Wiley & Sons, New York, 1994. The compounds of the present invention typically exist in more than one form, and therefore the formulas of the present invention include all crystalline and amorphous forms of the compounds they represent. Amorphous forms include embodiments that are solids, such as waxes and gums, and embodiments that are liquids, such as solutions and melts. Crystalline forms include embodiments that represent essentially a single crystal type and embodiments that represent a mixture of polymorphs (i.e., different crystal 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. Polymorphs may have the same chemical composition, but may differ in composition due to the presence or absence of co-crystallized water or other molecules that may be weakly or strongly bound in the lattice. Polymorphs may differ in chemical, physical, and biological properties such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, dissolution rate, and bioavailability.Those skilled in the art will understand that polymorphs of the compounds of the present invention may exhibit beneficial effects (e.g., suitability for the preparation of useful formulations, improved biological performance) compared to other polymorphs or mixtures of polymorphs of the same compound. Preparation and isolation of a particular polymorph of the compounds of the present invention may be achieved by methods known to those skilled in the art, including, for example, crystallization using a selected solvent and temperature. For a comprehensive discussion of polymorphs, see R. Hilfiker, Ed., Polymorphism in Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.

[0060] Those skilled in the art will recognize that salts of chemical compounds are in equilibrium with their corresponding non-salt forms in the environment and under physiological conditions, so that salts share the biological usefulness of the non-salt forms. Thus, a wide variety of salts of the compounds of the present invention are useful for controlling undesirable vegetation (i.e., agriculturally suitable). Salts of the compounds of the present invention include acid addition salts with inorganic or organic acids, such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, butyric acid, fumaric acid, lactic acid, maleic acid, malonic acid, oxalic acid, propionic acid, salicylic acid, tartaric acid, 4-toluenesulfonic acid, or valeric acid. When the compounds of the present invention contain an acidic moiety, such as a carboxylic acid or a 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.

[0061] Furthermore, the present invention features processes and intermediates for preparing the compounds of the present invention.These compounds can be prepared by the general methods known in the field of synthetic organic chemistry.One or more of the following methods and variations, as described in Schemes 1 and 2, can be used.

[0062] In one general example, compounds of formula (II) and (III) can be prepared as shown in Scheme 1. [ka]

[0063] Thus, as shown in Scheme 1, Step 1, a compound of formula c, where R 2 and R 3 can each be Cl or F, R 4 , R 5 and R 6 can each be H or F, and ring A contains at least four F atoms) can be prepared by reacting a boronate of formula (a) (e.g., pinacol boronate) or a boronic acid with a substituted phenyl of formula (b) (where Hal is Br or I) using metal-catalyzed cross-coupling reaction conditions. Suitable catalysts include palladium catalysts such as Pd(OAc)2 or [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II). Similar Suzuki-Miyarua reaction conditions are known to those skilled in the art. Compounds of formula (c) can be converted to sulfonyl chlorides of formula (d) via a sulfonation reaction using heated sulfonic acid chloride, as shown in step 2. Sulfonyl chlorides of formula (d) can be converted to thiols of formula (e) by reduction, for example, by using SnCl2 as a reducing agent, as shown in step 3. Other reducing agents such as triphenylphosphine, zinc / dichlorodimethylsilane can also be used. Thereafter, as shown in Step 4, a thiol of formula (e) is reacted with an alkylating agent of formula (f), 1a is as defined elsewhere herein, but is not H, and is L 1 is a leaving group such as a halide or sulfonate to produce a compound of formula (II), 1a is as defined elsewhere herein.

[0064] Alternatively, reaction of the sulfonyl chloride of formula (d) with an ammonia source, such as ammonium hydroxide, produces a compound of formula (g), as shown in step 5. Subsequent reaction of the compound of formula (g) with an alkylating, sulfonating, or acylating reagent of formula (h), where R 1b is as defined elsewhere herein, but is not H, but L 2 is a halogen or an active ester leaving group) to produce a compound of formula (III), 1 is -S(O)2NHR 1b where R 1b is as defined elsewhere herein.

[0065] Alternatively, as shown in step 6, the sulfonyl chloride of formula (e) can be converted to a thiol of formula (i) by reduction, for example, by using SnCl2 as the reducing agent. Other reducing agents such as triphenylphosphine, zinc / dichlorodimethylsilane can also be used. Then, as shown in step 7, the thiol of formula (i) is reacted with an alkylating agent of formula (j), where R 1a is as defined elsewhere herein, but is not H, and is L 2 is a leaving group such as a halide or sulfonate to produce a compound of formula (II), 1a is as defined elsewhere herein.

[0066] In another general example, compounds of formula (II) and (III) can also be prepared as shown in Scheme 2. [ka]

[0067] Thus, as shown in Scheme 2, Step 1, a compound of formula (i) can be reacted with a fluorobenzene compound of formula (j) in which ring A contains at least four fluorine atoms. Such aryl-aryl couplings are known to those skilled in the art and require the use of a metal catalyst such as Pd(OAc)2.

[0068] Alternatively, as shown in step 2, a compound of formula (i) can be reacted with a compound of formula (k), + or K + (either 1,2-dichlorophenyl) or 1,3-dichlorophenyl) under conditions that favor decarboxylative aryl-aryl coupling. Examples of copper-mediated couplings are known to those skilled in the art and typically involve a ligand such as 1,10-phenanthroline.

[0069] As shown in step 3, another option for preparing a compound of formula (c) involves reacting a compound of formula (c) with a boronic acid or boronate salt of formula (m) using Suzuki-Miyaura conditions known to those skilled in the art. The compound of formula (c) can then be converted to a compound of formula (II) or (III) as described above in Scheme 1.

[0070] In one aspect, there is provided a process for preparing a compound of formula (II) as described herein, or a salt thereof, comprising: reacting a boronate (e.g., pinacol boronate) or boronic acid of formula (a) with a substituted phenyl of formula (b) (wherein Hal is Br or I) to produce a fluorinated compound of formula (c); [ka] reacting the halogenated compound of formula (c) with chlorosulfonic acid to produce a sulfonyl chloride of formula (d); [ka] reducing a sulfonyl chloride of formula (d) to a thiol of formula (e); [ka] formula R 1a -L 1 (In the formula, L 1 is a leaving group, and R 1a is as defined elsewhere herein) to form a compound of formula (II); [ka] In the formula, X, R 1a , R 2 , R 3 , R 4 , R 5 , and R 6 is as described elsewhere herein.

[0071] In one embodiment, the compound of formula (c) can be formed by reacting a phenyl bromide or phenyl iodide of formula (i) with a fluorinated benzene of formula (j): [ka] In the formula, R 2 , R 3 , R 4 , R 5 , and R 6 is as described elsewhere herein, or when X is N, R 2 may be NH2.

[0072] In another embodiment, the compound of formula (c) can be formed by reacting a phenyl bromide or phenyl iodide of formula (i) with a phenyl chloride or potassium carbonate of formula (k); [ka] In the formula, X, R 2 , R 3 , R 4 , R 5 , and R6 is as described elsewhere herein.

[0073] In yet another embodiment, the compound of formula (c) can be formed by reacting a phenyl bromide or phenyl iodide of formula (i) with a phenyl boronate or boronic acid of formula (m): [ka] In the formula, R 2 , R 3 , R 4 , R 5 , and R 6 is as described elsewhere herein, or when X is N, R 2 may be NH2.

[0074] In another aspect, there is provided a process for preparing a compound of formula (III) as described herein, or a salt thereof, comprising the steps of: converting a compound of formula (a) to a sulfonyl chloride of formula (d) as above and reacting the sulfonyl chloride with an ammonia source to form a compound of formula (g); [ka] The compound of formula (g) is reacted with a compound of formula R 1b ~L 2 with an alkylating, acylating, or sulfonating agent of the formula 2 is a halogen or an active ester leaving group, and R 1b is as described elsewhere herein) to form a compound of formula (III). [ka]

[0075] In one embodiment, R 1b is an alkylating agent. In another embodiment, R 1b is an acylating agent, and in yet another embodiment, R1b is a sulfonating agent.

[0076] Any of the embodiments and variations described herein for compounds of formula (II) or (III) also apply to intermediates of formula (d), (e), or (g). In some aspects, a compound of formula (d), (e), or (g): [ka] or a salt thereof (including agriculturally suitable salts thereof) is provided.

[0077] Those skilled in the art will recognize that various functional groups can be converted to other functional groups to provide different compounds of the invention. For a valuable resource showing the interconversion of functional groups in a simple and straightforward manner, see Larock, RC, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2001, pp. 111-115, 2001. nd Ed., Wiley- VCH, New York, 1999.

[0078] It is also recognized that some of the reagents and reaction conditions described above for preparing the compounds of the present invention may not be compatible with certain functional groups present in the intermediates. In these cases, incorporating a protection / deprotection sequence or functional group interconversion into the synthesis will help to obtain the desired product. The use and selection of protecting groups will be apparent to those skilled in the art of chemical synthesis (see, for example, Greene, TW; Wuts, PGM, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Those skilled in the art will recognize that in some cases, after the introduction of a given reagent as shown in any individual scheme, it may be necessary to carry out additional routine synthetic steps not detailed in order to complete the synthesis of the compounds of the present invention. Those skilled in the art will also recognize that it may be necessary to carry out combinations of steps shown in the above schemes in an order other than that implied by the details presented in order to prepare the compounds of the present invention.

[0079] Those skilled in the art will also recognize that the compounds of the present invention, and the intermediates described herein, may be subjected to a variety of electrophilic, nucleophilic, radical, organometallic, oxidative, and reductive reactions to add substituents or modify existing substituents.

[0080] composition In certain embodiments, the compounds of the present disclosure, including agriculturally suitable salts thereof, may be used as herbicidally active ingredients in formulations that include at least one additional ingredient selected from the group consisting of surfactants, solid diluents that function as carriers, and liquid diluents. The formulation ingredients are selected to match the physical properties of the active ingredient, the mode of application, and environmental factors such as soil type, moisture, and temperature.

[0081] In some variations, the compositions provided herein are herbicides.In some variations, the compositions comprise the compounds of the present disclosure that control or modify plant growth.In certain variations, the compositions comprise a herbicidally effective amount of the compound, and such an amount of the compound can produce a control or modification effect on plant growth.Control or modification effect includes any deviation from natural growth, such as killing, delaying, defoliation, bleaching, dwarfing, etc.

[0082] Emulsion liquid formulations include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions, oil-in-water emulsions, flowable concentrates and / or suspoemulsions), etc., which may be optionally thickened into gels. Common types of aqueous liquid formulations are soluble concentrates, suspension concentrates, capsule suspensions, concentrated emulsions, microemulsions, oil-in-water emulsions, flowable concentrates, and suspoemulsions. Common types of non-aqueous liquid formulations are emulsifiable concentrates, microemulsifiable concentrates, dispersible concentrates, and oil dispersions.

[0083] Common types of solid formulations are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings), etc., 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. The active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation. Alternatively, the entire formulation of the active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay the release of the active ingredient. Emulsifiable granules combine the advantages of both emulsifiable concentrate and dry granule formulations. High-strength formulations are mainly used as intermediates for further formulation.

[0084] Sprayable formulations are typically made up in a suitable medium before spraying. Such liquid and solid formulations are formulated to be easily diluted with the spray medium, usually water, but sometimes another suitable medium such as aromatic or paraffinic hydrocarbons or vegetable oils. Spray volumes can range from about one to several thousand liters per hectare, but more typically range from about 10 to several hundred liters per hectare. Sprayable formulations may be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to plant growth medium.

[0085] Liquid and dry formulations can be metered directly into a drip irrigation system or metered into furrow within the plantings.

[0086] The formulations typically contain effective amounts of active ingredients, diluents, and surfactants within the following approximate ranges, as shown in Table 2, totaling 100% by weight. [Table 2]

[0087] 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 sodium 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.

[0088] 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 oil, ordinary paraffin, isoparaffin); alkylbenzenes; alkylnaphthalenes; glycerin; glycerol triacetate; sorbitol; aromatic hydrocarbons; dearomatized aliphatics; alkylbenzenes; alkylnaphthalenes; ketones such as cyclohexanone, 2-heptanone, isophorone, and 4-hydroxy-4-methyl-2-pentanone; isoacetate. acetates such as phenyl, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate, and isobornyl acetate; alkylated lactates, dibasic esters, alkyl and aryl benzoates, and other esters such as gamma-butyrolactone; and alcohols which may be linear, branched, saturated, or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 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-C8 fatty acids), such as vegetable seed and fruit oils (e.g., olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grape seed, safflower, cottonseed, soybean, rapeseed, coconut, and palm kernel oils), fats of animal origin (e.g., beef tallow, pork fat, lard, cod liver oil, fish oil), and mixtures thereof. 22Liquid diluents include alkylated fatty acids (e.g., methylated, ethylated, butylated), which can be obtained by hydrolysis of glycerol esters from vegetable and animal sources and purified by distillation. Typical liquid diluents are described in C. Marsden & S. Mann, Solvents Guide, Cleaver-Hume Press, London, 1963.

[0089] Surfactants can be classified as nonionic, anionic, or cationic. Nonionic surfactants useful in the formulations of the present invention include, but are not limited to, alcohol alkoxylates, such as alcohol alkoxylates (which may be branched or linear) based on natural and synthetic alcohols prepared from alcohols and ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof; amine ethoxylates, alkanolamides, and ethoxylated alkanolamides; alkoxylated triglycerides, such as ethoxylated soybean oil, castor oil, and rapeseed oil; alkylphenol alkoxylates, such as octylphenol ethoxylate, nonylphenol ethoxylate, dinonylphenol ethoxylate, and dodecylphenol ethoxylate, prepared from phenol and ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof; block polymers prepared from ethylene oxide or propylene oxide, and reverse block copolymers in which the end blocks are prepared from propylene oxide. ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenols (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 glycol (PEG); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar derivatives such as sucrose esters, alkyl polyglycosides, and alkyl polysaccharides.

[0090] Useful anionic surfactants include, but are not limited to, alkylarylsulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenylsulfonic acid derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acid or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates, and phosphate esters of styrylphenol ethoxylates; protein-based surfactants; sarcosine derivatives; styrylphenol ethoxylates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzene; sulfonates of condensed naphthalene; sulfonates of naphthalene and alkylnaphthalenes; sulfonates of fractionated petroleum; sulfosuccinates; and sulfosuccinates and derivatives thereof, such as dialkyl sulfosuccinates.

[0091] Useful cationic surfactants include, but are not limited to, amides and ethoxylated amides; amines such as N-alkylpropanediamines, tripropylenetriamines, and dipropylenetetraamines, as well as ethoxylated amines, ethoxylated diamines, and propoxylated amines (prepared from 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.

[0092] Also useful in the formulations of the present invention 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 various 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.

[0093] The formulations of the present invention may also contain formulation aids and additives known to those skilled in the art as formulation adjuvants (some of which may be considered to function as solid diluents, liquid diluents, or surfactants). Such formulation aids and additives may control: pH (buffers), foaming during processing (antifoaming agents such as polyorganosiloxanes), active ingredient settling (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antibacterial agents), product freezing (antifreeze), color (dye / pigment dispersions), wash-off (film formers or spreading agents), evaporation (evaporation inhibitors), and other formulation attributes. Film formers include, for example, polyvinyl acetate, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohol, polyvinyl alcohol copolymers, and waxes. Examples of formulation adjuvants 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 WO 03 / 024222.

[0094] The compounds of the present invention and any other active ingredients are typically incorporated into the formulations of the present invention by dissolving the active ingredients 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 formulation intended for use as an emulsifiable concentrate is immiscible in water, an emulsifier is typically added to emulsify the active ingredient-containing solvent when diluted with water. Active ingredient slurries having particle sizes up to 2,000 microns can be wet-milled using a media mill to obtain particles with an average diameter of less than 3 microns. The aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. Pat. No. 3,060,084) or can be further processed by spray drying to form water-dispersible granules. Dry formulations usually require a dry milling process that produces an average particle diameter in the range of 2 microns to 10 microns. Dusts and powders can be prepared by blending and usually grinding (such as a hammer mill or a fluid-energy mill). Granules and pellets can be prepared by spraying the active material onto a preformed granular carrier 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 International Patent Publication No. 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 Patent No. 3,246,493. Tablets can be prepared as taught in U.S. Patent Nos. 5,180,587, 5,232,701, and 5,208,030. Films can be prepared as taught in British Patent No. 2,095,558 and U.S. Patent No. 3,299,566.

[0095] For details regarding formulation technology, 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 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. U.S. Patent No. 3,235,361, column 6, lines 16-7, line 19, and Examples 10-41; U.S. Patent No. 3,309,192, column 5, lines 43-7, line 62, and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167, and 169-182; U.S. Patent No. 2,891,855, column 3, lines 66-5, 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 See also, U.S. Patent Publications, Richmond, UK, 2000.

[0096] biological activity The test results show that the compounds of the present invention are highly active pre-emergence and / or post-emergence herbicides and / or plant growth inhibitors. The compounds of the present invention generally show the highest activity for post-emergence weed control (e.g., applied after weed seedlings emerge from the soil) and pre-emergence weed control (e.g., applied before weed seedlings emerge from the soil). Many of them have utility for broad spectrum pre-emergence and / or post-emergence weed control in areas where complete control of all vegetation is desired, such as fuel storage tanks, industrial storage areas, parking lots, drive-in theaters, airports, river banks, irrigation, and around other waterways, around billboards and highway and railroad structures. Many of the compounds of the present disclosure are useful for selective control of grass and broadleaf weeds in crop / weed mixtures by selective metabolism in the crop against weeds, or by selective activity at loci of physiological inhibition in the crop and weed, or by selective placement on or in the environment of the crop and weed mixture. Those skilled in the art will recognize that preferred combinations of these selection factors within a compound, or group of compounds, can be readily determined by performing routine biological and / or biochemical assays.

[0097] In some variations, provided herein are methods of controlling undesirable vegetation comprising applying a compound of formula (II), (II), or (III), or a salt thereof (including an agriculturally suitable salt thereof). In some variations, the compound is applied at a low application rate. In certain variations, the compound is applied at a low application rate of 10,000 m. 2 1~10,000g per 10,000m 2 2~5,000g per 10,000m 2 5~2,000g per 10,000m 2 1~1000g per 10,000m 2 1-500g per 10,000m 2 1-100g per 10,000m 2 1-75g per 10,000m 2 15~1000g per 10,000m 2 15-100g per 10,000m 215-75g per 10,000m 2 In certain variations of the foregoing, application of the compounds at the above application rates results in post-emergence control of undesirable vegetation and / or pre-emergence control of undesirable vegetation.

[0098] In certain variations, application of the compound with the aforementioned application rates results in burn down. In one variation, burn down refers to when a herbicide is used to reduce the presence of weeds at the time of treatment. Burn down is often used in minimum or no-till fields because weeds cannot be controlled by excavating the soil. Burn down applications can be used after harvest and / or before crop emergence. Burn down can be useful for weeds that emerge during the growing season.

[0099] In certain variations, application of the compounds, including the application rates described above, confers residual control. The compounds described herein may be used as pre-emergence herbicides that may be applied after planting of the crop, but prior to crop and / or weed emergence. Herbicides that are considered pre-emergence may also be referred to as herbicides that confer "residual control" and provide extended control of emerging or newly emerged weeds.

[0100] In one variation, the undesirable vegetation is controlled by 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%. In some variations of the above, the undesirable vegetation is a weed. In one variation, the undesirable vegetation is a PPO inhibitor-resistant weed.

[0101] Examples of crop fields treated with the compounds of the present invention include food 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 rapeseed fields, and sugar crop fields such as sugarcane fields and sugar beet fields. In one variation, the crop fields treated with the compounds of the present invention include corn, soybean, wheat, and cotton fields.

[0102] Examples of vegetable fields to be treated with the compound of the present invention include fields for growing Solanaceae vegetables (eggplant, tomato, green pepper, red pepper, potato, etc.), fields for growing Cucurbitaceae vegetables (cucumber, pumpkin, zucchini, watermelon, melon, etc.), fields for growing Cruciferae vegetables (radish, turnip, wasabi, kohlrabi, Chinese cabbage, cabbage, mustard, broccoli, cauliflower, etc.), fields for growing Asteraceae vegetables (burdock, chrysanthemum, almond, etc.), and fields for growing Medicinal plants (eggplant, tomato, bell pepper, red pepper, potato, etc.). These include fields for cultivating lily family vegetables (such as leeks, onions, garlic, and asparagus), fields for cultivating umbelliferous vegetables (such as carrots, parsley, celery, and parsnips), fields for cultivating chenopodiaceae vegetables (such as spinach and chard), fields for cultivating lamiaceae vegetables (such as perilla, mint, basil, and lavender), strawberry fields, sweet potato fields, yams, and taro fields.

[0103] Examples of land under perennial crops in the present invention include orchards, tea fields, mulberry fields, coffee fields, banana fields, palm fields, flowering tree plantations, flowering tree fields, plantation fields, nurseries, forests, and gardens. Examples of fruit trees in the present invention include pome fruits (apples, pears, Japanese pears, quince, quince, etc.), stone fruits (peaches, plums, nectarines, Japanese apricots, cherries, apricots, prunes, etc.), citrus fruits (unshu mandarins, oranges, lemons, limes, grapefruits, etc.), nuts (chestnuts, walnuts, hazelnut trees, almonds, pistachios, cashew nut trees, macadamia nut trees, etc.), berries (grapes, blueberries, cranberries, blackberries, raspberries, etc.), persimmons, olives, and loquats.

[0104] Examples of non-crop land in the present invention include playgrounds, vacant lots, railroad berms, parks, parking lots, roadside berms, dry river bottoms, land under power lines, residential areas, and industrial areas.

[0105] The crops cultivated in the crop field in the present invention are not limited, so long as the crops are varieties that are commonly cultivated as crops.

[0106] The above-mentioned varieties of plants can be plants that can be produced by natural crossing, plants that can be produced by mutation, F1 hybrid plants, or transgenic plants (also called genetically modified plants).Plants generally have characteristics such as acquired resistance to herbicides, accumulation of toxic substances to pests, suppression of susceptibility to diseases, increased potential yield, improved resistance to biotic and abiotic stress factors, accumulation of substances, and improved storage and processability.

[0107] F1 hybrid plants are first generation hybrids obtained by crossing two different strain varieties and generally have heterosis characteristics, with traits superior to those of either of the parents.Transgenic plants have foreign genes introduced into them, such as from another organism, such as a microorganism, and have properties that are not readily obtainable by crossing, mutagenesis, or natural recombination in their natural environment.

[0108] Techniques for producing the above-mentioned plants include, for example, conventional breeding techniques, genetic engineering techniques, genomic breeding techniques, new breeding techniques, and genome editing techniques. Conventional breeding techniques are for obtaining plants with desired characteristics by mutation or crossbreeding. Genetic engineering techniques include techniques for imparting new characteristics to a target organism by extracting a target gene (DNA) from another organism (e.g., a microorganism) and introducing the target gene into the genome of the target organism. Genetic engineering techniques also include antisense or RNA interference techniques for imparting new or improved characteristics by silencing another gene present in the plant. Genomic breeding techniques are for improving breeding efficiency using genomic information, and examples of genomic breeding techniques include DNA marker (also called genomic marker or gene marker) breeding techniques and genomic selection. For example, DNA marker breeding is a method of selecting progeny having a targeted useful trait gene from a large number of crossbreeding progeny using a DNA marker, which is a DNA sequence that serves as a marker for the location of a specific useful trait gene on the genome. In this method, the cross progeny, when it is a seedling, is analyzed using DNA markers, effectively shortening the time required for breeding.

[0109] Genomic selection is a technique that creates a prediction formula from previously obtained phenotype and genomic information, and predicts characteristics from the prediction formula and genomic information without evaluating the phenotype, and can contribute to improving breeding efficiency. The term "new breeding technology" is a general term for breeding improvement (breeding) techniques that combine molecular biological techniques. Examples of new breeding techniques include cisgenesis / intragenesis, oligonucleotide-directed mutagenesis, RNA-dependent DNA methylation, genome editing, grafting into GM rootstocks or scions, reverse crossing, agroinfiltration, and seed production technology (SPT). Genome editing technology is a technique that converts genetic information in a sequence-specific manner, and this technology can be used to delete base sequences, replace amino acid sequences, introduce foreign genes, etc. Examples of tools include sequence-specific genome modification techniques such as zinc finger nucleases (ZFNs), TALENs, CRISPR-Cas9, CRISPER-Cpf1, meganucleases, and CAS9 nickases capable of sequence-specific DNA cleavage, as well as target-AIDs created by modifying the above-mentioned tools.

[0110] Examples of the above-mentioned plants include those listed in the database of genetically modified crops (GM approved database) registered on the electronic information site of the International Service for Acquisition of Agri-biotech Applications (ISAAA) (http: / / www.isaaa.org / ). More specific examples are herbicide-resistant plants, pest-resistant plants, disease-resistant plants, plants with modified product (e.g., starch, amino acids, and fatty acids) quality (e.g., with increased or decreased content or altered composition), reproductive trait-modified plants, abiotic stress-tolerant plants, and plants with modified growth or yield-related traits.

[0111] Mechanisms of herbicide resistance include reduced affinity between the drug and its target, rapid metabolism (degradation, modification, etc.) of the drug by expressed enzymes that inactivate the drug, or inhibition of drug uptake or translocation within the plant. Examples of plants that have been made tolerant to herbicides by genetic engineering techniques include plants that have been made tolerant to 4-hydroxyphenylpyruvate dioxygenase (hereinafter abbreviated as HPPD) inhibitors such as isoxaflutole and mesotrione, acetolactate synthase (hereinafter abbreviated as ALS) inhibitors such as imazethapyr-containing imidazolinone herbicides and thifensulfuron-methyl-containing sulfonylurea herbicides, 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 oxynil herbicides including bromoxylin. Preferred herbicide-tolerant transgenic plants to be treated with the combination of the present invention are cereals such as wheat, barley, rye, and oats, canola, sorghum, soybean, rice, rapeseed, sugar beet, sugarcane, grapes, lentils, sunflower, alfalfa, apples, drupes, coffee, tea, strawberry, turf, vegetables such as tomatoes, potatoes, cucumbers, and lettuce, more preferred herbicide-tolerant transgenic plants are cereals such as wheat, barley, rye, and oats, soybeans, rice, grapes, tomatoes, potatoes, and apples.

[0112] In one embodiment, to obtain a glyphosate herbicide-tolerant plant, one or more genes are introduced from glyphosate-tolerant EPSPS genes from Agrobacterium tumefaciens strain CP4 (CP4 epsps); glyphosate-metabolizing enzyme genes (glyphosate N-acetyltransferase) from Bacillus licheniformis whose metabolic activity is enhanced by shuffling technology (gat4601, gat4621); glyphosate-metabolizing enzymes (glyphosate oxidase genes, goxv247) from Ochrobacterum anthropi strain LBAA, and EPSPS genes (mepsps, 2mepsps) from maize with glyphosate-tolerant mutations. Prime examples of plants are alfalfa (Medicago sativa), Argentine canola (Brassica napus), cotton (Gossypium hirsutum L.), creeping bentgrass (Agrostis stolonifera), corn (Zea mays L.), Poland canola (Brassica rapa), potato (Solanum tuberosum L.), soybean (Glycine max L.), sugar beet (Beta vulgaris), and wheat (Triticum aestivum). Several glyphosate-tolerant transgenic plants are commercially available. For example, genetically modified plants expressing glyphosate-tolerant EPSPS derived from Agrobacterium are commercially available under trade names such as "Roundup Ready (registered trademark)", genetically modified plants expressing glyphosate-metabolizing enzymes having metabolic activity enhanced by Bacillus-derived shuffling technology are commercially available under trade names such as "Optimum (registered trademark) GAT (registered trademark)" or "Optimum (registered trademark) Gly Canola", and genetically modified plants expressing EPSPS having a glyphosate-tolerant mutation derived from corn are commercially available under trade names such as "GlyTol (registered trademark)".

[0113] In another example, to obtain a glufosinate herbicide-tolerant plant, one or more genes are introduced from the glufosinate metabolic enzyme phosphinothricin N-acetyltransferase (PAT) gene (bar) from Streptomyces hygroscopicus, the glufosinate metabolic enzyme phosphinothricin N-acetyltransferase (PAT) enzyme gene (pat) from Streptomyces viridochromogenes, and the synthetic pat gene (pat syn) from Streptomyces viridochromogenes strain Tu494. Major examples of plants include Argentine canola (Brassica napus), chicory (Cichorium intybus), cotton (Gossypium hirsutum L.), corn (Zea mays L.), Polish canola (Brassica rapa), rice (Oryza sativa L.), soybean (Glycine max L.), and sugar beet (Beta vulgaris). Some glufosinate-tolerant transgenic plants are commercially available. For example, transgenic plants derived from glufosinate-metabolizing enzymes (bar) derived from Streptomyces hygroscopicus and Streptomyces viridochromogenes are commercially available under the trade names "LibertyLink®", "InVigor®", or "WideStrike®".

[0114] In another embodiment, oxynil herbicide-resistant plants are known. For example, bromoxynil-resistant transgenic plants in which the nitrilase gene (bxn) is introduced from the oxynil herbicide-metabolizing enzyme from Klebsiella pneumoniae subsp. ozaenae. Main examples of plants are Argentine canola (Brassica napus), cotton (Gossypium hirsutum L.), and tobacco (Nicotiana tabacum L.). These plants are commercially available under trade names such as "Navigator® canola" or "BXN®".

[0115] ALS herbicide-resistant plants are also known. Examples include carnations (Dianthus caryophyllus) obtained by introducing an ALS herbicide-resistant ALS gene (surB) as a selection marker from tobacco (Nicotiana tabacum) and commercially available under the names "Moondust (registered trademark)", "Moonshadow (registered trademark)", "Moonshade (registered trademark)", "Moonlite (registered trademark)", "Moonaqua (registered trademark)", "Moonvista (registered trademark)", "Moonique (registered trademark)", "Moonpearl (registered trademark)", "Moonberry (registered trademark)" and "Moonvelvet (registered trademark)", flaxseed (Linum usitatissumum L.) into which an ALS herbicide-resistant ALS gene (als) derived from Arabidopsis thaliana has been introduced and which is commercially available under the trade name "CDC Triffid Flax", and corn (Zea mays) into which an ALS herbicide-resistant ALS gene (zm-hra) from corn has been introduced and which is resistant to sulfonylurea herbicides and imidazolinone herbicides. L.) is commercially available under the trade name "Optimum® GAT™", imidazolinone herbicide tolerant soybeans introduced with the ALS herbicide resistance gene (csr1-2) from Arabidopsis thaliana are commercially available under the trade name "Cultivance™", and sulfonylurea herbicide tolerant soybeans introduced with the ALS herbicide resistance gene (gm-hra) from soybean (Glycine max) are commercially available under the trade names "Treus™", "Plenish™" and "Optimum® GAT™". Cotton introduced with the ALS herbicide resistance gene (S4-HrA) from tobacco (Nicotiana tabacum cv. Xanthi) is also available.

[0116] HPPD herbicide-tolerant plants are also known. In one example, soybean is introduced simultaneously with the mesotrione-tolerant HPPD gene (avhppd-03) from oat (Avena sativa) and the phynothricin N-acetyltransferase (PAT) enzyme gene (pat). In another example, mesotrione-tolerant soybean is commercially available that is introduced with the glufosinate-metabolizing enzyme from Streptomyces viridochromogenes.

[0117] In another example, examples of 2,4-D-tolerant plants include corn into which the aryloxyalkanoate dioxygenase gene (aad-1) for the 2,4-D metabolic enzyme derived from Sphingobium herbicidovorans has been introduced, which is commercially available under the trade name "Enlist (registered trademark) corn," and soybeans and cotton into which the aryloxyalkanoate dioxygenase gene (aad-12) for the 2,4-D metabolic enzyme derived from Delftia acidovorans has been introduced, which are commercially available under the trade name "Enlist (registered trademark) soybeans."

[0118] In another embodiment, dicamba-tolerant plants include soybean and cotton introduced with a dicamba monooxygenase gene (dmo) having dicamba-metabolizing enzymes from Stenotrophomonas maltophilia strain DI-6; and soybean (Glycine max L.) introduced with a glyphosate-tolerant EPSPS gene (CP4 epsps) from Agrobacterium tumefaciens strain CP4 simultaneously with the above-mentioned genes, and are commercially available under the trade name "Genuity® Roundup Ready™ 2 Xtend®."

[0119] Further examples of commercially available transgenic plants conferring herbicide tolerance include glyphosate tolerant corn "Roundup Ready® Maize", "Roundup Ready® 2", "Agrisure® GT", "Agrisure® GT / CB / LL", "Agrisure® GT / RW", "Agrisure® 3000GT", "YieldGard™ VT™ Rootworm / RR2", and "YieldGard™ VT™ Triple"; glyphosate tolerant soybean "Roundup Ready® Soybean" and "Optimum® GAT"; glyphosate tolerant cotton "Roundup Ready® Cotton" and "Roundup Ready® Flex"; glyphosate tolerant canola "Roundup Ready® Canola"; glyphosate tolerant alfalfa "Roundup Ready® Alfalfa"; glyphosate tolerant rice "Roundup Ready® Rice ... Ready® rice; glufosinate-tolerant corn "Roundup Ready® 2", "LibertyLink®", "Herculex® 1", "Herculex® RW", "Herculex® Xtra", "Agrisure® GT / CB / LL", "Agrisure® CB / LL / RW", and "Bt10"; glufosinate-tolerant cotton "FiberMax® LibertyLink®"; glufosinate-tolerant canola "InVigor®"; glufosinate-tolerant rice "LibertyLink® Rice" (manufactured by Bayer AG); bromoxynil-tolerant cotton "BXN"; bromoxynil-tolerant canola "Navigator®" and "Compass®"; and glufosinate-tolerant canola "InVigor®".Additional plants modified with herbicides are widely known, and exemplary plants include glyphosate-tolerant alfalfa, apple, barley, eucalyptus, linseed, grapes, lentils, rapeseed, peas, potatoes, rice, sugar beets, sunflowers, tobacco, tomatoes, turf, and wheat (see, e.g., U.S. Pat. Nos. 5,188,642, 4,940,835, 5,633,435, 5,804,425, and 5,627,061). Dicamba-tolerant beans, cotton, soybeans, peas, potatoes, sunflowers, tomatoes, tobacco, corn, sorghum, and sugarcane (see, e.g., WO2008051633, U.S. Pat. Nos. 7,105,724, and 5,670,454); glufosinate-tolerant soybeans, sugar beets, potatoes, tomatoes, and tobacco (see, e.g., U.S. Pat. Nos. 6,376,754, 5,646,024, and 5,561,236); 2,4-D-tolerant cotton, peppers, apples, tomatoes, sunflowers, tobacco, potatoes, corn, cucumbers, wheat, soybeans, sorghum, and cereals (see, e.g., U.S. Pat. Nos. 6,153,401, 6,100,446, WO2005 107437, U.S. Pat. Nos. 5,608,147, and 5,670,454); and canola, corn, millet, barley, cotton, mustard, lettuce, lentil, melon, millet, oats, sword beans, potato, rice, rye, sorghum, soybean, and other crops that are resistant to acetolactate synthase (ALS) inhibitor herbicides. Sugar beet, sunflower, tobacco, tomato, and wheat (e.g., sulfonylurea and imidazolinone herbicides) (see, e.g., 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).Rice that is tolerant to imidazolinone herbicides is particularly known, examples of which include rice with specific mutations (e.g., S653N, S654K, A122T, S653(At)N, S654(At)K, and A122(At)T) in the acetolactate synthase gene (see, e.g., US 2003 / 0217381 and WO 200520673), such as HPPD inhibitor herbicides (e.g., isoxaflutole, etc.). Examples of herbicides that can be used include barley, sugarcane, rice, corn, tobacco, soybean, cotton, rapeseed, sugar beet, wheat, and potato that are resistant to herbicides such as xazole herbicides, triketone herbicides such as sulcotrione or mesotrione, pyrazole herbicides such as pyrazophosphates, or diketonitriles, which are degradation products of isoxaflutole (see, e.g., WO2004 / 055191, WO199638567, WO1997049816, and U.S. Pat. No. 6,791,014).

[0120] Examples of plants that have been conferred herbicide resistance by classical or genomic breeding techniques include rice "Clearfield® Rice", wheat "Clearfield® Wheat", sunflower "Clearfield® Sunflower", lentil "Clearfield® Lentil", and canola "Clearfield® Canola" (BASF SE), soybean "STS® Soybean" that is resistant to sulfonyl ALS inhibitor herbicides such as thifensulfuron-methyl, sethoxydim-tolerant corn "SR® Maize" and "Poast" that is resistant to acetyl-CoA carboxylase inhibitors such as trione oxime herbicides or aryloxyphenoxypropionic acid herbicides. "ExpressSun®" sunflower tolerant to sulfonylurea herbicides such as tribenuron; "Provisia™ Rice" rice tolerant to acetyl-CoA carboxylase inhibitors such as quizalofop; and "Triazine Tolerant Canola" canola tolerant to PSII inhibitors.

[0121] An example of a plant that has been given herbicide resistance by genome editing technology is the sulfonylurea herbicide-resistant canola "SU Canola" using the Rapid Trait Development System (RTDS). RTDS corresponds to the oligonucleotide-directed mutagenesis of genome editing technology, and RTDS allows for the introduction of mutations into the DNA of a plant without cleaving the DNA, via gene repair oligonucleotides (GRONs), i.e., chimeric oligonucleotides of DNA and RNA. Examples of plants include corn that has been given herbicide resistance and reduced phytic acid content by deleting the endogenous gene IPK1 using zinc finger nucleases (see, for example, Nature 459,437-441 2009), and rice that has been given herbicide resistance using CRISPR-Cas9 (see, for example, Rice,7,5 2014).

[0122] In the present invention, examples of crops that are resistant to a particular PPO inhibitor include crops that have a PPO with reduced affinity for the inhibitor imparted by genetic engineering techniques. Alternatively, the crop may have a substance that detoxifies and decomposes the PPO inhibitor by cytochrome P450 monooxygenase, either alone or in combination with the above-mentioned PPO. Resistant crops are described, for example, in patent literature such as WO2011085221, WO2012080975, WO2014030090, WO2015022640, WO2015022636, WO2015022639, WO2015092706, WO2016203377, WO2017198859, WO2018019860, WO2018022777, WO2017112589, WO2017087672, WO2017039969, and WO2017023778, as well as in the non-patent literature Li & Nicholl in Pest Management Science (2005), Vol. 61, pgs. 277-285.

[0123] An example of a plant that has been made herbicide-tolerant through new breeding techniques in which grafting is used to impart GM rootstock characteristics to the scion is a non-transgenic soybean scion that has been made glyphosate-tolerant using the glyphosate-tolerant soybean Roundup Ready® as the rootstock (see Jiang, et al., in Weed Technology (2013) Vol. 27, pgs. 412-416).

[0124] The above-mentioned plants include lines that have been imparted with two or more traits from among the above-mentioned abiotic stress resistance, disease resistance, herbicide resistance, pest resistance, growth traits, yield traits, nutritional intake, product quality, and reproduction traits using genetic engineering techniques, classical breeding techniques, genomic breeding techniques, new breeding techniques, genome editing techniques, etc., and lines that have been imparted with two or more traits from the characteristics of parent lines by crossing plants with the same or different characteristics.

[0125] Examples of commercially available plants that are resistant to two or more herbicides include "GlyTol™ LibertyLink™" and "GlyTol™ LibertyLink™" cotton tolerant to glyphosate and glufosinate; "Roundup Ready™ LibertyLink™ Corn" corn tolerant to glyphosate and glufosinate; "Enlist™ Soybean" soybean tolerant to glufosinate and 2,4-D; "Genuity® Roundup Ready™ 2 Xtend™" soybean tolerant to glyphosate and dicamba; "OptimumGAT™" corn and soybean tolerant to glyphosate and ALS inhibitors; and "Enlist E3™" and "Enlist™ Roundup™" genetically modified soybeans tolerant to glyphosate, glufosinate, and 2,4-D. "Enlist(TM) Roundup Ready(TM) Corn 2" genetically modified corn resistant to glyphosate, 2,4-D, and aryloxyphenoxypropionate (FOP) herbicides; "Enlist(TM) Roundup Ready(TM) Corn 2" genetically modified corn resistant to glyphosate, 2,4-D, and aryloxyphenoxypropionate (FOP) herbicides; "Bollgard II(TM) XtendFlex(TM) Cotton" genetically modified cotton resistant to dicamba, glyphosate, and glufosinate; and "Enlist(TM) Cotton" genetically modified cotton resistant to glyphosate, glufosinate, and 2,4-D herbicides. In addition, cotton tolerant to glufosinate and 2,4-D, cotton tolerant to both glufosinate and dicamba, corn tolerant to both glyphosate and 2,4-D, soybean tolerant to both glyphosate and HPPD herbicides, and genetically modified corn tolerant to glyphosate, glufosinate, 2,4-D, aryloxyphenoxypropionate (FOP) herbicides, and cyclohexanedione (DIM) herbicides have also been developed.

[0126] Examples of commercially available plants that are provided with herbicide tolerance and pest resistance include YieldGard Roundup Ready® and YieldGard Roundup Ready® 2 corn tolerant to glyphosate and resistant to pine moth; Agrisure® CB / LL corn tolerant to glufosinate and resistant to pine moth; Yield Gard® VT Rootworm / RR2 corn tolerant to glyphosate and resistant to corn rootworm and pine moth; Gard® VT Triple; corn tolerant to glufosinate and resistant to lepidopteran corn pests (Cry1F) (e.g., resistant to western bean cutworm, pine moth, cutworm moth, and fall armyworm); corn tolerant to glyphosate and resistant to corn rootworm; corn tolerant to glyphosate and resistant to corn rootworm; "Agrisure® GT / RW" corn tolerant to glufosinate and resistant to coleopteran corn pests (Cry3A) (e.g., resistant to western corn rootworm, northern corn rootworm, and Mexican corn rootworm); "Herculex® RW" corn tolerant to glufosinate and resistant to coleopteran corn pests (Cry34 / 35Abl) (e.g., resistant to western corn rootworm, northern corn rootworm, and Mexican corn rootworm); "Yield® RW" corn tolerant to glyphosate and resistant to corn rootworm; Gard® VT Rootworm / RR2; and Bollgard 3® XtendFlex®, a cotton that is tolerant to dicamba, glyphosate, and glufosinate and resistant to coleopteran cotton pests (e.g., resistant to bollworm, cotton bollworm, and armyworm).

[0127] In the present invention, the composition of the present invention is applied to the place where the weeds are growing or may grow. Examples of the method of applying the composition include spraying the composition on the soil and spraying the composition on the weeds.

[0128] In some variations, the application rate of the compositions of the invention is generally about 10,000 m of total amount of compound of formula I, II, III, or IV, or a salt thereof (including agriculturally suitable salts thereof). 2 1~10,000g per 10,000m 2 2~5,000g per 10,000m 2 5~2000g per 10,000m 2 1~1000g per 10,000m 2 1-500g per 10,000m 2 1-100g per 10,000m 2 1-75g per 10,000m 2 15~1000g per 10,000m 2 15-100g per 10,000m 2 15-75g per 10,000m 2 Each serving weighs 15 to 60 grams.

[0129] In one variant, the application rate of the composition of the present invention is the total amount of the compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener compound group C, generally in an amount of 10,000 m 2 1~10,000g per 10,000m 2 2~5,000g per 10,000m 2 5~2,000g per 10,000m 2 1~1,000g per 10,000m 2 1-500g per 10,000m 2 1-100g per 10,000m 2 1-75g per 10,000m 2 15~1000g per 10,000m 215-100g per 10,000m 2 15-75g per 10,000m 2 Each serving weighs 15 to 60 grams.

[0130] In this method, the adjuvant can be mixed in the composition of the present invention and then applied.The type of adjuvant is not particularly limited, and examples of adjuvants include oil adjuvants such as Agri-Dex (registered trademark) and methylated rapeseed oil (MSO), non-ionic (polyoxyethylene ester or ether) such as Induce, anionic (substituted sulfonate) such as Gramine S, cationic (polyoxyethylene amine) such as Genamin (registered trademark) T200BM, and organic silicone such as Silwet (registered trademark) L77.

[0131] The pH and hardness of the spray liquid prepared when applying the composition of the present invention are not particularly limited. The pH is usually in the range of 5-9, and the hardness is usually in the range of 0-500.

[0132] The period for applying the composition of the present invention is not particularly limited, and is usually in the range of 5:00 a.m. to 9:00 p.m., and the photon flux density is usually 10 to 2,500 μmol / m 2 / s.

[0133] When the composition of the present invention is applied to the crop field, it can be applied before sowing the crop seed, at the same time as sowing the crop seed, and / or after sowing the crop seed.That is, the frequency of application of the composition of the present invention is once before sowing the crop seed, at the same time as sowing, or after sowing, twice except before sowing, twice except at the same time as sowing, or twice except after sowing, or three times at all timings.

[0134] When the composition of the present invention is applied prior to sowing the crop seeds, it is applied from 50 days prior to sowing to just before, preferably from 30 days prior to sowing to just before, more preferably from 20 days prior to sowing to just before, and even more preferably from 10 days prior to sowing to just before.

[0135] When the composition of the present invention is applied after sowing the crop seeds, it is usually applied from immediately after sowing to before flowering. More preferably, the composition is applied from immediately after sowing to before emergence or from the 1-6 leaf stage of the crop. When the composition of the present invention is applied simultaneously with sowing the crop seeds, it is when the seeding machine and the sprayer are integrated with each other.

[0136] In the step of applying the composition of the present invention to the cultivation area, the compound or compounds of formula I and at least one further compound selected from the group consisting of herbicide compound group B and safener group C are usually mixed with a carrier such as a solid carrier or liquid carrier, and a formulation auxiliary such as a surfactant is added as necessary to prepare a formulation. Preferred 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 preferred formulation types are emulsifiable concentrates. Furthermore, a formulation containing only the compound of formula I as an active ingredient may be used in combination with a formulation containing at least one compound selected from the group consisting of herbicide compound group B and safener group C as an active ingredient. Furthermore, a formulation containing the composition of the present invention as an active ingredient and a formulation containing another herbicide as an active ingredient may be used in combination.

[0137] Examples of the method of applying the composition of the present invention to a cultivated area include spraying it on the soil of the cultivated area and spraying the composition of the present invention on growing weeds. The composition is usually diluted with water and then sprayed. The spray volume is not particularly limited, and is usually 50 to 1,000 L / ha, preferably 100 to 500 L / ha, more preferably 140 to 300 L / ha.

[0138] Specific examples of weed species controlled by the present compositions include, but are not limited to, the weed species listed below.

[0139] Urticaceae weeds to be controlled include Urtica urens.

[0140] Polygonaceae weeds 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.

[0141] Portulacaceae weeds controlled include Portulaca oleracea.

[0142] Caryophyllaceae weeds controlled include Stellaria media, Stellaria aquatica, Cerastium holosteoides, Cerastium glomeratum, Spergula arvensis, and Silene gallica.

[0143] Weeds in the Garland family that are controlled include Mollugo verticillate.

[0144] Chenopodiaceae weeds controlled include Chenopodium album, Chenopodium ambrosioides, Kochia scoparia, Salsola kali, and Atriplex spp.

[0145] Amaranthaceae weeds 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.

[0146] Papaveraceae weeds controlled include Papaver rhoeas, Papaver dubium, and Argemone Mexicana.

[0147] Cruciferous weeds 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.

[0148] Capparaceae weeds controlled include Cleome affinis.

[0149] Leguminous weeds controlled include Aeschynomene indica, Aeschynomene rudis, Sesbania exaltata, Cassia obtusifolia, Cassia occidentalis, Desmodium adscendens, Desmodium illinoense, Trifolium repens, Pueraria lobata, Vicia angustifolia, Indigofera hirsuta, Indigofera truxillensis, and Vigna sinensis.

[0150] Oxalid weeds controlled include Oxalis, Oxalis strica, and Oxalis oxyptera.

[0151] Geranium weeds controlled include Geranium carolinense and Erodium cicutarium.

[0152] Euphorbiaceae weeds 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.

[0153] Malvaceae weeds controlled include Abutilon theophrasti, Sida rhombiforia, Sida cordifolia, Sida spinosa, Sida glaziovii, Sida santaremnensis, Hibiscus trionum, Anoda cristata, and Malvastrum coromandelianum.

[0154] Onagraceae weeds controlled include Ludwigia epilobioides, Ludwigia octovalvis, Ludwigia decurre, Oenothera biennis, and Oenothera laciniata.

[0155] Sterculiaceae weeds controlled include Waltheria indica.

[0156] Violet weeds controlled include Viola arvensis and Viola tricolor.

[0157] Cucurbitaceae weeds controlled include Sichyos angulatus, Echinocystis lobata, and Momordica charantia.

[0158] Lythraceae weeds controlled include Ammannia multiflora, Ammannia auriculata, Ammannia coccinea, Lythrum salicaria, and Rotala indica.

[0159] The Lycopersicon gracilis weeds controlled include Elatine triandra and Elatine californica.

[0160] Umbelliferous weeds controlled include Oenanthe javanica, Daucus carota, and Conium maculatum.

[0161] Pine algae weeds controlled include Ceratophyllum demersum.

[0162] The Cabomba family weeds controlled include Cabomba caroliniana.

[0163] Weeds of the family Myriophyllum family that are controlled include Myriophyllum aquaticum, Myriophyllum verticillatum, Myriophyllum spicatum, and Myriophyllum heterophyllum.

[0164] Sapindaceae weeds controlled include Cardiospermum halicacabum.

[0165] Primulaceae weeds controlled include Anagallis arvensis.

[0166] Asclepiadaceae weeds controlled include Asclepias syriaca and Ampelamus albidus.

[0167] Rubiaceae weeds controlled include Galium aparine, Galium spurium var. echinospermon, Spermacoce latifolia, Richardia brasiliensis, and Borreria alata.

[0168] Rubiaceae weeds 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.

[0169] Purple flowering weeds controlled include Myosotis arvensis.

[0170] Lamiaceae weeds controlled include Lamium purpureum, Lamium amplexicaule, Leonotis nepetaefolia, Hyptis suaveolens, Hyptis lophanta, Leonurus sibiricus, and Stachys arvensis.

[0171] Solanaceous weeds 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.

[0172] Scrophulariaceae weeds controlled include Veronica hederaefolia, Veronica persica, Veronica arvensis, Lindernia procumbens, Lindernia dubia, Lindernia angustifolia, Bacopa rotundifolia, Dopatrium junceum, and Gratiola japonica.

[0173] Plantago family weeds controlled include Plantago asiatica, Plantago lanceolata, Plantago major, and Callitriche palustris.

[0174] The aster family weeds 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 hispidus, Cardiospermum halicacabum, Ageratum conyzoides, Eupatorium perfoliatum, Eclipta alba, Erechtites hieracifolia, Gamochaeta spicata, Gnaphalium spicatum, Jaegeriahirta, Parthenium hysterophorus, Siegesbeckia orientalis, Soliva sessilis, Eclipta prostrata, Eclipta alba and Centipeda minima.

[0175] Weeds of the Albustaceae family that may be controlled include Sagittaria pygmaea, Sagittaria trifolia, Sagittaria sagittifolia, Sagittaria montevidensis, Sagittaria aginashi, Alisma canaliculatum, and Alisma plantago-aquatica.

[0176] Weeds in the Saxifraga family that are controlled include Limnocharis flava.

[0177] Hydrophila weeds controlled include Limnobium spongia, Hydrilla verticillata, and Najas guadalupensis.

[0178] Araceae weeds controlled include Pistia stratiotes.

[0179] Duckweed weeds controlled include Lemna aoukikusa, Spirodela polyrhiza, and Wolffia spp.

[0180] The Potamogeton family species controlled include Potamogeton distinctus, Potamogeton crispus, Potamogeton illinoensis, and Stuckenia pectinata.

[0181] Liliaceae weeds controlled include Allium canadense, Allium vineale, and Allium macrostemon.

[0182] Weeds of the Pontederiaceae family that are controlled include the genera Eichhornia crassipes, Heteranthera limosa, Monochoria korsakowii, and Monochoria vaginalis.

[0183] Daylily weeds controlled include Commelina communis, Commelina bengharensis, Commelina erecta, and Murdannia keisak.

[0184] The grass weeds 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 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, Chlorisgayana, 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.

[0185] Cyperus 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 These include Bolboschoenus nipponicus, Schoenoplectiella triqueter, Bolboschoenus koshevnikovii, and Bolboschoenus fluviatilis.

[0186] Equisetum weeds controlled include Equisetum arvense and Equisetum palustre.

[0187] Salvinaceae weeds controlled include Salvinia natans.

[0188] Azollaceae weeds controlled include Azolla japonica and Azolla imbricata.

[0189] Marsilea family weeds controlled include Marsilea quadrifolia.

[0190] Other weeds controlled include Pithophora, Cladophora, Bryophyta, Marchantiophyta, Anthocerotophyta, Cyanobacteria, Pteridophyta, and suckers of perennial crops (e.g., pome fruits, nuts, citrus, hops, grapes).

[0191] In the above-mentioned weeds to be controlled, the intraspecific mutation is not particularly limited. That is, the weeds include weeds with reduced sensitivity to a particular herbicide. The reduced sensitivity may be due to a mutation at the target site (target site mutation) or due to any factor other than a mutation at the target site (non-target site mutation). Examples of factors of reduced sensitivity due to non-target site mutation include increased metabolism, impaired absorption, impaired translocation, and excretion outside the system. Examples of factors of increased metabolism include increased activity of metabolic enzymes such as cytochrome P450 monooxygenase, aryl acylamidase, esterase, or glutathione S-transferase. Examples of excretion outside the system include transport to the vacuole by ABC transporters. Examples of weeds having reduced susceptibility due to a mutation at the target site include weeds having any one 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 weeds having reduced susceptibility due to target site mutations include weeds having any one 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.

[0192] Similarly, examples of weeds with reduced susceptibility due to mutations at the target site include PPO inhibitor-resistant weeds with one or more mutations selected from Arg128Leu mutation, Arg128Met mutation, Arg128Gly mutation, Arg128His mutation, Gly210 deletion mutation, and Gly399Ala mutation in PPO. The word "PPO" means protoporphyrinogen oxidase. Weeds usually have PPO1 and PPO2 in PPO, and the above-mentioned mutations can be present in either or both PPO1 or PPO2. It is preferable if the weed has a mutation in PPO2. 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 the PPO2 of Ambrosia artemisiaefolia, the mutation corresponds to a mutation at amino acid 98 (Rousonelos, et al., Weed Science (2012) Vol. 60, pgs. 335-344) and is known as Arg98Leu, where Arg98 is equivalent to Arg128 according to the present invention. The Arg128Met mutation and Arg128Gly mutation in the PPO of the weeds controlled by the present invention are known in 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 resistant weeds are particularly effectively controlled, but the weeds that are particularly effectively controlled are not limited thereto. That is, other weeds having amino acid mutations 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 mutations, Ambrosia artemisiaefolia having the above mutations, Lolium rigidum having the above mutations, Lolium multiflorum having the above mutations, and Euphorbia heterophylla having the above mutations are effectively controlled.

[0193] Similarly, examples of weeds with reduced susceptibility due to target site mutations include weeds with amino acid substitutions such as Thr102Ile, Pro106Ser, Pro106Ala, or Pro106Leu in the EPSP gene. In particular, Eleusine indica, Lolium multiflorum, Lolium rigidum, Digitaria insularis, waterhemp, Echinochloa colona, ​​etc., which are resistant to glyphosate and have one or both mutations, are effectively controlled. Similarly, examples of weeds with reduced susceptibility due to target site include weeds with increased copies of the EPSP gene, and Amaranthus palmeri, waterhemp, Kochia scoparia, etc., which are resistant to glyphosate and have mutations, are particularly effectively controlled. Conyza canadensis, Conyza smatrensis, and Conyza bonariensis, which are resistant to glyphosate involving ABC transporters, are also effectively controlled.

[0194] In the cultivation of the crop according to the present invention, the plant nutrition management in the general cultivation of the crop can be carried out. The pollination system can be based on precision agriculture or a conventional uniform one. In addition, nitrogen fixing bacteria or symbiotic bacteria can be inoculated in combination with seed treatment.

[0195] combination In certain embodiments, weed control effects are demonstrated by using a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) in combination with a specific compound.

[0196] Thus, the present invention features (i) a herbicide composition comprising a compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener group C, wherein the weight ratio of the compound of formula I to the at least one compound selected from the group consisting of herbicide compound group B and safener group C is 1:0.1 to 1:50, and herbicide compound group B is the 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 inhibitor, B-4 4-hydrophenylpyruvate dioxygenase inhibitors, B-5 phytoene desaturase inhibitors, B-6 Photosystem II inhibitors, B-7 Very long chain fatty acid synthesis inhibitor, B-8 microtubule formation inhibitor, 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 of each of B-1 to B-12).

[0197] The present invention also features a herbicidal composition according to (ii)(i), B-1 includes pyrithiobac, pyrithiobac-sodium salt, pyriminobac, pyriminobac-methyl, bispyribac, bispyribac-sodium salt, pyribenzoxim, pyrimisulfan, pyriftalid, triafamone, amidosulfuron, azimsulfuron, bensulfuron, bensulfuron-methyl, chlorimuron, chlorimuron-ethyl, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, flupyrsulfuron-methyl-sodium, foramsulfuronhalosulfuron, and flupyrsulfuron-methyl-sodium. Sulfuron, halosulfuron-methyl, imazosulfuron, mesosulfuron, mesosulfuron-methyl, metazosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron, primisulfuron, primisulfuron-methylpropyrisulfuron, pyrazosulfuron, pyrazosulfuron-ethyl, rimsulfuron, sulfometuron, sulfometuron-methyl, sulfosulfuron, trifloxysulfuron, trifloxysulfuron-sodium salt, chlorsulfuron, cinosulfuron, ethametsusulfuron, ethametsusulfuron-meth , 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 the group consisting of bazone-methyl, cloransulam, cloransulam-methyl, diclosulam, florasulam, flumetsusulam, 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); B-2 is the 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, propaxaxafop, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, alloxydim, clethodim, sethoxydim, tepriraloxydim, tralkoxydim, and pinoxaden (including their agriculturally acceptable salts and derivatives); B-3 is 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, thiafenacil, and ethyl [3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetate (including their agriculturally acceptable salts and derivatives); B-4 is benzobicyclon, bicyclopyrone, mesotrione, sulcotrione, tefuryltrione, tembotrione, isoxaclorthol, isoxaflutole, benzofenap, pyrasulfotole, pyrazolinate, pyrazoxyfen, fenquinotrion, 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: 140090 4-50-8), 2-chloro-N-(1-methyl-1H-tetrazol-5-yl)-3-(methylthio)-4-(trifluoromethylomethyl)-benzamide (CAS Registry Number: 1361139-71-0), and 4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexen-1-yl)carbonyl]-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione (CAS Registry Number: 1353870-34-4) (including their agriculturally acceptable salts and derivatives); B-5 is the group consisting of diflufenican, picolinafen, beflubutamid, norflurazon, fluridone, flurochloridone, and flutamone (including their agriculturally acceptable salts and derivatives); B-6 is a group consisting of ioxynil, ioxynil-octanoate, bentazon, pyridate, bromoxynil, bromoxynil-octanoate, chlorotoluron, dimefuron, diuron, linuron, fluometuron, isoproturon, isouron, tebuthiuron, benzthiazuron, methabenzthiazuron, propanil, metobromuron, methoxuron, monolinuron, siduronsimazine, atrazine, propazine, cyanazine, ametryn, simetryn, dimethametryn, prometryn, terbumeton, terbuthylazine, terbutryn, trietazine, hexazinone, metamitron, metribuzin, amicarbazone, bromacil, lenacil, terbacil, chloridazon, desmedipham, and phenmedipham (including their agriculturally acceptable salts and derivatives); B-7 is the group consisting of propachlor, metazachlor, alachlor, acetochlor, metolachlor, S-metolachlor, butachlor, pretilachlor, thienylchlor, indanofan, cafenstrole, fentrazamide, dimethenamid, dimethenamid-P, mefenacet, pyroxasulfone, fenoxasulfone, naproanilide, napropamide, anilofos, flufenacet, and ifencarbazone (including their agriculturally acceptable salts and derivatives); B-8 is the group consisting of trifluralin, pendimethalin, ethalfluralin, benfluralin, oryzalin, prodiamine, butamiphos, dithiopyr, and thiazopyr (including their agriculturally acceptable salts and derivatives); B-9 is 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, diolamine salt, ethadiyl 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 salts or esters (butocyl salt, dimethylammonium salt, 2-ethylhexyl ester, isooctyl ester, methyl ester, potassium salt, sodium salt, trolamine salt, and choline salt). the group consisting of triclopyr and its salts or esters (butotyl ester, triethylammonium salt), fluroxypyr, fluroxypyr meptyl, picloram and its salts (potassium salt, tris(2-hydroxypropyl)ammonium salt, choline salt), quinclorac, quinmelac, aminopyralid and its salts (potassium salt, tris(2-hydroxypropyl)ammonium salt, choline salt), clopyralid and its salts (olamine salt, potassium salt, triethylammonium salt, choline salt), clomeprop, aminocyclopyrachlor, halaxifene, halaxifene-methyl, florpyrauxifene, florpyrauxifene-benzyl (including their agriculturally acceptable salts and derivatives); 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 of each and derivatives thereof); B-11 is a group consisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, glufosinate-P-sodium salt, and baylaphos (including agriculturally acceptable salts and derivatives thereof); B-12 is an antioxidant that is effective against isoxaben, dichlobenil, methiozolin, diallate, butyrate, triallate, chlorpropham, asuram, phenisopham, benthiocarb, molinate, esprocarb, pyributicarb, prosulfocarb, orbencarb, EPTC, dimepiperate, swap, difenoxuron, methyl dimron, bromobutide, dimron, cumylron, diflufenzopyr, diflufenzopyr-sodium salt, etobenzanide, tridiphane, amylol, clomazone, 2-[(2,4-dichlorophenyl)methyl]-4,4-dimethylisoxazolidin-3-one ( The group consisting of (3S,4S)-N-(2-fluorophenyl)-1-methyl-2-oxo-4-[3-(trifluoromethyl)phenyl]-3-pyrrolidinecarboxamide (CAS Registry Number: 2053901-33-8), maleic hydrazide, oxaziclomefone, cinmethylin, benfuresate, ACN, dalapon, chlorthiamid, flupoxam, bensulide, paraquat, paraquat dichloride, diquat, diquat dibromide, MSMA, indaziflam, and triaziflam (including their agriculturally acceptable salts and derivatives).

[0198] The present invention also features the herbicidal composition according to (i) or (ii), wherein (iii) the safener group C is the group consisting of benoxacor, cloquintocet, chometrinil, cyprosulfamide, diclomid, dicyclonone, dietholic acid, 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]benzenesulfonamide.

[0199] In one embodiment, the present invention comprises a herbicide composition according to (i), wherein (iv) B-1 is the 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).

[0200] In another embodiment, the invention includes the herbicidal composition according to (i), wherein (v) B-2 is the group consisting of fenoxaprop-ethyl, fenoxaprop-P-ethyl, fluazifop-butyl, fluazifop-P-butyl, quizalofop-ethyl, quizalofop-P-ethyl, clethodim, and sethoxydim (each including an agriculturally acceptable salt and a derivative thereof).

[0201] In another embodiment, the present invention comprises the herbicide composition of [1], wherein [6]B-3 is the group consisting of carfentrazone-ethyl, saflufenacil, sulfentrazone, pyraflufen-ethyl, fluthiaceto-methyl, flufenpyr-ethyl, flumiclorac-pentyl, flumioxazin, oxyfluorfen, acifluorfen-sodium salt, fomesafen-sodium salt, lactofen, thiafenacil, and ethyl [(3-{2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridin-2-yl)oxy]acetate (including agriculturally acceptable salts and derivatives thereof).

[0202] In another embodiment, the present invention relates to a compound according to the present invention, wherein [7]B-4 is selected from the group consisting of bicyclopyrone, mesotrione, tembotrione, isoxaflutole, fenquinotrone, topramezone, torpiraric acid, 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) The herbicide composition according to [1], wherein the herbicide composition is selected from the group consisting of 4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexen-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).

[0203] In another embodiment, the present invention includes the herbicide composition according to [1], wherein -[8]B-5 is the group consisting of nofurazan and fluridone (including their agriculturally acceptable salts and derivatives thereof).

[0204] In another embodiment, the present invention includes the herbicide composition of [1], wherein [9]B-6 is the group consisting of bentazone, bromoxynil octanoate, diuron, linuron, fluometuron, simazine, atrazine, ametryn, prometryn, and metribuzin (including their agriculturally acceptable salts and derivatives thereof).

[0205] In another embodiment, the present invention includes the herbicide composition of [1], wherein

[10] B-7 is the group consisting of alachlor, acetochlor, metolachlor, S-metolachlor, dimethenamid, dimethenamid-P, pyroxasulfone, and flufenacet (including their agriculturally acceptable salts and derivatives thereof).

[0206] In another embodiment, the present invention includes the herbicide composition of [1], wherein

[11] B-8 is the group consisting of trifluralin, pendimethalin, and ethalfluralin (each of which includes an agriculturally acceptable salt and derivative thereof).

[0207] In another embodiment, the present invention includes the herbicide composition of [1], wherein

[12] B-9 is the group consisting of 2,4-DB, fluroxypyr, fluroxypyr-meptyl, clopyralid-amine salt, clopyralid-potassium salt, clopyralid-triethylammonium salt, halaxifen, halaxifen-methyl, furopyralixefen, and furopyralixefen-benzyl (including agriculturally acceptable salts and derivatives thereof).

[0208] In another embodiment, the present invention includes the herbicide composition according to [1], wherein

[13] B-10 is the 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).

[0209] In another embodiment, the present invention includes the herbicide composition according to [1], wherein

[14] B-11 is the group consisting of glufosinate, glufosinate-ammonium salt, glufosinate-P, and glufosinate-P-sodium salt (including agriculturally acceptable salts and derivatives thereof).

[0210] In another embodiment, the present invention includes the herbicide composition according to [1], wherein

[15] B-12 is the 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 their agriculturally acceptable salts and derivatives thereof).

[0211] In another embodiment, the present invention includes the herbicide composition according to [1], wherein the safener group C is the group consisting of benoxacor, cyprosulfamide, and isoxadifen-ethyl (including their agriculturally acceptable salts and derivatives).

[0212] The present invention also features a method for controlling weeds, comprising the steps of simultaneously or sequentially applying a compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener compound group C to a locus where the weeds are growing or are growing.

[0213] In one embodiment, the present invention includes the method according to

[18] , wherein the compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener group C are used in a weight ratio of 1:0.1 to 1:50.

[0214] In another embodiment, the present invention includes a method according to claim

[18] or

[19] , wherein the locus in which the weeds are growing or will grow is a crop field.

[0215] The present invention also features

[21] use of the herbicide composition according to any one of [1] to

[16] for controlling weeds.

[0216] The herbicidal composition according to the present invention also comprises a compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener group C.

[0217] The method for controlling weeds according to the present invention (hereinafter referred to as "the method") comprises the step of applying the composition to a locus where weeds are growing or likely to grow in a crop field, a vegetable field, land under a perennial crop, a non-crop land, etc. In crop and vegetable fields, the composition may be applied before, simultaneously with, and / or after sowing the crop seeds.

[0218] The method includes the steps of simultaneously or sequentially applying a compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener group C to a locus where weeds are growing or likely to grow. In the case of sequential application, the order of application is not particularly limited.

[0219] The composition of the present invention is usually a formulation prepared by mixing the compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener group C with a carrier such as a solid carrier or a liquid carrier, and adding formulation auxiliaries such as surfactants as necessary.Preferred formulation types of such formulations are aqueous liquid suspension concentrates, wettable powders, water-dispersible granules, granules, and emulsifiable concentrates.The composition can be used in combination with a formulation containing another herbicide as an active ingredient.

[0220] The total content of the compound of formula I and at least one compound selected from the group consisting of herbicide compound group B and safener compound group C in the present composition is in the range of 0.01 to 90% by weight, preferably 1 to 80% by weight.

[0221] Hereinafter, when at least one compound selected from the group consisting of herbicide compound group B is a salt (eg, glyphosate potassium salt), the weight of the at least one compound is expressed in terms of acid equivalent.

[0222] The mixing ratio of the compound of formula I to at least one compound selected from the group consisting of herbicide compound group B and safener compound group C in the composition of the present invention is within the range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50, by weight.

[0223] In this method, the ratio of the application rate of the compound of formula I to at least one compound selected from the group consisting of herbicide compound group B and safener group C is within the weight ratio range of 1:0.05 to 1:100, preferably 1:0.1 to 1:50.

[0224] In some variations, the mixing ratio of the compound of formula I to at least one compound selected from the group consisting of herbicide compound group B and safener compound group C in the composition of the present invention includes a weight ratio of 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.

[0225] In some variations, the ratio of the application rate of the compound of formula I to at least one compound selected from the group consisting of herbicide compound group B and safener group C in the method includes a weight ratio of 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.

[0226] The word "about" in the preceding paragraph means that the specified ratio includes ratios within a range of 10% by weight increase or decrease relative to the specified ratio. For example, a ratio of about 1:2 includes a range of 1:1.8 to 1:2.2.

[0227] In the present compositions and methods, particularly preferred examples of combinations of the compound of formula I with at least one compound selected from the group consisting of herbicide compound group B and safener group C, and ranges of their weight ratios include, but are not limited to, the following combinations and ranges: A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with pyrithiobac (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with pyrithiobac-sodium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with chlorimuron-ethyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with foramsulfuron (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with halosulfuron-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with nicosulfuron (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with primisulfuron-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with rimsulfuron (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with trifloxysulfuron-sodium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with chlorsulfuron (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with iodosulfuron-methyl-sodium (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with iofensulfuron-sodium (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with metsulfuron-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with prosulfuron (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with thifensulfuron-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with tribenuron methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with thiencarbazone-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with chloransulam-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with flumetsulam (1:0.1 to 1:20), A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with imazamethabenz-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with imazamox ammonium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with imazapine ammonium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with imazapyr-isopropylammonium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with imazaquin ammonium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with imazethapyr-ammonium salt (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fenoxaprop-ethyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fenoxaprop-p-ethyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fluazifop-butyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fluazifop-p-butyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with xalofop-ethyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with xalofop-p-ethyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with clethodim (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with sethoxydim (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with carfentrazone-ethyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with saflufenacil (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with sulfentrazone (1:0.1 to 1:30); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with pyraflufen-ethyl (1:0.1 to 1:30); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fluthiacet-methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with flufenpyr-ethyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with flumiclorac pentyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with flumioxazin (1:0.1 to 1:20), A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with oxyfluorfen (1:0.1 to 1:30); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with acifluorfen-sodium salt (1:0.1 to 1:30); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fomesafen-sodium salt (1:0.1 to 1:30); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with lactofen (1:0.1 to 1:30); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with thiaphenacyl (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with ethyl [(3-{2-chloro-4-fluoro-5-[3-methyl-4-(trifluoromethyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridin-2-yl)oxy]acetate (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with bicyclopyrone (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with mesotrione (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with tembotrione (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with isoxaflutole (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fenquinotrione (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with topramezone (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with torpiralate (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with lancotrione sodium salt (1:0.1 to 1:20); a combination of a compound of formula I with 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), (II), (III), (IV), (V), (VI), or (VII) with 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), (II), (III), (IV), (V), (VI) or (VII) with a compound of 4-(4-fluorophenyl)-6-[(2-hydroxy-6-oxo-1-cyclohexen-1-yl)carbonyl]-2-methyl-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), (II), (III), (IV), (V), (VI), or (VII) with norflurazon (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fluridone (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with bentazone (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with bromoxynil octanoate (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with diuron (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with Linuron (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fluometuron (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with simazine (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with atrazine (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with ametryn (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with prometryne (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with metribuzin (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with alachlor (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with acetochlor (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with metolachlor (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with S-metolachlor (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with dimethenamid (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with dimethenamid-P (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with pyroxasulfone (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with flufenacet (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with trifluralin (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with pendimethalin (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with ethalfluralin (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with 2,4-DB (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fluroxypyr (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with fluroxypyr meptyl (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with clopyralid-olamine salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with clopyralid potassium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with clopyralid triethylammonium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with haloxifene (1:0.1 to 1:20); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with haloxifene methyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with florpyrauxifen (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with florpyrauxifen-benzyl (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glyphosate (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glyphosate-isopropylammonium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glyphosate-ammonium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glyphosate-dimethylamine salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glyphosate-monoethanolamine salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glyphosate-potassium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glyphosate-guanidine salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glufosinate (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glufosinate-ammonium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glufosinate-P (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with glufosinate-P-sodium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with EPTC (1:1 to 1:50); a combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with diflufenzopyr (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) with diflufenzopyr-sodium salt (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with clomazone (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with 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), (II), (III), (IV), (V), (VI) or (VII) with (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), (II), (III), (IV), (V), (VI), or (VII) with cinmethylin (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with MSMA (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with paraquat (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with paraquat-dichloride (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with diquat (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with diquat-dibromide (1:1 to 1:50); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with benoxacor (1:0.1 to 1:20); A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with cyprosulfamide (1:0.1 to 1:20); or A combination of a compound of formula (I), (II), (III), (IV), (V), (VI), or (VII) with isoxadifen-ethyl (1:0.1 to 1:20).

[0228] The composition of the present invention may be applied to a field in which crop seeds have been or are to be sown before, simultaneously with, and / or after sowing crop seeds that have been treated with one or more compounds selected from the group consisting of insecticide compounds, nematicide compounds, fungicide compounds, and the like.

[0229] In some embodiments, the composition can be used in combination with another insecticidal active compound.The examples of insecticide compounds, nematicides and fungicide compounds that can be used in combination with the composition include neonicotinoid compounds, diamide compounds, carbamates, organophosphorus compounds, biological nematicides, other insecticides and nematicides, azole compounds, strobilurin compounds, metaxyl compounds, SDHI compounds, and other fungicide compounds and plant growth regulators. EXAMPLES

[0230] The subject matter of the present disclosure will be better understood by reference to the following examples, which are provided as illustrations of the invention, but not as limitations thereon.

[0231] Compound synthesis and characterization. The steps of the examples below show the sequence of each step in the overall synthetic transformation, and the starting material for each step may not necessarily be prepared by the sequence described in other examples or steps. 1 H-NMR spectra are reported in ppm downfield from tetramethylsilane, where "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 the isotopic abundances of the highest and lowest isotopes present in the molecule. + The parent ion (M+1) formed by adding (molecular weight of 1) or H from the molecule + The molecular weight is reported as the molecular weight of (M-1) formed by the loss of (the molecular weight of 1), observed using liquid chromatography coupled to a mass spectrometer (LCMS) using atmospheric pressure chemical ionization (AP+), where "amu" represents a single atomic mass unit, or electrospray ionization (ES+).

[0232] Example 1. Preparation of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonic acid (compound 1003) [ka] As shown in Scheme 3, Step 1, to a degassed solution of (4-chloro-2-fluorophenyl)boronic acid (compound 1001, 5.0 g, 28.7 mmol) in toluene (50 mL) and HO (10 mL) was added iodopentafluorobenzene (8.4 g, 28.7 mmol), KPO (12.1 g, 57.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl, 0.4 g, 0.7 mmol). The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere, cooled to 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 purified by flash chromatography (0% to 20% ethyl acetate in petroleum ether) to give 4'-chloro-2,2',3,4,5,6-hexafluoro-1,1'-biphenyl (compound 1002, 5.0 g, 58% yield) as a colorless oil. GCMS calculated C 12 H3ClF6=295.9, actual value 296.0.

[0233] As shown in Scheme 3, step 2, a mixture of 4'-chloro-2,2',3,4,5,6-hexafluoro-1,1'-biphenyl (5.0 g, 16.9 mmol) in HSO3Cl (15 mL) was stirred at 130 °C for 2 h under nitrogen atmosphere. The mixture was cooled, 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, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 35% acetonitrile in water) to give 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonic acid (compound 1003, 1.6 g, 25% yield) as a yellow solid. MS (ESI) calcd. C 12 H3ClF6O3S [M-1] - = 375.0, actual value 375.1.

[0234] Example 2. Preparation of methyl (S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoate (Compound 1), methyl (R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoate (Compound 2), (S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoic acid (Compound 3), and (R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)propanoic acid (Compound 4) [ka] As shown in Scheme 4, Step 1, a mixture of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonic acid (compound 1003, 500 mg, 1.32 mmol) in phosphorus oxychloride (2 mL) was stirred at 100° C. for 16 hours under nitrogen atmosphere. The mixture was cooled and the volatiles were removed under reduced pressure. The residue was 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 give 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (compound 1004, 490 mg, crude) as a yellow semi-solid. This material was used as is in the subsequent reaction.

[0235] As shown in Scheme 4, step 2, 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonyl chloride was dissolved in AcOH (10 mL) and concentrated HCl (2 mL) and SnCl2 (2.5 g, 13.3 mmol) was added in portions at 20 °C under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h, 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 give 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-thiol (compound 1005, 2.0 g, crude) as a yellow oil. MS (ESI) calcd. C 12 H3ClF6S [M-1] - = 327.1, found, 327.1. This material was used as is in subsequent reactions.

[0236] As shown in step 3 of scheme 4, to a stirred mixture of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-thiol (1.5 g, 4.56 mmol) in DMF (15 mL) was added methyl 2-bromopropanoate (1.5 g, 9.18 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h, 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 flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give methyl 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoate (compound 1006, 670 mg, 35% yield) as a yellow oil. GCMS calculated value C 16 H9ClF6O2S=414.0, measured value 414.0.

[0237] As shown in Scheme 4, Step 4, racemic methyl 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoate (670.0 mg) was separated into its enantiomers by preparative chiral HPLC using the following conditions - column: CHIRALPAK AD-3, 4.6 x 100 mm; 3 um; mobile phase 95:5 hexane / (1:1 MeOH:EtOH) to give methyl (S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoate (compound 1,350 mg, 40% yield) as a yellow oil: GCMS calculated value C 16 H9ClF6O2S, 414.0, found, 414.0. Methyl (R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoate (compound 2, 140 mg, 20% yield) was recovered as the second eluting compound as a yellow oil: GCMS calculated C 16 H9ClF6O2S=414.0, measured value 414.0.

[0238] As shown in Scheme 4, Step 5, to a stirred mixture of methyl (S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoate (300 mg, 0.08 mmol) in DCE (3 mL) was added trimethylstannanol (262 mg, 1.46 mmol). The resulting solution was stirred at 65 °C for 16 h, cooled to room temperature, diluted with water, acidified to pH 4-5 with formic 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 purified by reverse-phase flash chromatography (5% to 70% acetonitrile in water) to give (S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoic acid (compound 3, 237 mg, 81% yield) as a colorless oil. MS (ESI) calculated C 15 H7ClF6O2S [M-1] -= 398.9, measured value 398.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 4.15 - 4.05 (m, 1H), 1.43 (d, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -113.46, -140.46, -153.08, -161.97.

[0239] As shown in Scheme 4, step 6, a similar protocol as described in step 5 afforded (R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoic acid (compound 4, 73% yield) as a colorless oil. MS (ESI) calcd. C 15 H7ClF6O2S [M-1] - = 398.9, measured value 398.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 4.15 - 4.05 (m, 1H), 1.43 (d, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -113.46, -140.46, -153.08, -161.97.

[0240] Example 3. Methyl (S)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoate (Compound 5), Methyl (R)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoate ( Preparation of Compound 6), (S)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoic acid (Compound 7), and (R)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoic acid (Compound 8) [ka] As shown in Scheme 5, step 1, to a stirred mixture of methyl 2-({4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl}sulfanyl)propanoate (200 mg, 0.48 mmol) in THF (1.8 mL) and water (0.6 mL) was added LiOH (35 mg, 1.44 mmol). The resulting mixture was stirred at room temperature for 2 h, diluted with water, acidified to pH 4-5 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 pressure to give 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoic acid (compound 1007, 195 mg, crude) as a colorless oil. MS (ESI) Calculated value C 15 H7ClF6O2S [M-1] - = 389.9, actual value 390.0.

[0241] As shown in Scheme 5, Step 2, to a stirred mixture of 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoic acid (110 mg, 0.27 mmol) in DMF (1 mL) was added T3P (propylphosphonic anhydride, 174.6 mg, 0.54 mmol), methyl 3-aminopropanoic acid hydrochloride (38 mg, 0.54 mmol), and triethylamine (83 mg, 0.54 mmol) under a nitrogen atmosphere. The mixture was stirred at 25° C. under a nitrogen atmosphere for 16 h, 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 preparative-TLC (EtOAc / petroleum ether=1:1) to give methyl 3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoate (compound 1008, 65 mg, 48% yield) as a white solid. MS (ESI) calcd. C 19 H 16 ClF4NO3S [M+1] + = 486.0, actual value 486.1.

[0242] As shown in Scheme 5, step 3, racemic methyl 3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoate (65 mg) was separated by preparative chiral HPLC under the following conditions - column: CHIRALPAK IG, 2 x 25 cm, 5 μm, mobile phase 15% hexane (0.5% 2M NH3-MeOH) / EtOH to give methyl (R)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoate (compound 5, 19 mg, 38% yield) as a white solid: MS (ESI) calcd. C 19 H 16 ClF4NO3S [M+1] + = 486.0, actual value 486.1; 1H-NMR (400 MHz, DMSO-d6) δ 8.22 - 8.15 (m, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 4.01 - 3.92 (m, 1H), 3.56 (s, 3H), 3.29 - 3.19 (m, 2H), 2.45 - 2.27 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -113.69, -140.56, -153.17, -161.96. Also recovered as the second eluting peak was methyl (S)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoate (compound 6, 27 mg, 40% yield) as a white solid: MS (ESI) calcd. C 19 H 16 ClF4NO3S [M+1] + = 486.0, actual value 486.1; 1 H-NMR (400 MHz, DMSO-d6) δ 8.22 - 8.15 (m, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 4.01 - 3.92 (m, 1H), 3.56 (s, 3H), 3.29 - 3.19 (m, 2H), 2.45 - 2.27 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -113.69, -140.56, -153.17, -161.96.

[0243] As shown in Scheme 5, Steps 4 and 5, using a similar protocol described in Scheme 4, Step 5, (S)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanamido)propanoic acid (compound 7, 56% yield): MS (ESI) calcd. C 18 H12 ClF6NO3S [M+1] + , 472.0;Actual value, 472.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.18 (t, J = 5.6 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 4.00 - 3.95 (m, 1H), 3.22 - 3.17 (m, 2H), 2.29 - 2.21 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -113.77, -140.60, -153.10, -161.88; and (R)-3-(2-((4-chloro-2',3',4',5',6,6'-hexafluoro[1,1'-biphenyl]-3-yl)thio)propanamido)propanoic acid (compound 8, 53% yield) was obtained as a white solid: MS (ESI) calcd. C 18 H 12 ClF6NO3S [M+1] + = 472.0, Actual value 472.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.18 (t, J = 5.6 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 3.99 - 3.96 (m, 1H), 3.23 - 3.16 (m, 2H), 2.34 - 2.18 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -113.76, -140.61, -153.09, -161.88.

[0244] The following compounds were also prepared using the appropriate amino acid esters in similar transformations as described in Scheme 5, Steps 1-5: Methyl ((S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)-L-proline (compound 9), isolated as a white solid: MS (ESI) calculated C 21 H 16 ClF6NO3S [M+1] + = 512.0, Actual value 512.0; 1 H-NMR (400 MHz, CD3OD) δ 7.78 - 7.76 (m, 1H), 7.63 - 7.60 (m, 1H), 4.38 - 4.35 (m, 1H), 4.25 - 4.24 (m, 1H), 3.71 - 3.65 (m, 4H), 3.68 - 3.64 (m, 1H), 1.99 - 1.95 (m, 4H), 1.48 - 1.47 (m, 3H); 19 F-NMR (376 MHz, CD3OD) δ -112.1, -142.63, -156.1, -164.7; Methyl ((R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)-L-proline (compound 10), isolated as a white solid: MS (ESI) calculated (C 21 H 16 ClF6NO3S) [M+1] + = 512.0, actual value 512.2; 1 H-NMR (400 MHz, CD3OD) δ 7.82 - 7.80 (m, 1H), 7.59 - 7.57 (m, 1H), 4.42 - 4.39 (m, 1H), 4.28 - 4.24 (m, 1H), 3.77 - 3.72 (m, 2H), 3.55 (s, 3H), 2.28 - 2.25 (m, 1H), 2.02 - 1.95 (m, 3H), 1.46 - 1.44 (m, 3H); 19 F-NMR (376 MHz, CD3OD) δ -113.31, -142.45, -156.86, -165.33; ((S)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)-L-proline (compound 11), isolated as a white solid: MS (ESI) calcd. C 21 H 16 ClF6NO3S [M+1] + = 498.0, actual value 497.9; 1 H-NMR (400 MHz, CD3OD) δ 7.90 - 7.77 (m, 1H), 7.62 - 7.56 (m, 1H), 4.37 - 4.12 (m, 2H), 3.72 - 3.59 (m, 2H), 3.35 - 1.82 (m, 4H), 1.40 - 1.37 (m, 3H); 19 F-NMR (376 MHz, CD3OD) δ -112.22, -142.57, -156.09, -164.68; and ((R)-2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)-L-proline (compound 12), isolated as a white solid: MS (ESI) calcd. C 21 H 16 ClF6NO3S [M+1] + = 498.0, Actual value 498.0; 1 H-NMR (400 MHz, CD3OD) δ 7.90 - 7.77 (m, 1H), 7.63 - 7.56 (m, 1H), 4.27 - 4.20 (m, 1H), 4.06 - 4.01 (m, 1H), 3.59 - 3.55 (m, 1H), 3.35 - 3.30 (m, 1H), 2.12 - 1.70 (m, 4H), 1.48 - 1.46 (m, 3H); 19 F-NMR (376 MHz, CD3OD) δ -114.18, -142.72, -156.18, -164.75.

[0245] Example 4. Preparation of (S)-2-((2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)oxy)ethyl methacrylate (Compound 13) and (R)-2-((2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)oxy)ethyl methacrylate (Compound 14). [ka] As shown in Scheme 6, step 1, to a stirred mixture of 2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoic acid (180 mg, 0.45 mmol) in DCM (2 mL) was added 2-hydroxyethyl methacrylate (88 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCI, 129 mg, 0.67 mmol), and DMAP (55 mg, 0.45 mmol) under nitrogen atmosphere at 25° C. The mixture was stirred at 20° C. for 2 h, 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 prep-TLC (1:5 EtOAc / petroleum ether) to give racemic 2-((2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)oxy)ethyl methacrylate (compound 1009, 110 mg, 52% yield) as a colorless oil. GCMS calcd. C 21 H 15 ClF6O4S=512.0, measured value 512.0.

[0246] As shown in Scheme 6, step 2, racemic 2-((2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)oxy)ethyl methacrylate (110 mg) was separated by preparative chiral-HPLC using the following conditions - column: CHIRALPAK AD-H, 2 x 25 cm, 5 μm, mobile phase 5% EtOH / Hexane, to give (S)-2-((2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)oxy)ethyl methacrylate (compound 13, 47 mg, 30% yield) as a colorless oil: GCMS calculated (C 21 H 15 ClF6O4S) = 512.0, measured value 512.0; 1 H-NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 6.04 (s, 1H), 5.64 - 5.58 (m, 1H), 4.36 - 4.28 (m, 2H), 4.30 - 4.19 (m, 2H), 4.09 - 3.99 (m, 1H), 1.90 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -112.74, -142.42, -156.16, -164.62. Also, as the second eluting peak, (R)-2-((2-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)thio)propanoyl)oxy)-ethyl methacrylate (compound 14, 46 mg, 29% yield) was recovered as a colorless oil: GCMS calculated value C 21 H 15 ClF6O4S=512.0, measured value 512.0; 1H-NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 6.04 (s, 1H), 5.64 - 5.58 (m, 1H), 4.36 - 4.28 (m, 2H), 4.30 - 4.19 (m, 2H), 4.09 - 3.99 (m, 1H), 1.90 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, methanol-d4) δ -112.74, -142.42, -156.16, -164.62.

[0247] Example 5. Preparation of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide (Compound 15) [ka] As shown in Scheme 7, to a stirred mixture of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (100 mg, 0.50 mmol) in MeCN (2 mL) was added NH4OH (0.2 mL). The mixture was stirred at 20 °C under nitrogen atmosphere for 16 h, 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 reverse-phase flash chromatography (5% to 45% acetonitrile in water) to give 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 15, 11 mg, 10% yield) as a white solid: MS (ESI) calcd. C 12 H4ClF6NO2S [M-1] - = 374.0, actual value 373.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.2 Hz, 1H), 8.07 - 7.99 (m, 1H), 7.87 (s, 2H); 19F-NMR (376 MHz, DMSO-d6) δ -106.35, -140.80, -152.86, -161.83.

[0248] Example 6. Preparation of 4-chloro-N-(dimethylcarbamoyl)-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide (Compound 16) [ka] To a stirred mixture of 4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide (40 mg, 0.10 mmol) in DCM (1 mL) and DMF (0.3 mL) was added TEA (32 mg, 0.30 mmol), DMAP (1 mg, 0.01 mmol) and dimethylcarbamic chloride (17 mg, 0.15 mmol) as shown in Scheme 8. The resulting mixture was stirred at 25° C. under nitrogen atmosphere for 2 h, 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 reverse-phase flash chromatography (5% to 50% acetonitrile in water) to give 4-chloro-N-(dimethylcarbamoyl)-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 16, 21 mg, 44% yield) as a white solid: MS (ESI) calculated C 15 H9ClF6N2O3S [M-1] - = 446.9, actual value 447.1; 1 H-NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 2.83 (s, 6H); 19 F-NMR (376 MHz, DMSO-d6) δ -106.01, -140.55, -152.99, -161.91.

[0249] Using the appropriate acyl chloride, carbamic chloride or carbonochloridate in a similar transformation to that described to prepare 4-chloro-N-(dimethylcarbamoyl)-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide, the following compounds were also prepared: N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)acetamide (compound 17), isolated as a white solid: MS (ESI) calculated C 14 H6ClF6NO3S [M+1] + = 417.9, measured value 417.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 2.00 (s, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.56, -140.52, -152.82, -161.91; N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 18), isolated as a white solid: MS (ESI) calculated C 15 H8ClF6NO3S [M-1] - = 429.9, measured value 429.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.33 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 9.6 Hz, 1H), 2.30 (q, J = 7.2 Hz, 2H), 1.08 - 0.75 (t, J = 7.2Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.40, -140.48, -152.79, -161.89; N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)isobutyramide (compound 19), isolated as a white solid: MS (ESI) calculated C 16 H 10 ClF6NO3S [M+1] + = 446.0, Actual value 446.0; 1 H-NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 2.55 (d, J = 7.2 Hz, 1H), 0.99 (d, J = 6.8 Hz, 6H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.23, -140.65, -152.27, -161.58; N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-3-methylbutanamide (compound 20), isolated as a white solid: MS (ESI) calculated C 17 H 12 ClF6NO3S [M-1] - = 458.0, actual value 457.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 2.16 (d, J = 7.2 Hz, 2H), 1.94 - 1.90 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H); 19 F-NMR (400 MHz, DMSO-d6) δ -103.34, -140.47, -152.83, -161.91; N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2-phenylacetamide (compound 21), MS (ESI) calculated C 20 H 10 ClF6NO3S [M+1]+ = 494.0, Actual value 494.0; 1 H-NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.40 - 7.03 (m, 5H), 3.64 (s, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.24, -140.46, -152.78, -161.90; Methyl ((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)carbamate (compound 22), MS (ESI) calculated C 14 H6ClF6NO4S [M+1] + = 431.9, measured value 431.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.79 (s, 2H), 8.32 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 3.59 (s, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.50, -140.55, -152.83, -161.90; and N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzamide (compound 23), MS (ESI) calculated C 19 H8ClF6NO3S [M-1] - = 477.9, actual value 477.8; 1 H-NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.53 - 7.49 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.60, -140.43, -152.82, -161.89.

[0250] Example 7. Synthesis of N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2,2,2-trifluoroacetamide (Compound 24) [ka] A stirred mixture of 2,2,2-trifluoroacetic acid (35.2 mg, 0.26 mmol) in THF (1 mL) was added to a nitrogen atmosphere at 0 °C with SOCl 2( 284.99 mg, 2.39 mmol) and TEA (53.8 mg, 0.53 mmol) were added sequentially, and the mixture was stirred at 50° C. for 4 h, then concentrated under reduced pressure. The resulting acyl chloride was dissolved in DCM (1 mL) and added to a solution of 4-chloro-2′,3′,4′,5′,6,6′-hexafluoro-[1,1′-biphenyl]-3-sulfonamide (compound 15, 100 mg, 0.26 mmol), TEA (53 mg, 0.52 mmol), and DMAP (3 mg, 0.03 mmol) in DCM (1 mL) at 0° C. The resulting mixture was then stirred at 20° C. for 2 h. The mixture was quenched by the addition of water. The aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse-phase flash column chromatography using the following conditions (5%-50% MeCN in water (0.1% FA)) to give N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2,2,2-trifluoroacetamide (compound 24, 39 mg, 9% yield, 82.7% purity by LCMS) as a pale yellow solid. MS (ESI) calculated C 14 H3ClF9NO3S [M-1] - = 470.0, actual value 469.9. 1 H-NMR (400 MHz, chloroform-d) δ 8.39 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H); 19F-NMR (376 MHz, Chloroform-d) δ -75.51, -98.37, -139.14, -150.54, -160.29.

[0251] The ammonium salt of compound 24 was formed by applying it to a preparative reverse-phase HPLC column and eluting the column using the following conditions (Mobile phase A: water (10 mmol / L NH3H2O); Mobile phase B: ACN; Gradient: 30% B to 40% B in 10 min, then 40% B in 14 min) to give N-((4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2,2,2-trifluoroacetamide, ammonium salt (2.8 mg, 21% yield) as a yellow solid: MS (ESI) calcd. C 14 H3ClF9NO3S [M-1] - = 470.0, Actual Value, 469.9. 1 H NMR (400 MHz, methanol-d4) δ 8.26 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H). 19 F NMR (376 MHz, methanol-d4) δ -77.03, -108.86, -142.23, -155.98, -164.71.

[0252] The sodium salt of compound 24 was formed by treatment with NaOH (0.1N, 0.2 mL). The aqueous solution was washed with ethyl ether and lyophilized to give N-{4-chloro-2',3',4',5',6,6'-hexafluoro-[1,1'-biphenyl]-3-ylsulfonyl}-2,2,2-trifluoroacetamide, sodium salt (2.4 mg, 24% yield) as a pale yellow solid. MS (ESI) calcd. C 14 H3ClF9NO3S [M-1] - = 470.0, actual value 469.9; 1 H-NMR (400 MHz, Methanol-d4) δ 8.24(d, J = 7.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H);19 F-NMR (376 MHz, Methanol-d4) δ -76.80, -108.30, -142.23, -155.42, -164.27.

[0253] Example 8. Preparation of 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (Compound 25) and N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (Compound 26) [ka] As shown in step 1 of scheme 10, to a solution of 1,2,3,5-tetrafluorobenzene (80.0 g, 533 mmol, 1.0 equiv) in THF (400 mL) was added n-BuLi dropwise (2.5 M, 213 mL, 1.0 equiv) at -78 °C. After addition, the mixture was stirred at -78 °C for 1 h, followed by the addition of I2 solution (135 g, 533 mmol, 107 mL, 1.0 equiv) in THF (400 mL). The mixture was stirred at -78 °C for 1 h and poured into saturated NH4Cl solution (1.50 L). The mixture was extracted with EtOAc (800 mL x 2), brine (1.0 L x 2), and dried over Na2SO4. After filtration, the organics were concentrated under reduced pressure to give 1,2,3,5-tetrafluoro-4-iodobenzene (compound 1010) as a brown oil. This material was used directly in the subsequent reaction without further purification.

[0254] As shown in Scheme 10, Step 2, to a solution of 1,2,3,5-tetrafluoro-4-iodobenzene (130 g, 471 mmol, 1.0 equiv), (4-chloro-2-fluorophenyl)boronic acid (90.3 g, 518 mmol, 1.1 equiv) and K3PO4 (200 g, 942 mmol, 2.0 equiv) in toluene (1.30 L) and HO (260 mL) was added Pd(dtbpf)2 (6.14 g, 9.42 mmol, 0.02 equiv) at 25° C. The mixture was stirred at 90° C. for 16 h and then added to water (500 mL). The mixture was extracted with ethyl acetate (500 mL×2) and the combined organics were washed with brine (500 mL×2), dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (1-2% petroleum ether / EtOAc) to give 4'-chloro-2,2',3,4,6-pentafluoro-1,1'-biphenyl as a colorless oil (compound 1011, 130 g): 1 H-NMR (400 MHz, DMSO-d6) δ 7.67-7.65 (m, 1H), 7.58-7.48 (m, 2H), 7.16-7.12 (m, 1H).

[0255] As shown in Scheme 10, Step 3, 4'-chloro-2,2',3,4,6-pentafluoro-1,1'-biphenyl (compound 1011, 130 g, 466 mmol, 1.0 equiv.) was slowly added in portions to ClSO3H (544 g, 4.67 mol, 311 mL, 10 equiv.) at 0° C. The mixture was stirred at 70° C. for 16 h, poured into ice water (1 L), and extracted with ethyl acetate (500 mL×3). The combined organics were washed with brine (1 L x 2), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (1-2% petroleum ether / EtOAc) to give 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (compound 1012, 90 g, 238 mmol, 51% yield from compound 1010) as a yellow solid: 1 H-NMR δ 7.98-7.96 (m, 1H), 7.69-7.67 (m, 1H), 7.63-7.58 (m, 1H).

[0256] As shown in Scheme 10, step 4, to a solution of 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (90 g, 238 mmol, 1.0 equiv.) in DCM (900 mL) was added 28% NH4OH (328 mL, 2.39 mol, 10.0 equiv.) and the mixture was stirred at 25 °C for 1 h. The mixture was diluted with 1 L of water and extracted with DCM (800 mL x 2). The combined organics were washed with brine (1 L x 2), dried over Na2SO4, concentrated under reduced pressure, and triturated with petroleum ether (1 L) for 30 min to give 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 25, 77.0 g, 209 mmol, 88% yield) as a white solid. MS (ESI) Calculated value C 12 H5ClF5NO2S [M-1] - = 356.0, actual value 355.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 7.2 Hz, 1H), 7.95-7.82 (m, 1H), 7.77 (s, 2H), 7.75-7.72 (m, 1H).

[0257] As shown in Scheme 10, step 5, to a solution of 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (35.0 g, 97.8 mmol, 1.0 equiv) in DCM (350 mL) and DMF (90.0 mL) was added TEA (19.8 g, 196 mmol, 27.2 mL, 2.00 equiv) and DMAP (1.20 g, 9.79 mmol, 0.1 equiv) at 25° C. The mixture was cooled to 0° C. and propionyl chloride (13.6 g, 146 mmol, 13.6 mL, 1.5 equiv) was added, followed by stirring the reaction mixture at 25° C. for 1 h. The mixture was then diluted with HO (500 mL) and extracted with DCM (500 mL×2). The combined organics were washed with brine (500 mL × 2), dried over Na2SO4, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (50% to 80% acetonitrile / HO (0.1% FA). After concentrating the product-containing fractions under reduced pressure, the residue was triturated with EtOH (150 mL) at 25 °C for 16 h to give N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 26, 25.4 g, 63% yield) as a white solid. MS (ESI) calcd. C 15 H9ClF5NO3S [M-1] - = 412.0, Actual value 412.0; 1 H-NMR (400 MHz, DMSO-d6) δ 12.6 (brs, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 4.4 Hz, 1H),7.75-7.73 (m, 1H), 2.33-2.22 (m, 2H), 0.95-0.86 (m, 3H).

[0258] The following compounds were also prepared using the appropriate acyl chloride, carbamine chloride, anhydride, or carbonochloridate in a similar transformation to that described in Step 5 of Scheme 10 of Example 8: N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)acetamide (compound 27), isolated as a white solid: MS (ESI) calculated (C 14 H7ClF5NO3S) [M-1] - , 398.0;Actual value, 397.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.78 - 7.72 (m, 1H), 1.99 (s, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.84, -115.57, -130.71, -133.56, -164.64; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)tetrahydro-2H-pyran-4-carboxamide (compound 28), isolated as a white solid: MS (ESI) calculated (C 18 H 13 ClF5NO4S) [M-1] - = 468.0, actual value 467.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.82 - 7.71 (m, 1H), 3.83 - 3.81 (m, 2H), 3.32 - 3.22 (m, 2H), 2.68 - 2.60 (m, 1H), 1.69 - 1.65 (m, 2H), 1.51 - 1.37 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.53, -115.50, -130.93, -133.67, -164.63; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2-(4-chlorophenyl)acetamide (compound 29), isolated as a white solid: MS (ESI) calculated (C 20 H 10 Cl2F5NO3S) [M+1] + = 507.9, Actual, 507.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.23 ​​(d, J = 7.2 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.81 - 7.69 (m, 1H), 7.40 - 7.32 (m, 2H), 7.26 - 7.19 (m, 2H), 3.64 (s, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.53, -115.50, -130.63, -133.42, -164.52; 2-Chloro-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzamide (compound 30), isolated as a white solid: MS (ESI) calculated (C 18 H 10 Cl2F5NO3S) [M-1] - = 493.9, actual value 493.8; 1 H-NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.86 - 7.66 (m, 1H), 7.51 - 7.36 (m, 4H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.52, -115.45, -130.62, -133.53, -164.58; 4-Chloro-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzamide (compound 31), isolated as a white solid: MS (ESI) calculated (C 19H8Cl2F5NO3S) [M-1] - = 493.9, measured value 493.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 7.2 Hz, 1H), 8.03 - 7.86 (m, 3H), 7.82 - 7.66 (m, 1H), 7.64 - 7.48 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.56, -115.45, -130.75, -133.46, -164.58; 3-Chloro-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzamide (compound 32), isolated as a white solid: MS (ESI) calculated (C 19 H8Cl2F5NO3S) [M-1] - = 493.9, measured value 493.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.2 Hz, 1H), 8.03 - 7.89 (m, 2H), 7.86 (dt, J = 7.6, 1.2 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.68 (dd, J = 7.6, 2.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.58, -115.44, -130.74, -133.46, -164.52; Phenyl((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)carbamate (compound 33), isolated as a white solid: MS (ESI) calculated (C 19 H9ClF5NO4S) [M-1] - = 475.9, measured value 475.9; 1H-NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 7.6 Hz, 1H), 7.77 - 7.65 (m, 2H), 7.31 - 7.22 (m, 2H), 7.06 (t, J = 7.2 Hz, 1H), 6.94 - 6.87 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -110.34, -115.54, -131.31, -133.74, -164.61; 4-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl])-3-sulfonamido)-4-oxobutanoic acid (compound 55), isolated from dihydrofuran-2,5-dione as a white solid: MS (ESI) calcd. C 16 H9ClF5NO5S [M-1] - = 456.0;Actual value, 455.9; 1 H-NMR (400 MHz, CD3OD) δ 8.29 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.34 - 7.27 (m, 1H), 2.63 - 2.59 (m, 2H), 2.55 - 2.52 (m, 2H); 19 F-NMR (377 MHz, DMSO-d6) δ -105.09, -116.93, -132.45, -135.08, -167.38; After treatment of compound 55 in DMF with acetic anhydride and triethylamine at room temperature, 1-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)pyrrolidine-2,5-dione (compound 70): MS (ESI) calculated C 16 H7ClF5NO4S [M-1] - = 438.0, actual value 437.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 6.8 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.80 - 7.74 (m, 1H), 2.81 (s, 4H); 19F-NMR (377 MHz, DMSO-d6) δ -101.42, -115.45, -130.48, -133.46, -164.66; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)butyramide (compound 56), isolated as a white solid: MS (ESI) calculated C 16 H 11 ClF5NO3S [M-1] - = 426.0, actual value 425.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.64 (br, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.79 - 7.72 (m, 1H), 2.26 (t, J = 7.2 Hz, 2H), 1.51 - 1.52 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.66, -115.56, -130.70, -133.55, -164.66; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)isobutyramide (compound 59), isolated as a white solid: MS (ESI) calculated C 16 H 11 ClF5NO3S [M-1] - = 466.0, actual value 428.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.62 (br, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.78 - 7.72 (m, 1H), 2.59 - 2.54 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.52, -115.52, -130.43, -133.54, -164.66; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)pivalamide (compound 63), isolated as a white solid: MS (ESI) calculated C 17 H 13 ClF5NO3S [M+1] + = 442.0, Actual value 442.0; 1 H-NMR (400 MHz, DMSO-d6) δ 12.27 (br, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.78 - 7.72 (m, 1H), 1.13 (s, 9H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.61, -115.49, -131.64, -133.52, -164.65; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-3,3-dimethylbutanamide (compound 64), isolated as a white solid: MS (ESI) calculated C 18 H 15 ClF5NO3S [M-1] - = 454.0, Actual value 454.0; 1 H-NMR (400 MHz, DMSO-d6) δ 12.55 (br, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.78 - 7.72 (m, 1H), 2.15 (s, 2H), 0.90 (s, 9H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.62, -115.59, -130.71, -133.57, -164.69; 4-Chloro-N-(dimethylcarbamoyl)-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 66), isolated as a white solid: MS (ESI) calculated C 15 H 10 ClF5N2O3S [M+1] += 429.0, Actual value 429.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 7.2 Hz, 1H), 7.73 - 7.69 (m, 2H), 2.68 (s, 6H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.50, -115.49, -130.98, -133.63, -164.64; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)methacrylamide (compound 75), isolated as a white solid: MS (ESI) calculated C 16 H9ClF5NO3S [M+1] + = 426.0, Actual value 426.0; 1 H-NMR (400 MHz, DMSO-d6) δ 12.69 (br, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 6.05 (s, 1H), 5.75 (s, 1H), 1.77 (s, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.59, -115.51, -130.71, -133.48, -164.64; and After treatment of compound 75 with osmium tetroxide and sodium periodate in THF / water at 0° C., N-((4-chloro-2′,3′,4′,6,6′-pentafluoro-[1,1′-biphenyl]-3-yl)sulfonyl)-2-oxopropanamide (compound 77): MS (ESI) calculated C 15 H7ClF5NO4S [M-1] - = 426.0, actual value 425.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.28 - 8.26 (m, 1H), 7.98 - 7.82 (m, 1H), 7.77 - 7.73 (m, 1H), 2.25 (s, 3H); 19F-NMR (377 MHz, DMSO-d6) δ -103.66, -115.48, -130.81, -133.55, -164.60.

[0259] Example 9. Preparation of ethyl ((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)carbamate (Compound 34) and N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-4-hydroxypiperidine-1-carboxamide (Compound 35) [ka] As shown in Scheme 11, Step 1, to a stirred solution of 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (100 mg, 0.28 mmol) and K2CO3 (77 mg, 0.56 mmol) in acetone (2 mL) was added ethyl chloroformate (61 mg, 0.56 mmol). The resulting mixture was stirred at 25° C. for 16 h. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with HCl (aq, 0.5N), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (25%-50% acetonitrile / water) to give ethyl ((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)carbamate (compound 34, 8.2 mg, 7% yield) as a white solid. MS (ESI) calcd. C 15 H9ClF5NO4S) [M-1] - = 427.9, measured value 427.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.19 - 8.13 (m, 1H), 7.96 - 7.89 (m, 1H), 7.86 - 7.57 (m, 1H), 3.93 (q, J = 7.2 Hz, 2H), 1.07 - 0.94 (m, 3H); 19F-NMR (376 MHz, DMSO-d6) δ -103.58, -115.71, -130.72, -133.73, -164.59.

[0260] As shown in Scheme 11, step 2, to a stirred solution of ethyl ((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)carbamate (100 mg, 0.23 mmol) in toluene (2 mL) was added piperidin-4-ol (47 mg, 0.47 mmol). The resulting mixture was stirred at 80 °C for 16 h and then concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (65%-75% acetonitrile / water) to give N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-4-hydroxypiperidine-1-carboxamide (compound 35, 5.5 mg, 5% yield) as a white solid. MS (ESI) calcd. C 18 H 14 ClF5N2O4S) [M+1] + = 485.0, Actual value 485.0; 1 H-NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.86 - 7.66 (m, 1H), 4.72 (s, 1H), 3.68 - 3.64 (m, 3H), 3.02 - 3.01 (m, 2H), 1.68 - 1.66 (m, 2H), 1.27 - 1.23 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.56, -115.48, -130.45, -133.62, -164.42.

[0261] Using the appropriate amine and compound 33 or compound 34 in a similar transformation as described for step 2 of scheme 11 in Example 8, the following compounds were also prepared: N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)thiomorpholine-4-carboxamide (compound 54), isolated as a white solid: MS (ESI) calculated C 17 H 12 ClF5N2O3S2[M+1] + = 487.0, actual value 486.9; 1 H-NMR (400 MHz, DMSO-d6+ D2O) δ 8.00 (d, J = 8.0 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.59 (d, J = 9.6 Hz, 1H), 3.59 (s, 4H), 2.40 (s, 4H); 19 F-NMR (377 MHz, DMSO-d6) δ -111.97, -115.45, -131.53, -133.81, -164.74; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)thiomorpholine-4-carboxamide 1,1-dioxide (compound 57), isolated as a white solid: MS (ESI) calculated C 17 H 12 ClF5N2O5S2[M+1] + = 519.0, Actual value 519.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.0 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.63 (d, J = 9.2 Hz, 1H), 3.76 (s, 4H), 2.91 (s, 4H); 19 F-NMR (377 MHz, DMSO-d6) δ -111.41, -115.47, -131.47, -133.81, -164.75; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)morpholine-4-carboxamide (compound 58), isolated as a white solid: MS (ESI) calculated C 17 H 12 ClF5N2O4S [M-1]- = 469.0, actual value 468.9; 1 H-NMR (400 MHz, DMSO-d6+ D2O) δ 8.00 (d, J = 8.0 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.59 (d, J = 9.6 Hz, 1H), 3.45 (s, 4H), 3.27 (s, 4H); 19 F-NMR (377 MHz, DMSO-d6) δ -111.99, -115.48, -131.51, -133.84, -164.75; 4-Chloro-2',3',4',6,6'-pentafluoro-N-(phenylcarbamoyl)-[1,1'-biphenyl]-3-sulfonamide (compound 61), isolated as a white solid: MS (ESI) calculated C 19 H 10 ClF5N2O3S [M+1] + = 477.0, Actual value 477.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.61 (d, J = 9.6 Hz, 1H), 7.43 - 7.40 (m, 2H), 7.09 - 7.05 (m, 2H), 6.74 - 6.70 (m, 1H), 6.08 - 6.02 (br, 1H); 19 F-NMR (377 MHz, DMSO-d6) δ -111.40, -115.43, -131.33, -133.77, -164.64; and N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)piperidine-1-carboxamide (compound 62), isolated as a white solid: MS (ESI) calculated C 18 H 14 ClF5N2O3S [M+1] + = 469.0, Actual value 469.0; 1H-NMR (400 MHz, DMSO-d6+ D2O) δ 7.97 (d, J = 7.6 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.56 (d, J = 9.6 Hz, 1H), 3.27 - 3.26 (m, 4H), 1.46 - 1.44 (m, 2H), 1.32 - 1.28 (m, 4H); 19 F-NMR (377 MHz, DMSO-d6) δ -111.61, -115.36, -131.10, -133.74, -164.61.

[0262] Example 10. Preparation of N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2,5,6,9,10,13,14,17-octaoxanonadecane-19-amide (Compound 36) [ka] As shown in Scheme 12, to a stirred solution of 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (100 mg, 0.28 mmol) in dimethylacetamide (1 mL) was added 2-((2-((2-((2-(λ 1-oxidanyl)ethyl)peroxy)ethyl)peroxy)ethyl)-(2-methoxyethyl)peroxy)acetic acid (149 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 160 mg, 0.84 mmol) and 4-dimethylaminopyridine (DMAP, 3 mg, 0.03 mmol) were added. The resulting mixture was stirred at 25° C. for 2 hours, followed by the addition of water and extraction with EtOAc. The organics were washed with 0.5M HCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (46%-56% acetonitrile / 0.1% FA in HO) to give N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2,5,6,9,10,13,14,17-octaoxanonadecane-19-amide (compound 36, 18 mg, 11% yield) as a white semi-solid. MS (ESI) calcd. C 23 H 25 ClF5NO8S [M-1] - = 604.0, actual value 604.1; 1 H-NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.86 - 7.61 (m, 1H), 4.05 (s, 2H), 3.55 - 3.51 (m, 5H), 3.49 - 3.48 (m, 9H), 3.42 - 3.40 (m, 2H), 3.23 (s, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -104.72, -115.49, -130.70, -133.48, -164.55.

[0263] Using the appropriate carboxylic acid in a similar transformation as described in Scheme 12 of Example 10, the following compounds were also prepared: N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)tetrahydro-2H-thiopyran-4-carboxamide (compound 37), isolated as a white solid: MS (ESI) calculated C 18 H 13 ClF5NO3S2[M-1] - = 484.0, actual value 483.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.82 - 7.70 (m, 1H), 2.62 - 2.32 (m, 5H), 2.07 - 1.91 (m, 2H), 1.57 - 1.46 (m, 2H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.53, -115.49, -130.65, -133.48, -164.61; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2-(2-chlorophenyl)acetamide (compound 38), isolated as a white solid: MS (ESI) calculated C 20 H 10 Cl2F5NO3S [M-1] - = 507.9, measured value 507.9; 1 H-NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 7.83 - 7.68 (m, 1H), 7.43 - 7.34 (m, 1H), 7.37 - 7.29 (m, 1H), 7.33 - 7.22 (m, 2H), 3.83 (s, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.40, -115.45, -130.61, -133.48, -164.65; (1s,4s)-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-4-hydroxycyclohexane-1-carboxamide (compound 39), isolated as a white solid: MS (ESI) calcd. C 19 H 15 ClF5NO4S [M-1] - = 481.8, measured value 481.8; 1 H-NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.82 - 7.70 (m, 1H), 4.31 (s, 1H), 3.71 (s, 1H), 2.38 - 2.28 (m, 1H), 1.71 - 1.50 (m, 4H), 1.50 - 1.33 (m, 4H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.56, -115.49, -130.70, -133.48, -164.55; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (compound 40), isolated as a white solid: MS (ESI) calcd. C 18 H 13 ClF5NO5S2[M-1] - = 515.9, measured value 515.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.76 - 7.65 (m, 1H), 3.21 - 3.10 (m, 2H), 3.10 - 3.00 (m, 2H), 2.74 - 2.62 (m, 1H), 2.21 - 2.11 (m, 2H), 1.95 - 1.80 (m, 2H); 19F-NMR (376 MHz, DMSO-d6) δ -103.18, -115.48, -130.43, -133.56, -164.52; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-3,3,3,3,3,3,3,3,3,3,3,3-undecamethyl-λ, isolated as a white solid 16 -Butanamide (compound 41): C 27 H 33 ClF5NO3S[M-1] - =580.1, actual value 580.2; 1 H-NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.83 - 7.72 (m, 1H), 2.26 (t, J = 7.2 Hz, 2H), 1.43 (p, J = 7.2 Hz, 2H), 1.28 - 1.22 (m, 22H), 0.89 - 0.81 (m, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.61, -115.51, -130.66, -133.46, -164.60; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)cyclopropanecarboxamide (compound 60), isolated as a white solid: MS (ESI) calculated C 16 H9ClF5NO3S [M-1] - = 424.0, actual value 423.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.91 (br, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.78 - 7.71 (m, 1H), 1.82 - 1.77 (m, 1H), 0.88 - 0.65 (m, 4H); 19F-NMR (377 MHz, DMSO-d6) δ -103.55, -115.50, -130.95, -133.54, -164.66; and N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-3-methylbutanamide (compound 65), isolated as a white solid: MS (ESI) calculated C 17 H 13 ClF5NO3S [M-1] - = 440.0, Actual value 440.0; 1 H-NMR (400 MHz, DMSO-d6) δ 12.61 (br, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.78 - 7.74 (m, 1H), 2.15 (d, J = 7.2 Hz, 2H), 1.97 - 1.90 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.50, -115.55, -130.69, -133.57, -164.71.

[0264] Example 11. Preparation of 2-(tert-butoxy)-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)acetamide (Compound 42) and N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2-hydroxyacetamide (Compound 43) [ka] As shown in Scheme 13, Step 1, to a stirred mixture of 4-chloro-2',4',6,6'-tetrafluoro-[1,1'-biphenyl]-3-sulfonamide (50 mg, 0.14 mmol) and tert-butoxyacetic acid (19.4 mg, 0.14 mmol) in DMF (1 mL) was added DIEA (57.0 mg, 0.44 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphonate (PyBOP, 114.9 mg, 0.22 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 h, diluted with water, and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (67%-77% acetonitrile / 0.1% FA in HO) to afford 2-(tert-butoxy)-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)acetamide (compound 42, 24 mg, 21% yield) as a white solid: 1 H-NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 9.6 Hz, 1H), 7.83 - 7.71 (m, 1H), 3.95 (s, 2H), 1.09 (s, 9H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.52, -115.53, -130.64, -133.57, -169.36.

[0265] As shown in Scheme 13, step 2, to a stirred mixture of 2-(tert-butoxy)-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)acetamide (130 mg, 0.27 mmol) in DCM (1 mL) was added TFA (1 mL). The resulting mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase preparative HPLC (42%-52% acetonitrile / 0.1% FA in H2O) to give N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2-hydroxyacetamide (compound 43, 24 mg, 21% yield) as a white solid. MS (ESI) calcd. C 14 H7ClF5NO4S) [M-1] - = 414.0, actual value 413.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.82 - 7.71 (m, 1H), 5.22 (s, 1H), 3.95 (s, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -104.11, -115.55, -130.71, -133.54, -164.61.

[0266] Using the appropriate carboxylic acid in a similar transformation as described in Step 1 of Scheme 13 of Example 11, the following compounds were also prepared: N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2-(3-chlorophenyl)acetamide (compound 44), isolated as a white solid: MS (ESI) calculated (C 20 H 10 Cl2F5NO3S) [M-1] - = 507.9, measured value 507.9; 1H-NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.23 ​​(d, J = 7.2 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.80 - 7.68 (m, 1H), 7.37 - 7.29 (m, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.20 - 7.12 (m, 1H), 3.65 (s, 2H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.44, -115.50, -130.65, -133.56, -164.63; (1r,4r)-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-4-hydroxycyclohexane-1-carboxamide (compound 45), isolated as a white solid: MS (ESI) calculated (C 19 H 15 ClF5NO4S) [M+1] + = 484.03;Actual, 484.03; 1 H-NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.68 - 7.62 (m, 1H), 3.29 - 3.26 (m, 1H), 2.19 - 2.16 (m, 1H), 1.88 - 1.77 (m, 2H), 1.74 - 1.65 (m, 2H), 1.33 - 0.99 (m, 5H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.52, -115.53, -130.30, -133.50, -164.43; N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)cyclohexanecarboxamide (compound 46), isolated as a white solid: MS (ESI) calculated (C 19 H 15 ClF5NO3S) [M-1] - = 466.0, Actual value 466.0; 1H-NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.85 - 7.52 (m, 1H), 2.38 - 2.17 (m, 1H), 1.80 - 1.58 (m, 5H), 1.31 - 0.96 (m, 5H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.56, -115.48, -130.63, -133.43, -164.52; and N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-2-methoxyacetamide (compound 47), isolated as a white solid: MS (ESI) calculated (C 15 H9ClF5NO4S) [M-1] - = 428.0, actual value 427.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.82 - 7.71 (m, 1H), 3.97 (s, 2H), 3.24 (s, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -103.36, -115.51, -130.63, -133.43, -164.52.

[0267] Example 12. Preparation of 4-chloro-2',3',4',6,6'-pentafluoro-N-(methylsulfonyl)-[1,1'-biphenyl]-3-sulfonamide (Compound 48) [ka] As shown in Scheme 14, to a stirred mixture of 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (100 mg, 0.28 mmol), TEA (85 mg, 0.84 mmol), DMAP (0.3 mg, 0.01 mmol) in DCM (1 mL) was added methanesulfonyl chloride (64 mg, 0.56 mmol) in DMF (0.2 mL) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at 25° C. for 16 h, diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (42%-52% acetonitrile / 0.05% HCl in water) to give 4-chloro-2',3',4',6,6'-pentafluoro-N-(methylsulfonyl)-[1,1'-biphenyl]-3-sulfonamide (compound 48, 12 mg, 10% yield) as a white solid; MS (ESI) calculated C 13 H7ClF5NO4S2) [M-1] - = 433.9, measured value 433.8; 1 H-NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 7.6 Hz, 1H), 7.79 - 7.67 (m, 2H), 2.80 (s, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -110.04, -115.55, -131.24, -133.82, -164.61.

[0268] Using the same procedure as described in Scheme 14, but substituting methanesulfonyl chloride for ethanesulfonyl chloride, 4-chloro-N-(ethylsulfonyl)-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 49) was also produced as a white solid: MS (ESI) calculated (C 14 H9ClF5NO4S2) [M-1] - = 448.0, actual value 447.9; 1H-NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 7.6 Hz, 1H), 7.79 - 7.67 (m, 2H), 2.89 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -110.17, -115.55, -131.25, -133.81, -164.60.

[0269] Example 13. Preparation of N-((2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (Compound 50) [ka] As shown in Scheme 15, Step 1, to a stirred mixture of 1,2,3,5-tetrafluoro-4-iodobenzene (1.6 g, 5.79 mmol) and 2,4-difluorophenylboronic acid (0.92 g, 5.79 mmol) in 1,4-dioxane (20 mL) and HO (4 mL) was added XPhos Pd G3 (0.98 g, 1.16 mmol) and K3PO4 (2.5 g, 11.59 mmol). The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere, cooled, diluted with water, and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (1:1 DCM / petroleum ether) to give 2,2',3,4,4',6-hexafluoro-1,1'-biphenyl (compound 1013, 1.0 g, 65% yield) as a yellow solid; GCMS (ESI) calculated C 12 H4F 6= 262.0, actual value 262.0.

[0270] As shown in Scheme 15, step 2, to a stirred solution of chlorosulfonic acid (11.6 g, 99 mmol) in CHCl3 (10 mL) was added 2,2',3,4,4',6-hexafluoro-1,1'-biphenyl (compound 1013, 1.3 g, 5 mmol), followed by dropwise addition of SOCl2 (1.18 g, 9.9 mmol) at 0 °C. The resulting mixture was stirred at 150 °C for 16 h. After cooling, the solvent was removed under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonic acid (compound 1014, 1.3 g, crude) as a brown oil. This material was used directly as is in the subsequent reaction.

[0271] As shown in Scheme 15, Step 3, a solution of 2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonic acid (compound 1014, 1.3 g, 3.79 mmol) in POCl3 (13 mL) was stirred overnight at 110° C. After cooling, the mixture was concentrated under reduced pressure to give 2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (compound 1015, 1.3 g, crude) as a brown solid, which was used directly in the subsequent reaction without further purification.

[0272] As shown in Scheme 15, step 4, 2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (compound 1015, 1.3 g, 3.60 mmol) was added dropwise to a stirred solution of saturated aqueous NH3 (3 mL, 77.04 mmol) in MeCN (15 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (5% to 100% acetonitrile / water) to give 2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 1016, 160 mg, 13% yield) as a brown oil. MS (ESI) calculated (C 12 H5F6NO2S) [M-1]- = 340.0, actual value 340.0.

[0273] As shown in Scheme 15, Step 5, to a stirred solution of propanoyl chloride (122 mg, 1.32 mmol) and TEA (133 mg, 1.32 mmol) in DMAc (2 mL) was added 2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-sulfonamide (150 mg, 0.44 mmol) and DMAP (10 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 16 h, diluted with water, and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (45%-55% acetonitrile / 0.05FA in water) to give N-((2',3',4,4',6,6'-hexafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 50, 24 mg, 12% yield) as a white solid. MS (ESI) calcd. C 15 H9F6NO3S) [M-1] - = 396.0, actual value 395.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.15 (t, J = 7.6Hz, 1H), 7.87 (t, J = 10.0 Hz, 1H), 7.81 - 7.69 (m, 1H), 2.30 (q, J = 7.2 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -100.00, -103.41, -115.68, -130.92, -133.65, -164.80.

[0274] Example 14. Preparation of N-((4,6-dichloro-2',3',4',6'-tetrafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (Compound 51) [ka] As shown in Scheme 16, Step 1, to a stirred mixture of 1,2,3,5-tetrafluoro-4-iodobenzene (2.00 g, 7.24 mmol) and 2,4-dichlorophenylboronic acid (2.07 g, 10.87 mmol) in dioxane (20 mL) and HO (4 mL) was added XPhos Pd G3 (0.61 g, 0.72 mmol), XPhos (0.35 g, 0.72 mmol) and K3PO4 (3.08 g, 14.49 mmol). The resulting mixture was stirred at 100° C. for 16 h under a nitrogen atmosphere. After cooling, the mixture was filtered through diatomaceous earth, the filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure. The residue was taken up with EtOAc and the combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (0%-30% DCM / petroleum ether) to give 2',4'-dichloro-2,3,4,6-tetrafluoro-1,1'-biphenyl (compound 1017, 1.00 g, 46% yield) as a yellow oil. GCMS calculated C 12 H4Cl2F4=294.0, actual value 294.0.

[0275] As shown in Scheme 16, Step 2, a mixture of 2',4'-dichloro-2,3,4,6-tetrafluoro-1,1'-biphenyl (compound 1017, 900 mg, 3.05 mmol) and chlorosulfonic acid (10 mL) was stirred at 60° C. for 2 h. The mixture was cooled and concentrated under reduced pressure to give 4,6-dichloro-2',3',4',6'-tetrafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (compound 1018, 1.00 g, 83% yield) as a brown oil. This material was used in the subsequent step without further purification.

[0276] As shown in Scheme 16, step 3, to a mixture of 4,6-dichloro-2',3',4',6'-tetrafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (compound 1018, 1.00 g, 2.54 mmol) in MeCN (10 mL) was added concentrated NH4OH (aq) (1 mL). The resulting mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (46%-56% acetonitrile / 10 mM NH4HCO3 in water) to give 4,6-dichloro-2',3',4',6'-tetrafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 1019, 240 mg, 25% yield) as a white solid. MS (ESI) calcd. C 12 H5Cl2F4NO2S) [M-1] - = 371.9, measured value 371.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.11 (s, 1H), 7.84 (d, J = 3.6 Hz, 2H), 7.81 - 7.70 (m, 1H); 19 F-NMR (376 MHz, DMSO-d6) δ -115.27, -130.89, -133.49, -164.83.

[0277] As shown in Scheme 16, step 4, to a stirred mixture of 4,6-dichloro-2',3',4',6'-tetrafluoro-[1,1'-biphenyl]-3-sulfonamide (100 mg, 0.26 mmol) and K2CO3 (73 mg, 0.53 mmol) in acetone (2 mL) was added propanoyl chloride (49 mg, 0.53 mmol). The resulting mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (46%-56% acetonitrile / 0.1% FA in water) to give N-((4,6-dichloro-2',3',4',6'-tetrafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 51, 37 mg, 31% yield) as a white solid. MS (ESI) calcd. C 15 H9Cl2F4NO3S) [M-1] - = 428.0, actual value 427.9;1 H-NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.22 (d, J = 9.2 Hz, 2H), 7.82 - 7.70 (m, 1H), 2.31 (q, J = 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -115.29, -130.91, -133.49, -164.86.

[0278] Example 15. Preparation of N-((4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)acetamide (Compound 52) [ka] As shown in Scheme 17, Step 1, to a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (5.0 g, 23.87 mmol) in dioxane (20 mL) and HO (4 mL) under a nitrogen atmosphere was added 2,3,4,5-tetrafluorophenylboronic acid (4.6 g, 23.9 mmol), XPhos Pd G3 (4.0 g, 4.8 mmol), XPhos (2.3 g, 4.8 mmol) and K3PO4 (10.1 g, 47.7 mmol). The mixture was stirred at 80 °C for 2 h, diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 5% ethyl acetate / petroleum ether) to give 4'-chloro-2,2',3,4,5-pentafluoro-1,1'-biphenyl (compound 1020, 4.0 g, 36% yield) as a colorless oil. GCMS (ESI) calcd. C 12 H4ClF5=277.9, actual value 278.0.

[0279] As shown in Scheme 17, step 2, to a stirred solution of chlorosulfonic acid (0.8 g, 7.18 mmol) in 1 mL of CHCl3 at 0 °C was added dropwise a solution of 4'-chloro-2,2',3,4,5-pentafluoro-1,1'-biphenyl (100.0 mg, 0.35 mmol) in CHCl3 (1 mL) under nitrogen atmosphere. The resulting mixture was stirred at 50 °C under nitrogen atmosphere for 16 h, diluted with water, and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DMF (2 mL) which was purified by reverse phase flash chromatography (5% to 75% acetonitrile / water) to give 4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-sulfonic acid (compound 1021, 14.0 mg, 10% yield) as a white solid. MS (ESI) Calculated value C 12 H4ClF5O3S [M-1] - = 357.1, actual value 357.1; 1 H-NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.2 Hz, 1H), 7.61 - 7.50 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -112.64, -139.04, -140.20, -155.11, -155.64.

[0280] As shown in Scheme 17, Step 3, a solution of 4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-sulfonic acid (2.7 g, 7.53 mmol) in POCl3 (20 mL) was stirred at 100°C for 2 h. After cooling, the volatiles were removed under reduced pressure to give 4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (compound 1022, 2.7 g) as a brown oil. This material was used directly as is in the subsequent reaction.

[0281] As shown in Scheme 17, step 4, concentrated ammonia (1.5 g, 10.6 mmol) was added in portions to a stirred solution of 4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (1.0 g, 2.65 mmol) in acetonitrile (20 mL) at 0 °C. The resulting mixture was stirred at 0 °C for an additional 2 h, diluted with water, and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (6 mL) and purified by flash chromatography (0% to 65% ethyl acetate / petroleum ether) to give 4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 1023, 300 mg, 31% yield) as a brown solid. MS (ESI) calcd. C 12 H5ClF5NO2S [M-1] - = 355.9, measured value 355.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.78 (s, 2H), 7.75 - 7.64 (m, 1H); 19 F-NMR (377 MHz, DMSO-d6) δ -100.92, -139.11, -140.02, -154.58, -155.56.

[0282] As shown in Scheme 17, step 5, to a solution of 4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-sulfonamide (compound 1023, 200 mg, 0.56 mmol), DMAP (6.8 mg, 0.06 mmol) and TEA (113 mg, 1.12 mmol) in DCM (2 mL) and DMF (2 mL) was added acetyl chloride (125 mg, 1.6 mmol) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 3 h, diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in DMF (2 mL) and purified by reverse-phase flash chromatography (5% to 45% acetonitrile / water) to give N-((4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)acetamide (compound 52, 90 mg, 40% yield) as a white solid. MS (ESI) calculated C 14 H7ClF5NO3S [M-1] - = 397.9; Measured 397.9. 1 H-NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.78 - 7.67 (m, 1H), 1.99 (s, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -105.01, -139.08, -139.83, -154.48, -155.54.

[0283] Using the same procedure as described in step 5 of Scheme 17, but using propionyl chloride instead of acetyl chloride, N-((4-chloro-2',3',4',5',6-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 53) was produced as a white solid: MS (ESI) calcd. C 15 H9ClF5NO3S) [M-1] - = 412.0, actual value 411.9; 1H-NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.82 - 7.66 (m, 1H), 2.30 (q, J = 7.2 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -104.78, -139.08, -139.79, -154.45, -155.53.

[0284] Example 16. Preparation of 2-(benzylthio)-3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine (Compound 67), 3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine-2-sulfonamide (Compound 68), and N-((3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridin-2-yl)sulfonyl)propionamide (Compound 71) [ka] As shown in Scheme 18, Step 1, a degassed mixture of 4,4,5,5-tetramethyl-2-(2,3,4,6-tetrafluorophenyl)-1,3,2-dioxaborolane (4.34 g, 15.7 mmol), 6-bromo-5-fluoropyridin-3-amine (3.00 g, 15.7 mmol), P(t-Bu)3Palladacycle Gen.3 (0.90 g, 1.57 mmol), CyP(t-Bu)2.HBF4 (0.99 g, 3.14 mmol), and K3PO4 (6.67 g, 31.41 mmol) in toluene (10 mL) and HO (2 mL) was stirred at 100° C. for 16 h under a nitrogen atmosphere. After this time, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0% to 50% ethyl acetate in petroleum ether) to give 5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridin-3-amine (compound 1024, 2.90 g, 70% yield) as a yellow solid. GCMS calculated C 11 H5F5N2=261.0, actual value 261.0.

[0285] As shown in Scheme 18, Step 2, a mixture of 5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridin-3-amine (2.90 g, 11.14 mmol) and N-bromosuccinimide (2.46 g, 13.83 mmol) in DMF (30 mL) was stirred at 25° C. for 16 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (0% to 50% MeCN / water containing 0.1% formic acid) to give 2-bromo-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridin-3-amine (compound 1025, 2.20 g, 58% yield) as a white solid: MS (ESI) calcd. C 11 H4BrF5N2[M+1] + = 338.9, measured value 338.8; 1H-NMR (400 MHz, DMSO-d6) δ 7.71 - 7.59 (m, 1H), 7.08 (d, J = 11.2 Hz, 1H), 6.27 (s, 2H); 19 F-NMR (377 MHz, DMSO-d6) δ -116.16, -124.03, -131.39, -134.99, -164.91.

[0286] As shown in Scheme 18, step 3, a mixture of tert-butyl nitrite (0.91 g, 8.84 mmol) and CuCl2 (1.19 g, 8.84 mmol) in MeCN (20 mL) was stirred at 25 °C for 20 min, followed by the addition of 2-bromo-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridin-3-amine (2.00 g, 5.89 mmol). The resulting mixture was stirred at 60 °C for 16 h, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (0% to 50% MeCN / water containing 0.1% formic acid) to give 2-bromo-3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine (compound 1026, 1.6 g, 75% yield) as a white solid. MS (ESI) calcd. C 11 H2BrClF5N [M+1] + = 357.9, actual value 359.8; 1 H-NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.8 Hz, 1H), 7.83 - 7.71 (m, 1H); 19 F-NMR (377 MHz, DMSO-d6) δ -115.75, -120.39, -128.78, -134.45, -164.03.

[0287] As shown in Scheme 18, Step 4, to a stirred mixture of 2-bromo-3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine (1.6 g, 4.46 mmol) and 4-bromobenzyl mercaptan (1.00 g, 4.90 mmol) in toluene (25 mL) was added Pd2(dba)3 (0.40 g, 0.44 mmol, 0.1 equiv), XantPhos (0.51 g, 0.89 mmol), and DIEA (1.15 g, 8.89 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 16 h. After cooling, the mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (0% to 100% MeCN / water containing 0.1% formic acid) to give 2-(benzylthio)-3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine (compound 67, 1.2 g, 66% yield) as a white solid. MS (ESI) calculated C 18 H9ClF5NS [M+1] + = 402.0, actual value 401.9; 19 F-NMR (377 MHz, DMSO-d6) δ -115.63, -125.61, -129.45, -134.41, -164.32.

[0288] As shown in Scheme 18, step 5, to a stirred mixture of 2-(benzylsulfanyl)-3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine (500 mg, 1.24 mmol) in HO (0.5 mL), AcOH (0.5 mL), and MeCN (10 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (612 mg, 3.11 mmol). The resulting mixture was stirred at 0° C. for 2 h and concentrated under reduced pressure to give 3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine-2-sulfonyl chloride (compound 1027, 400 mg, crude) as a yellow oil. This material was used directly in the subsequent reaction without further purification.

[0289] As shown in Scheme 18, Step 6, a mixture of 3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine-2-sulfonyl chloride (200 mg, 0.52 mmol) and NH4OH (0.5 mL) in MeCN (2 mL) was stirred at 25° C. for 1 h and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (0% to 50% MeCN in 10 mM aqueous NH4HCO3) to give 3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine-2-sulfonamide (compound 68) as a white solid. MS (ESI) calcd. C 11 H4ClF5N2O2S [M-1] - = 357.0, actual value 356.9; 1 H-NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.8 Hz, 1H), 7.81 (s, 2H), 7.78 - 7.72 (m, 1H); 19 F-NMR (377 MHz, DMSO-d6) δ -114.46, -115.42, -128.39, -134.05, -164.17.

[0290] As shown in Scheme 18, Step 7, to a stirred mixture of 3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridine-2-sulfonamide (100 mg, 0.27 mmol) and TEA (56 mg, 0.55 mmol) in DCM (2 mL) was added propionyl chloride (38 mg, 0.41 mmol) and DMAP (3 mg, 0.02 mmol). The resulting mixture was stirred at 25° C. for 2 h, followed by the addition of 1 M HCl. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC (20%-30% MeCN / water containing 0.1% formic acid) to give N-((3-chloro-5-fluoro-6-(2,3,4,6-tetrafluorophenyl)pyridin-2-yl)sulfonyl)propionamide (compound 71, 47.6 mg, 41% yield) as a white solid. MS (ESI) calcd. C 14H8ClF5N2O3S [M-1] - = 413.0, actual value 412.9; 1 H-NMR (400 MHz, DMSO-d6) δ 12.41 (br, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.86 - 7.79 (m, 1H), 2.32 (q, J = 7.2 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -112.18, -115.56, -128.14, -134.29, -164.06.

[0291] Example 17. Preparation of N-benzyl-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (Compound 69) [ka] As shown in Scheme 19, to a solution of N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (140 mg, 0.33 mmol) and benzyl alcohol (43 mg, 0.40 mmol) in THF (2 mL) was added PPh3 (133 mg, 0.50 mmol) and DIAD (102 mg, 0.50 mmol) sequentially at 0° C. The reaction mixture was warmed to 25° C. and stirred for 2 h. 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, dissolved in DMF (2 mL) and purified by reverse-phase preparative HPLC (2%, then 65%-75% MeCN in 10 mM aqueous NH4HCO3) to give N-benzyl-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 69, 20.7 mg, 12% yield) as a white solid. MS (ESI) calcd. C 22 H 15 ClF5NO3S [M-1]- = 504.0, actual value 504.1; 1 H-NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.47 - 7.29 (m, 6H), 5.24 (s, 2H), 2.53 (q, J = 7.2 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -104.29, -117.01, -132.17, -135.12, -167.17.

[0292] Using the appropriate alcohol in a similar transformation as described in Scheme 13 of Example 19, the following compounds were also prepared: N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-N-methylpropionamide (compound 72): MS (ESI) calculated value C 16 H 11 ClF5NO3S [M+1] + = 428.0, Actual value 428.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.80 - 7.73 (m, 1H), 3.43 (s, 3H), 2.61 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.49, -115.50, -130.66, -133.53, -164.67; and N-Allyl-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 74): MS (ESI) calculated value C 18 H 13 ClF5NO3S [M+1] += 454.0, Actual value 454.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 6.06 - 5.97 (m, 1H), 5.32 - 5.26 (m, 2H), 4.58 (s, 2H), 2.59 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.27, -115.52, -130.65, -133.51, -164.66.

[0293] Example 18. Preparation of 4-chloro-2',3',4',6,6'-pentafluoro-N-methoxy-[1,1'-biphenyl]-3-sulfonamide (compound 73) and N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)-N-methoxypropionamide (compound 76). [ka] As shown in Scheme 20, step 1, to a stirred solution of 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfonyl chloride (200 mg, 0.53 mmol) in DCM (5 mL) was added O-methylhydroxylamine hydrochloride (88 mg, 1.06 mmol) and pyridine (84 mg, 1.06 mmol). The resulting mixture was stirred at 25°C for 2 h, diluted by adding 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 flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 4-chloro-2',3',4',6,6'-pentafluoro-N-methoxy-[1,1'-biphenyl]-3-sulfonamide (compound 73, 130 mg, 63% yield) as a white solid. MS (ESI) Calculated value C13 H7ClF5NO3S [M-1] - = 386.0, actual value 385.9; 1 H-NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.81 - 7.74 (m, 1H), 3.67 (s, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -103.66, -115.63, -130.50, -133.66, -164.57.

[0294] As shown in Scheme 20, Step 2, to a stirred solution of 4-chloro-2',3',4',6,6'-pentafluoro-N-methoxy-[1,1'-biphenyl]-3-sulfonamide (130 mg, 0.34 mmol) in DCM (3 mL) was added propionyl chloride (62 mg, 0.67 mmol), TEA (101 mg, 1.01 mmol), and DMAP (8 mg, 0.07 mmol). The resulting solution was stirred at 25° C. for 16 h, diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (0.5 mL) and purified by reverse-phase preparative HPLC (60-70% MeCN / 0.1% formic acid in water) to give N-benzyl-N-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propionamide (compound 76, 50 mg, 34% yield) as a white solid. MS (ESI) calculated C 16 H 11 ClF5NO3S [M+1] + = 444.0, Actual value 444.0; 1H-NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.80 - 7.73 (m, 1H), 4.01 (s, 3H), 2.69 (q, J = 7.2 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -101.75, -115.52, -130.55, -133.51, -164.68.

[0295] Example 19. Preparation of 1-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propan-2-one (Compound 78). [ka] As shown in Scheme 21, to a solution of sodium 4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-sulfinate (140 mg, 0.38 mmol) in EtOH (7 mL) was added bromoacetone (52 mg, 0.38 mmol) slowly at 25 °C. The reaction mixture was stirred at 25 °C for 16 h and then concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and purified by reverse phase preparative HPLC (44-54% MeCN / 0.1% formic acid in water) to give 1-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)propan-2-one (compound 78, 22.0 mg, 14%) as a white solid. MS (ESI) calcd. C 15 H8ClF5O3S [M-1] - = 397.0, Actual value 397.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.22 (d, J= 7.6 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.80 - 7.74 (m, 1H), 4.89 (s, 3H), 2.25 (s, 3H); 19F-NMR (377 MHz, DMSO-d6) δ -102.80, -115.60, -130.62, -133.65, -164.64.

[0296] Compound 1012 was reacted with 1-bromobutan-2-one in a manner similar to that used to convert compound 78 to give 1-((4-chloro-2',3',4',6,6'-pentafluoro-[1,1'-biphenyl]-3-yl)sulfonyl)butan-2-one (compound 79). MS (ESI) Calculated C 16 H 10 ClF5O3S [M-1] - = 411.0, Actual value 411.0; 1 H-NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.80 - 7.74 (m, 1H), 4.93 (s, 2H), 2.52 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H); 19 F-NMR (377 MHz, DMSO-d6) δ -102.84, -115.62, -130.62, -133.65, -164.59.

[0297] Biological Examples Example 20. Expression and purification of Amaranthus tuberculatum protoporphyrinogen oxidase (AmPPO) The coding sequence of AmPPO was optimized for E. coli expression and assembled from synthetic oligonucleotides. Synthetic fragments were introduced into the pET28b vector (Novagen) using a non-restrictive "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 verified. A construct encoding a mutant form of the enzyme (ΔG210-AmPPO) was generated via PCR-based mutagenesis using the Q5 Mutagenesis Kit (NEB).

[0298] Lysogeny medium (LB medium, 10 mL) supplemented with 100 μg / mL Kanaamishi 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 overnight at 37°C with shaking at 230 rpm. This culture was then used to inoculate 1 L of autoinduction medium (AIM) prepared as described in Fox, BG, & Blommel, PG (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 4-6 hours and at 18°C ​​for an additional 40-48 hours. The culture was harvested and centrifuged. The resulting AmPPO enzyme-containing cell pellet was frozen and stored at −80° C. for future use.

[0299] The same procedure used for producing AmPPO was used to produce mutant ΔG210-AmPPO (a PPO mutant lacking glycine at position 210) except that the E. coli used was transformed with pET28b_ΔG210 PPO_Chis.

[0300] 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 1 M TRIS buffer, pH 9.0, 15 mL of 5 M NaCl, 50 mL of glycerol, 2.5 mL of Triton-X100, and 1 mg of flavin adenine dinucleotide (FAD). A portion of this solution (approximately 80 mL to 100 mL) was removed and imidazole was added to a final concentration of 10 mM and pH 8.0. The remainder of the detergent solution was supplemented with hen egg white lysozyme (Gold Bio, 1 mg / mL) and Serratia endonuclease (manufactured in-house) and added to approximately 45 g of frozen enzyme-containing cell pellet, which was thawed in lysis solution with vigorous agitation at room temperature for 30 min and then briefly sonicated (30 s at 50% power using a VWR brand sonicator). Incubation was continued at 4° C. with agitation for an additional 15-30 min. The lysate was clarified by centrifugation at 14,000 RPM for 35 min. The resulting clarified lysate was incubated with His-SELECT® resin (Sigma, 20 mL of 50% slurry in 20% ethanol, 30 mM TRIS pH 8.1, 10% glycerol, washed twice with 220 mM NaCl) with gentle agitation at 4° C. for 1 h. 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 bound proteins were deemed sufficiently washed away from the lysate components (approximately 6-8 column volumes). The resin was then washed thoroughly (approximately 3 column volumes) with previously reserved detergent I-10 final buffer and subsequently eluted with the same buffer supplemented with 250 mM imidazole at pH 8.1. Enzyme-containing fractions were collected and pooled based on SDS-PAGE analysis. The pooled fractions were diluted with pure glycerol to a final concentration of 50% and the AmPPO enzyme or mutant ΔG210-AmPPO were stored in liquid form at −20° C.

[0301] Example 21. PPO in vitro assay Protoporphyrinogen IX (PPGIX) is prepared by reducing protoporphyrin IX (PPIX) with sodium amalgam as described by Jacobs and Jacobs, Enyzme 28:206 (1982). Once prepared, the PPGIX solution is kept in the dark and all subsequent manipulations are carried out in the dark.

[0302] The base buffer for the assay was 50 mM TRIS (pH 8.5), 160 mM NaCl, 2 mM DTT, 0.01% Triton X-100. Antifoam solutions were prepared by two serial 1-10 dilutions of antifoam B emulsion (SigmaAldrich) with Milli-Q water. Buffer A was freshly prepared by diluting AmPPO or mutant ΔG210-AmPPO in base buffer to a concentration of 3-8ug / ml of enzyme. Buffer B was prepared by adding 2ml of reduced 2mM PPIX to 60ml of base buffer and adjusting the pH back to 8.5 using glacial acetic acid. Finally, antifoam B (Sigma) was added to a final concentration of 0.01%. Buffer B was protected from light and used within 3 hours of its preparation.

[0303] A 384-well clear bottom plate was used for the assay. Each test compound was dissolved in DMSO to a concentration of 30 mM. Test compounds, butafenacil controls, and DMSO controls, tested in triplicate, were dispensed into wells of the plate as 1.2 μL droplets. Wells were serially diluted from 1 to 3 volumes over 7 dilutions by diluting with 60 μL of buffer A, removing 20 μL from the first well, mixing the well with 40 μL of buffer A in the second well, removing 20 μL from the second well, and continuing dilution 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 were mixed gently at least twice. The plate was centrifuged at 2000 rpm for 1 minute and absorbance or fluorescence was read at ambient temperature using a plate reader. IC 50 is the curve bottom and plate specific V constrained to zero averageThe dose-response model was calculated using a nonlinear regression sigmoidal dose-response model (GraphPad Prism, variable slope) with the curve tops constrained to be

[0304] Each of compounds 3-24, 26-34, 37-38, 41, 43-44, 46-54, 56, 59-67, and 69-79 had an IC of less than 100 nM in the PPO in vitro assay. 50 Compounds 25, 35-36, 39-40, 42, 45, 55, 57-58, and 68 had IC values ​​of less than 1 μM in this assay. 50 had.

[0305] Each of compounds 4, 13-14, 17-20, 22-24, 26-27, 29, 31-34, 38, 41, 44, 47, 51-53, 56, 59-60, 64-65, 75, and 77-79 had an IC of less than 100 nM in the ΔG210 PPO in vitro assay. 50 Compounds 3, 5-12, 15-16, 21, 28, 30, 37, 42-43, 46, 48-50, 61-63, 66-67, 70-74, and 76 had IC values ​​of less than 1 μM in this assay. 50 had.

[0306] Example 22. Testing the post-emergence herbicidal activity of compounds of the present invention Selected compounds of the present invention were screened at 100 PPM against Amaranthus retroflexus (AMARE), Echinochloa crus-galli (ECHCG), Kochia scoparia (KCHSC), and Setaria italica (SETIT).

[0307] Therefore, PPO-susceptible weed seeds were sown in 5″×5″ pots with quadrants containing Miracle-Gro potting mix (Scotts Miracle-Gro Company, Marysville, OH, USA) and grown under appropriate growth conditions (a photoperiod of 16 / 8 h day / night and 300 μmol m−1 supplemented by LED lamps). 2 s-1 Plants were grown in a Conviron growth chamber with a constant temperature of 26 / 22 °C with a light intensity of 100 Hz. Relative humidity in the growth chamber was maintained at approximately 65%. Plants were grown to the 2-4 leaf stage and thinned to 5-8 plants per quadrant per species.

[0308] Compounds were formulated in 25% acetone, 1% crop oil concentrate (COC-Agridex), 0.1% Tween-20, and 2.5% ammonium sulfate (AMS). Three replicate pots were treated with each compound. A treatment consisting of the above formulation excluding the active compound was applied as the treatment control (TC). Plants were irrigated at 187-200 L ha at 269 kPa. -1 Plants were treated with test compound solutions in a laboratory spray chamber equipped with 8003 flat fan nozzles calibrated to deliver 100% TC. Plants were returned to the growth chamber and evaluated for percent visual damage compared to TC 7 days after treatment (DAT). Data presented in Table 3 show percent control, with 100% control indicating complete inhibition of growth. [Table 3]

[0309] Example 23. Testing the pre-emergence herbicidal activity of compounds of the present invention. Selected compounds of the present invention were screened against Amaranthus retroflexus (AMARE) at 200 PPM.

[0310] Thus, PPO-susceptible weed seeds were planted in quadrants in 5” x 5” pots containing a custom field soil mix (Sandy loam at 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 sulfate (AMS). Three replicate pots were treated with each compound. A treatment consisting of the above formulation excluding the 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. Compounds were incorporated into the soil by simulating a 0.2 mm equivalent rainfall using the same orbital sprayer. Pots were then bottom irrigated until evaluated for growth and % germination inhibition. The pots were returned to the growth chamber and evaluated for growth and % inhibition of germination compared to TC 7 days after treatment (DAT). Growth conditions were similar to those mentioned for the post-emergence assay.

[0311] The data presented in Table 4 represents the percentage control, with 100% control indicating complete inhibition of growth and germination. [Table 4]

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a salt thereof, wherein X is -CH or -N; R １ But, -SR １ａ Or -S(O) ２ R １ｂ and R １ａ optionally phenyl, C(O)OR １ｃ or C(O)N(R １ｃ ) ２ C substituted with １～４ is alkyl, Each R １ｃ However, independently, H, CH ２ CH ２ O.C.(O)R １ｄ or optionally substituted C １～４ alkyl, and the optional substituents are ３～６ Cycloalkyl, C(O)OC １～４ alkyl, or up to three F atoms, or two R with an intervening nitrogen atom １ｃ optionally C(O)OH or C(O)OC １～４ Forming a 5- to 6-membered ring substituted with alkyl, R １ｄ But, C １～４ Alkyl or C １～４ alkenyl, R １ｂ But, CH ２ C(O)C １～４ Alkyl or N(R １ｅ ) R １ｆ and R １ｅ But, H, C １～４ Alkyl, C １～４ Alkenyl, C １～４ Alkynyl, C(O)C １～２ Alkyl, or O.C. １～４ is alkyl, R １ｆ But, H, C １～６ Alkyl, C(O)C(O)C １～４ Alkyl, C(O)R １ｇ , or S(O) ２ R １ｇ or R １ｅ and R １ｆ together with the intervening nitrogen atom form a 5-6 membered ring, optionally containing up to two C(O) ring members; R １ｇ But, C １～１４ Alkyl, C １～４ Alkenyl, phenyl, Het, N(R ｈ ) ２ , O.C. １～４ Alkyl, C ３～６ Cycloalkyl, or CH ２ (O.C.H. ２ CH ２ ) ４ CH ３ and each alkyl group optionally contains up to three F atoms, phenyl, C ３～６ Cycloalkyl, OH, OC １～４ each cycloalkyl group is optionally substituted with OH or OC １～４ each phenyl group is optionally substituted with up to three Cl or F atoms; Het is O, N, S, or S(O) ２ and optionally, OH or OC. １～４ is substituted with alkyl, Each R ｈ However, independently, H, C １～４ alkyl, benzyl, or phenyl; R ２ and R ３ is Cl or F; R ４ , R ５ , and R ６ is F or H, and ring A contains at least four F atoms, or a salt thereof.

2. R １ But, -SR １ａ and R １ａ is phenyl, C(O)OR １ｃ or C(O)N(R １ｃ ) ２ C substituted with １～４ 2. The compound of claim 1, or a salt thereof, wherein:

3. R １ But -S(O) ２ R １ｂ and R １ｂ But, CH ２ C(O)C １～４ 2. The compound of claim 1, or a salt thereof, wherein:

4. R １ But -S(O) ２ R １ｂ and R １ｂ N (R １ｅ ) R １ｆ 2. The compound of claim 1, wherein:

5. The compound of claim 1 having the formula (II): 【Chemistry 2】 Or its salt.

6. R ４ , R ５ , and R ６ Each of the following is F, or a salt thereof:

7. R ４ and R ６ Each of the following is F, or a salt thereof:

8. R ４ and R ５ Each of the following is F, or a salt thereof:

9. R １ａ is -CH(CH ３ ) CONHC ２ CH ２ CO ２ C １～４ 6. The compound of claim 5, or a salt thereof, wherein:

10. The compound of claim 1 having the formula (III): 【Chemistry 3】 Or its salt.

11. R ４ , R ５ , and R ６ Each of the following is F, or a salt thereof:

12. R ４ and R ６ Each of the following is F, or a salt thereof:

13. R ４ and R ５ Each of the following is F, or a salt thereof:

14. R １ｇ But C(O)C １～６ Alkyl, C(O)C ３～６ Cycloalkyl, C(O)OC １～６ Alkyl, or C(O)OC ３～６ 11. The compound of claim 10, or a salt thereof, which is cycloalkyl.

15. 2. The compound of claim 1, or a salt thereof, wherein the compound of formula (I) is selected from the compounds listed in Table 1, or a salt thereof.

16. 16. An agricultural composition comprising a compound according to any one of claims 1 to 15, or a salt thereof, and at least one additional ingredient which acts as a carrier.

17. 17. The composition of claim 16, wherein the at least one additional component is a surfactant or a diluent.

18. 18. The composition of claim 16 or 17, wherein the composition is a herbicide composition.

19. 19. A method for controlling undesirable vegetation, comprising contacting said vegetation or its environment with a herbicidally effective amount of a compound according to any one of claims 1 to 15, a salt thereof, or a composition according to any one of claims 16 to 18.

20. 20. The method of claim 19, wherein the undesirable vegetation comprises weeds.

21. 20. The method of claim 19, wherein the undesirable vegetation comprises protoporphyrinogen IX oxidase (PPO) inhibitor-resistant weeds.

22. The method of claim 21 , wherein the PPO inhibitor-resistant weed has a dG210 mutation.

23. The compound or composition is 10,000 m ２ 23. The method according to any one of claims 19 to 22, applied at a rate of 1 to 100 g per unit area.

24. 24. The method of any one of claims 19 to 23, wherein contacting the undesirable vegetation or its environment with the compound or composition results in post-emergence control of the undesirable vegetation.

25. 25. The method of any one of claims 19 to 24, wherein contacting said undesirable vegetation or its environment with said compound or composition results in a pre-emergence control of said undesirable vegetation.

26. The method of any one of claims 19 to 25, wherein the undesirable vegetation is controlled by at least 60%.

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